Class of enzymes
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3 episodes with p450
2 episodes with p450
2 episodes with p450
2 episodes with p450
2 episodes with p450
2 episodes with p450
2 episodes with p450
2 episodes with p450
7 episodes with p450
Ever thought about why medications work differently for different people? In this episode of Absolute Gene-ius, we explore the exciting field of pharmacogenomics with Wendy Wang, pharmacogenetic laboratory supervisor at Children's Mercy Hospital in Kansas City. Wendy shares how genetics can influence drug metabolism, offering a glimpse into how precision medicine can revolutionize healthcare by tailoring treatments based on an individual's unique genetic makeup.At the heart of Wendy's research is CYP2D6, a cytochrome P450 enzyme responsible for metabolizing around 20% of all prescribed medications. She explains how her lab uses digital PCR to analyze copy number variations (CNV), offering a reliable and precise method to predict drug metabolism. Wendy dives into the complexities of structural variants, the role of digital PCR in enhancing assay efficiency, and why pharmacogenomics is a critical piece of the precision medicine puzzle. Her use of delightful metaphors—like comparing genetic testing to ladling soup—makes complex science both relatable and engaging.In the Career Corner, Wendy opens up about her winding path to molecular biology, which included studying classical antiquity and nearly pursuing a career in history. She emphasizes the importance of resilience in research, embracing failure as a learning opportunity, and encourages budding scientists to reach out to mentors and explore diverse interests. Plus, hear about her most embarrassing lab mishap (hint: it involves a fire alarm) and the proud moment of publishing her first, first-author paper.Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System.
L'intelligence artificielle capte toutes les attentions, mais dans l'ombre, une autre révolution technologique se prépare. L'informatique quantique, encore méconnue du grand public, pourrait bien être le véritable tremplin du progrès pour les décennies à venir. Et ce n'est pas Google qui dira le contraire. En ce 14 avril, Journée mondiale de l'informatique quantique, la firme de Mountain View a partagé sa vision du futur : dans 10 à 15 ans, nos ordinateurs pourraient résoudre des problèmes aujourd'hui insolubles, propulsant l'humanité vers une nouvelle ère technologique. Trois domaines majeurs sont concernés par cette promesse.D'abord, l'énergie. Grâce à la puissance de calcul phénoménale des ordinateurs quantiques, la maîtrise de la fusion nucléaire pourrait devenir réalité. Une énergie quasi illimitée, produisant plus qu'elle ne consomme. Pour Google, les algorithmes quantiques permettront de simuler plus efficacement les réactions de fusion soutenues, jusque-là hors de portée des machines classiques. Deuxième promesse : les batteries. Le quantique pourrait aider les ingénieurs à concevoir de nouveaux matériaux, optimisant autonomie et performance, un enjeu crucial dans notre transition énergétique.Enfin, la santé. En collaboration avec le laboratoire Boehringer Ingelheim, Google a déjà montré des résultats prometteurs : les simulations quantiques des cytochromes P450, enzymes clés dans la transformation des médicaments par le corps, s'avèrent plus précises. À terme, cela pourrait accélérer le développement de traitements plus efficaces. Amazon, Microsoft, Google : les géants américains sont dans la course. Reste à savoir si l'Europe saura se positionner dans cette révolution silencieuse… mais potentiellement plus bouleversante que celle de l'intelligence artificielle. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.
Contributor: Jorge Chalit-Hernandez, OMS3 Educational Pearls: CYP enzymes are responsible for the metabolism of many medications, drugs, and other substances CYP3A4 is responsible for the majority Other common ones include CYP2D6 (antidepressants), CYP2E1 (alcohol), and CYP1A2 (cigarettes) CYP inducers lead to reduced concentrations of a particular medication CYP inhibitors effectively increase concentrations of certain medications in the body Examples of CYP inducers Phenobarbital Rifampin Cigarettes St. John's Wort Examples of CYP inhibitors -azole antifungals like itraconazole and ketoconazole Bactrim (trimethoprim-sulfamethoxazole) Ritonavir (found in Paxlovid) Grapefruit juice Clinical relevance Drug-drug interactions happen frequently and often go unrecognized or underrecognized in patients with significant polypharmacy A study conducted on patients receiving Bactrim and other antibiotics found increased rates of anticoagulation in patients receiving Bactrim Currently, Paxlovid is prescribed to patients with COVID-19, many of whom have multiple comorbidities and are on multiple medications Paxlovid contains ritonavir, a powerful CYP inhibitor that can increase concentrations of many other medications A complete list of clinically relevant CYP inhibitors can be found on the FDA website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers References Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20(7):653-656. doi:10.1111/j.1525-1497.2005.0136.x Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396. PAXLOVID™. Drug interactions. PAXLOVIDHCP. Accessed March 16, 2025. https://www.paxlovidhcp.com/drug-interactions Summarized & Edited by Jorge Chalit, OMS3 Donate: https://emergencymedicalminute.org/donate/
In this episode, we delve into the art of detoxification, focusing on two key areas: sleep and liver health. We'll also introduce Liver Boost, a supplement designed to support your liver's detoxification processes. Join us as we unravel the secrets of effective detox and discover how Liver Boost can enhance your journey to wellness. Show Notes: Improving Sleep for Effective Detox: Understanding the metabolic dysregulation caused by sleep issues[^1^]. The antioxidant role of melatonin in detoxification[^3^]. Genetic factors influencing sleep and the role of melatonin supplementation[^2^]. Studies: PMC on Sleep and Metabolism: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929498/ PMC on Genetic Influences on Sleep: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974368/ PubMed on Melatonin: @8/ Supporting Liver Detoxification (Phase I & II): The role of xenobiotic biotransforming enzymes in liver detox[^1^]. Phase I detoxification involving the cytochrome P450 enzymes[^1^]. Personalized dietary considerations for optimizing liver detoxification[^1^]. Crucial foods for Phase II detoxification[^1^]. Study: PubMed on Liver Detoxification: https://pubmed.ncbi.nlm.nih.gov/1749210/ Foods to Support Detox Organs: Nrf2/GST/Sulfurnarse supportive foods like curcumin, green tea, and garlic. Cruciferous vegetables, citrus fruits, and specific beverages beneficial for liver health[^1^]. Study: PMC on Foods and Liver Detox: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ Acute Exposure Detox with NAC (Liver Boost): The importance of N-acetyl cysteine (NAC) in increasing GST for liver detox[^1^][^2^]. Dietary sources to support methylation and Nrf2 activation[^2^]. Studies: PMC on NAC and Liver Health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ PMC on GSH and Metabolism: @icles/PMC3464379/ MTHFR Issues Hindering Detox: The impact of MTHFR polymorphisms on detoxification processes[^1^][^2^]. Importance of nutrient cofactors and methyl donors in managing MTHFR issues[^1^]. Studies: PMC on MTHFR and Detox: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ PMC on MTHFR Polymorphisms: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703276/ Remember that effective detoxification is crucial for overall health. To support your liver's natural detoxification processes, consider adding Liver Boost to your regimen. Formulated to enhance Phase I and II liver detoxification, Liver Boost can be your ally in achieving optimal health and vitality. Click https://www.mswnutrition.com/products/liver-love/?ref=nursedoza to embark on a journey towards a cleaner, more energized you.
The United States spends almost twice as much on healthcare compared to other developed nations. And in spite of all of the technologies, specialists, and medications we have available, The United States ranks dead last in terms of health outcomes. It's clear that something isn't working. The problem is, we don't have a healthcare system; we have a sickcare system that profits off of the farming of sick people. The pharmaceutical companies and the insurance companies only exist to make money. The United States healthcare system doesn't have an interest in helping our citizens find the root cause of their ailments. On this episode of The Model Health Show, our guest is Brigham Buhler, the founder and CEO of Ways2Well. He's here to share insider secrets from his previous career as a pharmaceutical representative. You're going to learn interesting facts about how insurance companies profit, the truth about Big Pharma, and how the American people can take control of their health. In this episode you'll discover: The amount of money the United States spends on healthcare. How corporate America got its grips on our healthcare system. Why the competitive field of medical sales leads to worse patient care. How health education quickly becomes obsolete. The first drug Big Pharma taught doctors to prescribe to a wide audience. How many American people die every year from chronic illnesses. The sad truth about how the opioid crisis and the valium crisis were created. How the incentive system hurts people. What a cytochrome P450 test is & how it could be used to change prescription practices. The dirty secret the insurance companies use to exacerbate illnesses. How insurance companies make money on your prescriptions. What a pharmacy benefit manager is. Why insulin prices have reached an all-time high. The shocking truth about the gag clause at your pharmacy. How insurance companies impact the way doctors provide care. The #1 reason for bankruptcy in America. Why metabolic health is an important lever we can pull. What Ways2Well does. Items mentioned in this episode include: Foursigmatic.com/model - Get an exclusive discount on your daily health elixirs! Onnit.com/model - Save an exclusive 10% on performance supplements & tools! Comprehensive Bloodwork Panel - Get 10% off Ways2Well your bloodwork panel! Connect with Brigham Buhler Website / Instagram Be sure you are subscribed to this podcast to automatically receive your episodes: Apple Podcasts Spotify Soundcloud Pandora YouTube This episode of The Model Health Show is brought to you by Foursigmatic and Onnit. Visit foursigmatic.com/model to get an exclusive 10% discount on mushroom and adaptogen-packed blends to improve your life. Visit Onnit.com/model for an exclusive 10% discount on human performance supplements and fitness equipment.
Explore effective strategies for enhancing recovery post-surgery through dietary adjustments and targeted supplements. 5 KEY TAKEAWAYS 1.Pre and Post-Surgery Nutrition: Changing your diet before and after surgery can significantly impact your recovery speed and quality. 2.Importance of Liver Health: Supporting your liver is crucial as it processes medications and helps in detoxifying your body post-surgery. 3.Benefits of Supplements: Specific supplements like Vitamin C, L-Arginine, and L-Glutamine can enhance wound healing and reduce recovery time. 4.Red Light Therapy: Utilizing red light therapy can aid in healing and potentially reduce scarring post-surgery. 5.Soft Tissue Therapy: Engaging in soft tissue therapy can help manage and minimize post-surgical scarring and improve flexibility. FEATURED PRODUCT Liver Boost and Berberine by MSW Nutrition are designed to support metabolic health, crucial for anyone recovering from surgery. These supplements aid in liver function, helping to process medications and reduce inflammation, which is essential for a smooth recovery. visit www.mswnutrition.com to learn more TIMESTAMPS 00:00 START: Introduction to surgery recovery and the importance of preparation. •01:00: Discussing the critical role of diet in surgery recovery. •02:00: The benefits of adjusting your diet pre-surgery. •03:00: How liver health impacts recovery and the importance of supporting the liver with Liver Boost. •05:00: The effectiveness of red light therapy in post-surgery care. •06:00: Exploring soft tissue therapy as a method to enhance recovery post-surgery. •07:00: The role of dietary changes in reducing post-operative complications. •08:00: Strategies for managing pain and inflammation with natural supplements. •09:00: How to integrate physical therapy early to speed up recovery. •13:00: Importance of following medical advice and the role of regular follow-ups. •17:00: The benefits of holistic approaches like meditation and yoga in recovery. •18:00: Preparing for surgery: what to do in the days leading up to it. •19:00: Closing advice on maintaining health post-recovery. •20:00: Recap of key points and final thoughts on effective recovery strategies. RESOURCES 1.“What to Eat During Your Recovery After Surgery” - Discusses nutritional strategies for postoperative healing 2.“Pharmacogenetics - Genes affecting cytochrome P450 enzymes” - Details how genetic factors influence drug metabolism 3.“The Importance of Antioxidants in Healing” - Explains the role of antioxidants like NAC and Curcumin in recovery 4.“Glutamine and Wound Healing” - Outlines how glutamine supports nitrogen balance and reduces hospital stays 5.“Vitamin C and Wound Healing” - Discusses the benefits of Vitamin C, especially in combination with other supplements for pressure ulcer patients 6.“Red Light Therapy and Its Benefits in Postoperative Care” - Details how low-level laser therapy aids in reducing scarring and enhancing healing 7.“Soft Tissue Management Post-Surgery” - Highlights the benefits of soft tissue therapy in post-surgical recovery CONNECT WITH NURSE DOZA •JOIN MY SCHOOL for $5: Sign Up Here •YouTube: https://www.youtube.com/channel/UCwcKyagDi468WscAOWM5VHA •Instagram: https://www.instagram.com/nursedoza/ •Website: http://www.nursedoza.com/ •LinkedIn: https://www.linkedin.com/in/jonathan-mendoza-dc-aprn-np-c-0609a038/ •TikTok: https://www.tiktok.com/@nursedoza •Twitter: https://twitter.com/nursedoza
Dr. Vrzal, a chiropractor and author of "The Headache Advantage" helps us understand helping the body from a whole person perspective and using symptoms to get to the actual cause of the problem.RESOURCES:https://headacheadvantage.com/https://www.drvrzal.com/https://www.youtube.com/@DrVrzalhttps://www.youtube.com/watch?v=YU7UrlpIEKUTIMESTAMPS:00:00 Intro Snip01:46 Why did Dr. Haley become a chiropractor?02:35 Why did Dr. Vrzal become a chiropractor?05:09 Dr. Haley tells of his first headache patient06:42 How is a headache an advantage?09:00 How is applied kinesiology used to help correct the problem10:00 What are common problems in people's diets?11:10 What is the difference between eastern and western medicine?14:15 Describe a first visit with Dr. Vrzal16:16 What is the Dr. Vrzal technique?18:00 What is Neuroemotional Technique?23:12 What does low back pain have to do with bowel function?25:30 What is yeast over-growth, leaky gut and how does that affect the gut brain connection?27:55 What are the various communication methods in the body?29:40 How does the diet log work?31:24 How you can use the blood type to figure things out32:23 What is the one best diet for everyone?34:50 Will the vegetarian diet work for you?35:35 will Paleo diet work for you?37:30 Does soda make you fat or is it the bubbles?38:18 What causes tinnitis?39:45 What causes Alzheimer's Disease?40:50 Are there safe sugar substitutes?42:10 How to kill lyme42:35 P450 the first phase of liver detoxification
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In the last episode, we discussed the fact that toxins come from food, air, water, personal care products, and pretty much everything we encounter. Detoxification is an ongoing process that is always at work in your body. Here are the basics about how detoxification happens, what resources your body needs, and why it sometimes feels yucky. Detoxification happens in three phases. Phase one involves chemical reactions, mostly in the cytochrome P450 system. Phase two comprises conjugation reactions so that substances can be transported out of the tissues, and phase three is the active transport of these toxins out of your tissues and into waste material. 00:00 - intro 00:29 - Why Detox is easy to get wrong 01:19 - Three phases of detoxification 01:40 - Detoxification Phase one and cytochrome P450 system 02:31 - Genetic Rockstars quick walk-through 04:36 - Detoxification Phase two, conjugation reactions, and gene SNPS 05:15 - Phase three reactions and toxin transport 05:43 - You have to eliminate to detox 06:26 - Water and detox 06:50 - Limit toxin exposure 08:05 - Detox uses energy and nutrients 09:01 - Practitioner support and detox kits GENETIC ROCKSTARS (an MTHFR community): community.tohealthwiththat.com FREE COURSE: MTHFR Basics: https://courses.tohealthwiththat.com/p/mthfr-basics WORK WITH DR. AMY ONE-ON-ONE: Set up a free meet and greet appointment to see if we're a good fit to work together, or if group coaching, community, or something else might be a better option: https://calendly.com/amy-tohealthwiththat/15min GROUP COACHING: https://www.tohealthwiththat.com/group-coaching/ WEBSITE: https://tohealthwiththat.com/ AFFILIATE LINKS: I appreciate you using these links to purchase products you would buy anyway, because they allow me to keep putting information out there. Thank you! SEEKING HEALTH (metylation and histamine support supplements - these ship internationally): https://bit.ly/3afXYH4 STRATEGENE REPORT (detailed genetics using 23andme or ancestry raw data): https://bit.ly/3retbm5 FULLSCRIPT (professional grade supplements): https://us.fullscript.com/welcome/thwt QUEEN OF THE THRONE (castor oil and castor oil packs): https://shop.queenofthethrones.com/amy-tohealthwiththat use code AMY_TOHEALTHWITHTHAT10 for 10% off of any order of $59 or more --- Send in a voice message: https://podcasters.spotify.com/pod/show/tohealthwiththat/message
Hasta aquí el programa de hoy del podcast de seguridad vial y educación vial. ¿Quieres escuchar episodios anteriores del podcast de educación vial y seguridad vial? • P6 Coronavirus y Seguridad Vial https://go.ivoox.com/rf/49513283 • P169 Seguridad vial en Onda Cero https://go.ivoox.com/rf/74292123 • P125 ¿Isofix en un SsangYong Rodius? Y mucha más seguridad vial https://go.ivoox.com/rf/71289331 • P196 Seguridad vial para bebés prematuros y CIPSEVI https://go.ivoox.com/rf/78652365 • P168 Sin ruedas no hay seguridad vial https://go.ivoox.com/rf/74292023 • P182 La educación vial en El Enfoque, Onda Madrid https://go.ivoox.com/rf/76018355 • P7 Mascarillas y guantes son al coronavirus lo que el cinturón de seguridad y los SRI a la violencia vial https://go.ivoox.com/rf/50038459 • P197 Estudio sobre la inseguridad vial en el contenido de las series en Capital Radio https://go.ivoox.com/rf/78897119 “El verdadero viaje es el que termina como comenzó, con felicidad e inocencia” Feliz viaje hasta el próximo programa. _______________________________________
In this episode, we delve into the art of detoxification, focusing on two key areas: sleep and liver health. We'll also introduce Liver Boost, a supplement designed to support your liver's detoxification processes. Join us as we unravel the secrets of effective detox and discover how Liver Boost can enhance your journey to wellness. Show Notes: Improving Sleep for Effective Detox: Understanding the metabolic dysregulation caused by sleep issues[^1^]. The antioxidant role of melatonin in detoxification[^3^]. Genetic factors influencing sleep and the role of melatonin supplementation[^2^]. Studies: PMC on Sleep and Metabolism: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929498/ PMC on Genetic Influences on Sleep: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8974368/ PubMed on Melatonin: @8/ Supporting Liver Detoxification (Phase I & II): The role of xenobiotic biotransforming enzymes in liver detox[^1^]. Phase I detoxification involving the cytochrome P450 enzymes[^1^]. Personalized dietary considerations for optimizing liver detoxification[^1^]. Crucial foods for Phase II detoxification[^1^]. Study: PubMed on Liver Detoxification: https://pubmed.ncbi.nlm.nih.gov/1749210/ Foods to Support Detox Organs: Nrf2/GST/Sulfurnarse supportive foods like curcumin, green tea, and garlic. Cruciferous vegetables, citrus fruits, and specific beverages beneficial for liver health[^1^]. Study: PMC on Foods and Liver Detox: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ Acute Exposure Detox with NAC (Liver Boost): The importance of N-acetyl cysteine (NAC) in increasing GST for liver detox[^1^][^2^]. Dietary sources to support methylation and Nrf2 activation[^2^]. Studies: PMC on NAC and Liver Health: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ PMC on GSH and Metabolism: @icles/PMC3464379/ MTHFR Issues Hindering Detox: The impact of MTHFR polymorphisms on detoxification processes[^1^][^2^]. Importance of nutrient cofactors and methyl donors in managing MTHFR issues[^1^]. Studies: PMC on MTHFR and Detox: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/ PMC on MTHFR Polymorphisms: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703276/ Remember that effective detoxification is crucial for overall health. To support your liver's natural detoxification processes, consider adding Liver Boost to your regimen. Formulated to enhance Phase I and II liver detoxification, Liver Boost can be your ally in achieving optimal health and vitality. Click https://www.mswnutrition.com/products/liver-love/?ref=nursedoza to embark on a journey towards a cleaner, more energized you.
We are diving into a pretty amazing bioregulator peptide called Svetinorm. Extracted from liver cells, this bioregulator peptide has been shown to help restore function to hepatocytes, improve conditions of hepatitis, decrease symptoms such as fatigue and indigestion, and more. All-in-all, the liver is critical for detoxification, processing excess hormones, producing bile, and more, so ensuring that the hepatocytes are functioning correctly is paramount! Stay tuned - this peptide is a game-changer... Topics: 1. Introduction to Liver Detoxification and Svetinorm - Overview of liver detoxification processes. - Introduction of Svetinorm as a bioregulatory peptide derived from cattle liver cells. 2. Liver Function and Structure - Exploration of the vital role of the liver in detoxification, metabolism, and overall health. - Description of the anatomical structure of the liver. - Introduction of hepatocytes as the primary functional cells responsible for various liver functions. 3. Blood Flow and Hepatic Lobules - Details about the intricate blood flow within the liver. - Discussion of hepatic lobules as the fundamental structural units of the liver. - Highlighting the hexagonal shape of hepatic lobules and their central hepatic vein. - Explanation of the role of sinusoidal endothelial cells in facilitating molecule exchange between blood and hepatocytes. - Description of how these cells line the walls of sinusoids within hepatic lobules. 4. Hepatocyte Detoxification Process - Toxins entering the bloodstream and reaching hepatocytes. - Explanation of Phase I metabolism, involving cytochrome P450 enzymes modifying toxins. - Introduction of Phase II metabolism or conjugation, where toxins become more water-soluble. - Examples of common conjugation agents such as glucuronic acid, sulfate groups, glutathione, amino acids, acetyl groups, methyl groups, and others. 5. Toxin Elimination Pathways - Explanation of the routes for water-soluble conjugates to exit the liver. - Details about options for conjugates to reenter the bloodstream or enter the bile. - Mention of how toxins may be further processed and eliminated through urine, feces, or bile. 6. Impaired Hepatocytes and Associated Symptoms - Discussion of the consequences of impaired detoxification pathways and dysfunctional hepatocytes. - Enumeration of common symptoms that may arise from liver dysfunction, such as fatigue, skin issues, digestive problems, bloating, fluid retention, inflammation, and hormone imbalances. 7. Svetinorm - Clinical studies - Proposed mechanisms: bioregulatory peptides 8. Administration - Details about recommended Svetinorm dosage and administration methods. - Highlights of clinical studies, primarily focused on chronic hepatitis patients. - Notation of the positive outcomes observed in these studies, such as improved energy and decreased dyspepsia. - Always work with a licensed medical professional. 9. Personal Experience with Svetinorm - Sharing personal perspectives and experiences with Svetinorm for detoxification and liver support during CIRS Thanks so much for tuning in! Order Chloe's Book "75 Gut-Healing Strategies & Biohacks" TODAY! If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com to purchase products, subscribe to our mailing list, and more! Or visit linktr.ee/synthesisofwellness to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
In this episode we combine many of the pharmacy school raps that have complemented to understanding and learning concepts in Pharmacy School. -- Note: Purpose of these episodes- not at all, for advice or medical suggestions. These are aimed to provide support for peer pharmacists in training in educational and intellectual stimulating ways. Again, these are not at all for medical advice, or for medical suggestions. Please see your local state and board certified physician, PA or NP, and pharmacist for medical advice and suggestions. --
Treba lieky zapíjať grapefruitovou šťavou? Je ľudská pamäť najspoľahlivejší harddisk na svete? Nahradíme betón kávovým gruntom? Aj na tieto otázky odpovieme v dnešnom Pseudocaste. Pseudocast 625 na YouTube Zdroje Drug Interactions with Grapefruit Juice Drug Interactions Reported with Grapefruit Juice Cytochróm P450 - izoenzým CYP3A4 Interaction of citrus juices with felodipine and nifedipine Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides Grapefruit False Memories for Ending of Events Video Experiment Scary Car Commercial - jumpscare! Scientists Discover Amazing Practical Use For Leftover Coffee Grounds Coffee offers performance boost for concrete Image by Bob from Pixabay
Thank you for listening to this episode of "Health and Fitness" from the Nezpod Studios! Enjoy your night or the start of your day, spiced by our top-notch health and fitness/wellness updates coined from the best sources around the globe: made only for your utmost enjoyment and enlightenment… Click on subscribe to get more spicy episodes for free! See you again soon on the next episode of Health and fitness updates! Learn more about your ad choices. Visit megaphone.fm/adchoices
Thank you for listening to this episode of "Health and Fitness" from the Nezpod Studios! Enjoy your night or the start of your day, spiced by our top-notch health and fitness/wellness updates coined from the best sources around the globe: made only for your utmost enjoyment and enlightenment… Click on subscribe to get more spicy episodes for free! See you again soon on the next episode of Health and fitness updates! Learn more about your ad choices. Visit megaphone.fm/adchoices
Thank you for listening to this episode of "Health and Fitness" from the Nezpod Studios! Enjoy your night or the start of your day, spiced by our top-notch health and fitness/wellness updates coined from the best sources around the globe: made only for your utmost enjoyment and enlightenment… Click on subscribe to get more spicy episodes for free! See you again soon on the next episode of Health and fitness updates! Learn more about your ad choices. Visit megaphone.fm/adchoices
Dear Wild One, if you have one or more fibroids, and you want to know all of the potential #naturalremedies to treat them non-surgically, this episode is for you! You'll learn: ☑️ Based on our understanding of what causes fibroids, what foods can we use to treat them naturally? ☑️ Is it even possible to shrink / reduce the size of fibroids using nutrition and strategic foods? ☑️ What is the best food plan to reduce the size of fibroids naturally? Check out the Fibroids playlist in case you missed last week's episode introducing this very hot topic. LIKE, SHARE and SUBSCRIBE as I post a new video weekly on a hot topic on the root cause solutions for women's health concerns!
References JLR 2014 55(6) Pages 1165-1172. JLR 2018 59(6): 1058–1070. --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message
Asetaminofen ismiyle de bilinen parasetamol, tüm dünyada yaygın kullanılan ve kolay erişilebilen bir analjezik ve antipiretiktir. Terapötik dozlarda güvenli kabul edilse de akut ya da kronik aşırı alımda toksik etkileri olabilir. Karaciğer yetmezliğinin en sık nedenlerinden biri olan parasetamol zehirlenmesi ve yönetimi üzerine hatırlatmalar yapmak istedim.1 2 3 İyi okumalar! Farmakokinetik ve Toksisite Mekanizması Parasetamol oral alımdan sonra duedonumdan tamamen emilir ve terapötik alımlarda serum konsantrasyonu yarım saat ila iki saat arasında pik yapar. Aşırı alımlarda serum konsantrasyonu dört saatte pik yapar, toksisitesinde 4. saat düzeyi bu nedenle değerlidir. Eğer gastrik boşalmayı uzatan ilaçlarla (opiatlar, antikolinerjik ajanlar vb.) birlikte alınmışsa ya da uzun salımlı preparatların alımı söz konusuysa pik süresi dört saatin üzerine uzayabilir. Özellikle parasetamol içeren kombine preparat alımı söz konusuysa bu nokta göz önünde bulundurulmalıdır. Parasetamolün toksik dozu genellikle erişkinlerde tek seferde ya da 24 saatte 10 gr ve üzeri, çocuklarda 150 mg/kg ve üzeri olarak kabul edilir.4 Ardışık 2 gün veya daha fazla 6 gr ve üzeri alım (çocuklarda 100 mg/kg üzeri alım) da akut toksisiteye neden olur. Altta yatan karaciğer hastalığı olan veya düzenli olarak alkol tüketen hastalarda uzun süre parasetamol kullanımı sonucu terapötik bir doz alımında da ortaya çıkabilir. Terapötik dozlarda parasetamol metabolizmasının %20-40'ı karaciğerde sülfasyon yoluyla, %40-67'si karaciğerde glukuronidasyon yoluyla olurken %5'ten azı böbrekten direkt elimine edilir. Düşük bir oranda sitokrom P450 sistemi ile N-asetil-p-benzokinonimin (NAPQI) reaktif metabolitine dönüşür. Normalde NAPQI, endojen bir antioksidan olan glutatyon tarafından detoksifiye edilir, ancak parasetamol doz aşımında, glutatyon depoları tükenir ve NAPQI hücresel proteinlere (özellikle mitokondriyal proteinlere) bağlanır. Artan mitokondriyal strese bağlı olarak intrasellüler sinyal artışı ve oksidatif hasar oluşur, ardından karaciğer hasarı ve nekroz gelişir.5 Toksisiteyi Etkileyen Faktörler Aşırı alım Alım ile N - asetilsistein (NAC) tedavisi arasındaki gecikme Aşırı sitokrom P450 aktivitesi Glukuronidasyon veya sülfasyon kapasitesinin azalması Glutatyon depolarının tükenmesi Toksisiteyi arttıran durumlardan biri kronik alkol alımıdır. Kronik alkol alımı, CYP2E1 sentezini ve aktivitesini iki kat arttırarak glutatyon depolarını tüketir. CYP2E1 enzimini indükleyen ilaçların veya bitkisel ürünlerin kullanımı da benzer sonuçlara neden olur, bazı antikonvülzanlar (karbamazepin, fenobarbital ve fenitoin) izoniazid ve rifampin bu gruptadır. Trimetoprim-sülfametoksazol, opioidler ve zidovudin gibi ilaçlar ise glukuronidasyon yolları için parasetamolle rekabet ederek hepatotoksisiteyi arttırır. Klinik Özellikler Parasetamol zehirlenmesinin klinik bulguları tipik olarak dört aşamada ortaya çıkar. İlk evre bulantı, kusma, karın ağrısı ve halsizlik gibi spesifik olmayan semptomlarla karakterizedir ve ilk 24 saatte görülür. Ciddi toksisitesi olmayan hastalarda bu evrede karaciğer fonksiyon testleri normal izlenebilir. İkinci evre alımdan 24-72 saat sonra ortaya çıkar ve hepatotoksisite ile karakterizedir. Hepatik aminotransferazlarda yükselme başlar ve hastalarda hepatomegali ile birlikte sağ üst kadran ağrısı gelişir. Üçüncü evre, alımdan 3-4 gün sonra ortaya çıkar ve bu evrede karaciğer fonksiyon testi anormallikleri en üst noktadadır. Sarılık, konfüzyon (hepatik ensefalopati), hiperamonyemi ve koagülopatiye bağlı kanama diyatezi ile birlikte karaciğer yetmezliğine bağlı sistemik semptomlar görülmeye başlar. Şiddetli hepatotoksisiteyi gösteren laboratuvar bulguları 10.000 IU/L üzeri plazma ALT ve AST seviyeleri, PT/INR'nin uzaması, hipoglisemi, laktik asidoz ve 4.0 mg/dL üzerinde total bilirubin düzeyidir. Toksisite şiddeti arttıkça akut böbrek yetmezliği tablosu da ortaya çıkar.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.05.522933v1?rss=1 Authors: Sarparast, M., Pourmand, E., Hinman, J., Vonarx, D., Reason, T., Zhang, F., Paithankar, S., Chen, B., Borhan, B., Watts, J. L., Alan, J., Lee, K. S. S. Abstract: Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA, dihomo gamma linolenic acid (DGLA), specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH, representing a new class of lipid metabolite that induces neurodegeneration via ferroptosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management. Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.” Thank you for being here, Dr. Paice and Dr. Bruera. Dr. Judith Paice: Thank you. Dr. Eduardo Bruera: Thank you for having us. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Judith Paice: I have no relevant disclosures. Brittany Harvey: Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Eduardo Bruera: Regrettably, I don't. Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline? Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids. We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs. We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer. Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic. So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered? Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain. So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease. And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain. Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer? Dr. Judith Paice: Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another. So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings. So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions. So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent. The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic. The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine. Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use. And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use. Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area. So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated? Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration. And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day. Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain. And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable. But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain. An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through. Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed? Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective. But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention. And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer. Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment? Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction. One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used. And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we're using to reduce the risk of accumulation in a given patient. There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure. With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important. But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver. So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids. Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain? Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough. And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose. But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain. Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose. And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency. And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about? So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose. Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated? Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing. The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects. Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion. And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects. But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another. So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline. But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist. There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa. We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there. And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough. And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this. Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients. So, I want to thank you both for reviewing all of those recommendations that the panel came up with. So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment? Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively. There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients. We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective. Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients. So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies? Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences. But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas. Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder. That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful. Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera. Dr. Judith Paice: Thank you. Dr. Eduardo Bruera:Thank you so much. Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.
Pomegranate Health is seeking fresh ears on the Podcast Editorial Group.Responsibilities of group members are to> discuss new podcast topics> suggest themes to explore and people to interview> listen to audio drafts and provide feedback before publicationGroup communication is done informally by email and there's a time commitment of approximately 90 minutes per month. Please download an application form and return it before February 2023 to podcast@racp.edu.au. ******About two thirds of Australians use complementary and alternative medicines but only around half of these people will mention it to their doctor. Patients in palliative care settings may be more inclined than most to try therapies from outside the box. But they are also more vulnerable to side effects and interactions given that their drug metabolism and clearance mechanisms are often impaired. In this podcast you'll hear the authors of a Clinical Perspectives article titled "Complementary and alternative therapies in the palliative setting." It's published in the in the October issue of the Internal Medicine Journal which can be accessed by all RACP members at the login page racp.edu.au/fellows/resources/journals.Professor Jennifer Martin and Joanne Patel describe how cannabinoid products, especially, have become more readily accessible to patients in recent years and often considered a panacea for many different symptoms. But given the wide variety of products each with a different concentration of active ingredients, drug effects are not always as a patient or doctor might expect. These compounds also have suppressive effects on P450 and other clearance enzymes which can alter the outcomes of other prescribed drugs. But practitioners also need to consider their relationship with a patient when giving advice on the use of complementary medicines. GuestsDr Jonathan Brett FRACP FAChAM (St Vincent's Hospital, Sydney)Professor Jennifer Martin FRACP (University of Newcastle, John Hunter Hospital)Dr Joanne Patel FRACP FAChPM (University of Newcastle, John Hunter Hospital)ProductionWritten and produced by Mic Cavazzini DPhil. Music licenced from Epidemic Sound includes ‘Crossing Borders' by Mindserver Unlimited. Image by DrAfter123 licenced from Getty Images.Please visit the Pomegranate Health web page for a transcript and supporting references. To claim learning credits login to MyCPD at this link, review/amend the prefilled activity details and click save. Subscribe to new episode email alerts or search for ‘Pomegranate Health' in Apple Podcasts, Spotify, Castbox, or any podcasting app.
Deportres en Comunicante Mx 28 de Septiembre del 2022 En el Deportres de hoy: La selección mexicana de futbol, la tenía ganada, y Colombia le dio la vuelta para sacarle el partido e intensificar la ola de comentarios adversos contra el Tri del Tata Martino, y todos los resultados de la fecha FIFA, mientras que en las grandes ligas, los Padres vencieron a los Dodgers en un partido lleno de emociones, como siempre, dinámicas NBA, lo mejor de la NFL, tu participación y ¡mucho mas! Visitanos en www.deportres.com --- Support this podcast: https://anchor.fm/deportres/support
Deportres en Comunicante Mx 28 de Septiembre del 2022 En el Deportres de hoy: La selección mexicana de futbol, la tenía ganada, y Colombia le dio la vuelta para sacarle el partido e intensificar la ola de comentarios adversos contra el Tri del Tata Martino, y todos los resultados de la fecha FIFA, mientras que en las grandes ligas, los Padres vencieron a los Dodgers en un partido lleno de emociones, como siempre, dinámicas NBA, lo mejor de la NFL, tu participación y ¡mucho mas! --- Support this podcast: https://anchor.fm/deportres/support
Seguimos con las interacciones fármaco-alimento: - Cefuroxima axetilo (Zinnat)Los alimentos favorecen la absorción de la cefuroxima axetilo. Se desconoce a través de qué mecanismo.Para aumentar la biodisponibilidad del antibiótico se recomienda administrarlo juntamente con alimentos. - EtanolLa ingesta continuada o puntual de alcohol, habitual durante las comidas de la cultura occidental, puede provocar también la inhibición o la inducción de ciertos fármacos, especialmente de la mayoría de los que actúan sobre el sistema nervioso central. De hecho, el alcohol interacciona con casi el 50% de los medicamentos más dispensados en la oficina de farmacia (psicofármacos, analgésicos, anticoagulantes, antihipertensivos, antihistamínicos). Muchos de estos fármacos son EFP (p. ej., los antigripales).Es importante desaconsejar la administración conjunta de alcohol mientras dure el tratamiento, así como tener un mayor cuidado en el manejo de maquinaria o vehículos. - Fenilpropanolamina (presente en algunos preparados antigripales)El efecto hipertensor de la fenilpropanolamina puede resultar potenciado por el efecto de la cafeína. La fenilpropanolamina puede también aumentar significativamente las concentraciones plasmáticas de la cafeína. Existe el peligro de crisis hipertensivas y hemorragias intracraneales.Deben evitar el uso de este fármaco los pacientes vulnerables, como los hipertensos (atención a los antigripales EFP como Aspirina Complex y Vincigrip) y evitar la cafeína. - Furosemida (Seguril, Salidur)No se conoce el mecanismo de acción, pero la administración de furosemida conjuntamente con alimentos disminuye su biodisponibilidad.En caso de inicio del tratamiento, hay que recomendar la toma de furosemida en ayunas. Si no es así, no modificar la pauta de administración. - IMAO (Inhibidor de la monoaminoxidasa o un tipo de antidepresivos)Cuando hay interacción de cierto grupo de alimentos con los inhibidores de la monoaminooxidasa (IMAO) se trata de una interacción farmacodinámica.Los fármacos IMAO son un grupo de sustancias que tienen en común su capacidad de bloquear la desaminación oxidativa de aminas endógenas como la noradrenalina y la adrenalina y también la serotonina y la dopamina. También inhiben la metabolización de la tiramina, histamina, betafeniletilamina y triptamina tanto de origen endógeno como ingeridas a través de la alimentación. Podría ocasionarse una crisis hipertensiva a causa de la interacción entre aminas biógenas contenidas en ciertos alimentos (tabla 1) en el caso de una administración conjunta con alguno de estos fármacos.Como consecuencia de la interacción pueden aparecer crisis hipertensivas que pueden ser graves e incluso provocar la muerte por hemorragias intracraneales. Otros posibles síntomas son midriasis, dolor de cabeza, diaforesis, palpitaciones, y nauseas.La medida más adecuada es restringir la ingesta de ciertos alimentos que pueden aportar una concentración variable de estas aminas. - Quinolonas más derivados lácteosCiprofloxacina (Baycip) y norfloxacina (Noroxin) forman quelatos con el calcio si se administran conjuntamente con lácteos. Se interfiere en su absorción y la biodisponibilidad será también mucho menor.Se recomienda no administrar estas quinolonas con derivados lácteos ni ingerir lácteos hasta 2 horas después de la administración del medicamento. Con ello se respetará la eficacia antibacteriana de los fármacos. - TetraciclinasLa administración conjunta de tetraciclinas (Bristaciclina dental) con leche o derivados lácteos es una interacción ampliamente conocida. A causa de la formación de quelatos con el calcio la absorción del fármaco es mucho menor con estos alimentos. Dicha interacción se produce también con otros alimentos que contengan calcio. La doxiciclina (Vibracina) y la minociclina (Minocin), mucho más actuales, interaccionan mucho menos con estos alimentos (se reduce su biodisponibidad en tan sólo un 25-30%).Se deben evitar los lácteos al administrar tetraciclinas. Las tetraciclinas de acción prolonagada (minociclina y doxiciclina) son, además, de elección por ser tratamientos largos. Es preferible la administración del fármaco en ayunas, ya que la quelación puede ser también con otros cationes divalentes distintos del calcio y que se hallen presentes en la comida.- Zumo de pomelo más fármacosLa administración conjunta de ciertos fármacos con zumo de pomelo provoca un incremento significativo en la concentración plasmática de muchos de ellos. Ello es debido a la supresión de la enzima CYP3A4 del citocromo P450 en la pared del intestino delgado, lo que provoca una disminución del metabolismo de primer paso. Ello implica un aumento en la biodisponibilidad y concentraciones plasmáticas más elevadas de los sustratos de esta enzima. En algunos fármacos se pueden encontrar incrementos en el área bajo la curva y la concentración máxima de más del 70%. Hay que añadir a esto que la administración a largo plazo del zumo de pomelo no disminuye la magnitud de la interacción ni se desarrolla tolerancia.Los componentes que tienen una mayor probabilidad de ser los responsables de la interacción son los flavonoides y los derivados cumarínicos.Son muchos los fármacos que interaccionan con el zumo de pomelo y pertenecen a distintas estructuras farmacológicas.Los primeros fármacos que se estudiaron fueron antagonistas de los canales del calcio como felodipina (Perfudal), nifedipina, nitrendipina (Tensogradal), nisoldipina (Syscor) y amlodipina (Norvas); también en otros como diltiazem (Masdil) y verapamilo (Manidon).En algunos casos, al aumentar la concentración del principio activo en sangre se puede aumentar la frecuencia de ciertos efectos secundarios que son dosisdependientes como, por ejemplo, un antiarrítmico como la amiodarona (Trangorex).El incremento de las concentraciones plasmáticas tras la administración conjunta de un fármaco con zumo de pomelo puede ser una ventaja o un inconveniente. Sería una ventaja en fármacos en los que es difícil alcanzar la biodisponibilidad deseada, que son caros y que la pauta posológica requiere mucha frecuencia. Pero, por otro lado, no todos los pacientes reaccionan igual (amplia variabilidad interindividual). La administración conjunta con zumo de pomelo demandaría una complicada monitorización del fármaco o efectos adversos importantes en alguno de los fármacos. Por ello, se recomienda evitar tanto el pomelo como su zumo si se está llevando a cabo un tratamiento con algún fármaco de los antes mencionados. Con otros principios activos que sean extensamente metabolizados hay que evitar esta fruta, a menos que se haya demostrado para los fármacos una ausencia total de interacciones con el pomelo.*
Your liver is seriously pretty amazing. I'm a 'mechanisms' kind of guy, and the liver is the king of mechanisms, including:- The liver is crucial for metabolism, regulating blood sugar, lipid, and protein metabolism.- The liver participates in immune surveillance and pathogen clearance, and is intimately connected with the gut. - The liver performs "hepatic biotransformation", or transforming toxins into things that can be excreted, aka DETOXIFICATION. The liver can be damaged by many things including lifestyle, alcohol, viruses, parasites, and especially toxins. As liver damage progresses, the liver becomes more congested, toxins begin to accumulate, and metabolic dysfunction can follow. Liver damage is generally a spectrum of worsening fibrosis, and often starts with "fatty liver" and then progresses toward cirrhosis, which is liver scarring. Liver damage can be detected by several labs, and I discuss these labs in detail. In the liver there are many functions, but this podcast focuses mostly on hepatic biotransformation, or detoxification. This includes Phase 1 and Phase 2 of liver detox, cytochrome P450, and includes processes like methylation, sulfation, conjugation, and more. These processes require many cofactors such as B vitamins and amino acids, and I discuss these all in detail. There are also many genetic mutations that can affect liver and detoxification, so I discuss these as well, along with the common and popular liver supplements and what their mechanisms are. All together this is a comprehensive overview of everything I know about the liver and how I use that information clinically in helping sick people get well!Youtube video about Liver, Carnitine, and Depression....
See all the Healthcasts at https://www.biobalancehealth.com/healthcast-blog/ Women always ask about my goal for their blood level of free Testosterone after insertion of testosterone pellets. That is a good question, and it is not easily answered. When I was trained by Dr Gino Tutera in 2002, and he taught me that the optimal range for Free T in women who take T pellets to be over 15 pg/ml. He taught me that each woman is an individual and the blood level that they need is specific to their metabolism and genetics. To determine the perfect level of T free for an individual we should follow the resolution of her symptoms after her T pellets are inserted. Today we will talk about the research done by Dr Rebecca Glaser, published in Maturitis 74(2013) that confirms my practice of adjusting the dose of pellets based primarily on the resolution of Low T symptoms. Prescribing pellet Testosterone for woman is not easy and her doctor must find her own ideal blood level. Testosterone replacement for women has been ignored as an essential hormone replacement for women, and until recently was not considered a major sex hormone in women. Premenopausal women have 15-20 times more testosterone than estradiol circulating in their blood streams. This makes testosterone the most prevalent sex hormone in premenopausal women, yet it is still mislabeled as a strictly male hormone! After late 30s to mid 40s women develop a deficiency in testosterone and develop a host of symptoms that doctors have sadly called the symptoms of “aging”, when the symptoms are directly related to the lack of free T in a woman's circulation. Both pre- and post-menopausal women over 36 may experience the following symptoms of testosterone deficiency: Sexual dysfunction-lack of libido and loss of orgasmic function Anxiety, irritability, depression Physical fatigue Lack of the feeling of well-being Poor cognition Memory loss Insomnia Hot flashes New autoimmune diseases Arthritis Weight gain Muscle loss and physical weakness Pain Vaginal Dryness Irritable Bladder Migraine headaches Osteoporosis One of the reasons that the majority of doctors don't use T pellets is because it takes intense individual training after residency and time and attention to each patient, her symptoms, and time for multiple adjustments of dose before the maintenance dose is determined. This is something a doctor or nurse must do all the time to be good at it and the doctor must have a complete grasp of endocrinology, nutrition, and gynecology to become good at this type of T hormone treatment. Once the pellet dose is determined it is the most convenient dosing schedule (once q 4 months, only 3 doctor visits a year) with 100% compliance because the T Pellet dose is given in the office, very rare complications, and an amazingly complete resolution of symptoms, which has not been seen in any other T preparations, bio-identical or not, given with a different delivery system. With the right doctor or Nurse Practitioner, a knowledge of pharmacology, endocrinology, gynecology and nutrition, this form of T delivery to women brings them back to a more youthful body and mind as well as prevents diseases of old age such as Osteoporosis, Heart disease, Sexual Dysfunction, mood disorders and autoimmune diseases to name a few. In the research paper by Dr Rebecca Glaser: Testosterone implants in women: Maturitis 2013 Dr Glaser explains that there are many problems secondary to following blood levels to determine dosage, and explains why following symptom resolution is the preferred way to provide this type of Testosterone replacement: Specifically, Blood tests of free T are rarely repeatable and often wrong—it is not a good, repeatable blood test. The only thing less reliable is saliva testing which I don't recommend. No single blood test represents the true daily blood level of free T in pellet patients. How fast your body uses the available T up, varies by number of hours or sleep, stress level, estradiol and estrone levels and amount of exercise engaged in per day. Fat metabolic activity: T pellets are inserted into fat in the hip and as we are now discovering, the ability of fat to dissolve a steroid hormone placed in fat is individual and determines how quickly the pellet is dissolved and needs to be re-dosed. There is no test for this, so trial and error is needed using different dosage to determine ongoing maintenance dose. ARs (Androgen receptors) are distributed throughout the body and the number of Ars plus the “stickiness” of the receptors for free-Testosterone in the blood, is determined both by genetic makeup and age. ARs of people with dominant genetics from the northern latitudes, are relatively resistant to binding, and these receptors must have a higher blood level to respond at an optimal level. Women who have their dominant genetics closer to the equator, require less free T to achieve optimal symptom relief. The genes are not specifically discovered as of yet, it is impossible to test a patient to see if they have strong or weak receptors. This discovery is found through trial and error. Age also causes a loss of the # of receptor sites, therefore more T mgs are needed in the pellets. Estrogen interferes with the free T level from a particular dose: Binding to SHBG decreases the active form of T (T free) per dose of T pellet. The amount of estradiol and estrone a woman has been given or makes, decreases the amount of active T free. The lower the Estrogen levels, the lower the SHBG and the more T free is available. Cortisol Binding Globulin goes up when Cortisol increases secondary to life stress, surgeries and illness. This binding globulin inactivates the testosterone and decreases the percentage of active T. Speed of a woman's Liver metabolism is increased by multiple drugs that go through the P450 system, alcohol intake, fatty food intake, and amount of environmental chemicals that act like estrogens. One patient's liver metabolism of T through the P450 system is individual and is not the same for another woman of the same age, weight, etc. The speed of breakdown of T determines how fast the T pellet is used up. There are several other dosing issues that are addressed after the first pellet insertion in preparation for the second insertion. Most important is whether their symptoms are completely gone. If they are, we leave the dose the same, if not they usually need more T dose, or they are converting T into E1 and E2 which binds the T free and lowers the effect. For this we exchange one of the T100 mg pellets with one TA 90/10 pellets, which blocks the conversion, and releases the T free and stops increasing the E1 and E2. There is a small percentage of women of women who do not tolerate TA pellets. They feel like they have no sex drive and don't feel their T free as they should….it is an opposite reaction, because in everyone else the T free is higher, they feel more sex drive and lose belly fat. If the “opposite” patients still need to lose belly fat and lower their T-free, DIM, zinc, and Calcium D glucarate can be used to lower the Estrogen in the circulation. I agree with Dr Rebecca Glaser MD, who states that dosage should be guided by safety, tolerability and clinical response, rather than a random T or T free levels, yet I always draw blood levels to find out if a woman's ideal blood level specific to her has been reached, and if it is repeatable.
Polycystic ovary syndrome (PCOS) is a common condition impacting roughly one in four women of reproductive age. , In this show we discuss natural ways to reverse the underlying factors driving PCOS. Save 15% OFF on Berberine HCl and Myo-Inositol containing Sleep Formulations from MYOXCIENCE Save with code podcast at checkout Links to Studies, Images and the Video Version: https://bit.ly/3nMt9QJ Time Stamps 00:04 PCOS (polycystic ovarian syndrome) is about 1 in 5 of women of childbearing age. 00:26 The root cause of PCOS is poor metabolic health. 01:54 Ovaries hyper secrete androgens that are linked with challenges within the ovaries and the formation of water-forming cysts. 02:39 Hormonal birth control is frequently prescribed to increase sex hormone binding globulin and neutralize the elevated androgens. 04:04 Some cytochrome P450 enzymes are involved in the formation of steroid-like hormones, like testosterone. 05:04 Insulin and IGF-1 increase the activity of a cytochrome P450 enzyme called CYP17A1, which then increases testosterone, dihydrotestosterone, and DHEA within the ovaries. 06:36 Excessive levels of androgens cause hair loss, infertility, lack of ovulation, and cause the formation of water forming cysts within the ovaries. 08:24 Autoimmunity often co-occurs with PCOS. 08:44 Deliberate cold exposure helps metabolic health by stimulating brown and beige fat cells. 09:54 Metabolic health increases the activity of enzymes that create hormones. It does the inverse in men and women. 10:04 Men's poor metabolic health drives the formation of extra estrogen. 10:14 Women's poor metabolic health drives the formation of extra testosterone. 12:44 97% of obese women have PCOS. 65% of non-obese women have PCOS. 13:14 Fat cells secrete hormones, called adipocytokines. One of these is leptin. 13:54 Leptin decreases activity of T-regulatory cells that help to prevent autoimmunity. 16:04 Belly fat cells convert androgens into estrogens. This is impacted by insulin. 18:14 Nutrition and exercise are fundamental ways to address poor metabolic health. 18:24 A ketogenic or low carb diet is helpful because it manages blood sugar and insulin, and ketones have immune signaling properties. 19:24 Intermittent fasting can support glycemic variability and improve insulin sensitivity. 19:46 Time restricted feeding with a 16 or 18 hour fast is also helpful for longevity, burning fat, and supporting metabolic health. 20:14 Poor sleep exacerbates insulin resistance. Tape your mouth shut when you sleep. 21:24 Resistance training decreases androgens in women with PCOS. All exercise supports underlying metabolic dysfunction. 22:24 Magnesium is helpful for supporting insulin sensitivity. 23:15 Myo-inositol and inositol makes ovaries more sensitive to insulin, preventing the increase in androgens. 24:04 Vitamin D is involved in blood sugar regulation, immune health, and sleep quality. 24:19 Gut health is important to metabolic health. Eat real food and ferments. 24:54 Berberine hydrochloride, 500 mg 1 to 3 times per day, is a natural Metformin. Studies Mentioned Witchel, S. F., & Plant, T. M. (2020). Intertwined reproductive endocrinology: Puberty and polycystic ovary syndrome. Current Opinion in Endocrine and Metabolic Research, 14, 127–136. http://doi.org/10.1016/j.coemr.2020.07.004 Stefanaki, C., Bacopoulou, F., Kandaraki, E., Boschiero, D., & Diamandi-Kandarakis, E. (2019). Lean Women on Metformin and Oral Contraceptives for Polycystic Ovary Syndrome Demonstrate a Dehydrated Osteosarcopenic Phenotype: A Pilot Study. Nutrients, 11(9), 2055. http://doi.org/10.3390/nu11092055 Moghetti, P., & Tosi, F. (2020). Insulin resistance and PCOS: chicken or egg? Journal of Endocrinological Investigation, 44(2), 233–244. http://doi.org/10.1007/s40618-020-01351-0 Scarfò, G., Daniele, S., Fusi, J., Gesi, M., Martini, C., Franzoni, F., et al. (2022). Metabolic and Molecular Mechanisms of Diet and Physical Exercise in the Management of Polycystic Ovarian Syndrome. Biomedicines, 10(6), 1305. http://doi.org/10.3390/biomedicines10061305 Witchel, S. F., & Plant, T. M. (2020). Intertwined reproductive endocrinology: Puberty and polycystic ovary syndrome. Current Opinion in Endocrine and Metabolic Research, 14, 127–136. http://doi.org/10.1016/j.coemr.2020.07.004 Optimal management of polycystic ovary syndrome in adolescence. (2015). Optimal management of polycystic ovary syndrome in adolescence, 1–8. http://doi.org/10.1136/archdischild-2014-306471&domain=pdf&date_stamp=2015-06-22
Detox Pathways and Protocols (Youtube)Free 15-min phone consult!Website and Supplement Store So - yup, toxins are a big problem. We are exposed to tons of them, and if our bodies aren't detoxifying properly, they can accumulate or cause damage to our cells, organs, and systems and wreak havoc on our lives. So how do you make sure you aren't overflowing your bucket? Here are 10 Important Concepts:Bucket Theory explains everything - keep this in mind if things are NOT getting better. SOMETHING is still filling the bucket from somewhere if you are actively trying to detoxify and leading a non-toxic life and you aren't improving. You have to empty the bucket faster than you are filling - you either aren't emptying it well, or you are still exposed somewhere.Breathing - There are only a few "exits" for things to get out of the body, breath is one of them. Think about a roadside alcohol test - you breathe out toxins to get rid of them.Peeing - this one is more obvious that you are "getting rid of waste", but the kidneys filter toxins and toxic metabolites, and you pee them out, so that system has to be working well too. Pooping - This one is the most obvious - - waste is bad so you want to get it out of you!! Your poop is how you get rid of MANY MANY toxins, and if your gut is not moving well, everything else backs up. Sweating - You are slightly limited on how much you can speed up your breathing, peeing, and pooping, but you can always open the other exit - sweat. Many toxins have been found excreted in the sweat - mycotoxins, BPA, parabens, metals, etc, so sweating is crucial for detoxification.Liver/Bile Flow - The liver filters toxins (through many processes - phase I and II, cytochrome P450 enzymes, glutathione, conjugation, glucuronidation, methylation, etc). These toxins are then put into bile, which is stored and released by the gallbladder. You have to have good liver function to filter the toxins, and then you have to have good gallbladder function and bile flow for the toxins to get into the gut, then you have to be pooping for them to get out.Lymph Drainage - The lymphatic system is one way that toxins and waste products are transported around the body to be excreted, and your lymphatic system has to be moving, it can't be stagnant. Cell Membranes - Toxins damage your cell membranes (including mitochondrial membrane), causing lipid peroxidation, stiffening, and poor membrane fluidity. Then toxins can also STORE in the cell membranes, so you need good healthy cell membrane support - this can be really important for detoxification.Mitochondria - THEY DO IT ALL!!!! Toxins store in the mitochondria, they damage the mitochondria, they affect fatty acid beta oxidation, Kreb's Cycle, Oxidative Phosphorylation, all the things - and mitochondria power detoxification in the liver, organs, cells, etc. It's all mitochondrial!Relevant Genes - There are a lot of relevant genes in detoxification, and it's super important. Many of them relate to "methylation", like MTHFR, COMT, PEMT, HNMT, but there are many others that regulate processes like glutathione recycling, cytochrome P450 activity, and many many more.
How do you talk to patients about medicinal cannabis? Dr. Ashley Glode (University of Colorado) moderates a discussion on effectiveness and safety, misconceptions and more. Featuring Drs. Ilana Braun (Dana-Farber Cancer Institute), Daniel Bowles (University of Colorado), and Kent Hutchison (University of Colorado). Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 1/19/22 TRANSCRIPT ASHLEY GLODE: Hello, and welcome to ASCO Education's podcast on medical cannabis, also referred to as medical marijuana. My name is Ashley Glode, and I am an associate professor with the University of Colorado School of Pharmacy. It's my pleasure to introduce our three guest speakers Dr. Ilana Braun is chief of the division of adult psychosocial oncology at Dana-Farber Cancer Institute, and an assistant professor of psychiatry at Harvard Medical School. Dr. Daniel Bowles is an associate professor of Medical Oncology at the University of Colorado. We're also joined by Dr. Kent Hutchison, a professor of psychology and neuroscience at the University of Colorado Institute of Cognitive Science. Let's start with a simple but fundamental question. What is medical cannabis or medical marijuana? ILANA BRAUN: So Ashley, I think that's such a great first question. I think of medicinal cannabis as herbal nonpharmaceutical cannabis products that patients use for medicinal purposes. And typically they're recommended by a physician in compliance with state law. DANIEL BOWLES: Dr. Braun makes a really good point. And I think it's important to know when patients are referring to medical cannabis, there's a wide variety of different things they could be referring to. Sometimes they would be referring to smoked herbal products, but there are also edibles, tinctures, ointments, creams, all sorts of herbal-based products that people use and call medical cannabis. And then there are also the components that make up medical cannabis-- largely, the cannabinoids. And I think the big ones people think about are THC and CBD. And sometimes those are used in their own special way. So I think that it's important for us as providers to be able to ask our patients, what is it that you mean when you say, I'm using medical cannabis? ILANA BRAUN: I think that's such a great point. And I will add I think it's also important to remember that when you offer a medicinal cannabis card to a patient, you're giving them license in most states to access any number of products. It's not an insurmountable challenge, but it's a whole new world for traditional prescribers who are used to writing a prescription and defining what is the active ingredient, how often a patient will take the medicine, by what means. DANIEL BOWLES: I think the other thing we need to be very aware of, as hopefully people are listening to this across the country and elsewhere, is the laws vary wildly from jurisdiction to jurisdiction about what consists of medical cannabis, who is allowed to use it, and in what quantities. So I think it's really important that as we learn about these and we think about these, we think about how they apply to any of our specific situations in which we live in practice. KENT HUTCHISON: So it's interesting-- just follow up on what Dr. Braun and Dr. Bowles, what they're saying, those two words-- right-- medical and cannabis. I think the medical part is somewhat easier because it can refer to the reason the person is using. Are they using for medical reasons are they using for recreational reasons, even though that's a blur? But the cannabis part I think is what's really complicated. And this is what Dan was getting at. All the different products, all the different cannabinoids, I mean all the different bioactive terpenes and everything else in the material, all different forms of administration. That is where it gets super complicated to really define what that is. And then of course, there's so little research we don't really know what all those constituents do. ASHLEY GLODE: Now that we kind of have a little bit of familiarity with medical cannabis, can you comment on adult use cannabis and what that might mean for a patient? ILANA BRAUN: Ashley, I think it's a really good question. And in some of the early research I did to try to understand where medicinal ended and adult use began, or adult use ended and medicinal began, I began to discover a theme that emerged, which is they sort of blend into each other often. In other words, some of the oncologists that I spoke to believed that it was not such a bad thing for a patient with serious illness, and pain, and many other symptoms to have a sense of high or well-being. And conversely, when I spoke to patients using cannabis, sometimes a cancer patient used medicinal cannabis for enjoyment, and sometimes they used it for symptom management, and sometimes they used it for both. And so I think it is somewhat of a slippery slope between the two. Would you agree? DANIEL BOWLES: I think there are definitely blurred lines between the two. I think that the advantages of what most states would recognize as medicinal cannabis is usually they're less expensive, patients can use them in larger quantities. There are certain advantages. But there's also paperwork that goes along with medicinal cannabis that some patients don't feel comfortable with. Or particularly I think when you have a patient who's interested in trying cannabis or a cannabinoid for the first time, they might not want to go through all the extra steps required getting that medical marijuana card, whereas adult use, I think people feel more comfortable, at least in my state, sometimes walking into a dispensary to discuss the options with people who work at the dispensary and then get it from more of an adult use or recreational cannabis initially. And then if that's something that they find helpful for their symptom management, to then take those extra steps and try to get a medicinal card. ILANA BRAUN: I agree with Dr. Bowles that the target symptoms or the target effect is often similar and access can differ. KENT HUTCHISON: Yeah. Just to chime in, I agree. I agree also. It's definitely-- the lines get blurred. The recreational user might also appreciate-- for example, college students, I hear them say a lot of times that they appreciate some of the anxiety-reducing aspects-- right-- even though they're not necessarily a person who has an anxiety disorder. And then of course, patients appreciate a slight increase in euphoria or positive affect, and what does that mean? Is I mean they're also using for recreational reasons? Or is that completely, I guess, legitimate? On the other hand, there are sometimes I feel like when-- especially on the recreational side-- when people are using for the more psychological effects, the sort of psychotropic effects, I know sometimes the medical patients refer to that as being a little bit loopy as a side effect. So I feel like there's definitely some blurred lines. And maybe there are some places where we can think about in perhaps in a less blurred kind of way. ASHLEY GLODE: How often do you guys have a patient ask you about medical cannabis? And what are the most common questions they might have for you? ILANA BRAUN: In my psycho-oncology practice, patients frequently tell me they're using cannabis, often with good effect and minimal side effects for polysymptom management-- for instance to address nausea, or pain, or poor appetite, or sleep, or mood, or quality of life. But they don't ask me a lot of questions. For instance, one of my longest-standing patients. A man with metastatic cancer and gastroparesis. Vaporizes cannabis before meals to keep his weight up. And many of my patients also use cannabis as cancer-directed therapy. And for these patients, side effects can sometimes be more pronounced. For instance, I have a lovely patient with metastatic cancer who follows a Rick Simpson protocol. So what is that? That's an online recipe marketed with an antineoplastic claim. And so this patient targets hundreds milligrams of cannabinoids daily. And with such high cannabinoid doses, she sometimes feels spicy, or out of it, as she describes it. And then I had another patient who targeted high daily doses and developed a debilitating nausea and vomiting that was initially diagnosed as chemotherapy-induced nausea vomiting because it was so hard to tease out in the setting of so many medicinal agents, what was what. But the symptoms resolved completely within weeks of the cannabinoids being halted. And so as I mentioned, what's notable about all three of these patients, and many of the others I see, is that they are quite open with their oncology teams and me about their medicinal cannabis use. But they don't seem to rely me or other members of their oncology team for their therapeutic advice . We insert ourselves when we see potential harm, but much of the decision-making seems to be made-- I don't know in the naturopath's office, at the dispensary counter, or by trial and error. And this anecdotal experience in my practice is borne out in my research findings as well. Patients are just not getting the bulk of their cannabis therapeutics information from their medical teams. DANIEL BOWLES: In my clinical practice, I am asked about cannabis or cannabinoids a fair, amount often in the context that Dr. Braun is describing, where a patient is coming in and they're already using a cannabinoid or they are planning on doing it and they just want my opinion. And I think unlike talking about more conventional cancer-directed therapies where they really rely, I think, on their medical team for information and guidance, we are often more a supplement I think in terms of information. In terms of the patients who come to ask me about cannabis or let me know that they're using cannabis, it's a very wide selection of people. I see young people, old people talking about it, men, women, a variety of different malignancies. So there really is a lot of usage or are thought about usage of cannabis or cannabinoids amongst our cancer patients. I think if you look at the studies, they'll tell us that depending on where we're working, anywhere between 20% to 60% of patients have used cannabis in the last year to help manage some sort of cancer-related symptoms. And I think the other thing that is notable is you'll find people asking about cannabis or cannabinoids who I think we might not have otherwise expected. So for instance, Just this past week, I had a patient with anaplastic thyroid cancer in his 70s, and his daughter was wondering whether he could try CBD to help with his sleep and anxiety. She wanted to make sure that it wasn't going to interact with this cancer therapies. And I appreciated her bringing it up, and we could have a frank discussion about the pluses and minuses of it, just like we might any other therapeutic intervention. So I think that particularly as the laws have changed across the country, more and more people are willing to tell us that they're trying cannabinoids and cannabis than maybe would have even 10 or 15 years ago. KENT HUTCHISON: I think in an ideal world, patients would be talking a lot more with their physicians about this topic. And I think unfortunately that a lot of people do get their information from dispensaries. From the media, from social media, from their kids, and from whoever. And I think that's something that I hope will change in the future. DANIEL BOWLES: In terms of questions that I'm often asked, I'll be asked if it's going to interact with their cancer treatments, in terms of making their medications more or less effective. I do get questions about how I think their cannabis use might affect some of their symptoms. I get questions about other drug-drug interactions-- let's say, interactions with opiates, or benzodiazepines, or some of these other medications that a lot of our patients are on. ASHLEY GLODE: In a recent survey 80% of medical oncologists who discussed medical cannabis with their patients, 50% recommended it in the past year, but only 30% felt knowledgeable enough to make recommendations. What do you guys think needs to be done to address this knowledge gap? And what resources do clinicians have to get and stay informed? DANIEL BOWLES: So I'm a big fan of the NCI's PDQ as a great resource. It has a fairly objective information about cannabis and cancer specifically. So I think that's a nice reference for people who are interested in getting an initial overview on the topic. I think there are also a number of different educational programs. I know the University of Colorado, for instance, has a Cannabis Science Master's and also a certificate program. So there are courses available for people who want to educate themselves more on this topic. ILANA BRAUN: Yeah. I guess when I think about what needs to be done, I think that cannabis needs to become a routine part of medical training curricula and CME programs. I think that a federal funding for high-quality clinical trials and a loosening of federal restrictions on accessing study drug were to occur, that would be really a big boon for the medical community. And my colleagues on this podcast I know are doing some very creative pragmatic clinical trials naturalistic studying what is happening in the field. And I am doing clinical trials using an FDA-approved version of cannabinoids. But it's still very hard to study whole-plant cannabis in a form that is sort of a standardized trial drug in a cancer patient. And then when I think about where I would begin to read, I don't think there is a single source, unfortunately. But a great place to start reading is actually a project that Dr. Hutchinson was a part of, which was an expert panel that was assembled by the National Institute of Science Engineering and Medicine in 2017. And they produced a monograph on the health effects of cannabis and cannabinoids. And it's several hundred pages long, including sections devoted just to oncology. So in other words, there is scientific evidence to evaluate, and it's sizable. DANIEL BOWLES: The Austrian Center for Cannabinoid Clinical and Research Excellence also is a helpful resource. One of the nice things about that is they actually give some dosing suggestions or ideas for people who really don't quite know where to start. Right now, there aren't a lot of people in that position to say, here's how it should be done. Here's how it gets dosed. Here are the data to support those decisions. And so the folks in the next level of training don't learn it in the same way that we have learned how to prescribe other medications. And they can't then lay it down. So because the data are scant, in some respects, and particularly for herbal products that So. Many of our patients are using, I think it falls outside the medical model that we've all become so used to using to learn how to take care of patients. And I think that's one reason that so many oncology providers feel interested in learning more about this topic, but don't feel comfortable giving patients guidance on how to use them. KENT HUTCHISON: So both Dr. Braun and Dr. Bowles identified some of the key resources out there. And certainly the training issues that Dr. Bowles just talked about are important. And I do want to emphasize the one thing that Dr. Braun mentioned, which is basically that we do-- we lack research and we lack data on some key important issues, like dosing, for example. What dose is effective? So cannabidiol has been out there for a long time, but what dose is effective for what? We don't know, right? So we definitely lack research. And there are definitely obstacles to doing that research. ASHLEY GLODE: So you guys brought up some good points about there being a lack of data, but also there is some evidence. So what is the current research and evidence on the efficacy of medical cannabis for management of cancer symptoms and cancer pain, specifically? DANIEL BOWLES: So there was a really nice review article that just came out in the BMJ looking at cannabis and cannabinoids, not specific to cancer pain, but including cancer pain. And what they found-- they looked at different preparations from herbal products-- smoked herbal products, oral agents-- cannabinoids, more specifically. They found there is a modest, but a real improvement in pain in patients or research subjects treated with cannabinoids versus those usually typically treated with placebo. In particular, the data are supported in neuropathic pain, I'd say more so than the other pains. I think the data are less compelling with regards to many of the other symptoms that people often use cannabinoids for, such as sleep, anxiety, appetite, things along those lines. ILANA BRAUN: So I'll tell you a little bit about how I think about the evidence base in oncology for cannabis use. So I'll preface this with two points. The first is that, as I mentioned, cannabis products tend not to be one active ingredient, but hundreds of active ingredients-- cannabinoids, phenols, terpenes, they all have bioactivity. And they don't work individually, they work through complicated synergistic and inhibitory interactions that have been termed entourage effects. So I don't think one can easily extrapolate from clinical trials of, say, purified THC, to understand whole-plant cannabis' activity in the body and how it might perform in humans. And then the other point I'll make is that when I think about the types of clinical evidence that we as clinicians hold dearest, it's clinical trials of our agent of interest in our population of interest. So cancer patients using whole-plant full-spectrum cannabis that they would access at a dispensary or grow in their own home. With this in mind, I believe the strongest evidence, randomized double-blind placebo controlled trials of whole-plant cannabis and oncology populations begins to support its utility for chemotherapy-induced nausea and vomiting. So there have been a few studies that have looked at this. But just in 2020, the most recent is a study by Grimison, et al. It was a multicenter randomized double-blind placebo controlled crossover trial comparing cannabis extract. And I think the extract they use was a 1 to 1 THC to CBD ratio versus a placebo in patients with refractory chemotherapy-induced nausea and vomiting. And what they found was that with active drug, there was a complete response in 25% of participants versus only 14% with the placebo. And although a third of participants experienced additional side effects with the active drug-- so remember, this was a crossover trial, so they saw both arms-- 80% preferred cannabis to the placebo medication. So that's clinical trials of cannabis and cancer. But if we expand the base of the pyramid of acceptable evidence to include high-quality clinical trials for health conditions other than cancer and extrapolate back, then I agree fully with Dr. Bowles that there's a growing body of evidence that cannabis may be beneficial in pain management. And there have been many clinical trials done in this arena, and they span myriad pain syndromes, including diabetic neuropathy, post-surgical pain, MS pain, sickle cell pain. And so it does seem like cannabis works for pain management in several other illness models, so we could extrapolate back and hope that it works in cancer pain. And then there is a small body of evidence with nabiximols, which is a pharmaceutical that has a 1 to 1 THC to CBD ratio. And it's a sublingual metered dose spray. And it has been trialed for opioid-resistant cancer pain. And this is not as a single agent, but as an adjuvant to opioids. In early trials, two times as many participants in the active arm as compared to the placebo arm demonstrated a 30% pain reduction. And for the pain specialists who are listening, they will know that is a substantial pain reduction. But then, additional studies fail to meet primary endpoints. I think there were three clinical trials that followed. Nabiximols was found to be safe and effective by some secondary measures, but the FDA opted not to approve nabiximols for cancer pain. So I think there's some suggestion of effect, but there's some smoke, but no fire-- no pun intended. DANIEL BOWLES: I think many of the studies that have been done looking at cannabis-- or cannabinoids-- have been compared to placebo or they've been crossover. And I would say fairly consistently, there is some improvement in pain scores with the cannabis products versus placebo kind of across a wide variety of disease spectrums with regards to pain. I think one of the other questions that a lot of people have asked is, can you decrease people's opiate usage using cannabis? As we know, there's a huge epidemic of opiate misuse in the United States of America right now. And I think many people are looking for ways to decrease opiate usage. There was a nice study done from Minnesota in conjunction with the Minnesota dispensaries-- or state marijuana program-- where some researchers randomized people to starting kind of herbal cannabis products early in their study or three months into their study. So it was kind of a built-in control. And they looked at opiate usage rates, pain scores, quality of life scores, et cetera. What they found is there, again, was some improvement in pain control overall in the cannabis users. However, it did not equate to a decrease in opiate usage. So I think that it's an open question that I think a lot of people want to know the answers to before they start recommending or incorporating cannabis or cannabinoids more widely into their practice. KENT HUTCHISON: It's certainly a complicated issue, in some ways, right? Because the research which is summarized very nicely by both Dr. Braun and Dr. Bowles, it is suggested, but not overwhelming, by any stretch, right? It's not clear-cut. And I think that one of the big issues here we talked about the very beginning is how complicated this cannabis thing is. and Dr. Braun alluded to this also, that there are obviously many different formulations, many potentially active constituents in cannabis. And so what has mostly been studied so far is either synthetic versions of THC or nabiximols, which is probably the closest thing to what some people are using. So I think the jury's still out, for sure. And I think hopefully at some point, what will happen is that some of the products that are actually being used by people-- because most people aren't using nabiximols, most people are not using THC only, hopefully there'll be some trials of the things that people are actually using out there in the real world that will tell us something more about whether it's effective or not. And maybe even more specifically, which constituents-- which parts, together are most effective with respect to pain. DANIEL BOWLES: I think one of the other topics that some of my colleagues have alluded to already is not just cannabis' role in symptom management. I think pain is often what people think of, and people are using it for chemo-induced nausea and vomiting, anxiety, sleep, appetite, but a fair number of patients are also using cannabis or cannabinoids with the hopes that it is going to treat their cancer like a chemotherapy or an immunotherapy may. And oftentimes, patients will point to preclinical studies looking at oftentimes very high doses of THC or CBD that might show tumor cell death or tumor reduction in test tubes. And I spent a fair amount of time-- and I know some of my colleagues spent a fair amount of time-- talking with patients about how it's a big step between cannabis or cannabinoids working to slow cancer growth in a test tube, to working in an animal system, to working in people. ASHLEY GLODE: So what are the most important considerations clinicians should keep in mind before recommending medical cannabis to patients with cancer? DANIEL BOWLES: We should be asking why they want to use cannabinoids. I think just like we might any other medication that people are thinking about trying-- or herbal product that people are thinking about trying-- I think we need to ask why they're interested in using these products. So is it for symptom management? Is it for some of the ancillary side effects of cannabinoids or cannabis? Why are they wanting to use it? And I think trying to incorporate that more than into the medical model, I ask my patients, hey, if you're using this particular product, do you feel like it's doing what you intended it for it to do? If it is and it's legal in your state, great. Do it as you feel fit. If it's not meeting your goals, if it's not helping with the pain, or if it's not helping with the anxiety, or it's not helping with the nausea and vomiting, maybe we should rethink whether we would use it. Just as if I was prescribing more conventional anti-nausea medication and you didn't think it was working, we wouldn't keep using it. So I think that's a really important thing to keep in mind. I think the other thing to know from a safety standpoint is, who else is in the household? We have a psychiatrist on the call with us today. I think there is an ample amount of data that cannabis is not safe for young people. It's not safe for growing brains. And I think we need to make sure, just as we would want people's opiates to be secured, that their cannabinoids and cannabis products are secured as well, from those who do not want to use them. ILANA BRAUN: And the thing I would keep in mind is that in most states, giving patients a medicinal cannabis card is allowing them to access any number of products with different ratios of active ingredients, delivery mechanisms, onset of action, potencies. And if you don't discuss all of these issues with your patients, these are things that they will decide at the dispensary counter, or by discussing with friends and family, or by trial and error. And I think it's really important that we clinicians guide this narrative. ASHLEY GLODE: So what kinds of patients are not good candidates for medical cannabis? DANIEL BOWLES: I would not recommend medical cannabis for people who can't meet some of the criteria we already discussed. So people who can't keep it safe in their households or have concerns about diversion in their own households. Those are people who I think would not be great candidates for medicinal cannabis or cannabinoids. ILANA BRAUN: As the psychiatrist on the call, I would add that I worry for people with a strong history of psychosis, or currently psychotic, or with a strong family history of psychosis. And perhaps those severely immunocompromised, since there is evidence of fungal and mold contamination in some cannabis products. DANIEL BOWLES: The other group of people I discussed this with are patients on immunotherapies. One of the ways that cannabis may be effective in some of the symptoms we discussed is it's an anti-inflammatory agent. One of the ways it could be detrimental for patients on immunotherapies is that it's an anti-inflammatory agent. There is one small study that suggested that patients might have worse responses to immunotherapy who are cannabis users versus those who are not. So that is a conversation I like to have, just so patients feel like they can be informed. I think lastly, cannabis even for people with medical cards, is not free. So there can be a financial burden for people who are using it. So that's something that I'll often bring up with people as well. KENT HUTCHISON: One thing I would add to this would be history of a substance use disorder might also be a consideration here as well. Mainly because you don't know what the person is going to get, and it could be something that lends itself to relapse or encourages a problem. So I would add that to list. ILANA BRAUN: And I would second what Dr. Bowles said about the financial challenges of using cannabis regularly medicinally. It's not something that's covered by insurance, either. So these are out-of-pocket expenses, and they can add up fast, particularly for patients in the oncology space using it for antineoplastic therapy. ASHLEY GLODE: So is there a concern about drug-drug interactions for patients currently undergoing active cancer treatment? DANIEL BOWLES: There are some data that there can be drug-drug interactions with cannabis and certain agents. In particular, cannabidiol, or CBD, is a CYP3A4 inhibitor. And there are a lot of drugs that are metabolized through that particular system. So I think that that's the clinical relevance of those interactions, I think, is sometimes unknown. But that is another topic that I do think we need to make sure we bring up with our patients. ASHLEY GLODE: Thank you. Yeah. So a lot of what we'll do is from a drug interaction perspective, use the FDA-approved products that we have available to run through a drug interaction checker, like Dr. Bowles mentioned. So we'll use dronabinol as the THC-based product and epidiolex as the CBD-based product. There's also some resources, such as natural Medicines Database. And some of the pharmacy programs that we use, you can actually put in marijuana or cannabis as a drug and run drug interaction checks. So there's multiple potential interactions, like he mentioned, through the immune system. But through the cytochrome P450 pathway, cannabis has been shown in some instances to be an inhibitor, sometimes an inducer of certain enzymes, as well as a substrate. So it's really important to work with your pharmacy colleagues to run through different potential interactions that may be present. ILANA BRAUN: I'll just add one thing, just in case that's helpful. I mentioned earlier in the episode that I had a patient who used cannabis as an antineoplastic drug, and targeted very high doses and developed a terrible nausea and vomiting. And when she stopped, so did the nausea and vomiting, even though her chemotherapeutic continued. And I, to this day, don't know if that was a cyclic nausea and vomiting syndrome, which has been known to plague some heavy cannabis users, or whether drug-drug interactions led to her high-dose cannabis triggering high blood concentrations of her cancer-directed therapy at the time. And so I think that drug-drug interactions do need to be carefully weighed. ASHLEY GLODE: So wrapping up, has the medical community stance on medical marijuana shifted in recent years with legalization in many states? ILANA BRAUN: I don't think we know the answer to this, about how sentiment has shifted because there aren't longitudinal studies that I know of examining this question. But we need some. And one could imagine that as medicinal cannabis becomes are commonplace, providers are increasingly confronted with questions about how to guide care and the desire for high-quality clinical trials and in-depth cannabis therapeutics trainings increases-- and as one piece of evidence for this, at the end of 2020 the National Cancer Institute held a first-in-kind four-day conference at the intersection of cannabis and cancer. And so I'm hopeful that grant opportunities will follow from that. DANIEL BOWLES: I think overall there has been more willingness to discuss cannabis in the context of patient care in the last decade. A couple of ways that I see this is I much more frequently see cannabis use described not necessarily in the drug history, or in the social history, but in the medical history, or in their medications, if they're using it for medical or therapeutic purposes. I think the other place that I've noticed cannabis usage become a bit more mainstream is in the clinical trial setting-- not in clinical trials of cannabis, but one of the things that many of us do is clinical trials of new drugs. And very frequently, 10 years ago we ran into trouble trying to get our patients who were using cannabis products for cancer symptom control onto these clinical trials because of potential drug-drug interactions, or just the fear of the unknown. And I feel like we run into that less commonly now. KENT HUTCHISON: I think it's also worth pointing out that there have been more and more podcasts like this one, right? So to the credit of this organization, I think we are seeing some change. I just wanted to highlight that. And I compliment everyone here for putting us together and putting it out there. ASHLEY GLODE: All right. Well, thank you. That is all we have for today. And thank you very much Drs. Braun, Bowles, and Hutchison for a delightful conversation. Thank you so much to all the listeners tuning into this episode of the ASCO Education Podcast. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode to make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit elearning.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
00:00 - Prepping, not having access to the financial system, gold and silver, alternative economy to the new technocracy 02:47 - Ray's thoughts on 2021, the common English attitude towards authority, 'covid is so dangerous that any tyrannical measure is justified' 09:32 - Guillain barre syndrome origin in the intestine? Viruses, leaky intestine, sepsis, cytokine storm 13:05 - Ray's thoughts on oat bran, possible issues with the carrot salad, oat bran as a breakfast, oat bran's phytic acid content 17:07 - Strategies for an antiinflammatory home, turning off wifi and bluetooth, using ethernet, the bioenergetic perspective of grounding 26:07 - Ray's metabolic rate before he supplemented thyroid, inability to gain weight, magnesium retention 01:15:41 - Who is in a worse position: people who can't put on weight or people that gain too much weight? 34:05 - Are huge doses of magnesium necessary? 34:42 - Ray's take on negative ion generators, serotonin, sleeping, altitude 37:02 - Increased suicide at high altitude? Azerbaijan 40:15 - Ray's newsletter, books, and Progest-E from Kenogen 42:45 - The importance of cycling progesterone for women, P450, topical vs. oral, Ray's DHEA patent, testosterone used to not be a regulated substance 47:52 - The unfavorable redox reaction that occurs when vitamin E and vitamin K are mixed, riboflavin, methylene blue and red light 51:30 - Wein VI-2500 negative ion generator 52:12 - Coronavirus variants are pure marketing nonsense 58:18 - Medical Nemesis by Ivan Illich (1975), allopathic medicine essentialism 01:03:29 - Question: what is an electron? 01:08:28 - Question: thoughts on human auras? 01:09:49 - Question: what does Ray see in his mind when he thinks of the cell? 01:11:09 - Question: a bioenergetic view of sex determination? Decline in child IQ due to coronavirus psychological operation 01:15:17 - Question: are Sheldrake's morphic fields and Vernadsky's noosphere the same thing? 01:18:55 - Question: what themes or styles would Ray like to see in a counter-culture art movement? Frans Hals 01:20:33 - Question: is starch responsible for the atrocities since the beginning of agriculture? 01:21:14 - Question: what is the cost of getting blackout drunk? Liver glycogen 01:23:37 - Does Ray have any ruling class psychological operation predictions for 2022? Marburg virus
Episode 21 of Cracking Addiction explores methadone pharmacokinetics, breakdown and interactions within the body and interactions with other drugs. Methadone is a drug with a wide variability in its absorption with oral bio-availability ranges from 35% to 100%. This is a significant amount of variability and explains why the same dose of Methadone can impact different patients differently. Methadone is metabolised within the liver by the cytochrome P450 enzymes but mainly 3A4. There is a 17-fold inter-individual variation of methadone blood concentration for a given dosage and variations in metabolism account for a large part of this variation. Kinetic interactions influenced by the CYP 450 enzyme can affect plasma methadone levels. • Inducers of CYP450 can • Accelerate the metabolism of methadone • lower methadone plasma levels • Precipitate opioid withdrawal • Inhibitors of CYP450 can • Slow the metabolism of methadone • Increase plasma levels • Produce opioid toxicity (sedation, overdose) Methadone is excreted renally with approximately 10% of drug renally eliminated unchanged. Renal excretion of methadone urinary pH dependent with increased Methadone excretion noted at pH less than 6 and decreased Methadone excretion at higher pH levels. About Meducate ® Meducate provides online education for doctors, clinicians, health professionals and the public. See the website to browse the many different talks and courses availablehttps://www.meducate.com.au
Let's talk about acne. This isn't an old problem. Acne has been around for hundreds of years. This NIH article dates acne back to the 16th century. What does that tell you about acne? It's been a problem for a long time and we haven't solved it yet. If we had, then perhaps it wouldn't impact 50 million Americans each year (American Academy of Dermatology Association). How many of you have seen a dermatologist about acne?
Gilani B, Cassagnol M. Bioquímica, Citocromo P450. [Actualizado el 29 de abril de 2021]. En: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 enero-. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK557698/ --- Send in a voice message: https://anchor.fm/las-poderosas-celulas-nk/message
If you listen to the Awaken Beauty Podcast, you're a woman in pursuit of high-quality thoughts, beauty, and lifestyle products. You also are probably aware that we are exposed to hundreds of chemicals every single day -In fact, to dial it in, Studies show that we are exposed to over 500 synthetic chemicals every day - within our homes. One of the leading chemicals that wreaks havoc on our hormones and endocrine system is called Xenoestrogens.Our guest today matches my passion for awakening individuals at any point in their health journey by providing highly researched, vetted, and efficient optimal health and aging solutions. For over a decade, I've been educating and creating beauty and wellness products - before organic “was status quo” - and ladies, this is far deeper than “clean products.” So through a Functional Medicine lens, joining us today is Dr. Anthony Jay - who is a scientist, author, and leading expert on a wealth of topics including xenoestrogens, epigenetics, and even stem cells.In this epic episode, we'll explore the macro and micro on how our environment, diet, genetic expression, and endocrine disruptors affect the aging process, our health, and even the brain. Of course, what you can do about it. About Doctor Anthony Jay: Not falling short of credibility - Dr. Jay is the founder of AJ Consulting Company and a scientist at the Mayo Clinic. He offers incredible insights into your health and how to improve it with precision through high-level DNA testing, where he has experience of analyzing the DNA of individuals in the NFL, U.S. special forces, MMA fighters, and 100's of individuals seeking peak health. In addition - Dr. Jay is a bestselling author of the book called: Estrogeneration - which we'll be cracking open today. On Today's Episode You'll Awaken to:Dr. Jay's Estrogeneration book shares the progression of a sick nation and how we're passing on a health crisis to our children and the next generations. Overall, chemicals increase hormone-sensitive Cancers + Increase aging + Weight Gain + Brain/Emotional Symptoms.Exposure to xenoestrogens can predispose us to PCOS, Endometriosis, and Fibroids, and fertility. HOW THEY ENTERMost exposure comes from our very own home- but we can be masters of our home. Endocrine disrupters are a thousand times than normal estrogen. Not all are manmade: one of the strongest xenoestrogens out there come from mold toxins as a mycotoxin - namely “ZEA.” Bruce Blumberg's book “The obesogen effect” proves how critical detoxing efficiently is if you want to beat the battle of the bulge.HOW WE METABOLIZE & AFFECT OUR HEALTHHow Xenoestrogens affect the mind by dropping natural motivationHow estrogen can SAVE your health and damage your health: The difference between natural and artificial estrogen.The rate of breast cancer has increased by 250% since the 1980s.Gut Dysbiosis – Insufficient good bacteria in the gut inhibits the conversion of estrogen into water-soluble molecules. This causes the estrogens to recirculate back into the bloodstream where it can re-exert their effects. Gut health is very important for the metabolism of all hormones.WHAT TO LOOK FORBirth-control Pills - whether taking them or not, they're found in our water - filter!A Shower filter can reduce toxins in the water getting into our pores (step out of the shower, our pores are open, and we start to overload the system with lotions, creams, and perfumes). Environmentally, the air within the home hosts sheetrock that has a high mercury content which is a heavy metal and is an endocrine disrupter. Cannabis SMOKE is estrogenic[Top Beauty INGREDIENTS Lookout!]Phthalates: Are round in cosmetics, cleaning products, food packaging, and detergents, PVC plastic, toys, and plastic wrap.Parabens: Found in deodorant, antiperspirant, moisturizer, sunscreen, and makeup. Formaldehyde: A known carcinogen and irritant found in nail products, hair dye, and eyelash adhesives Fragrance: Has hormone-disrupting effects. Lead: A known carcinogen and hormone disruptor found in certain eyeliners, hair dye, and lipsticks.Mercury: accumulation over time, can impair the brain and nervous system.Oxybenzone: An active ingredient in chemical sunscreens that accumulates in fatty tissues. Sunscreen Study: Oxybenzone application after 7 days, were still found in the bloodstream The advantage of Zinc-based Mineral Makeup: At Beauty Ecology we offer La Bella Donna Makeup which is a Triple Mill Weight to block makeup from leaking into the skin. DEA/TEA/MEA (Ethanolamines): Used as emulsifiers and foaming agents for shampoos, hair color. Sodium lauryl sulfate (SLS, SLES) Diethylene glycol (or DEG)HOW WE EXCRETEHow endocrine disruptors affect our DNA ExpressionIt's all in the pathways: Liver enzyme P450 issues commonly are attributed to irregular estrogen production. Best detox option: Red light therapy sauna, Health gut biome, Supplementation through the phased protocol with a professional, and vitamin C. How to test if you are able to effectively biologically remove xenoestrogens. The impact of Alpha and Beta receptors and ho fake estrogen impacts the alpha receptors - causing increased breast cancer risks. How DIM can have adverse effects: it is dose-dependent and may increase estrogen. Resources:Find out more about Dr. J's Services at the following link:Dr. J's consulting company: https://www.ajconsultingcompany.com/Blog Post: http://beautyecology.com/blog/2019/8/how-to-detoxify-harmful-xenoestrogens-from-your-beauty-rituals-part-2Podcast: https://awakenbeautypodcast.simplecast.com/episodes/part-2-mini-draft Share the Love:If you like The Awakened Beauty Podcast…Subscribe, Rate & Review via iTunesVisit us at awakenedbeautyhq.com for updates.Businesses: www.evoqbeauty.com | www.beautyecology.comInstagram @awakenbeautyhqInstagram @evoqbeautyWatch on Youtube at my channel: Awaken Beauty PodcastShop natural health and beauty products with EVOQHere's how!Go to AwakenBeauty-hq on ITunes and write your biggest takeaway in the rate and review section. Just pretend it says “ah ha” here!! Don't just review the episode, I would love your ah-ha moment from this episode that is more specific so you can confirm your takeaway as you write, but also help others capture your brilliance. It'll take 3 minutes from your day. What you declare will be life to others. So remember, go to I tunes to rate and review.Comment or question you'd like to ask Kassandra.P.S!Your review is not only paramount in helping others discover the show, but we also read each and every submission personally…and they mean the world to us.Love and Light! - KassandraIn the Meantime, STAY IN THE CONVERSATION! @awakenbeautyhq | #awakenbeautyLeave a comment below - let us know what you think!
Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay. Wonder is the beginning of wisdom!! I'd rather open my mind with wonder than close it with belief!! That's the mantra for today as I start the topic of day which goes on like "Drug Metabolising Enzymes-1" I will start my convo by classifying metabolising enzymes into Microsomal and Non microsomal. Then I will throw light on each of the characteristics, features, sub heads and examples of each type, their details though not in much depth will be conversed upon!! i will in detail cover variety of isoenzymes of superfamily cytochrome P450, their different isoenzymes, features, inducers, inhibitors, etc. I will be talking in detail about nomenclature, specificity and genetic variability. That is the time and moment not to give in or give up, rather listen to clock's command to call it for the day and pack it all in! For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also. You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!! You can access various links via https://linktr.ee/ispharmacologydifficult
Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay.Wonder is the beginning of wisdom!! I'd rather open my mind with wonder than close it with belief!! That's the mantra for today as I start the topic of day which goes on like "Drug Metabolising Enzymes-1"I will start my convo by classifying metabolising enzymes into Microsomal and Non microsomal. Then I will throw light on each of the characteristics, features, sub heads and examples of each type, their details though not in much depth will be conversed upon!!i will in detail cover variety of isoenzymes of superfamily cytochrome P450, their different isoenzymes, features, inducers, inhibitors, etc.I will be talking in detail about nomenclature, specificity and genetic variability.That is the time and moment not to give in or give up, rather listen to clock's command to call it for the day and pack it all in! For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also. You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!You can access various links viahttps://linktr.ee/ispharmacologydifficult
Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay.Wonder is the beginning of wisdom!! I'd rather open my mind with wonder than close it with belief!! That's the mantra for today as I start the topic of day which goes on like "Drug Metabolising Enzymes-1"I will start my convo by classifying metabolising enzymes into Microsomal and Non microsomal. Then I will throw light on each of the characteristics, features, sub heads and examples of each type, their details though not in much depth will be conversed upon!!i will in detail cover variety of isoenzymes of superfamily cytochrome P450, their different isoenzymes, features, inducers, inhibitors, etc.I will be talking in detail about nomenclature, specificity and genetic variability.That is the time and moment not to give in or give up, rather listen to clock's command to call it for the day and pack it all in! For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also. You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!You can access various links viahttps://linktr.ee/ispharmacologydifficult
Läkemedelsinteraktioner med CBDolja Vad betyder läkemedelsinteraktion? Definition: Ett läkemedels påverkan på ett annat läkemedels verkningsmekanism, metabolism eller toxicitet. När det kommer till CBD är läkemedelsinteraktion väligt ovanligt men det kan förekomma. Det finns en särskild familj (grupp) av enzymer i levern som kallas för cytochrome P450. Cytochrome P450 enzymen metaboliserar ca 60% av de farmaceptiska läkemdel som finns på marknaden. Stora doser CBD kan förhindra aktiviteten av just denna enzym (Cytochrome P450) Att enzymens aktivitet minskar kan leda till att upptagningsförmågan av andra läkemedel som (metaboliseras av Cytochrome P450 emzymet ) fördröjs. Eftersom varje individs endocannabinoida system är unikt för en själv. Finns det ingen standard CBDdos för att undvika interaktion med enzymgruppen P450. Detta innebör att du ska prata med din cannabisrådgivare innan du intar CBD produkter ihop med receptbelagda läkemedel. Här följer en lista på läkemedel (droger) som metaboliseras av enzymgruppen P450: Steorider HMG-CoA reduktashämmare Kalciumkanalblockerare Antihistaminer Prokinetics HIV antivirala immunmodulerande Bensodiazepiner Antiarytmika Antibiotika Bedövningsmedel Antipsykotiska Antidepressiva Bedövningsmedel Beta blockerare Protonpumpshämmare Icke-steroida antiinflammatoriska läkemedel Angiotensin II receptorblockerare Orala hypoglykemiska medel Vill du stödja GreenMovements kan du göra det genom att handla i någon av våra nedanstående shoppar. För cannabisälskaren med en aktiv och hälsosam livsstil: https://greenmovement.se/ Hampa shoppen https://iriearoma.com/
In today's episode of the podcast, we will be doing a deep dive into duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). In part one of this two-part series, we will cover the history of SNRIs as well as mechanisms of action, cytochrome P450 issues, side effects, and contraindications to consider when prescribing duloxetine and this class of medications. Link to Blog. Link to Resource Library.
Need a quicker way to learn medical information? Does cytochrome P450 intimidate you? Do you ever feel that it is to difficult to memorize drug interactions to even try? Well, not anymore! My quirky ways of thinking has brought us yet another great way to learn this complex system in a fun, and thorough way!
Mehri Coulter (@so_bipolar) is a bipolar disorder advocate, wife, and mother of three. She has created photography exhibits that display symptoms of bipolar disorder. She openly discusses the loss of her 16 year old nephew, who lost his life to suicide from bipolar disorder as well. She shares other experiences of grief from suicide. She discusses her how pharmacogenetic testing helped her find psychiatric medication that helped her tremendously. We both share our view on how living openly with bipolar disorder does not require bravery or courage as we once thought.
A group of researchers led by Heping Han from AHRI, including researchers from Bayer and Zhejiang University in China have identified the P450 gene responsible for cross resistance to herbicides of at least five modes of action. The gene is CYP81A10v7. Paper author, Prof Steve Powles joins us in this AHRI Snapshots to provide a history of this research and what the finding means in both a fundamental and practical sense. AHRI recently published a paper on this and last week Peter Newman wrote an AHRI insight on it. You can read the insight here: https://ahri.uwa.edu.au/weve-cracked-the-p450-code/ ________________________________________________________ Podcast Presenter & Producer: Jessica Strauss
View the show notes in Google Docs here: http://bit.ly/3bFS43j Gonorrhea Updates Gonorrhea Treatment and Care. Centers for Disease Control and Prevention Website. https://www.cdc.gov/std/gonorrhea/treatment.htm. Published December 14, 2020. Accessed January 11, 2021. CDC No Longer Recommends Oral Drug for Gonorrhea Treatment. Centers for Disease Control and Prevention. https://www.cdc.gov/nchhstp/newsroom/2012/gctx-guidelines-pressrelease.html. Published August 9, 2012. Accessed January 11, 2021. Recurrent UTI Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline (2019). American Urological Association. https://www.auanet.org/guidelines/recurrent-uti?fbclid=IwAR1TwSTQNHv8PDWLfW7WjsDan46D_9b6Qs1ptJxaXr6YFnDpBeptpW3BY. Published 2019. Accessed January 11, 2021. Combo Ibuprofen and Acetaminophen / Pain Advil® Dual Action. GSK Expert Portal. https://www.gskhealthpartner.com/en-us/pain-relief/brands/advil/products/dual-action/?utmsource=google&utmmedium=cpc&utmterm=ibuprofen+acetaminophen&utmcampaign=GS+-+Unbranded+Advil+DA+-+Alone+-+PH. Accessed January 11, 2021. FDA approves GSK's Advil Dual Action with Acetaminophen for over-the-counter use in the United States. GSK. https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-advil-dual-action-with-acetaminophen-for-over-the-counter-use-in-the-united-states/. Published March 2, 2020. Accessed January 11, 2021. Tanner T, Aspley S, Munn A, Thomas T. The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol. BMC clinical pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906415/. Published July 5, 2010. Accessed January 11, 2021. Searle S, Muse D, Paluch E, et al. Efficacy and Safety of Single and Multiple Doses of a Fixed-dose Combination of Ibuprofen and Acetaminophen in the Treatment of Postsurgical Dental Pain: Results From 2 Phase 3, Randomized, Parallel-group, Double-blind, Placebo-controlled Studies. The Clinical journal of pain. https://pubmed.ncbi.nlm.nih.gov/32271183/. Published July 2020. Accessed January 11, 2021. 1000 mg versus 600/650 mg Acetaminophen for Pain or Fever: A Review of the Clinical Efficacy. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK373467/. Published June 17, 2016. Accessed January 11, 2021. Motov S. Is There a Limit to the Analgesic Effect of Pain Medications? Medscape. https://www.medscape.com/viewarticle/574279. Published June 17, 2008. Accessed January 11, 2021. Motov, Sergey. Faculty Forum: A Practical Approach to Pain Management. YouTube. https://www.youtube.com/watch?v=lJSioPsGw3A. The Center for Medical Education. Published December 2, 2020. Accessed January 1, 2021. Wuhrman E, Cooney MF. Acute Pain: Assessment and Treatment. Medscape. https://www.medscape.com/viewarticle/735034_4. Published January 3, 2011. Accessed January 11, 2021. Social Pain Dewall CN, Macdonald G, Webster GD, et al. Acetaminophen reduces social pain: behavioral and neural evidence. Psychological science. https://pubmed.ncbi.nlm.nih.gov/20548058/. Published June 14, 2010. Accessed January 11, 2021. Mischkowski D, Crocker J, Way BM. From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain. Social cognitive and affective neuroscience. https://pubmed.ncbi.nlm.nih.gov/27217114/. Published May 5, 2016. Accessed January 11, 2021. Other / Recurrent liner notes Center for Medical Education. https://courses.ccme.org/. Accessed January 11, 2021. Roberts M, Roberts JR. The Proceduralist. https://www.theproceduralist.org/. Accessed January 11, 2021. The Procedural Pause by James R. Roberts, MD, & Martha Roberts, ACNP, PNP. Emergency Medicine News. https://journals.lww.com/em-news/blog/theproceduralpause/pages/default.aspx. Accessed January 11, 2021. The Skeptics' Guide to Emergency Medicine. sgem.ccme.org. https://sgem.ccme.org/. Accessed January 11, 2021. Trivia Question: Send answers to 2viewcast@gmail.com Please note that you must answer the 2 part question to win a copy of the EMRA Pain Guide. “What controversial drug was given a black box warning for prolonged QT and torsades in 2012 and now has been declared by WHICH organization to be an effective and safe treatment use for nausea, vomiting, headache and agitation?” Practical Pain Management in Acute Care Setting Handout Sergey Motov, MD @painfreeED • Pain is one of the most common reasons for patients to visit the emergency department and other acute care settings. Due to the extensive number of visits related to pain, clinicians and midlevel providers should be aware of the various options, both pharmacological and nonpharmacological, available to treat patients with acute pain. • As the death toll from the opioid epidemic continues to grow, the use of opioids in the acute care setting as a first-line treatment for analgesia is becoming increasingly controversial and challenging. • There is a growing body of literature that is advocating for more judicious use of opioids and well as their prescribing and for broader use of non-pharmacological and non-opioid pain management strategies. • The channels/enzymes/receptors targeted analgesia (CERTA) concept is based on our improved understanding of the neurobiological aspect of pain with a shift from a symptom-based approach to pain to a mechanistic approach. This targeted analgesic approach allows for a broader utilization of synergistic combinations of nonopioid analgesia and more refined and judicious (rescue) use of opioids. These synergistic combinations result in greater analgesia, fewer side effects, lesser sedation, and shorter LOS. (Motov et al 2016) General Principles: Management of acute pain in the acute care setting should be patient-centered and pain syndrome-specific by using multimodal approach that include non-pharmacological modalities and pharmacological ones that include non-opioid and opioid analgesics. Assessment of acute pain should be based on a need for analgesics to improve functionality, rather than patients-reported pain scores. Brief pain inventory short form BPI-SF is better than NRS/VAS as it assesses quantitative and qualitative impact of pain (Im et al 2020). ED clinicians should engage patients in shared decision-making about overall treatment goals and expectations, the natural trajectory of the specific painful condition, and analgesic options including short-term and long-term benefits and risks of adverse effects. If acute pain lasting beyond the expected duration, complications of acute pain should be ruled out and transition to non-opioid therapy and non-pharmacological therapy should be attempted. Non-Pharmacologic Therapies • Acute care providers should consider applications of heat or cold as well as specific recommendations regarding activity and exercise. • Music therapy is a useful non-pharmacologic therapy for pain reduction in acute care setting (music-assisted relaxation, therapeutic listening/musical requests, musical diversion, song writing, and therapeutic singing (Mandel 2019). • The use of alternative and complementary therapies, such as acupuncture, guided imagery, cognitive-behavioral therapy, and hypnosis have not been systemically evaluated for use in the Acute care setting including ED. (Dillan 2005, Hoffman 2007) • In general, their application may be limited for a single visit, but continued investigation in their safety and efficacy is strongly encouraged. • Practitioners may also consider utilization of osteopathic manipulation techniques, such as high velocity, low amplitude techniques, muscle energy techniques, and soft tissue techniques for patients presenting to the acute care setting with pain syndromes of skeletal, arthroidal, or myofascial origins. (Eisenhart 2003) Opioids • Acute Care providers are uniquely positioned to combat the opioid epidemic by thoughtful prescribing of parenteral and oral opioids in inpatient setting and upon discharge, and through their engagement with opioid addicted patients in acute care setting. • Acute Care providers should make every effort to utilize non-pharmacological modalities and non-opioid analgesics to alleviate pain, and to use opioid analgesics only when the benefits of opioids are felt to outweigh the risks. (not routinely) • When opioids are used for acute pain, clinicians should combine them with non-pharmacologic and non-opioid pharmacologic therapy: Yoga, exercise, cognitive behavioral therapy, complementary/alternative medical therapies (acupuncture); NSAID's, Acetaminophen, Topical Analgesics, Nerve blocks, etc. • When considering opioids for acute pain, Acute Care providers should involve patients in shared decision-making about analgesic options and opioid alternatives, risks and benefits of opioid therapies, and rational expectations about the pain trajectory and management approach. • When considering opioids for acute pain, acute care providers should counsel patients regarding serious adverse effects such as sedation and respiratory depression, pruritus and constipation, and rapid development of tolerance and hyperalgesia. • When considering administration of opioids for acute pain, acute care providers should make every effort to accesses respective state's Prescription Drug Monitoring Program (PDMP). The data obtained from PDMP's to be used to identify excessive dosages and dangerous combinations, identify and counsel patients with opioid use disorder, offer referral for addiction treatment. • PDMPs can provide clinicians with comprehensive prescribing information to improve clinical decisions around opioids. However, PDMPs vary tremendously in their accessibility and usability in the ED, which limits their effectiveness at the point of care. Problems are complicated by varying state-to-state requirements for data availability and accessibility. Several potential solutions to improving the utility of PDMPs in EDs include integrating PDMPs with electronic health records, implementing unsolicited reporting and prescription context, improving PDMP accessibility, data analytics, and expanding the scope of PDMPs. (Eldert et al, 2018) • Parenteral opioids when used in titratable fashion are effective, safe, and easily reversible analgesics that quickly relieve pain. • Acute care clinicians should consider administering these analgesics for patients in acute pain where the likelihood of analgesic benefit is judged to exceed the likelihood of harm. • Parenteral opioids must be titrated regardless of their initial dosing regimens (weight-based or fixed) until pain is optimized to acceptable level (functionality status) or side effects become intolerable. • When parenteral opioids are used, patients should be engaged in shared-decision making regarding the route of administration, as repetitive attempts of IV cannulation and intramuscular injections are associated with pain. In addition, intramuscular injections are associated with unpredictable absorption rates, and complications such as muscle necrosis, soft tissue infection and the need for dose escalation. (Von Kemp 1989, Yamanaka 1985, Johnson 1976) • Morphine sulfate provides better balance of analgesic efficacy and safety among all parenteral opioids. a. Dosing regimens and routes: b. IV: 0.05-0.1mg/kg to start, titrate q 10-20 min c. IV: 4-6 mg fixed, titrate q 10-20 min d. SQ: 4-6 mg fixed, titrate q 20 min e. Nebulized: 0.2 mg/kg or 10-20 mg fixed, repeat q 15-20 min f. PCA: prone to dosing errors g. IM: should be avoided (pain, muscle fibrosis, necrosis, increase in dosing requirements) • Hydromorphone should be avoided as a first-line opioid due to significant euphoria and severe respiratory depression requiring naloxone reversal. Due to higher lipophilicity, Hydromorphone use is associated with higher rates of euphoria and subsequent development of addiction. Should hydromorphone be administered in higher than equi-analgesic morphine milligram equivalents, close cardiopulmonary monitoring is strongly recommended. Dosing h. IV: 0.2-0.5 mg initial, titrate q10-15 min i. IM: to be avoided (pain, muscle fibrosis, necrosis, increase in dosing requirements) j. PCA: prone to dosing errors (severe CNS and respiratory depression) k. Significantly worse AE profile in comparison to Morphine l. Equianalgesic IV conversion (1 mg HM=8mg of MS) m. Overprescribed in >50% of patients n. Inappropriately large dosing in EM literature: 2 mg IVP o. Abuse potential (severely euphoric due to lipophilicity) • Fentanyl is the most potent opioid, short-acting, requires frequent titration. Dosing: p. IV: 0.25-0.5 μg/kg (WB), titrate q10 min q. IV: 25-50 μg (fixed), titrate q10 min r. Nebulization: 2-4 μg/kg, titrate q20-30 min s. IN: 1-2 μg/kg, titrate q5-10min t. Transbuccal: 100-200μg disolvable tablets u. Transmucosal: 15-20 mcg/kg Lollypops • Opioids in Renal Insufficiency/Renal Failure Patients-requires balance of ORAE with pain control by starting with lower-than-recommended doses and slowly titrate up the dose while extending the dosing interval. (Dean 2004, Wright 2011) • Opioid-induced pruritus is centrally mediated process via μ-opioid receptors as naloxone, nalbuphine reverse it, and can be caused by opioids w/o histamine release (Fentanyl). Use ultra-low-dose naloxone of 0.25 -1 mcg/kg/hr with NNT of 3.5. (Kjellberg 2001) • When intravascular access is unobtainable, acute care clinicians should consider utilization of intranasal (fentanyl), nebulized (fentanyl and morphine), or transmucosal (rapidly dissolvable fentanyl tablets) routes of analgesic administration for patients with acute painful conditions. • Breath actuated nebulizer (BAN): enclosed canister, dual mode: continuous and on-demand, less occupational exposures. a. Fentanyl: 2-4 mcg//kg for children, 4 mcg/kg for adults: titration q 10 min up to three doses via breath-actuated nebulizer (BAN): systemic bioavailability of 50-60% of IV route. (Miner 2007, Furyk 2009, Farahmand 2014) b. Morphine: 10-20 mg g10 min up to 3 doses via breath-actuated nebulizer (BAN)-Systemic bioavailability (concentration) of 30-35% of IV Route. (Fulda 2005, Bounes 2009, Grissa 2015) c. Intranasal Fentanyl: IN via MAD at 1-2 mcg/kg titration q 5 min (use highly concentrated solution of 100mcg/ml for adults and 50 mcg/ml for children)- systemic bioavailability of 90% of IV dosing. (Karisen 2013, Borland 2007, Saunders 2010, Holdgate 2010) d. IN route: shorter time to analgesia, titratable, comparable pain relief to IV route, minimal amount of side effects, similar rates of rescue analgesia, great patients and staff satisfaction. Disadvantages: requires highly concentrated solutions that not readily available in the ED, contraindicated in facial/nasal trauma. Oral Opioids • Oral opioid administration is effective for most patients in the acute care setting, however, there is no appreciable analgesic difference between commonly used opioids (oxycodone, hydrocodone and morphine sulfate immediate release (MSIR). • When oral opioids are used for acute pain, the lowest effective dose and fewest number of tablets needed should be prescribed. In most cases, less than 3 days' worth are necessary, and rarely more than 5 days' worth are needed. • If painful condition outlasts three-day supply, re-evaluation in health-care facility is beneficial. Consider expediting follow-up care if the patient's condition is expected to require more than a three-day supply of opioid analgesics. • Only Immediate release (short-acting) formulary are to be prescribed in the acute care setting and at discharge. • Clinicians should not administer or prescribe long-acting, extended-release, or sustained-release opioid formulations, which include both oral and transdermal (fentanyl) medications in the acute care setting. These formulations are not indicated for acute pain and carry a high risk of overdose, particularly in opioid-naïve patients. • Acute care providers should counsel patients about safe medication storage and disposal, as well as the consequences of failure to do this; potential for abuse and misuse by others (teens and young adults), and potential for overdose and death (children and teens). • Oxycodone is no more effective than other opioids (hydrocodone, MSIR). Oxycodone has highest potential for abuse, misuse and diversion as well as increased risks of overdose, addiction and death. Oxycodone should be avoided as a first-line oral opioid for acute pain. ( Strayer 2016) • If still prescribed, lowest dose (5mg) in combination with acetaminophen (lowest dose of 325 mg) should be considered as it associated with less abuse and diversion (in theory). Potential for acetaminophen overdose exist though with combination. • Hydrocodone is three times more prescribed than oxycodone, but three times less used for non-medical purpose. Combo with APAP (Vicodin)-Use lowest effective dose for hydrocodone and APAP (5/325). (Quinn 1997, Adams 2006) • Immediate release morphine sulfate (MSIR) administration is associated with lesser degree of euphoria and consequently, less abuse potential (Wightman 2012). ED providers should consider prescribing Morphine Sulfate Immediate Release Tablets (MSIR) (Wong 2012, Campos 2014) for acute pain due to: o Similar analgesic efficacy to Oxycodone and Hydrocodone o Less euphoria (less abuse potential) o Less street value (less diversion) o More dysphoria in large doses o Less abuse liability and likeability • Tramadol should not be used in acute care setting and at discharge due to severe risks of adverse effects, drug-drug interactions, and overdose. There is very limited data supporting better analgesic efficacy of tramadol in comparison to placebo, or better analgesia than APAP or Ibuprofen. Tramadol dose not match analgesic efficacy of traditional opioids. (Juurlink 2018, Jasinski 1993, Babalonis 2013) • Side effects are: o Seizures o Hypoglycemia o Hyponatremia o Serotonin syndrome o Abuse and addiction • Codeine and Codeine/APAP is a weak analgesic that provides no better pain relief than placebo. Codeine must not be administered to children due to: o dangers of the polymorphisms of the cytochrome P450 iso-enzyme: o ultra-rapid metabolizers: respiratory depression and death o poor metabolizers: absent or insufficient pain relief • Transmucosal fentanyl (15 and 20 mcg/kg lollypops) has an onset of analgesia in 5 to 15 minutes with a peak effect seen in 15 to 30 minutes (Arthur 2012). • Transbuccal route can be used right at the triage to provide rapid analgesia and as a bridge to intravenous analgesia in acute care setting. (Ashburn 2011). A rapidly dissolving trans-buccal fentanyl (100mcg dose) provides fast pain relief onset (median 10 min), great analgesics efficacy, minimal need for rescue medication and lack of side effects in comparison to oxycodone/acetaminophen tablet (Shear 2010) • Morphine Milligram Equivalent (MME) is a numerical standard against which most opioids can be compared, yielding a comparison of each medication's potency. MME does not give any information of medications efficacy or how well medication works, but it is used to assess comparative potency of other analgesics. • By converting the dose of an opioid to a morphine equivalent dose, a clinician can determine whether a cumulative daily dose of opioids approaches an amount associated with increased risk of overdose and to identify patients who may benefit from closer monitoring, reduction or tapering of opioids, prescribing of naloxone, and other measures to reduce risk of overdose. • Opioid-induced hyperalgesia: o opioid-induced hyperalgesia (OIH) is a rare syndrome of increasing pain, often accompanied by neuroexcitatory effects, in the setting of increasing opioid therapy. o Morphine is by far the most common opiate implicated in OIH. Hydromorphone and oxycodone, members of the same class of opiate as morphine (phenanthrenes), can also cause OIH. Fentanyl, a synthetic opioid in the class of phenylpiperidine, is less likely to precipitate OIH. Existing data suggests that OIH is caused by multiple opioid-induced changes to the central nervous system including: -Activation of N-methyl-D-aspartate (NMDA) receptors -Inhibition of the glutamate transporter system -Increased levels of the pro-nociceptive peptides within the dorsal root ganglia -Activation of descending pain facilitation from the rostral ventromedial medulla -Neuroexcitatory effects provoked by metabolites of morphine and hydromorphone • OIH can be confused with tolerance as in both cases patients report increased pain on opioids. The two conditions can be differentiated based on the patient's response to opioids. In tolerance, the patient's pain will improve with dose escalation. In OIH, pain will worsen with opioid administration. This paradoxical effect is one of the hallmarks of the syndrome. Non-opioid analgesics • Acetaminophen is indicated for management of mild to moderate pain and as a single analgesic and has modest efficacy at most. Addition of Acetaminophen to Ibuprofen does not provide better analgesia for patients with acute low back pain. The greatest limitation to the use of intravenous (IV) versus oral acetaminophen is the nearly 100-fold cost differential, which is likely not justified by any marginal improvement in pain relief. Furthermore, IV APAP provide faster onset of analgesia only after an initial dose. (Yeh 2012, Serinken 2012) • NSAIDs should be administered at their lowest effective analgesic doses both in the ED and upon discharge and should be given for the shortest appropriate treatment course. Caution is strongly advised when NSAIDs are used in patients at risk for renal insufficiency, heart failure, and gastrointestinal hemorrhage, as well as in the elderly. Strong consideration should be given to topical NSAID's in managing as variety of acute and chronic painful Musculo-skeletal syndromes. The analgesic ceiling refers to the dose of a drug beyond which any further dose increase will not result in additional analgesic efficacy. Thus, the analgesics ceiling for ibuprofen is 400 mg per dose (1200 mg/24 h) and for ketorolac is 10 mg per dose (10 mg/24 h). These doses are less than those often prescribed for control of inflammation and fever. When it comes to equipotent doses of different NSAIDs, there is no difference in analgesic efficacy. • Ketamine, at sub-dissociative doses (also known as low-dose ketamine or analgesic dose ketamine) of 0.1 to 0.4 mg/kg, provided effective analgesia as a single agent or as an adjunct to opioids (reducing the need for opioids) in the treatment of acute traumatic and nontraumatic pain in the ED. This effective analgesia, however, must be balanced against high rates of minor adverse side effects (14%–80%), though typically short-lived and not requiring intervention. In addition to IV rout, ketamine can be administered via IN,SQ, and Nebulized route. • Local anesthetics are widely used in the ED for topical, local, regional, intra-articular, and systemic anesthesia and analgesia. Local anesthetics (esters and amides) possess analgesic and anti-hyperalgesic properties by non-competitively blocking neuronal sodium channels. o Topical analgesics containing lidocaine come in patches, ointments, and creams have been used to treat pain from acute sprains, strains, and contusions as well as variety of acute inflammatory and chronic neuropathic conditions, including postherpetic neuralgia (PHN), complex regional pain syndromes (CRPS) and painful diabetic neuropathy (PDN). o UGRA used for patients with lower extremity fractures or dislocations (eg, femoral nerve block, fascia iliaca compartment block) demonstrated significant pain control, decreased need for rescue analgesia, and first-attempt procedural success. In addition, UGRA demonstrated few procedural complications, minimal need for rescue analgesia, and great patient satisfaction. o Analgesic efficacy and safety of IV lidocaine has been evaluated in patients with renal colic and acute lower back pain. Although promising, this therapy will need to be studied in larger populations with underlying cardiac disease before it can be broadly used. o knvlsd • Antidopaminergic and Neuroleptics are frequently used in acute care settings for treatment of migraine headache, chronic abdominal pain, cannabis-induced hyperemesis. • Anti-convulsant (gabapentin and pregabalin) are not recommended for management of acute pain unless pain is of neuropathic origin. Side effects, particularly when combined with opioids (potentiation of euphoria and respiratory depression), titration to effect, and poor patients' compliance are limiting factors to their use. (Peckham 2018) References: Chang HY, Daubresse M, Kruszewski SP, et al. Prevalence and treatment of pain in EDs in the United States, 2000 to 2010. Am J Emerg Med 2014;32(5):421–31. Green SM. There is oligo-evidence for oligoanalgesia. Ann Emerg Med 2012;60: 212–4. Strayer RJ, Motov SM, Nelson LS. Something for pain: Responsible opioid use in emergency medicine. Am J Emerg Med. 2017 Feb;35(2):337-341. Smith RJ, Rhodes K, Paciotti B, Kelly S,et al. Patient Perspectives of Acute Pain Management in the Era of the Opioid Epidemic. Ann Emerg Med. 2015 Sep;66(3):246-252 Meisel ZF, Smith RJ. Engaging patients around the risks of opioid misuse in the emergency department. Pain Manag. 2015 Sep;5(5):323-6. Wightman R, Perrone J. (2017). Opioids. In Strayer R, Motov S, Nelson L (Eds.), Management of Pain and Procedural Sedation in Acute Care. http://painandpsa.org/opioids/ Motov S, Nelson L, Advanced Concepts and Controversies in Emergency Department Pain Management. Anesthesiol Clin. 2016 Jun;34(2):271-85. doi: 10.1016/j.anclin.2016.01.006. Ducharme J. Non-opioid pain medications to consider for emergency department patients. Available at: http://www.acepnow.com/article/non-opioid-painmedications- consider-emergency-department-patients/. 2015. Wightman R, Perrone J, Portelli I, et al. Likeability and Abuse Liability of Commonly Prescribed Opioids. J Med Toxicol. September 2012. doi: 10.1007/s12181-012-0263-x Zacny JP, Lichtor SA. Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers. Psychopharmacology (Berl) 2008 Jan;196(1):105–16. Hoppe JA, Nelson LS, Perrone J, Weiner SG, Prescribing Opioids Safely in the Emergency Department (POSED) Study Investigators. Opioid Prescribing in a Cross Section of US Emergency Departments. Ann Emerg Med. 2015;66(3):253–259. Baehren DF, Marco CA, Droz DE, et al. A statewide prescription monitoring program affects emergency department prescribing behaviors. Ann Emerg Med. 2010; 56(1):19–23 Weiner SG, Griggs CA, Mitchell PM, et al. Clinician impression versus prescription drug monitoring program criteria in the assessment of drug-seeking behavior in the emergency department. Ann Emerg Med 2013;62(4):281–9. Greenwood-Ericksen MB, Poon SJ, Nelson LS, Weiner SG, et al. Best Practices for Prescription Drug Monitoring Programs in the Emergency Department Setting: Results of an Expert Panel. Ann Emerg Med. 2016 Jun;67(6):755-764 Patanwala AE, Keim SM, Erstad BL. Intravenous opioids for severe acute pain in the emergency department. Ann Pharmacother 2010;44(11):1800–9. Bijur PE, Kenny MK, Gallagher EJ. Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients. Ann Emerg Med 2005; 46:362–7. Birnbaum A, Esses D, Bijur PE, et al. Randomized double-blind placebo- controlled trial of two intravenous morphine dosages (0.10 mg/kg and 0.15 mg/kg) in emergency department patients with moderate to severe acute pain. Ann Emerg Med. 2007;49(4):445–53. Patanwala AE, Edwards CJ, Stolz L, et al. Should morphine dosing be weight based for analgesia in the emergency department? J Opioid Manag 2012; 8(1):51–5. Lvovschi V, Auburn F, Bonnet P, et al. Intravenous morphine titration to treat severe pain in the ED. Am J Emerg Med 2008;26:676–82. Chang AK, Bijur PE, Napolitano A, Lupow J, et al. Two milligrams i.v. hydromorphone is efficacious for treating pain but is associated with oxygen desaturation. J Opioid Manag. 2009 Mar-Apr;5(2):75-80. Sutter ME, Wintemute GJ, Clarke SO, et al. The changing use of intravenous opioids in an emergency department. West J Emerg Med 2015;16:1079-83. Miner JR, Kletti C, Herold M, et al. Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to the emergency department with acute pain. Acad Emerg Med 2007;14:895–8. Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emerg Med Australas 2009;21:203–9. Borland M, Jacobs I, King B, et al. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med 2007;49:335–40 Im DD, Jambaulikar GD, Kikut A, Gale J, Weiner SG. Brief Pain Inventory-Short Form: A New Method for Assessing Pain in the Emergency Department. Pain Med. 2020 Sep 11:ppnaa269. doi: 10.1093/pm/pnaa269. Epub ahead of print. PMID: 32918473. Mandel SE, Davis BA, Secic M. Patient Satisfaction and Benefits of Music Therapy Services to Manage Stress and Pain in the Hospital Emergency Department. J Music Ther. 2019 May 10;56(2):149-173. Piatka C, Beckett RD. Propofol for Treatment of Acute Migraine in the Emergency Department: A Systematic Review. Acad Emerg Med. 2020 Feb;27(2):148-160. Tzabazis A, Kori S, Mechanic J, Miller J, Pascual C, Manering N, Carson D, Klukinov M, Spierings E, Jacobs D, Cuellar J, Frey WH 2nd, Hanson L, Angst M, Yeomans DC. Oxytocin and Migraine Headache. Headache. 2017 May;57 Suppl 2:64-75. doi: 10.1111/head.13082. PMID: 28485846. Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacotherapy 2012;32(6):559–79. Serinken M, Eken C, Turkcuer I, et al. Intravenous paracetamol versus morphine for renal colic in the emergency department: a randomised double-blinded controlled trial. Emerg Med J 2012;29(11):902–5. Wright JM, Price SD, Watson WA. NSAID use and efficacy in the emergency department: single doses of oral ibuprofen versus intramuscular ketorolac. Ann Pharmacother 1994;28(3):309–12. Turturro MA, Paris PM, Seaberg DC. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med 1995;26(2):117–20. Catapano MS. The analgesic efficacy of ketorolac for acute pain [review]. J Emerg Med 1996;14(1):67–75 Dillard JN, Knapp S. Complementary and alternative pain therapy in the emergency department. Emerg Med Clin North Am 2005; 23:529–549. Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol 2007;26:1–9. Eisenhart AW, Gaeta TJ, Yens DP. Osteopathic manipulative treatment in the emergency department for patients with acute ankle injuries. J Am Osteopath Assoc 2003;103:417–421.
This episode covers P450 interactions!
FDA 批准颈动脉窦压力反射刺激疗法治疗心衰Lancet 血ACE2水平与心血管疾病及死亡的关系Science子刊 一种具有几何适应性的人工心脏瓣膜BAROSTIM NEO系统BAROSTIM NEO系统包括一个植入式脉冲发生器（IPG）、一个颈动脉窦含铅套件和一个程序。医生将BAROSTIM NEO脉冲发生器植入晚期心力衰竭患者的左或右锁骨下方，并在患者的左或右颈动脉窦处放置颈动脉窦导线，然后将脉冲发生器连接到颈动脉窦导线上。医生根据病人的个人需求制定脉冲发生器程序，然后向颈动脉的压力感受器传递电脉冲。压力反射激活（BAT）疗法的目的是激活颈动脉壁的压力感受器，刺激自主神经系统的传入和传出神经，大脑接收到神经信号作出相应反应：松弛血管、降低心率、并通过改善肾功能来减少液体储留。2019年8月，FDA批准BAROSTIM NEO系统用于药物治疗无效的、不符合心脏再同步化治疗适应症的、难治性心力衰竭患者。《BeAT-HF研究：这项研究证明了压力反射刺激疗法（BAT）对射血分数降低的心力衰竭患者的安全性和有效性》Journal of American College of Cardiology，2020年7月 (1) BeAT-HF研究是一项多中心、前瞻性、随机对照研究，纳入408名射血分数降低的心力衰竭（HFrEF）患者中，入组要求：纽约心功能分级II-III级、射血分数≤35%、药物治疗方案稳定≥4周、不符合心脏再同步化治疗的I类指征。这篇报告重点汇报了D队列中、NT-proBNP
Jon Bloom, MD, CEO & Co-Founder, Podimetrics Dr. Jon Bloom is a board-certified physician and entrepreneur with over 15 years of experience in technology development, patient monitoring, biomedical research, and health care delivery. He is the chief executive officer of Podimetrics, a virtual care management company dedicated to preventing diabetic amputations, one of the most debilitating and costly complications of diabetes. Dr. Bloom was inspired to create a solution to help prevent diabetic foot complications while practicing anesthesia. He frequently treated patients with diabetes who required foot amputations, and knew there had to be a less drastic way to manage common complications of that disease. Dr. Bloom co-founded Podimetrics in 2011 while a student at the MIT Sloan School of Management. Podimetrics combines an FDA-cleared SmartMat™ with wraparound care management to spot early warning signs weeks before they usually would present clinically. By combining cutting-edge technology with best-in-class care management, Podimetrics earns high engagement rates from patients and achieves unparalleled outcomes - keeping vulnerable patients healthy at home and saving limbs, lives, and money. Dr. Bloom served as a Clinical Assistant Professor and staff anesthesiologist at the University of Pittsburgh Medical Center. He also served as the Director of Global Medical Affairs for Covidien's Respiratory and Monitoring Solutions division in Boulder, Colorado. Dr. Bloom is a diplomate of the American Board of Anesthesiology, completing residency at the Massachusetts General Hospital. He has co-authored more than 20 peer-reviewed publications with a primary focus on health care economics and perioperative complications. Prior to his career in medicine Dr. Bloom studied cytochrome P450 drug metabolism at The Scripps Research Institute.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.19.344887v1?rss=1 Authors: Tang, M., Zeng, L., Zeng, Z., Liu, J., Yuan, J., Wu, D., Lu, Y., Zi, J., Ye, M. Abstract: Colorectal cancer (CRC) is a malignant tumour with high morbidity and mortality worldwide. Efficient screening strategies for CRC and pre-cancerous lesions will promote early medical intervention and treatment, thus reducing morbidity and mortality. Proteins are generally considered key biomarkers of cancer. Herein, we performed a quantitative, tissue-original proteomics study in a cohort of ninety patients from pre-cancerous to cancerous conditions by liquid chromatography-tandem mass spectrometry. A total of 134,812 peptides, 8,697 proteins, 2,355 (27.08%) union differentially expressed proteins (DEPs), and 409 shared DEPs (compared with adjacent tissues) were identified. The number of DEPs showed a positive correlation with increasing severity of illness. The union and shared DEPs were both enriched in the KEGG pathway of focal adhesion, metabolism of xenobiotics by cytochrome P450, and drug metabolism - cytochrome P450. Among the 2,355 union DEPs, 32 were selected for identification and validation by multiple reaction monitoring from twenty plasma specimens. Of these, three proteins, transferrin receptor protein 1 (TFR1), adenosylhomocysteinase (SAHH), and immunoglobulin heavy variable 3-7 (HV307), were significantly differentially expressed and displayed the same expression pattern in plasma as observed in the tissue data. In conclusion, TFR1, SAHH, and HV307 may be considered as potential biomarkers for screening of CRC. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.15.340745v1?rss=1 Authors: Souza, S. A., Held, A., Lu, W., Drouhard, B., Avila, B., Leyva-Montes, R., Hu, M. G., Miller, B. R., Ng, H. L. Abstract: Aromatase (Cyp19) catalyzes the last biosynthetic step of estrogens in mammals and is a primary therapeutic target for postmenopausal women with hormone-related breast cancer. However, treatment with aromatase inhibitors is often associated with adverse effects and drug resistance. In this study, we used virtual screening to target a potential cytochrome P450 reductase binding site to discover four novel non-steroidal aromatase inhibitors. The inhibitors have potencies comparable to the noncompetitive tamoxifen metabolite, endoxifen. Our two most potent inhibitors, AR11 and AR13, exhibit mixed-type and competitive-type inhibition. The cytochrome P450 reductase binding site likely acts as a transient binding site. Modeling shows that our inhibitors actually bind better at various sites near the catalytic site. These structures may serve as chemical scaffolds to inhibit aromatase with different adverse effects profiles than clinically used aromatase inhibitors. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.23.310391v1?rss=1 Authors: Jensen, S. B., Thodberg, S., Parween, S., Moses, M. E., Hansen, C. C., Thomsen, J., Sletfjerding, M. B., Knudsen, C., Giudice, R. D., Lund, P. M., Castano, P. R., Bustamante, Y. G., Jorgensen, F. S., Pandey, A. V., Laursen, T., Moller, B. L., Hatzakis, N. S. Abstract: Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes. A key element in these assemblies, the P450 oxidoreductase (POR), donates electrons and selectively activates numerous (>50 in humans and >300 in plants) cytochromes P450 (CYPs) controlling metabolism of drugs, steroids and xenobiotics in humans and natural product biosynthesis in plants. The mechanisms underlying POR-mediated CYP metabolism remain poorly understood and to date no ligand binding has been described to regulate the specificity of POR. Here, using a combination of computational modeling and functional assays, we identified ligands that dock on POR and bias its specificity towards CYP redox partners. Single molecule FRET studies revealed ligand docking to alter POR conformational sampling, which resulted in biased activation of metabolic cascades in whole cell assays. We propose the model of biased metabolism, a mechanism akin to biased signaling of GPCRs, where ligand docking on POR stabilizes different conformational states that are linked to distinct metabolic outcomes. Biased metabolism may allow designing pathway-specific therapeutics or personalized food suppressing undesired, disease related, metabolic pathways. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.14.296467v1?rss=1 Authors: Connick, J. P., Reed, J. R., Cawley, G. F., Backes, W. L. Abstract: Heme oxygenase 1 (HO-1) and the cytochromes P450 (P450s) are endoplasmic reticulum-bound enzymes that rely on the same protein, NADPH-cytochrome P450 reductase (POR), to provide the electrons necessary for substrate metabolism. Although the HO-1 and P450 systems are interconnected due to their common electron donor, they generally have been studied separately. As the expression of both HO-1 and P450s are affected by xenobiotic exposure, changes in HO-1 expression can potentially affect P450 function, and conversely, changes in P450 expression can influence HO-1. The goal of this study was to examine interactions between the P450 and HO-1 systems. Using bioluminescence resonance energy transfer (BRET), HO-1 formed HO-1P450 complexes with CYP1A2, CYP1A1, and CYP2D6, but not all P450s. Studies then focused on the HO-1/CYP1A2 interaction. CYP1A2 formed a physical complex with HO-1 that was stable in the presence of POR. As expected, both HO-1 and CYP1A2 formed BRET-detectable complexes with POR. Whereas the PORCYP1A2 complex was readily disrupted by the addition of HO-1, the PORHO-1 complex was not significantly affected by the addition of CYP1A2. Interestingly, enzyme activities did not follow this pattern. Whereas BRET data suggested substantial inhibition of CYP1A2-mediated 7-ethoxyresorufin deethylation in the presence of HO-1, its activity was actually stimulated at subsaturating POR. In contrast, HO-1-mediated heme metabolism was inhibited at subsaturating POR. These results indicate that HO-1 and CYP1A2 form a stable complex and have mutual effects on the catalytic behavior of both proteins that cannot be explained by simple competition for POR. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.28.265934v1?rss=1 Authors: Rodriguez-Lopez, C. E., Hong, B., Paetz, C., Nakamura, Y., Koudounas, K., Passeri, V., Baldoni, L., Alagna, F., Calderini, O., O'Connor, S. E. Abstract: Olive (Olea europaea) is an important crop in Europe, with high cultural, economic, and nutritional significance. Olive oil flavor and quality depend on phenolic secoiridoids, but the biosynthetic pathway of these iridoids remains largely uncharacterized. We discovered two novel, bi-functional cytochrome P450 enzymes, catalysing the rare oxidative C-C bond cleavage of 7-epi-loganin to produce oleoside methyl ester (OeOMES) and secoxyloganin (OeSXS), both through a ketologanin intermediary. Although these enzymes are homologous to the previously reported Catharanthus roseus Secologanin Synthase (CrSLS), the substrate and product profiles differ. Biochemical assays provided mechanistic insights into the two-step OeOMES and CrSLS reactions. Model-guided mutations of OeOMES changed the product profile in a predictable manner, revealing insights into the molecular basis for this change in product specificity. Our results suggest that, in contrast to published hypotheses, in planta production of secoxy-iridoids is secologanin independent. Notably, sequence data of cultivated and wild olives, points to a relation between domestication and OeOMES expression. Thus, the discovery of this key biosynthetic gene suggests a link between domestication and secondary metabolism, and could potentially be used as a genetic marker to guide next-generation breeding programs. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.27.269936v1?rss=1 Authors: Bukhdruker, S., Varaksa, T., Grabovec, I., Marin, E., Shabunya, P., Kadukova, M., Grudinin, S., Kavaleuski, A., Gusach, A., Gilep, A., Borshchevskiy, V., Strushkevich, N. Abstract: Spreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25-[A] resolution crystal structure of the CYP124-SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the {omega}-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, i.e., the Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs. Copy rights belong to original authors. Visit the link for more info
Matt Cooper is a nutrition consultant, integrative health coach, and strength & conditioning coach from Los Angeles, California. You can tell by looking at his website’s bio at RewirePerformance.com that he’s an avid learner who applies and combines his knowledge from different fields to craft tailormade training programs for his clients ranging from professional athletes and celebrities to everyday gym members and local kids from the Compton area. Matt openly speaks about psychedelics as performance and fitness enhancers, for example, on The Third Wave podcast, where he’s also a consultant. Although Matt can speak about a range of topics, we’re going to discuss a common physical discomfort caused by long bouts of immobility during iboga experiences, that is to say, muscle cramps, and, nutritional considerations tied to psychedelic use, specifically how it relates to the iboga experience. Topics of our discussion include: the difference between cramps and strains; (de)hydration and the importance of electrolytes; purging of toxins; fitness tips for iboga/psychedelic users to proactively reduce muscle soreness; nutrient “reloading” or “loading up” prior to experiences; foods to avoid while on iboga because of how they affect drug metabolism by the cytochrome P450 enzyme modulator; what and why the Bwiti eat and don’t eat before and after an iboga experience; and how it is that the body communicates its nutritional needs via cravings to be satisfied. Also, please visit my Podcast Supplements article regarding afterthoughts of Matt and I's conversation (https://amhouot.com/61-ep2-2_build-up-for-breakdown_matt-cooper/).CONNECTTwitter (https://twitter.com/AMhouot)LinkedIn (https://www.linkedin.com/in/amhouot/)Academia (https://independent.academia.edu/AMHouot)ResearchGate (https://www.researchgate.net/profile/Am_Houot)DISCLAIMERIBOGANAUTICS podcast is for informational and educational purposes only. Efforts are made to broadcast correct information, but no guarantee is given regarding the accuracy of any statements or opinions. Contributors are not responsible for any damages arising from podcast consumption. Iboga has potential psychosomatic risks and therefore is not suitable for everyone. If wanting to consume iboga, seek out countries where it is administered legally and under professional supervision. Views discussed are not substitute for medical advice nor should be construed as best practice. Comments, suggestions, or correction of errors are welcome considering psychedelic science and related fields steadily advance.
The Investigation Gluten intolerance is an issue for a lot of people. As we explored in episode 066, it can cause a wide range of symptoms including fatigue, bloating, skin irritations, and migraines. For some people, gluten may seem like the root cause, but it could actually be something else. In this episode, we examine a chemical closely tied to wheat that could be the real issue. Root Cause of Gluten Intolerance in America Ever wonder why wheat seems to give people so many issues in this country? While gluten certainly plays a huge role, the question we are often asked is why people who are so sensitive to wheat in the US seem ok with it when traveling to other countries. It has been said that the genetic modification of wheat and hybridization plays a big role and while that is true, the new hybrid wheat has spread all over the world so it’s no longer specifically concentrated here in the US. So what is the issue? There was a wonderful article in The Healthy Economist titled The Real Reason Wheat is Toxic. The article points out that, believe it or not, it is actually a common wheat harvest protocol in the United States to drench the wheat fields with Roundup several days before the combine harvesters work through the fields as the practice allows for an earlier, easier and bigger harvest. “Pre-harvest application of the herbicide Roundup or other herbicides containing the deadly active ingredient glyphosate to wheat and barley as a desiccant was suggested as early as 1980. It has since become routine over the past 15 years and is used as a drying agent 7-10 days before harvest within the conventional farming community.” According to Dr. Stephanie Seneff of MIT who has studied the issue in depth, desiccating non-organic wheat crops with glyphosate just before harvest came into vogue late in the 90s with the result that most of the non-organic wheat in the United States is now contaminated with it. Seneff explains that when you expose wheat to a toxic chemical like glyphosate, it actually releases more seeds resulting in a slightly greater yield: “It ‘goes to seed’ as it dies. At its last gasp, it releases the seed” says Dr. Seneff.” The article goes on to explain that while the herbicide industry tells us glyphosate is supposedly non toxic, there are multiple studies showing its effects on the cytochrome P450 system (which is the pathway our liver uses to detoxify). Just because it doesn’t kill us instantly, certainly does not mean it's non-toxic and that doesn’t have serious and long term effects. Roundup disrupts the balance of healthy bacteria in the gut which then leads to intestinal permeability which is the breeding ground for autoimmunity. In fact, since roundup has been introduced in this practice in the 90’s, the amounts used have skyrocketed. Interestingly, celiac disease has as well. There is a very interesting study from December, 2013 connecting glyphosate in Roundup to many of the things that are thought to be celiac symptoms. Specifically, the abstract of the study (published by Interdisciplinary Toxicology) reads: “Celiac disease is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on gut bacteria. Characteristics of celiac disease point to impairment in many cytochrome P450 enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in iron, cobalt, molybdenum, copper and other rare metals associated with celiac disease can be attributed to glyphosate's strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine and selenomethionine associated with celiac disease match glyphosate's known depletion of these amino acids. ” Furthermore, this exposure happens a little at a time over years which slowly damages the cells contributing to high levels of inflammation and inflammation is linked to a myriad of diseases. This can lead to a perfect storm where things are just enough ‘off balance’ that the body is not able to self correct, leading to chronic disease. Banned in Other Countries While Roundup and the use of Glyphosate is legal in the United States, countries around the world are labeling it a toxic chemical that is carcinogenic and banning it. For example, Australia, Luxembourg, France, Denmark, Holland, Portugal, and some cities in Spain have all banned it or are in the process of banning it. This may explain why you can eat wheat in other countries and feel fine but not at home. Eliminating Health Mysteries You don’t have to travel to another country to experiment with glyphosate-free wheat. You can try organic wheat sold in the US to find out if you feel better than eating genetically modified wheat. Imagine if all of the health issues you’ve assumed were related to gluten intolerance were actually related to glyphosate! Links: Related Podcast Episodes: Could You be Gluten Sensitive Even if you Tested Negative? Demystifying Food Sensitivities (and What You Can do About Them) Thanks for Listening If you like what you heard, please rate and review this podcast. Every piece of feedback not only helps me create better shows, it helps more people find this important information. Never miss an episode - Subscribe NOW to Health Mysteries Solved with host, Inna Topiler on Apple Podcasts, Spotify, Stitcher or Google Podcasts and remember to rate and review the show! Find out more at http://healthmysteriessolved.com PLEASE NOTE All information, content, and material on this podcast is for informational purposes only and is not intended to serve as a substitute for the consultation, diagnosis, and/or medical treatment of a qualified physician or healthcare provider. Some of the links provided are affiliate links. This means we may make a very small amount of money should you choose to buy after clicking on them. 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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.01.231993v1?rss=1 Authors: Yan, B., Ai, Y., Zhang, Z., Wang, X. Abstract: The inhibition of antioxidant systems of glutathione peroxidase 4 (GPX4) or ferroptosis suppressor protein 1 (FSP1) causes iron-dependent peroxidation of polyunsaturated phospholipids that leads to cell death, a process known as ferroptosis. The mechanisms underlying iron-dependent lipid peroxidation are under active debate. Here, we report that two endoplasmic reticulum-residing oxidoreductases, NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), are responsible for the iron-dependent peroxidation of polyunsaturated phospholipids and membrane disruption that executes ferroptosis. Genetic ablation of POR and CYB5R1 or mutations that eliminate the electron transfer activity blocked ferroptosis. In vitro enzymatic assays established that POR and CYB5R1 catalyze hydrogen peroxide production by transferring electrons from NADPH/NADH to oxygen, which is then used to carry out iron-dependent lipid peroxidation via a Fenton reaction. The lipid peroxidation reaction catalyzed by POR and CYB5R1 additively disrupts polyunsaturated phospholipid-containing liposomes. Finally, POR knockdown confers significant protective effects during concanavalin A-induced, ferroptosis-associated acute liver injury in vivo. Our study thus indicates that POR and CYB5R1 are the enzymes of the oxidant system that operates to contravene the antioxidant GPX4/FSP1 systems; the balance between these two systems determines cell commitment to ferroptosis. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.225110v1?rss=1 Authors: Sun, G., Putkaradze, N., Bohnacker, S., Joncyk, R., Fida, T., Hoffmann, T., Bernhardt, R., Härtl, K., Schwab, W. Abstract: C13-apocarotenoids (norisoprenoids) are carotenoid-derived oxidation products, which perform important physiological functions in plants. Although their biosynthetic pathways have been extensively studied, their metabolism including glycosylation remains elusive. Candidate uridine-diphosphate glycosyltransferase genes (UGTs) were selected for their high transcript abundance in comparison with other UGTs in vegetative tissues of Nicotiana benthamiana and Mentha x piperita, as these tissues are rich sources of apocarotenoid glucosides. Hydroxylated C13-apocarotenol substrates were produced by P450-catalyzed biotransformation and microbial/plant enzyme systems were established for the synthesis of glycosides. Natural substrates were identified by physiological aglycone libraries prepared from isolated plant glycosides. In total, we identified six UGTs that catalyze the unprecedented glucosylation of C13-apocarotenols, where glucose is bound either to the cyclohexene ring or butane side chain. MpUGT86C10 is a superior novel enzyme that catalyzes the glucosylation of allelopathic 3-hydroxy--damascone, 3-oxo--ionol, 3-oxo-7,8-dihydro--ionol (Blumenol C) and 3-hydroxy-7,8-dihydro-{beta}-ionol, while a germination test demonstrated the higher phytotoxic potential of a norisoprenoid glucoside in comparison to its aglycone. Glycosylation of C13-apocarotenoids has several functions in plants, including increased allelopathic activity of the aglycone, facilitating exudation by roots and allowing symbiosis with arbuscular mycorrhizal fungi. The results enable in-depth analyses of the roles of glycosylated norisoprenoid allelochemicals, the physiological functions of apocarotenoids during arbuscular mycorrhizal colonization and the associated maintenance of carotenoid homeostasis. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.26.222265v1?rss=1 Authors: Li, Y., Qiao, B., Olvera de la Cruz, M. Abstract: The surface of proteins is vital in determining protein functions. Herein, a program, Protein Surface Printer(PSP), is built that performs multiple functions in quantifying protein surface domains. Two proteins, PETase and cytochrome P450, are used to validate that the program supports atomistic simulations with different combinations of programs and force fields. A case study is conducted on the structural analysis of the spike proteins of SARS-CoV-2 and SARS-CoV, and the human cell receptor ACE2. Although the surface domains of both spike proteins are highly similar, their receptor binding domains (RBDs) and the O-linked glycan domains are structurally different. Statistically, the outer surface of ACE2 displays less correlation with the RBD of SARS-CoV-2 than that of SARS-CoV. The O-linked glycan domain of SARS-CoV-2 is highly positively charged, which may promote binding to negatively charged human cells. Our program paves the way for an accurate understanding of protein binding for aggregation and ligand recognition. Copy rights belong to original authors. Visit the link for more info
Multi-omics is the layering of genetic information (genomics) with laboratory biomarker results (metabolomics) to understand the root cause of disease and risk. This educational series focuses on genetic variants in specific enzymes and explains how to evaluate the systemic effects. Today’s episode is a discussion of the cytochrome P450 enzyme CYP1B1. This enzyme is important in hormone detoxification. Genetic variants (single nucleotide polymorphisms or SNPs) in CYP1B1 might predispose a patient for risk regarding many hormonally mediated diseases, though this is not always the case. Listen to find out more about the enzyme pathways used in estrogen detoxification, what to look for when deciding if a genetic variant in CYP1B1 is expressed, and learn what you can do to about it. “Some SNPs result in an enzyme that works faster (upregulation). Some SNPs result in an enzyme that works slower (downregulation).” – Michael Chapman, ND Today on The Lab Report: 2:30 Cytochrome P450 enzymes and CYP1B1 2:55 Review of general Phase I and Phase II detoxification 7:00 Basics of estrogen detoxification pathways and where CYP1B1 works 9:00 What does a SNP in CYB1B1 do? 11:45 What profiles and biomarkers are helpful to assess expression of a CYPB1B1 SNP? 17:00 How do we support patients with a CYP1B1 SNP? 21:05 Question of the day: “What is the difference between FMV and 24hour Complete Hormones?” Subscribe, Rate, & Review The Lab Report Thanks for tuning in to this week’s episode of The Lab Report, presented by Genova Diagnostics, with your hosts Michael Chapman and Patti Devers. If you enjoyed this episode, please hit the subscribe button and give us a rating or leave a review. Don’t forget to visit our website, like us on Facebook, follow us on Twitter, Instagram, and LinkedIn. Email Patti and Michael with your most interesting and pressing questions on functional medicine: podcast@gdx.net. And, be sure to share your favorite Lab Report episodes with your friends and colleagues on social media to help others learn more about Genova and all things related to functional medicine and specialty lab testing. Disclaimer: The content and information shared in The Lab Report is for educational purposes only and show not be taken as medical advice. The views and opinions expressed in The Lab Report represent the opinions and views of Michael Chapman and Patti Devers and their guests. See omnystudio.com/listener for privacy information.
Giriş Uzamış QT sendromu (UQS), elektrokardiyogramda (EKG) uzun bir QT aralığı ile karakterize miyokardiyal repolarizasyon bozukluğudur. Bu sendrom, torsades de pointes (TdP) olarak da bilinen karakteristik hayatı tehdit eden kalp aritmisi olan polimorfik ventriküler taşikardi riskinde artışla ilişkilidir. UQS'li hastalarda semptomlar çarpıntı, senkop, nöbetler ve ani kardiyak ölümdür. UQS konjenital veya edinsel olabilir. Edinilmiş UQS genellikle ilaç tedavisinden kaynaklanır, ancak hipokalemi, hipomagnezemi ve bradikardi ilaca bağlı UQS riskini artırabilir1. Semptomlar Aritmilerin yokluğunda, edinilmiş UQS'li hastalar asemptomatik olacaktır. Bir aritmi geliştiğinde, belirtilerin tipi ve yoğunluğu, varsa, TdP oranına, süresine ve önemli komorbid koşulların varlığına veya yokluğuna bağlı olarak değişecektir. Semptomları fark eden edinilmiş UQS'si olan hastalar tipik olarak aşağıdaki semptomlardan bir veya daha fazlası ile başvururlar: ÇarpıntıSenkop veya presenkopAni kardiyak arrest İnsidans QT uzaması ile ilişkili birçok ilacın mutlak ve karşılaştırmalı riskini belirlemek zordur, çünkü mevcut verilerin çoğu olgu raporlarından veya küçük gözlem serilerinden gelir. Ek olarak, TdP olmadan QT uzaması insidansı muhtemelen TdP'nin insidansından çok daha yüksektir. Altı aylık süre içinde tek merkeze yapılan tüm hastaneye başvuruların geriye dönük gözden geçirilmesinde 41.649 hastanın 293'ünde (yüzde 0.7) QTc ≥ 500 milisaniye olduğu, ancak ciddi QT uzaması olanların yüzde 6'sından azında senkop veya hayatı tehdit eden bir aritminin yaşandığı kaydedilmiştir. Hollanda'da, dokuz yıldan biraz daha az bir sürede 775 ani kardiyak ölüm (AKÖ) tespit edilen 500.000 kişiyle yapılan gözlemsel bir çalışmada, AKÖ'lü 775 hastanın 24'ünde (% 3.1) halihazırda QT uzatan ilaç mevcuttu. Kardiyak olmayan QT uzatan herhangi bir ilacın halihazırda kullanımı belirgin şekilde artmış AKÖ riskiyle (OR: 2.7) ve en yüksek risk antipsikotik ilaçlarla (OR: 5.0) ilişkiliydi. Her ne kadar bu sonuçlar ilaca bağlı TdP'nin belgelenmiş vakalardan daha yaygın olabileceğini düşündürse de, mutlak olay sayısı hala düşüktür ve AKÖ olaylarının küçük bir kısmını temsil etmektedir (AKÖ'lü 775 hastanın 24'ü (%3.1) halihazırda bir QT uzatan ilaç kullanıyordu). Risk Faktörleri Birden fazla risk faktörü olan hastalar daha fazla riskle karşılaşabilir. Bu faktörler aşağıdaki gibi sınıflandırılabilir. İlaç rejimi ile ilgili olarak: Yüksek ilaç dozları veya QT uzatan ilaç konsantrasyonları diğer kardiyak risklerin varlığında daha da riskli olabilir.QT uzatıcı ilacın hızlı intravenöz infüzyonu.QT aralığını uzatabilen birden fazla ilacın eş zamanlı kullanımı, hepatik sitokrom P450 enzimlerinin inhibisyonu nedeniyle ilaç metabolizmasını yavaşlatan bir ilaç ile QT uzatan bir ilacın kullanımı, CYP3A4'ü inhibe eden greyfurt suyunun eşzamanlı alımı gibi olası mekanizmalar ile QT aralığı artabilir.Diüretik tedavisi, elektrolit anormallikleri ile ilişkisi veya bazı diüretiklerin potasyum akımını doğrudan bloke etmesinden dolayı bir risk faktörü olabilir. İlaçla ilişkili risk faktörlerinin dışında EKG anormallikleri, metabolik faktörler, genetik faktörler, altta yatan kalp hastalıkları ile ilgili risk faktörleri de vardır. Kadın cinsiyet, ileri yaş, hipomagnezemi, hipokalemi, bradikardi ve daha az olarak hipokalsemi de risk faktörleri arasındadır2,3. Çalışmalar ABD'de 1995-2009 yılları arasında acil servise başvurulardaki QT'yi uzatan ilaçları içeren reçetelemelerin yıllık oranlarının incelendiği bir çalışmada bu ilaçların reçetelenme sıklığı, risk faktörleri ortaya konmuştur. Sonuç olarak yılda yaklaşık 16.5 milyon muayene (%15.0) QT uzatan bir ilacın reçetelenmesini ve 1.7 milyon (% 1.6) birden fazla reçetelemeyi içeriyordu. QT'yi uzatan ilaçlarla ilişkili muayeneler, çalışma süresi boyunca iki kattan fazla artmıştır (% 10.4 ila % 22.2). Difenhidramin, azitromisin ve ondansetron en sık reçete edilen ilaçlar olmuştur (vakaların% 46...
Guidance Recap Podcast | In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Final Guidance - Podcast Transcript
Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Final Guidance - Podcast Transcript
All right. Welcome to the gut check project. I'm here with your host, Dr. Kenneth Brown. I'm Eric Rieger. This is gut check project, Episode Number 26. We're going to wind up 2019 with some awesome info. What's up, Ken?What's going on Eric? How are you doing, man? Episode 26. Unbelievable. I apologize if I'm a little too sexy today because I'm just coming off of a small cold. I think the hottest people are those that are sick.Well, I'm not sick. I'm post sick. Remember, the viral prodrome. The reason why we always like pass so many viruses is that you tend to pass the virus before you even know that you're sick by the time you're actually sick. You're probably okayYeah. At that point you can go back and say I heard you might be sick. I was too back then.Yeah, exactly. Good to see you?Well, today's episode is going to be pretty awesome. We're going to tackle number one, we've received tons of email in your clinic because you also sell the KBMD CBD at your clinic, you get these questions. These have been coming in Fast and Furious over the last little over 14 days. And it's questions about the safety of CBD oil and its application. So we're going to tackle that I do need to tell everyone. Thank you. We're on episode 26 because the first 25 shows were so well supported by all of you who've been keeping up with a gut check project. We grow every single day. Paul, the guy who's helping us put together the production now and helping us spread the word. We just hung up the phone with him. We've gotten more and more downloads each week. So thank thank you every single one of you for liking, sharing, emailing, telling your friends about it. We sincerely appreciate it.We learned so much about it like today we have a new a different guests we do Instead of gutsy our little mascot or green frog, but since we do film on a green screen, he gets blocked out did not know that didn't even realize that. So now we're going to go with a dung beetle, right here? Yeah, yeah, we did. So that's Dilbert, the dung beetle,Dilbert, the dung beetle. So one of my favorite things is whenever we're bringing any patients back and somebody sees you, and they're like, hey, you're Eric, I watch your show that just warms my heart. So if you happen to be a patient and show up and you watch the show, if you say that it just makes us both feel really, really well...needed wanted, appreciated.Yeah. At least outside of me putting you to sleep. Take five or six good deep breaths. Exactly. Today's episode is sponsored by Atrantil. Your bloating relief, it's what we do. So go to Atrantil.com or lovemytummy.com/KBMD. Today it's also sponsored by KBMD CBD oil. You can find your own KBMD CBD oil at kbmdhealth.com which of course, the initials KB, Kenneth Brown, it's endorsed by the guy who's sitting across the table from me. So Ken, why is...What does MD stand for? Well, I'm not really sure.I thought it was your buddy Mike Doyle, but I don't know.Yeah, it's probably. So tell us a little bit about KBMD CBD. Alright, so KBMD CBD oil. I got involved with the science of CBD because I saw the beneficial effect with my patients when we developed Atrantil I then learned that the science of Atrantil the polyphenols in it actually augment CBD. So I'm seeing this combination do incredible things for people. So this particular CBD is one that we have researched, I've seen it work clinically. And we know that it comes with a certificate of analysis. It is organically grown, it is naturally extracted with co2, so it meets all the criteria that you want in your CBD because this is important. The rest of this podcast is going to be all about the dangers of CBD.Definitely and It's really interesting since we do have so many people who have begun to purchase CBD find benefit. It's really kind of weird what's occurred over the last two weeks. And what I would say is a little bit of misinformation. But it's more or less probably just misunderstood information and or or misapplied information. But regardless, the benefits of CBD used correctly, have been undeniable with the people who've come back through the clinic with people that we've scoped, and how well that they are doing. And so, hopefully today, we're going to provide some context on why more or less the dangers that you may or may not have read about in the news recently are really a little concerned. But we'll, we'll see. We'll see how far along we get in at the last. The last thing. Our last sponsor is the KBMD health box. You can find KBMD health box by going to kbmdbox.com. Now last week we did a full unboxing which is something I think we're going to try to do at least once a month. But essentially, if you want almost $300 of physician vetted supplements that can help you benefit your life and get them for only $147 which you would spend, not you would spend more than $147 worth of time driving somewhere to pick them out for yourself and having someone handpick them for you. Go to KBMDbox.com. What was one of the things that we had a patient come through just earlier this week, who showed us his lab results that he took to his primary care physician? So we're starting to make a difference in the landscape of health here in the DFW Metroplex and different places. I've been getting emails and calls from people around the country that will actually hear the podcast and then they'll want to sign up for the box. And what we're seeing is that these vetted supplements actually are making a difference with both subjective how they feel and objective the labs. So the reason why I chose these things is they all have third party analysis. And they all have some scientific background that actually explains how they're going to help you. So much so that I'm thinking of ordering my household, another box. So although it is the KBMD Health box, I actually I love the fact that I can get these things that I'm going to purchase anyways, they come into my house, so my whole family's on it. Now we're running out of stuff. So I'm gonna end up having to double up on everything. So it's one of those things that I feel really good that we can look at different aspects. And when somebody says, Oh, I tried X, Y, and Z, I didn't notice anything. I'm like, oh, did you try one that had a third party analysis? No. And then they do and they're like, Oh my gosh, big difference. Same thing with CBD. I mean, a lot of CBD out there doesn't really have what's on the label. And we're going to get into that because we're going to talk about what the FDA thinks about it. We're going to talk about the different media and what they're doing, and hopefully get into all that but that's the whole point of that box is I want to deliver these vetted things to your house monthly so that you can continue to improve your health. Hundred percent. So without further adieu, be sure to like and share the gut check project. We certainly appreciate all of the support to date. We're going to hop right into it. So what we've received here recently is a lot of speculation and concern from people who have said, Hey, I'm interested in CBD. I know that you and Dr. Brown have heavily studied, been entrenched with CBD and its application over the last few years. I just learned that the FDA is associated or made public a study that says that it may be hepatic toxic or bad for my liver. It's, unfortunately, it's a weird jump off point. So I'm going to kick it to you. Because immediately I had lots of different thoughts and instead of getting emotional, what did we do? We went and tried to find the sources of where this information came from. We want to backtrack on how they got to that conclusion. And I think that we can put a lot of questions at ease and even help people learn how to be a little bit more critical with the data that they receive when they receive it. Because let's face it, lots of stuff that we see on the internet, or that we hear on the news or reading the paper, it's basically clickbait. It's basically things to keep you engaged, whether or not the actual substance is worth the headlines that are written so...So what you're referring to is recently the FDA put out a statement, a consensus statement in the news and it's making all kinds of traction in the news that they're saying that CBD is not as safe as people think not only that it can be harmful. Now this has bled onto TV and my patients have been asking me about this FDA statement. Then there's been other news articles like the one that Forbes published, read said that CBD causes liver failure. Failure. That was the title liver failure caused by CBD. I want to get into all that I wanted to take a really deep dive into the science of all of this as a gastroenterologist, I'm board certified gastroenterologist, which means not only am I a simple country, butt doctor from Texas, but we actually have to learn liver disease, hepatology, I'm not a hepatologist like some of my other friends where I send like really complex things, but we at least have to understand the liver, how it works and what it does. So a lot of these articles discuss this but they don't clarify so many little things. Because and they shouldn't it's a it's a journalist writing an article they want they want it to be shared. And anytime you mentioned CBD, anytime that that is thrown out there, you're going to get some clicks, you're going to get a whole lot more clicks. If you say you're going to die from taking CBD. It reminds me of the I remember Jerry Seinfeld was on Saturday Night Live one time and they were making fun of the nightly news where they always do the promo at like three o'clock. Like five household items that are guaranteed to kill you, tonight at six.You're like what? If it was so important, they probably wouldn't make you wait.No, I'm gonna die before you put this on the air. So what I'd like to do is talk about the briefly the science of the endocannabinoid system and CBD, then do a little bit deeper dive into the liver. So everyone's going to get a primer on the liver 101 here, because these studies don't make sense unless you know, some of this knowledge. It's just sensationalism. For some of it, some of it is a little bit unfair. I think some of it is for what the FDA got, and it's there. But I just want this podcast today to be something that can be useful for industry people that can be useful for patients or people that are thinking about taking CBD and it can be useful for a subset a small subset of people that may be should not consider taking it. Yeah. So all of this is kind of, you know, for the future of this podcast, It's almost going to be a bit of a rebuttal. Not necessarily a defense of hemp derived CBD. But let's just buckle up and kick some science. This might be a little bit I don't know how long we're going to go where we're going to go with this. We're just going to feel it out and see what happens. But I at least want to be able to explain why I still believe that a lot of people should be taking CBD even though Forbes is like you're gonna die from this.Yeah. It's not arsenic people. No it isn't and I think another cool application here is there are people out there who have been on the fence on whether or not I should try CBD or is this something that's good for a family member for me? And unfortunately, there you hit this intersection, where a news headline is written that CBD causes liver failure. Well, if they've been on the fence, that's a pretty big No, no, right? So now you've taken away maybe an avenue that they were considering to help them out. What I hope that we can do with this particular episode is basically let's temper and let's see things in context. I think context is a word that as you get into sensationalism is something that is kind of the rescue item. If I could put something into context, then at least I'm giving someone a fair chance to understand the information that's before them. I don't feel like sensationalized headlines do things like that. Then again, I also don't feel like someone who shakes, hand picked or cherry pick studies is doing that either. So what I think today that we can do is fairly evaluate and talk about the process of how the liver works, and why some of these studies are or are not applicable to the nature they were presented.Absolutely. So the first one we got to discuss is what what what the heck did the FDA say? Sure. So the FDA came out and they mentioned that they've got several issues with the safety of CBD. The two main ones that they're really concerned about are potential for liver injury, and interactions with other drugs. What they actually said is that they're concerned that people may mistakenly believe that trying CBD can't hurt the agency wants to be clear that they have seen only limited data about CBD safety. And these data point to two real risks that need to be considered as part of the drug review and approval process for the prescription drug containing CBD. Interesting. Now, what I say this is because the FDA is referring to the data that was presented to them by GW Pharmaceuticals, who has a epid... eipdi..x you know?E-p-i-d-i-o-l-e-xYes, which is the first FDA approved prescription CBD isolate,Right,for seizure disorders.It's important to point out that is not full spectrum. Correct. That is not full spectrum. And there's some that's important because here later in the podcast, and think we're going to draw some comparisons and just if you're listening, just remember, epidiolex is a CBD Only isolate it is not a full spectrum product.So let's talk about what the FBA what the FDA actually does. So the FDA has a really daunting task. The Food and Drug Administration is responsible for protecting the public health by ensuring the safety, efficacy and security of products. So it is super daunting because there's a lot of products hitting the market, and the FDA has tried keep up with this to try and protect people. And let's be honest, let's look at the elephant in the room. The elephant in the room is that there are a lot of bad CBD products out there. Yep. In fact, in a jam article 2017 showed that 70% of the CBD products that they looked at did not have what was on the label and what was there could be higher levels of CBD could be lower levels of CBD. So it's a gamesmanship that's going on right now. So it is totally true that you need to make sure that you've done your homework on what type of CBD that you're actually taking. There currently is little to no regulation in the CBD industry. There is the President and CEO of Natural Products Association NPA. His name is Daniel Fabricant. He's a PhD. I love this quote. He's quoted as saying it is well past time to bring science into the equation, as federal rules require safety and Consumer Protection must come first. I agree. And we all agree with that. Sure. And I think that all companies that have reputable CBD companies, they all want that. Problem is when you have these different stories leaking out, which gain much more traction, it just starts creating a little bit of confusion misconception, and then people don't really know where to turn. So the feeling is, is that possibly statements by the FDA saying that it creates this narrative that questions the safety of CBD overall, strictly to address a few number of companies which are producing quite frankly, some crap products.What was the number that we learned the last time that we were in Utah at meeting I believe it was one out of every 23 to 24, I could be off it was definitely in the 20s. But every to every 23 or 24,25, CBD labels available for retail purchase. One is seen as a reputable well marketed or correctly labeled product, which means that even if it happens to be off a little bit, you've got 23 or 24 other labels which are just not truthful or probably not correct, don't have a certificate of analysis or are blatantly, just not even what's in the bottle.100%. There's a lot of people out there trying to take advantage of this wave that's coming. So I do not. I believe that the FDA is doing their job by looking at the data that was actually presented to them Agree. So let's take some time and break all this down for the consumers, health care providers, industry personnel. Starting with the question, does CBD cause liver damage? Unfortunately, or fortunately, because I like science we really need to talk about what the endocannabinoid system is. Because if somebody's listening to this, they're like, Well, I was thinking about taking this but I'm worried becasue it can cause liver failure. I don't know why I'm taking it. Why in the world should I be taking it? So let's do a quick one minute discussion of the endocannabinoid system. Let's do it!All right, the endocannabinoid system. The endocannabinoid system is a system which was discovered in the 90s that we now realize it's probably everywhere in the body. There's primarily two different types of receptors, but essentially, the way that I try to explain it to my patients, it's concentrated more so in the neural areas, nerves, brain and the immune areas. Although we now know it's in every single organ, that's where all the original research was. We now realize that its job, the endocannabinoid system is to produce these products called endocannabinoids. Which work as traffic cops. They just kind of get your body to get back to an area of balance. If you've got too much activity, they go Whoa, slow down a little bit. If it's not enough, they go, come on. Let's go ahead and get some more going here. So you have this fantastic system in your body that really just tries to keep balanced. Think of it that way. And you're going to hear a little bit later why I think most of America is out of balance. I think most of America needs some replenishment of their own endocannabinoid system. So that's the important thing is is that there's a dire need to try and get us all back to a certain balance, because the reality is we're getting sicker as a nation. And one of the causes could be that we took hemp derived foods out of our diet and out of our livestock diet. And there's a theory on that, that possibly that's one of the reasons why we're having more autoimmune diseases, why we're having more of the other problems that we're seeing, Well at least contributing factor.Certainly at least a contributing factor. So keep this in mind. So the the primer on the endocannabinoid system is if you're, if you have ears and you're hearing this, you also have an endocannabinoid system, and you have a higher than likely chance that you are out of balance with that. And if you are out of balance with that, then you probably could benefit from some of this. Sure. So right now you're going well, I'm out of balance, I'm going to probably benefit but I'm going to go into liver failure if I do this. So let's talk about what liver failure means. You have a genius living within you. You probably have multiple geniuses living within you.Thank you. That feels great. Sometimes the voices in your head don't say to do bad things.The evil genius. Yeah.Well, one of the geniuses living within you as this beautiful origin called your liver. So you have this and it's amazing. So to understand where they're going with this, let's talk about what the liver actually does. So we all have livers. And they work differently in every single person, and they can continue to adapt, evolve and change. One of the only organs that you can transplant a partial portion of it and it will grow into a full liver. So the nephrologist think that the kidneys, the smartest organ, the neurologists will think that the brain is the smartest organ The cardiologist says if you don't have blood, you can't think so It must be the heart. Yeah, yeah, exactly. I'm gonna say, well, for health span, smartest organ in the body is the endocannabinoid system. So eventually, we're going to have Endocannabinoidologists. Because what ends up turning out is that the endocannabinoid system is in all these different organs.Correct.They're not completely separated. So let's talk about the liver. The liver is responsible if you ever wonder what the liver does. So do you have any idea what the liver does? I've got a little bit of an idea... Little bit of an idea. So the liver is responsible for selective uptake, concentration, metabolism, and excretion of the majority of drugs and toxins, also known as xenobiotics. So let me just say that again. Basically, the liver takes the crap that you bring into the world. And it says, I'm going to convert it to something useful, or I'm gonna get rid of it for you. Yeah, it can detoxify it, or it can say, Oh, you need to be this and then you're useful. That's why I say it's a genius in your body. And it the liver figures this out, it figures out what you need, and it determines if it's a drug, or if it's a toxin, and it can turn into a better form. Now, one of the problems I have with these different articles that I've been reading, is that they discuss that then enzymatic process called the P 450 system, and they just write it like that they're like, CBD has been shown to affect the P 450 system. What doesn't affect the P450? So that's the issue. So let me break that down, I bring up the P 450 because in the lay literature without even describing what it is, it is a complex. It's called a phase one metabolism of the liver. Under p 450. It's an umbrella term that has over 60 different genes, that code for hundreds of enzymes to break down anything that comes your way. So the P 450 enzyme is like saying, Oh, I don't even know an analogy, but it's top of the funnel down. It's like you just so generic, that you can't just say that. So but they write it in the lay literature almost as a sounds sciency so I'm sure that it's, I'm sure that it's right. That's kind of my feeling on I'm like, why would and all these people it's almost like these news articles parrot each other. And nobody's stopping going, wait a minute, because as it turns out, the P450 system, not the P450 enzyme, the system breaks down almost everything that we put in our bodies. Yeah, no joke. So a lot of going back to the pharmaceutical days, I remember that was one of the biggest challenges with with any of the drugs that we detailed a physician on was, how is it affecting the P 450. And that would be something that they would be all salespeople be coached on that before they would go on calling a physician. But the truth is, it doesn't have to be a compound. It doesn't have to be a medical pharmaceutical compound for that to be somewhat important. Something as simple as grapefruit juice. Also, detectibily inhibits the metabolic ability of the P 450. So there's all there's a handful of different drugs that people who are elderly, maybe caution, don't drink grapefruit juice, because it will inhibit your ability for your body to clear this particular drug. And I say that to say this. It's not nothing is inherently just special because it does or does not directly affect the P450, almost everything you take into your body is either cleared quickly or slowly by that same system.Yeah, so they kind of imply like CBD is the only thing that gets...Not even close....that gets processed in the in the P450 system. In fact, we know that there are multiple medications that can be altered by certain foods. Grapefruit is the most common one, and that really affects like immunosuppressants tremendously and that's where it really came up. When they realized, oh my gosh, you have these different drugs, let's say blood thinners and immunosuppressants, which have a very narrow therapeutic window, you have to have these things like right dialed in. Yeah. And then people talk about grapefruit but you know, other things that have actually been shown to do this cranberry juice, black tea, pepper, even chocolate Yep. has been shown to affect drug absorption and they have been shown to affect certain pharmaceuticals. We don't even know the tip of the iceberg on this because you have to do the study on it. You have to do the pharmaco kinetics, the PK is what it's called to actually determine that which is so funny because they say oh CBD is metabolized by the P450 system. That means nothing. And so if you take CBD and or chocolate and or drink tea, be careful. I mean...I think a good analogy a seriously a good analogy is it the P450 being metabolized by the P450. It may be good for base knowledge, but the truth is, is does it overwhelm that, as you put it system, if it is overwhelming that system, chocolate, for instance, for most intents and purposes would be like a single car driving down a six lane highway by itself. It's not really if the highway was a P450 and the car was the chocolate. It doesn't take anything to funnel that that car through.Correct.The problem is is whenever you happen to overwhelm that system. And that is important to know. But I would say in terms of context, kind of the way that we started this discussion in context. It's not my belief through what I've read and seen that CBD inherently overwhelms or becomes more than a single car down that six lane highway.So not only is it just one single car going down the highway, remember that not only foods but drugs, nobody's talking about drug drug interaction.Right.So there's a reason. So I see a lot of patients that one drug may be very effective one thing may be very effective, but there's so many variables like for instance, drugs, the sex of the person plays a role, you may have different levels, the age of the person and any diseases can all affect this whole system called the P 450 which produces enzymes. So not only that, but then genetics play a huge factor, alcohol intake.Alcohol intake, all of that. I mean, genetically, this may be why some drugs work on certain people and why they don't work and others fact there's a whole field of science right now where people are trying to determine the genetics ato go, Oh, you're going to need a higher level of whatever Plavix which is one that they've actually looked at. Or you can, you're going to take less. So we this is a whole field of this beautiful science where we can go Okay, genetically, you're going to be predisposed to need more medications. So when these enzymes get used up, basically if you've got this one chocolate, which is a car, one on six lane highway, and then you add fluconazole, which is an antifungal, that's an but that's not a car, that's a semi now and then you add alcohol, which is a minivan could be ccould be a couple minivansand then you do whatever something else, but you can see that the liver has to try and process this right. So what happens is it becomes this once it becomes a traffic jam. Then people start getting angry, they start honking their horn that is a rise in your what we call lfts liver function panels liver function test Yeah, so AST and ATL are the two ones that we always talk about, that's exactly what the FDA was referencing. So I want everybody hear this. When you overwhelm the liver with multiple cars using your analogy, then honking starts and the honking the warning sign is this rise in AST and ALT. So, for instance, your body can adapt to it. We've seen this all the time. If you drink alcohol on a regular basis. you build more lanes, you build more lanes, you get really good at metabolizing alcohol. Build tollways. I'll use myself as an example.Not with alcohol.With coffee, Okay.I always have to laugh. Whenever I go to the my own doctor. They say how much coffee do you take? I just write obscene amount because I've down regulated by receptors or I've had the ability to ramp up my my livers ability to convert that coffee into an inert thing and there it is. So you see it as an anesthesiologist or as a crna. I mean, describe what your experiences whenever you try and put somebody to sleep using propofols, different medications.Yeah, well, I mean, definitely, if someone says that they happen to be a large consumer of or a consumer of large amounts of alcohol, it generally takes anywhere between 20 and 30% more of an agent to put them to, to sleep safely, say, But back to your point of body habitus, for whatever reason, even just something as simple as someone being a redhead fair skinned, those people generally take more agent to make them go to sleep. Yeah, let's go ahead and clarify this. This is a well known thing in anesthesia. You're not being prejudiced? No, not at all. No, they literally just for whatever reason, the metabolism rate of someone who's fair skinned with red hair is typically higher than the average calculation and you can go through any types of weight based medications that we use to bring sedation to someone and generally fair skin redhead folks just take more. Is that interesting?Yeah, it is. So that is more than just anecdotal like they've actually done some studies on this and they've actually shown probably because whatever lineage, they come from Scotland, Ireland, they have a higher P450 to metabolize that particular or a higher subset of the P450 systems. So just keep that in mind. So when you take certain foods or drugs, everything's competing for your liver, to do to just say, hey, fix me, you know, figure out what's going on. Fortunately, it is a badass organ and the liver is tough and it can handle a lot, the largest solid organ that we have in the body. So usually it can handle everything. Now the most common example like we've talked about, if you take grapefruit juice with certain immunosuppressants and things then that particular combo because those drugs need exact or how they were manufactured need exact metabolism numbers. Not only that, did you know that like nutrition plays a big role. So, high protein diet will actually affect your P 450 and malnutrition will affect it. of course it will. So those are all of our paleo friends over at paleo FX and such those guys have revved up p 450s. Eating a lot of protein working out a whole lot, they're able to do this. Unfortunately, malnourished people probably can't tolerate as muchNo and they aren't they aren't they honestly they don't have the supply to rebuild the enzymes that are that are used within the P 450 I mean it's just malnutrition is going to deplete all different types of systems, not just the liver.So in the intro, I kind of mentioned that we're getting sicker. And so let's use nutrition as an example. federal policies tightened by the controlled substance act of 1970 essentially banned the production of industrial hemp during the war on drugs effectively we made hemp CBD illegal and put it under the umbrella of cannabis cultivation. Now what were we were talking with Will Clyden of O-hi energetics right, who actually discussed this and he said some cool stuff on this. He back before this when they were they were using hemp and hemp has been used for ever like since we landed in America, hemp has been using hemp has been used in China for thousands of years and all this other stuff that we were feeding because it's a fantastic crop. It's it detoxifies the soil. And it actually works. It grows quick. It's a great crop industrial. What were we thinking making it a banned substance, I don't know, separate discussion. But they've got data to show that when they were feeding chickens, so for everybody out there I had a patient today who said I said Oh, she was suffering from some things and I think CBD would help with and I mentioned Hey, have you ever considered CBD Oh, I would never ever, ever, ever do anything like that. I am not like that. I said, Okay, that's cool. said hey, let me tell you something. Do you know that before 1970 we were actually feeding animals like chickens and cattle. One of the primary things that we would feed them would be hemp, and it's been shown that you can take a chicken egg and it had over 250 milligrams of CBD, right so right now if you're somebody that just spent $200 on your CBD that has 300 milligrams in 1968 you could've just had an egg.A three cent egg.I know 3 cent egg. And I looked at the literature and I and I could not find anything that said death by egg otoxicity. It didn't so everybody that's sitting there thinking oh my gosh, no. I'm not going to do CBD. We were having CBD in our diet. A great Great example, to learn a lot more about this and do a deep dive. Our friend Chris kresser had Will Clyden and the CEO of O-hi, O-hi energetics on and he went into this tremendously. It was so cool. It was just like I just it's crazy that we stopped like, and I as a physician have seen that we are getting sicker as a country. So in 1970, we've got since 1970. We've got more chronic disease, we've got more dementia, we've got more autoimmune disease. coincidence, like we said in the intro, maybe it's at least a contributing factor. And now we have the FDA saying that CBD can be harmful yet it was in our food supply up until 1970.That's nuts, dude.It is nuts. And it doesn't make sense and if you look at mean hemp seed, birds eat seeds, birds consume seeds, they do all kinds of things where they can they take in product, What's the matter? No, I'm just looking at I'm trying to make sure we get through everything.Okay good, but I mean they eat everything and people have been consuming eggs from not just chickens they've been consuming eggs from all different birds on the planet for that long. The fact that we've restricted hemp growth etc has only taken away one of the natural things that birds were eating.If you're if you're really interested in this like I said go to Chris Cressors podcast where he's got Will Clyden on there is really cool wills smart dude Chris is super smart dude. So those guys those guys kick some crazy knowledge.Right?So that is it's weird that we're talking on this episode about CBD causing hepatotoxicity. And we've already shown that the liver's pretty badass, right? It can do a whole lot and we've already shown that the endocannabinoid system is necessary and since 1970, or up until 1970. We are taking in significant amounts of CBD in our dietRight.Weird.It is weird, but it's not so weird when we get down to why everyone's alarmed. So you want to get into a...Now let's go ahead and look at the studies. So that is sort of the phase one of this podcast because now we're going to start geeking out a lot. So I hope I didn't hope I didn't lose everybody with a but you kind of need that background to understand what we're going to talk about next.Sure, you definitely that background.Alright. So what they're talking about is the FDA published this revised consumer update. So this is the consumer update that they put out there for everybody detailing the safety concerns about CBD products. Now, this was based on the studies provided by GW Pharmaceuticals, GW Pharmaceuticals has done multiple different studies looking at different things to get their FDA approval. And I'm going to say right now, that kudos to GW for being the first company to step up and really try and make something for a group of people with intractable seizures have an alternative. Kudos to the FDA for doing their job and looking at the data that was presented to them. What I'm going to do is go next level and say, Well, you didn't look at everything. That's the bottom line here. So I'm not bashing anybody. Let's make let's make certain of this. Sure. So there have been several randomized, controlled and open label trials that studied the effects of epidolex, I'm going to call it epidolex from now on it's just easier, which is a 99% pure oral CBD extract on patients with refractory epilepsy. So this in turn led to the FDA approval for two diseases, dravet syndrome and Lennox-Gestaut syndrome. So if you recognize those names, bless you, because you're dealing with some serious stuff, It's a serious seizure issue. If you don't know those. Count your blessings. It's one of those times to go well, no matter where you're at in life. It's like well, thank goodness that I don't have to Deal with a child that has this because that's, that's a really big deal. These are intractable seizures. So they looked at the data on that. And in these studies, the kicker here is I'm going to say it again, getting back to the lane highway, the patients maintained on their stable drug regimen with a median of three anticonvulsant drugs. That's important. It's super important. Three anticonvulsant drugs. So when we use the analogy of the car on the road, imagine a six lane road. And three of those roads. Three of those lanes are double semis.Yeah, that are closed construction... Or closed, Yeah, that's more likely or closed. So let's talk about that. So when we're talking about three different agents used to control seizures, some of those agents would be and I'm assuming here, but probably Depakote, probably Dilantin, also known as phenytoin, or fosphenytoin, which is seravex. There's a handful of anti seizure medications and through my knowledge, all of them, all of them have been recorded as raising the enzyme levels used by the liver which of course would lead to ALT and AST elevation, showing that the liver is essentially working overtime to long term process these drugs right or wrong?Correct. Correct, which is exactly what the FDA is supposed to do. They're supposed to look at this data and go Okay, so let's just look at the study that they're talking about. So the FDA accumulated this data, and they looked at what GW presented GW presented in isolette of CBD, not a full spectrum. And the dose they ramped up to 20 mg's per kick 20 mg's per kick. What that means is a guy like me would take 1954 milligrams a day.That's a lot more...of CBD isolate. Now I see the effects, beneficial effects of taking KBMD health CBD 15 milligrams twice a day,that's 30 milligrams,that's 30 milligrams.The exact dose of what makes people feel better is very argued because all the data coming out of Israel shows that a lot higher doses, but I'm seeing effects at these doses So let's be real quick let's stop for context. So right now at this intersection what we're what you're saying is with a full spectrum and we said this at the beginning of the podcast that what GW Pharmaceuticals has with epidiolex is a CBD isolate and what they've done...You're saying epidiolex now that's funny. Yeah, whatever it is, Well, because I started with that. Then you told me no, that's not how you say it.I think we should switch it up the whole time. EPA max the way it was edimax. What they did is they were able to establish that almost 2000 milligrams for you would be the ideal dosage however, you...isn't that correct? That's the dosage that they went for or the dosage that they felt was safe, Safe. Okay, I'm sorry. So but but on the upper end of... That was what they were aiming for on everybody. In essence, though, from where you have had beneficial effects, you're talking 60 times that amount, two months worth, is what they are saying the safe level would be in one day where you're finding the beneficial spectrum. So just just in terms of context, full spectrum, CBD, one 60th of the dose that they're saying it's a it's a safe level is really all that you need from our experience.Yeah. Now in GW's defense, let's look at the data. So in dravet syndrome, seizures dropped 39% and in Lennox-Gestaut 42%. So... that's good. So they probably did their homework and said, well, we need to get up that high to actually help that so I don't know anything about that. I'm not a neurologist. That's where it's at. But I'm just saying that when we look at that dose, no average consumer is going to be able to consume that Much CBD in a single day, unless it comes through this 2 full grams a day is more than most take Yes,yeah. Now here's the problem 94% of the people had side effects. Okay 94% at the highest dose compared to 75% placebo, kind of weird. So there's just a huge placebo side effect profile that doesn't get discussed at all.Did they say what it just had a curiosity do they state with the placebo was for the control,They did not stay with the placebo was oh, I take that back. I don't know what they use, but basically they left people on the same medications. So, essentially, let's just look at this and say okay, but the good news is, most of it was not a big deal. Most of it was what the FDA also discussed beyond the liver tests and beyond the drug metabolism. They also said Oh, CBD can cause nausea. It can cause drowsiness. It can cause all these other kind of nuisance things. That's what they're referring to right here. It's interesting though, that have a side effect profile assigned to a placebo that's that exceeds around the 30% range, because that's generally the throwaway number. Yeah. So we've gone twice away from the throwaway number. And they've had they've had reported side effects, which I'm not trying to over draw conclusions here, but it could at least indicate that side effect profiles assigned to CBD in this study probably weren't solely to CBD, Well, you're dealing with one of the highest risk populations you can get your hands on, when I did clinical research and when we would do a moderate to severe Chron's study. The placebo arm would have tons of side effects because the disease is bad. That's what's going on here also. So most was not a big deal, upper respiratory tract infection, somnolence, decreased appetite, diarrhea, blah, blah, blah, blah, blah. But the one that they focused on is the increase in amino transferase concentrations. This once again was a revised consumer update, they put this out to the public and their statement is increase in liver amino transferase concentrations when I just got done explaining what the liver does. Did I ever say amino transferase concentrations? No. I said liver enzymes. right? frickin talk to the public if you're going to release a consumer paper. yeah, liver enzymes. AST ALT. This is hiding behind scientific garbaly goop. It's like you're doing half science half anyway. But but whatever. So a patient show up and they're like, I need you to check my amino transferase concentrations. I'm like, Whoa, why? They Hand me this, this, this news article. Right? This is what we're trying to address right here. So what they found is that in the higher dose, 20 mgs per kg, there was a rise in some patients in three times the level which is significant, so if your normal is 20. You can be 60 if your normal is 40 it can be 120. When patients come into me and it's three times the level it sounds alarming. Do you know what happens when somebody gets hepatitis A acute infection? It's way more than that thousands of times the level when somebody goes into foaming at failure there AST and ALT will go from 40 to 10,000.AST and ALT have risen for almost everyone who's listened here, way more than three times throughout their lifetime multiple times in acute or in very isolated settings. It happens with illness.So getting back to your highway analogy, which I think is really cool analogy. I'm glad you came up with that. Thank you .Getting back to the highway analogy. 80% of them were taking a drug called valproic it matters Depakote Yeah, that matters. That matters a lot.It's when you take these medications, which is why at the beginning of the show, I said you're more likely don't have to worry about it. But if you're on certain medications, keep it in mind. Now that being said at the lower dose didn't see this stuff. So there is a dose dependent usage of the P450 enzyme you can if I give you one drink, or if I give you a bottle of tequila 512 which in my opinion is really one of the tastiest, most fantastic tequilas you can ever get your hands on. It is delicious. It's delicious. I'm gonna I'm gonna digress right here. Oh my God, Tequila 512... Also sponsored by Tequila 512Tt was really good seriously, ummm in every single person with liver test rose.They went back to normal if they decreased the anticonvulsant or decreased the CBD. So either one it went back to normal. So it wasn't number one, it wasn't permanent liver damage. More than likely correct they were able to return back to normal. And number two, it was simply A case of an overwhelmed P450 pathway more more than likely.So you want to get really confusing? Not really but we might as well try. I don't want to but here's what's really interesting, then they kind of get a little geeky. So GW presented their their stuff and then they showed that the P450 in this enzymes and they went into will, the CYP to, 2c19 CYP three a four can inhibit the CYP blah, blah, blah. Those are all just cytochromes people. Those are all just cytochromes It's under the umbrella of P 450. That's how complex this is. Yeah,It is nuts how complex. The highest plasma concentration to CBD occurs within two to three hours after exposure to the Epidolex. With medication, so timing of these medications going to play a role, which actually got me down a weird rabbit hole where i started thinking. We haven't done this much analysis on what happens if you take your Ace inhibiter and you take your cholesterol medicine, timing wise PK analysis on different people and everything. Because when they do these pharmacokinetics, they do it to get the FDA approval, they do it on people that are healthy, that they can understand it. Let's put this into context again, if you're listening to this you've ever taken tagamet. Have you ever thought about when you take your tagamet, you probably only take it whenever you're afraid that you're going to have acid problems, right? Cimetidine?Yeah, guess what? It's also known as a high level p 450 inhibitor if it's over consumed. So I guess what I'm saying here is, there's probably way more alarms being driven over something that yes, is handled by the P 450 system, but is far less invasive or it's much it's a much smaller vehicle on this highway than some of the other things that the alarms are not sounding over.And then surprise surprise after I just got done talking about the liver and the genetic variability and all these other things. When they looked at the pharmacokinetics there was tremendous variation. Hmm. Weird. Yeah. Odd, right? So and anybody that's listening to this that is a, a pharmacist or is a scientist or like Well, yeah, duh. Like I know, duh. But why put out such an alarming statement? Yeah. Without context.Yeah, yeah, you're right. So it for Okay, so it's a little bit of clickbait stuff, right. And so maybe even the journalist who wrote it doesn't understand specifically, the implication, they may have only seen P450, written somewhere turned to a health care provider and said, What is this? Well, that's indicating that things are rising up, they freak out. They write a headline that says CBD causes liver failure. I just learned that from this health care provider. So I'm going to write this piece.Well, that we're going to get into that. The liver failure. This is still just the FDA. Oh, yeah. To the consumer. So I hope that the FDA looks at this and says, You know what? That's right. All that stuff that was just being said it's right. But we didn't have the time to do it. We couldn't sit there put that on paper, we'd lose everybody. I get it. It's quite true. We all we all but we all have a responsibility, much like any doctor to try and explain. You and I have this ability to have this forum to reach hundreds of trillions of people.Yeah. It eflects in our subscriptions on YouTube. They so many trillions of people subscribed, they started his back over to about 200. Yeah, so every time we got trillions, they start back over. Yeah. So So anyways, so what what you're realizing here is exactly what we're talking about. When you put stress on the liver. The liver honks its horn and does a little rise and the lfts goes, Well, hey, guys, maybe not so much. Can we just back off the traffic a little bit and see what's happening here. So additional studies have shown that levels of the anticonvulsant drugs actually caused the daily effects. So now we start wondering that the that the CBD may actually rise some of the anticonvulsants and then you have more side effects from that comes down to the same thing we're talking about how many things do you want to tax your liver, that's the bottom line. To summarize high dose of a pure CBD isolate, not full spectrum, while using a mean of three other anticonvulsants can cause temporary rise in liver tests and affect the metabolism slightly of the anticonvulsant. Of note, it did not happen at lower doses. So one more time, if you are on an anticonvulsant discuss with your doctor and make sure that you stay well below the 2000 milligrams a day. Yep. So this whole thing of Oh We're going to block the P 450 the P450 is So frickin complex, it is nuts. So anything you want to add to that, because I'm going to move on to the thing that I really want to, like kind of make fun of No, not really, I just want to say that I think that the FDA, unfortunately, is a very important and serious organization within our government. And I think that for all of the flack that they take their, unfortunately, with any other entity, there are limitations on what it is that they can do. And I do believe that they try their best to fairly ascertain and address situations as they are presented to them. Regardless of how frustrated that one of this may get is we don't get a result from them. A lot of it is just simply because there's not enough manpower. Oh, absolutely. They get thrown everything think about, think if you're in an organization where you know that 70% of the crap that's out there needs to be pulled off the shelves and you're limited. It's a government organization. These people making these statements are MD's. I'm really limited fortunately, I have well, we have the show where I kind of enjoy looking up some of this stuff. Fortunately, we have some friends of ours that are that work in the nutrition industry that are fantastic at researching articles. And some of that gets gets brought to me I want to make sure that we all get better this is the whole purpose of this.Hundred percent.I want to help the FDA and help GW I want to help the CBD industry. I want to help all of it. But let's just talk about this because something super weird happened. And this is the one that got the most press A Forbes article came out that promoted a mouse study and made the sensational claim that CBD causes liver failure.Yeah, that's kind of what I was referencing earlier. I may steal the thunder but yeah, you're right.Yeah, so this is you're exactly right. In the intro, you said it was clickbait. I really after looking at this study after pulling the study, because how many people read that article are actually going to pull the study.Well is the is the person who wrote this study that well versed in reading studies like that. I mean, that's that's an important thing. I mean, they I think that probably even the author of the article feels like that they are doing a service to the reader, but probably doesn't understand. And if they do, then shame on them, but if they don't, I think that would be a better explanation doesn't fully understand how to read the study and the quality and the qualifications of that study to make a statement like that.Yeah. And you know, this, this could be an arguable point, I'm sure that the person that that wrote this feels very strongly that what they said was right, the bottom line is the goal of this study was to investigate CBD cannabidiol hepatic toxicity, meaning liver issues in an eight week old male mouse. So they they took a group of eight week old male mice, and then they gave them a CBD that they produced. The CBD that they produced and Will Clyden will just jump up and down when he hears this because he decided Is this on Chris Cresser's podcast. The CBD that they produced was used to extract using hexane, which is a molecule that is known to be hepatotoxic. Yeah, you're not supposed to have heaxane. Don't do that! Will Clyden talked about the fact that if you find a CBD with an outrageously high amount of of CB, if you find a full spectrum CBD with an outrageously high amount of CBD more so and the price ranges, okay? Because what they did is they extracted that with hexane in a cheap way and threw it in their bottle and said, there you go. Now you can check that's got 10,000 milligrams of CBD or whatever. And it's really interesting because there's so much going on in the industry like this. So this particular study out of the University of Arkansas, took the CBD, or they made their own CBD using hexane which is a hepatotoxic in itself and in their certificate of analysis. It was there and then they gave it to these mice. Second thing neatI don't even know there has to be a second but we can hear it. Because I mean seriously, that's, that's like saying, I know your stomach hurts. You should take this Pepto bismol. And then I don't tell you that I've broken up some glass shards and have you drink it and you're like i'm bleeding now! What's going on? I'm like, I don't know. Yeah, but you only paid half the price.I made it myself.Which, by the way, that last batch of propophol that you did in your bathtub is working phenomenally. I'm sure it is. Now we do not make propophol in our bathtubs.Alright, so the second issue. If we have any mice that are subscribers to our show, or listening, I would like you to have your children removed from the room at this moment. Because they took these poor mice, and they gavaged to them. Would you mind defining what gavaged is? I think it's when you kind of force feed somebody I don't think it's willing. That's your I think gavaged something you kind of threw one at me there I think to gavaged someone you basically introduce a funnel to the esophagus and well you kind of get after it, don't you? Yes, I'm currently gavaging my mic right now trying to figure it out. I just undid everything. You're gavaging our ears with your, your microphone adjustments?All right, so gavage is they forcibly give these mice?The CBD extract? Yeah, I don't think it's comfortable nor pleasant.No typically through a tube feeding or down the throat to the stomach is how they generally gavage things. A quick side note, now because I'm now all of a sudden I feel like I'm living in a glass house when I was an undergraduate student. I actually did my first surgery on a rat and we took out their adrenal glands. And I'm just saying that so I don't want to sit there and pretend like I'm not done mean things to an animal. But that was when I knew immediately I could not be a bench researcher. I did not like that. At all, now I was like, I need to, I want to heal. I want to heal. I don't want to hurt these animals, but it's it's a whole separate discussion. So anyways, so they gavage these animals with different doses, and it's really interesting. Now in what they call their defense, they call it allometric dosing, which means they're trying to get the body weight to human weight ratio appropriate. I've read some rebuttals of this article where it is a joke, you just can't do that. And when I read vitamin weed Michelle Ross? Michelle Ross, when I read vitamin weed she dis... she specifically discusses why research on CBD versus mice is very difficult to do because the weight basing the endocannabinoid system is different, all these other things. So allometric dosing being said, assuming that they're saying it's right, so the dose would be the equivalent of what they gave and What a human would give So I'm doing the allometric dosing, which I think is actually higher than what it actually is separate thing. They took mice and they gavaged them with zero milligrams of hexane derived CBD 246 milligrams per kilogram 738 milligrams per kilogram or 2460 milligrams per kilogram of dirty CBD. It doesn't make sense dirty CBD isolate. So for instance, in a horrible alternate universe where humans are now the test subjects and we have large mice which are running tests on us, and they decided to gavage me with the same thing. That would be the equivalent at the highest dose of 241,080 milligrams of hexane derived CBD isolate. I'm not even sure what the hexane would do it 240,000 milligrams 242,000 milligrams.No I mean that being the more or less than now at this point, it's just an additive. It's just I mean it's it's not an excipient It's a straight up additive. That would not make sense at all. Oh, it's crazy.It's poison.This article came out in Forbes and said CBD causes hepatotoxicity. Also hexane causes hepatotoxicity.It is nuts. Alright, spoiler alert. The mice suffered hepatic toxicity and death at the highest dose. Shocking... You know what? I also hear it's bad to have breakfast cereal with not milk but drain-o. Just something that I'm gonna go out on a whim. Don't think you're supposed to do that. It just doesn't make sense. It's It's It's not. That is not an apples to apples comparison if you're talking Okay, so we talked about it earlier. reputable CBD source there is no reputable CBD producer that's going to have and Will special shout out to you it's going to have hexane as a byproduct or an excipient in their full spectrum COA approved which is also why KBMD Health with powered by olyxenol hundred percent is does not have that. I mean they do co2 extraction, which is the important thing which is a reason why we partnered with them to make that product. So we are the one out of the 23 or 24 that is the safe and trusted COA back no hexane etc etc. Doing this study is not an apples to apples comparison on what would happen because who knows? Who Okay, I don't get it because GW we already did that study. They determined that 20 Meg's per kg which is still a shit ton. It's a lot. It's a lot. Yeahis the safe maximum dose. These guys went times it by 100.Yeah, they did.And see what happens? Yeah, it's it's a bad it's a bad comparison. I mean, yeah, honestly, if you wanted to find out if CBD plus hexane causes liver toxicity at a ridiculous amount, top to bottom, then that's a great study outside of that, since nobody does it, I would say it's a bad study. Speaking of road, that's a road to nowhere.Yeah. And so study like this, uh, like you had mentioned is essentially it's not science. It's clickbait. Yeah. And right now that that author, that journalist is just kind of laughing. He's like, I know, and now you're bringing it up, and I'm going to get another whatever, because that's what people are trying to do. They're trying to get attention at this point.So at that point, good for you, you got to click but I would be truly interested if possibly that particular journalists would say, you know what, I didn't fully understand it. I mean, that's okay. Let's look reading studies, right? There's there's a study to reading studies. I mean, we heard that we heard the breakdown that kresser did on Joe Rogan is he Twice had to address his approach to completely different topic about the the plant based diet and then how he had to re approach that with the rebuttal. All that just simply to say, there is a science to reading studies and being really good at understanding what is and is not applicable and then how to find studies that you can compare to each other for good meta analyses. So what we're doing right now is I'm telling you that maybe sometimes there aren't studies, but my anecdotal evidence, I have a busy practice, you hear the patients, we hear them talk I listen to them, when they say that doesn't work. I go, Okay, I'm not publishing it. I don't have time to do that. I wish I did. If I published everything that we're gathering data on, if we're looking at, you know, just so many different things, CBD is just one of them. We've got I love I'm a huge fan of brain.FM for the ability to use sound to change your mood. I Would love to they're unpublished, a lot of studies on stuff like that. There's, there's tons of stuff. So when people go, oh, the studies aren't out there, there is something to be said about the Socratic method, or I'm sorry, the paternalistic method, the way that medicine used to be where the guy in front of you that saw thousands of patients, this is the method that he has. You see me scope, I mean, there's a difference in scope techniques.So they, although some may even still say it qualifies as anecdotal, I will say that there's objective data in both in a scope, somebody can't just come, anybody can come to you say I feel better. Anybody can even if they don't mean it. But they can't make the disease disappear from the imaging that we see in their colonoscopy, or the the mucosal samples that you take. And that's something that's completely objective data. That we see. So those are the everyday results that we see from these types of applications where you just, look it's not made up whenever we okay full pleasure when we first started looking at CBD, I thought was bullshit. Who you looking at?Just anybody who's out there. But when we first started talking about it, I didn't believe it. I was like, man, let's see, because we've been down this road before but we tried new, new without throwing a bunch of things under the bus. We tried new or innovative different things and high hopes. And unfortunately, low expectations and the expectations get met and the hopes are never never realized. The opposite for me personally occurred with CBD over the last three and a half years. And that is it actually stinking works.Dude, I knew that we were onto something with Atrantil, because after we did the initial studies, everybody came back and said, I want more. I knew that I was onto something or I was not on something. I knew that CBD had a viable place in my practice, because I bought and the story goes all the way back which is why we work with which is why it's powered by elyxenol right now, when we went to paleo FX, and I ordered a couple cases and I just gave them away to patients. That was not cheap. Not because I was sitting there trying to be altruistic, not because I was doing charity. I'm like, I don't know. I didn't. And I told everybody, I don't have a clue. I haven't even looked at this yet. All I know is try this. Tell me what happens. And when about 80% of them came back said I want more. And I went, Okay, we're onto something. And that's when I took my clothes off the deep dive into the science and went, holy cow. Yeah,this is crazyUp until that point, I just didn't know there was a whole lot to it. I mean, it really didn't. And then the fact is, oh, and to clarify, it's not like Brown just handed out CBD to just anybody who came to the clinic. You literally just like we did with Atrantil you found very diseased patients to say and who had gone through a gamut of different pharmaceuticals and weren't finding relief, and suddenly they're like, this is working for me. Tell me more about it. And I was, I was blown away.So let's talk a little bit. So we're I'm over here going well studies I haven't published and everything. Let's talk about a few studies. So I've got a Mendeley account, I know how to look at PubMed. I know how to get a Google Scholar, I just want to talk about a couple studies have come out recently. And let's kind of compare it and see if it still makes people concerned that they're going to die of liver failure.Sure. Alright. So in the Journal of Clinical Pharmacology published in 2019, the this was actually a study, also sponsored by GW Pharmaceuticals, as part of the process of getting the FDA approval that the FDA did not reference the best I can tell they did not reference this. This is way more complex and it gets super cool, because what they're looking at is the pharmacokinetics or how CBD is actually metabolized by that beautiful genius called a liver. In high doses in people with liver disease. Yeah, they went through the trouble to take high doses of CBD and give it to people People that did not have liver disease had mild liver disease moderate and severe. This was ballsy to say the least, because using a product like this in somebody with liver disease is is risky. This thing could backfire and it could shut down the whole process. Here's what's nuts, the pharmacologic and safety of a single oral dose of 200 milligrams of epidolex, which is the CBD isolate. They were assessed in subjects they had eight people with moderate or with mild disease, six people with moderate and eight people with severe and then they had this collection of normal people. Blood samples were collected to check for the pharmacokinetics This is how drugs are looked at. They give you a drug and then they check your levels. Basically, the blood concentration was higher in the hepatic impairment and they describe it in nanograms. So the nanogram comparison is that it's a little bit higher in those with severe hepatic impairment. But this is what's nuts there was no increase in adverse reactions. There was no change in blood levels. So basically, the only adverse reaction that they found was a little bit of diarrhea. And it all happened in the mild hepatic impairment. So the FDA had mentioned Oh, studies have shown that it causes diarrhea. What was really funny about
Michael Lewis, MD, FACPM, FACN, is the president of the Brain Health Education and Research Institute, which he founded in 2011 upon retiring as a Colonel after a distinguished 31-year career in the US Army. In this interview, Lewis provides listeners with an overview and update on the clinical applications of cannabidiol (CBD). In addition to discussing recent research, Lewis describes mechanisms of action, safety, and dosage of CBD in clinical practice. About the Expert Michael D. Lewis, MD, FACPM, FACN, is an expert on nutritional interventions for brain health, particularly the prevention and rehabilitation of brain injury. In 2012 upon retiring as a Colonel after 31 years in the US Army, he founded the nonprofit Brain Health Education and Research Institute. He is a graduate of the US Military Academy at West Point and Tulane University School of Medicine. Lewis is board-certified and a Fellow of the American College of Preventive Medicine and American College of Nutrition. He completed postgraduate training at Walter Reed Army Medical Center, Johns Hopkins University, and Walter Reed Army Institute of Research. He is in private practice in Potomac, MD, and is a consultant to the US Army and Navy as well as several nutrition companies around the world. A highly sought-after speaker, Lewis has done hundreds of radio shows, podcasts, medical conferences, and television appearances and is the author of the Amazon best-selling book, When Brains Collide: What Every Athlete and Parent Should Know About the Prevention and Treatment of Concussions and Head Injuries. About the Sponsor CV Sciences is on a mission to improve the well‐being of people and planet. We believe that the future of hemp is unlimited. Through innovative and responsible application of science, we strive to enhance the prosperity and health of our employees, customers, and communities. We are committed to pioneering the CBD evolution as the leading producer of quality hemp CBD products under the PlusCBD™ Oil brand. For more information please visit www.PlusCBDoil.com. Transcript Karolyn Gazella: Hello. I'm Karolyn Gazella, publisher of the Natural Medicine Journal. Today I'll be talking with Dr Michael Lewis about the clinical applications of cannabidiol, or CBD. Before we begin, I'd like to thank the sponsor of this topic, who is CV Sciences Incorporated. Dr Michael Lewis is the president of the Brain Health Education and Research Institute, which he founded after retiring as a colonel in the US army. Dr Lewis, thank you so much for joining me. Michael Lewis, MD, FACPM, FACN: Oh, it's a great pleasure to be with you today. Gazella: So before we begin, I'm always curious about why physicians are interested in what they're interested in. So, as a physician, what draws you to the use of CBD in clinical practice? Lewis: Well, the easy answer is because it's effective, but of course there's always a longer story. How did I fall into this? I mean, I spent 31 and a half years, my entire adult life in the army. And cannabis is not something that's a particularly ... It's rather frowned upon as, as you might guess. And so I really had no experience with cannabis or cannabidiol at all, but I've always been open to nutrition, and in the last 10, 15 years more much more open towards is there ways we can use targeted nutrition or nutritional therapy to ... I was in the army, so I was looking at it for helping people, helping soldiers recover from traumatic brain injury or concussions. So it really started out of fish oil and omega 3s, because the brain's made of fat. And then it kind of ... As I started to learn more and more, there started to be this interaction with the CBD industry. I finally, after I retired from the army, took a good look at it, and, more importantly, started to get great experiences with my patients using the combination of fish oil and CBD. Gazella: Yeah. And you focus a lot on brain health, so that makes sense, the connection between a traumatic brain injury. So what conditions ... In addition to, I'm assuming traumatic brain injury, what conditions do you feel that CBD works well for either as a primary or adjuvant treatment or even as proactive prevention? Lewis: Well, the biggest thing is as far as any specific one thing I would have to say anxiety, for sure. So 100% of my patients have issues with anxiety, and pretty much there's lots of anxiety just in today's society, with a 24-hour news cycle and all the craziness that's going on in the world. So it's about balance, and CBD, it interacts with our cannabinoid receptors and it's really about kind of achieving that balance. Not so much like that pharmaceutical model where you kind of hit something and you shut off a process and relieve the symptoms. The use of CBD is really much more about achieving a better balance, and nowhere has that been more important for my patients than in the world of anxiety. Helping calm that voice down in the back of your head. But I also find that it helps with chronic pain, particularly headaches. Can help decrease it. It doesn't always eliminate them, but I can tell you without a doubt, anxiety is my number one reason, whether you have a head injury or just dealing with anxiety. Gazella: Yeah. That makes a lot of sense. Now you're talking about balance and that speaks to potential mechanisms of action, how CBD actually works in the body. Can you expand on that a little bit more? How much do we really know about how CBD works in the human body? Lewis: Well, the interesting thing is we've known about CBD and its uses medicinally for thousands of years. Every major culture in the history of the world has used cannabis for medicinal purposes. So we know a lot, but yet we don't. Because of the issues with prohibition and then the war on drugs … we really kind of missed this golden era of clinical research, scientific research where we're really able to understand the mechanisms. Whereas in for thousands of years it was used because we just knew it was effective. Now we have a much better way of understanding why, and the why is really ... The why and the how is really it turned out that we have these indigenous cannabinoid receptors throughout our body and principally in our brains, CB1, or cannabinoid type one receptors, CB1 receptors in our brain associated with neurons and, and neuronal function and CB2 type receptors more closely associated with our immune system. So when you're out of bounds and you think about you're out of balance on your immune system, you're more susceptible to colds and viruses and infections and stuff like that. So it's about this homeostasis, this balance, not just with your immune system but with our brains, with how we're thinking. And the really neat and interesting thing is ... One way to try to describe it is the CB1 receptors in particular, we have these chemicals that are in our bodies. I mean, we know about serotonin and therefore you have serotonin reuptake inhibitors, for example, SSRIs for antidepressant medicines. Well, we also have these internal cannabinoids that we now know about. One in particular, anandamide ananda meaning bliss, or an anandamide bliss molecule, and it's an on-demand thing. So we used to call them endorphins. That runner's high, we would say that's an endorphin rush. We now know that that's our own body making on demand this stuff called anandamide that interacts with these receptors that keeps us happy, keeps us calm, keeps us thinking more clearly. And you can imagine, as somebody that's struggling with brain health issues maybe from concussion or from chemotherapy or just chronic stress in life, that can really make a difference. Whether or not somebody's happy and functioning in life is whether their cannabinoid system is working internally, but nature also gives us a way to interact with that through the cannabis plant, and as well as diet and exercise. Gazella: Yeah, it does seem like we're learning more and more about the endocannabinoid system and the fact that that system in the body has such wide-reaching health effects, and I'd like to talk a little bit about the research. I understand what you're saying that we lost some opportunities in researching this plant because it was, frankly, hard to get and illegal and researchers had difficulty in doing really highly organized research. However, it does seem like the research is increasing. Now recently I read a study that was presented at the International Society of Sports Nutrition conference specifically on CBD. Can you tell us a little bit about that study? Lewis: Well, I wasn't involved in the study. I'm only somewhat familiar with it, but it was a placebo-controlled randomized clinical trial and it was really looking at healthy people and to see if CBD versus a placebo would make a difference in everyday life events, such as quality of sleep and perception of how clear am I thinking, how am I doing throughout the day, energy levels and so on. And there was a ... It hasn't been published yet, but there was a, I'll say, statistically significant difference, particularly, my understanding is with the quality of sleep that those people that were put on the active CBD versus the placebo had a much greater reported quality of sleep, using very standardized sleep quality indexes that are used in research every day. Gazella: Yeah. That's what drew me to this study is the fact that it was done on healthy people and it did in fact impact sleep quality, because that's a huge issue. And somebody can be deemed as being healthy and yet still struggle with sleep. So I really liked that about that study. Now, what else does the previous published research tell us about the efficacy of CBD? Have there been a lot of studies on efficacy and CBD? Lewis: There's not been ... Relative to a lot of other things, whether you're talking omega 3s, fish oil or pharmaceuticals, there's not been a lot of research, published research. So it's really just because we're kind of coming out of this prohibition era, there's lots of research starting to get done, and there's some issues on how to actually go about doing some of the research, because your cannabis plant and my cannabis plant may not be the same. Gazella: So Dr Lewis, you were just talking about the variance between the plants, the cannabis plant, like one plant can be different from another plant. So when we're dealing with any botanical, the way that we extract the active compounds is so important. Tell us about the extraction process that's used for CBD oil. Lewis: Well, so the extraction is really important, but it actually starts way before that. If you want a consistent product at the end, you've got to have consistency all the way through. And one of the things about Plus CBD Oil that I really like is ever since they even began, when they started to import ... And they're the largest importer of European hemp. It's grown in the Netherlands, it's processed in Germany. But ever since the very beginning, they've only used 2 strains of the cannabis plant. And so the seeds are highly controlled, always using these 2 strains, and so you get consistency all the way from the seed through the entire process. If you're buying hemp left and right from Colorado and from California and from Europe and from Kentucky, you're not going to get that kind of consistency. And I would hope that that's what people want in a product. Certainly one of the things that I think sets Plus CBD Oil apart is that consistency. And then when it's extracted from the plant, it's not using solvents and alcohol or other things that can adulterate the plant. And we certainly see that with some of the cheap brands that are out on the market. But what we use is a CO2 extraction. So you're not getting that issue with solvents and other things that can adulterate it. And so consistency is really, really important. Not just to me, but to the product and hopefully to the consumer, all the way from the seed to the end product that sits on the shelf. Gazella: Yeah, that makes a lot of sense. Consistency from seed to extraction. Now, is there anything else that you look for when choosing an effective CBD product? Lewis: Well, one of the things of course is good documented third party testing. So as an example, there's a barcode or what's the ... QRS code? I always forget the name of those little square codes, but they're on the label of every product and you can scan that and actually pull down that third party certificate of analysis of what's in that particular lot of that particular bottle of that product. And so you're able to look at that and that's really, I think, very important to know what it is that you're taking. One of the concerns is the cannabis plant is widely varied. Everything from how much THC content to CBD content to the turpines to the flavonoids, to the minerals and so on, and different strains, different products are going to be widely varied and so you really want to know what you're going to consume. It's helpful to have that kind of a third party analysis that's right there available to anybody that wants it. Gazella: Oh, I agree. And the convenience factor alone is great for our healthcare professionals who want to look at that third party testing. That's great. Let's talk a little bit about dosage. So what dosage do you recommend for CBD, and more importantly, does the dosage vary based on if you're using it for proactive prevention or if you're using it for treatment, and if you're using it for treatment for anxiety versus dramatic brain injury? Talk a little bit about dosage and how it's used in clinical practice. Lewis: Well, it's one of the greatest challenges, I think, that we face as practitioners is knowing what dosage to use because everybody's different. And here's the problem is that your dose and my dose may be very different. And so we've got to start somewhere. And I've got a pretty typical way that I like to start with patients, but I'm always ... It's all about educating the patient and to emphasize that you've got to find your individual dose. So if we look at the Plus CBD Oil products, I think the thing that's made the biggest difference for me and my patients was about 3 or so ... 3 or 4 years ago, they came out with little soft gels, tiny little pearl-sized soft gels. That to me may make all the difference in the world. I mean, tinctures and drops under the tongue and lysosomal and all these different ways to do and deliver CBD are great, but patient compliance is so much better when it's just a tiny little pill, and you know, for example, the gold soft gel, you're getting 15 milligrams of CBD as part of the whole plant, broad-spectrum hemp complex. But you know every soft gel you're getting 15 milligrams, and you can look at the certificate of analysis and third party studies by consumer labs and so on to know that they're always dead on, and there that's not necessarily the case with a lot of other products. They're widely varied. So I think that that is really important. I like 2 different products and the 3 main lines, they have soft gels, they have a red label, which is for their raw product and that's actually mostly CBDA, the acidic form of the cannabinoid, of CBD and the other cannabinoids. And then it's gently heated because you have to decarboxylase the CBDA and the other cannabinoids to make them active, which is why in terms of marijuana you have to smoke marijuana or bake it because you have to activate it for it to be active for it to cross the blood-brain barrier and do the job on the brain that you want to use THC for. But with hemp of course we're only dealing with trace amounts of THC, virtually none, but still trace amounts. So I actually ... The function of CBDA in their raw product is very different than the CBD. It's great for inflammation, great for the body. And then I like to combine that with one that's really good for the brain, and that's their more concentrated product, their gold product. So I actually start patients on a gold and a red soft gel, and I start them twice a day, one of both morning and bedtime, and then have to educate. Some people, they don't like how the gold makes them feel during the day and they like to only take it at night. I have patients that take 3 at night and none during the day. I have people that take 2 every couple of hours during the day. So it just really depends on the person. But the easiest thing is start twice a day and adjust from there, either more frequently, or to a higher amount. Gazella: Yeah, that makes a lot of sense. Because we are very individualized, especially when it comes to a substance like this. So let's talk a little bit about the future. As a clinician, I'm curious as to what you would like to see happen with CBD in the future? What more needs to be done from a research or clinical perspective when it comes to the use of CBD? Lewis: Well, I think the obvious thing is that it's not widely accepted, and this holds true for a lot of botanicals, but the stigma that cannabis has had for the last 70, 80 years, it's going to take a little bit of time to overcome that. And one of the ways we can overcome that is with good science to prove that it works, but we'd certainly have challenges because the variability in a plant and the variability in products. We always try to boil it down to what's that one thing? And that one thing we always [inaudible 00:19:04] nomenclature we say at CBD ... Well, when we talk about CBD oil, almost always we're talking about not really CBD oil. We're talking about industrial hemp oil that happens to have CBD and has a lack of THC. But that strain and this strain can be very different. So that consistency among products is really difficult. How do you do research around something that varies so widely? And that's one of the bigger challenges. Well, again, we will always want to boil it down to that one thing and that's why the FDA approved Epidiolex, because it's 99.9% pure CBD, but it misses out on all of those other important things in the hemp plant that make that entourage effect, that synergistic effect between all the different things. And so the safety profile is actually very different compared to something like Plus CBD Oil that has a tremendous safety profile. Gazella: Yeah, I was actually going to ask you about safety. So are there any patients who should not use CBD? Lewis: Every once in a while you run into a patient that just is exquisitely sensitive to pretty much anything. And so whether it's Tylenol or Benadryl or other things. Most patients, if you give them Benadryl, it makes them sleepy. That's why I send Tylenol PM or Advil PM, so on. But every once in a while you run into that patient that is a hyper metabolizer, and Benadryl makes them wired. It keeps them awake. Well, you can have a similar thing with CBD, it's processed through the P450 system in the liver. So genetically some people are just prone to have different effects in medications that are metabolized by the liver. So those are the ones that you have to watch out for. So what I typically do is I drop them way back and start them really, really low dose, like get a dropper, and we just do one drop or one spray once a day and see how they do, and then go to 2 and then 3 and then 4 and build them up so that their body gets used to it. It doesn't mean that they don't need CBD or else I wouldn't be doing this with a patient, but their bodies just need a much slower ramp up to be able to adjust to it. Gazella: You know, that makes a lot of sense. Because I've heard about the reverse effect with other substances like melatonin, you mentioned Benadryl. It's good to know that if there is that reverse effect that you don't have to just stop completely. You can just do this titration where you start really small and just ramp up slowly, so that's good to know. And you've had good luck with that in clinical practice? Lewis: Very much so. And those are the patients that ... I'm dealing, again, with head injury patients or concussion patients that have been struggling for months or even years with the symptoms following a concussion and they're the ones that really need it. They really need the CBD. And so I'm not so quick to just say, "Stop taking it." But where I've found the success is, all right, we're going to start back over at ground zero and we're going to step up really cautiously, really slowly. And once you work through that process over a month or so, it is absolutely life-changing for those patients. Gazella: That's great. That's good to know. And I would agree with you. I think in the future it would be good to see the stigma ... To overcome that stigma, to get some more consistency with the plant and some more human trials associated with the efficacy of CBD. I think those are all really great future goals for this particular substance. Well, Dr Lewis, once again, thank you for joining me today, and I'd also like to thank the sponsor of this topic, and that is CV Sciences Incorporated. Thanks again, Dr Lewis. Lewis: Oh, my pleasure. Hopefully we can do it again sometime soon. Gazella: Absolutely. Let's stay in touch. Well, have a great day everyone.
Learn about our pricing, packaging, and steps to move forward working with us to change your health – FOR THE BETTER! Connect with Lahana over on Instagram, Facebook, YouTube, and the blog! About Lahana Vigliano, CCN Lahana Vigliano is a Certified Clinical Nutritionist and CEO of Thrival Nutrition. She has her Bachelor’s Degree in Nutrition Science and currently pursing her Masters Degree in Nutrition Science and Functional Medicine. Lahana and her team help support women who struggle with weight loss, hormonal imbalances, digestive issues, chronic fatigue, and many other lingering issues that leaves women not feeling their best. She uses food as medicine, as well as herbs and supplements when needed, to support her clients. She looks at the whole body holistically making sure women are understanding how nutrition, sleep, stress, and their environment impact their health. She creates tons of free resources in her blog (www.thrivalnutrition.com) and the Thrival Nutrition Podcast that share real food recipes + content that helps women who are wanting to feed and take care of their families healthier + more holistically. She is also the creator of Thrival Nutrition Supplements, which she formulates bioavailable and organic supplements to better support women’s lifestyle. Transcript I hope everyone is well + embracing what is left of summer. I can’t believe it’s almost over and my little girl goes to KINDERGARTEN! Ya’ll this is huge. We will have officially two kiddos in regular school. A turning point that is bittersweet. Today, I wanted to hop on solo and talk with you guys about a topic that I feel is VERY important when you’re looking at your hormones and it’s not tested by your conventional doctor. This is why in our practice we use the DUTCH test for hormones to get a really deep look into what you’re hormones are actually doing. We’re not just looking at the levels of hormones you have, like estrogen, progesterone, testosterone, but we’re looking at the metabolites + how you’re using it through the body and the different phases of detoxification. This shows SO much about not just your hormonal health, but your overall health and can really answer questions if you have mysterious symptoms, but your doctor tells you that your hormone levels are “fine”. We’re really focusing in on estrogen today. So, let’s get started. The dried urine hormone test we use tests for your three main estrogens: E1, E2, E3. Your doctor will probably only test for E2 when they check hormones via the blood. E1, also known as estrone, is pretty weak + is the estrogen that becomes dominate during menopause. E2, known as estradiol, is the main estrogen during our reproduction years and also is the most potent. E3, known as estriol, is a big estrogen that happens during pregnancy. E1 and E2 can convert to each other, but E3 can’t convert to any of the other estrogens. What happens to the estrogen once it’s ready to go through the detoxification pathway? Phase 1 brings out cytochrome P450 enzymes to metabolize them + this can go down three different pathways. You have your 2-OH pathway that is super protective and this pathway should be the MAJORITY of what you metabolize. There is another pathway called 4-OH pathway that can be dangerous as it can cause DNA damage, increasing your risk of estrogen related cancers, like breast cancer. While some of our estrogen will go down this pathway, it should NOT be the majority. This is the more inflammatory pathway. Last, but not least, another pathway called the 16-OH pathway is very symptomatic and can cause you to have estrogen dominant symptoms and it binds very strong to the receptors on our cell. E3 is usually formed in this 16-OH pathway originating from E1. The metabolite going through the 16-OH pathway has been studied to also be a potential tumor initiator causing DNA changes, which also increases your risk of estrogen related health problems. During phase 1 detoxification, you need to make sure that you have plenty of B vitamins, vitamin C, selenium, zinc, and magnesium. These nutrients are the cofactors to this phase of detox. Without them, you’re phase 1 will be wonky. This is WHY you need to make sure when you’re looking into your hormones, LOOK AT THE TOTAL PICTURE. Do not think that your one serum marker tells you everything you need to know about your estrogen levels and your health. This is why we do the lab test we do in our practice. Now you might ask, how does food relate to estrogen phase one detox? That’s a great question. When you know which pathway your estrogen is choosing to go down, we can influence the better pathway by eating certain foods, like more crucferious vegetables. That’s like broccoli, kale, Brussel sprouts, cabbage, cauliflower, etc. These foods help increase that protective 2-OH pathway. There are some supplements that can help as well, like DIM or I3C, but I would never recommend taking these until you KNOW your levels because certain supplements like DIM can actually lower estrogen. You wouldn’t want to lower estrogen if you are low or have a low normal amount. Definitely the statement – “test, don’t guess” works here very well. We can help you figure out what your meals should look like + what nutraceuticals can support your body. Another thing that we look at in our practice is your environment – such as skincare, cleaning products, things that hold endocrine disrupting ingredients that can change your hormones. We take a holistic approach looking at mainly your diet, but also other lifestyle factors as well.
Está no ar o episódio 22 do Microbiando! E vamos falar sobre como um produto da dieta induz alterações transcricionais e metabólicas em macrófagos e interfere no potencial microbicida destas células, contribuindo para o controle de infecções bacterianas entéricas. No Microlitros de notícias, a Isabella Campelo vai falar sobre a descoberta de uma enzima que é capaz de transformar biomassa em bioprodutos; a Vitória Fernanda vai contar uma história incrível sobre a febre tifóide e o Thiago Silva trouxe relatos sobre um fungo misterioso que anda aterrorizando hospitais por ai. Bibliografia: The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages.A promiscuous cytochrome P450 aromatic O-demethylase for lignin bioconversionMary Mallon: ‘Typhoid Mary’FEBRE TIFÓIDEPerfil epidemiológico e caracterização molecular de Salmonella Typhi isoladas no Estado do Pará, BrasilAntifungal therapy: new advances in the understanding and treatment of mycosisA Mysterious Infection, Spanning the Globe in a Climate of Secrecy Sobre o Podcast Microbiando A ideia do Microbiando é discutir artigos científicos de ponta em todas as áreas da microbiologia e imunologia. Vamos utilizar uma linguagem bem acessível para destrinchar esses artigos para vocês, mas sem perder o rigor científico e analítico necessário para essa tarefa. Além de discutir artigos nós teremos o quadro Microlitros de Notícias, onde nossos microbiologistas e imunologistas de plantão irão abordar pequenas reportagens e trazer novidades para vocês. No quadro filogenia da Ciência vamos contar um pouco sobre a vida de grandes personalidades que revolucionaram a Microbiologia e Imunologia com suas descobertas. Você pode nos ouvir no Spotify, Google Podcast, Player FM, Podcast Addict, CastBox, Blubrry Podcasting, iTunes e outros agregadores de podcasts. Contatos E-mail: microbiando@micro.ufrj.br TwitterFacebookInstagram O podcast Microbiando tem o apoio do Instituto de Microbiologia Professor Paulo de Góes e do Instituto de Biofísica Carlos Chagas Filho, ambos da UFRJ. Além da Sociedade Brasileira para o Progresso da Ciência, da Sociedade Brasileira de Imunologia, da Sociedade Brasileira de Microbiologia, da Sociedade Brasileira de Virologia, do Marketplace iBench e do site de divulgação científica A Ciência Explica. Imagem de WikiImages por Pixabay Apoiadores do A Ciência Explica Leandro LoboGabriel SiqueiraCarlos Eduardo da SilvaMasashi C. InoueCelia Campos Tobaldini-Mansbach Obrigado por nos apoiarem através do financiamento coletivo! Apoie você também e ganhe recompensas, como canecas, bottons, adesivos e livros exclusivos. Não pode ajudar financeiramente? Siga nossas redes sociais e compartilhe nossas matérias com seus amigos!
Celery Juice, How Detox Actually Works & Food as Medicine. Are you curious about the celery juice trend? Is it a super food or a super fad? In episode 14, I am joined by Ali Miller, RD, LD, CDE who is hitting us with the facts with her food-as-medicine approach that is grounded in nature and supported by scientific evidence. We talk through the misinformation, the redeeming qualities of celery and why you may want to reconsider downing gallons of celery juice each and every week. From debunking some of the massive claims to talking through why some folks may be having great results drinking daily celery juice, Ali shares more about how the body's natural detox pathways work. Learn how you are better off consuming foods rich in sulfur, glycine, glutathione, cysteine, and nutrients that drive phase 2 encapsulation with ample fiber in the diet (that's right celery juice contains none of these things) to support the excretion of toxins from your body to actually detox vs. prevent detox process for short-term outcomes. Finally, Ali shares more about her food-as-medicine approach when it comes to anxiety, depression and cognitive dysfunction. I hope you enjoy this episode and if you have anecdotal evidence or personal experiences with celery juice that you would like to share, please feel free to use the comments below, we'd love to hear from you. Find Ali Miller RD: Her website AliMillerRD.com Instagram @AliMillerRd The Naturally Nourished Podcast Mentioned in this Episode: Ali's IGTV episode about why she will never drink celery juice Celery Juice is NOT a Miracle Drink Rat study showing the effect of celery and parsley juices on pharmacodynamic activity of drugs involving cytochrome P450 in their metabolism 10 Day Real Food DetoxProgram The Anti-Anxiety Diet: A Whole Body Program to Stop Racing Thoughts, Banish Worry and Live Panic-Free Ali's rebuttal to Jillian Michael'srecent rants on the Keto Diet Show Notes: http://tasty-yummies.com/beweenmeals14
Thanks for this week’s topic suggestion from Jideobi! This week we’re going to learn all about koalas and some of their strange friends! The Blood on the Rocks podcast (not for kids) where you can hear a segment by me in the WWI megasode! An unlocked Patreon episode about wombats So cuddly, little koala: I am dying of cute y'all: I have actually died. I am ded because this mama koala is feeding her baby a leaf: I came back to life but then I died again because of this monito del monte: Show transcript: Welcome to Strange Animals Podcast. I’m your host, Kate Shaw. It’s another listener suggestion week! But before we get started, a quick shout-out to the podcast Blood on the Rocks. I was one of about a dozen podcasters who participated in their recent epic World War I megasode. It’s not a podcast for kids since it covers dark topics like true crime and the more gruesome bits of history, but if you are a grown-up type person who finds that sort of thing interesting, I’ll put a link in the show notes so you can check it out. My part of the show was a short segment about the animals of WWI. I also released a different version of the segment as a patreon bonus episode earlier this month. Anyway, let’s start off this week’s episode about koalas. Thanks to Jideobi, who suggested we learn about the koala. I can’t believe I haven’t covered koalas on the podcast before. They’re such amazing, weird animals. Many people call the koala a koala bear, but it’s not related to bears. The koala is a marsupial—you know, where the babies stay in their mama’s pouch. It’s most closely related to the wombat, and I was going to talk about the wombat in this episode until I remembered I had a whole Patreon episode about the wombat. I’ve unlocked it so anyone can listen to it. There’s a link in the show notes and you can click on it and listen in your browser, no login needed. The koala lives near the coasts of eastern and southern Australia in eucalyptus trees. It’s gray, gray-brown, or brown in color, with no tail, short floofy ears, a flat face with a big black nose, and long claws that help it cling to tree trunks. You may already know all this about the koala, and you probably know that almost all it eats is the leaves of the eucalyptus tree. But there is so much more to learn about the koala. For one thing, its diet. Eucalyptus trees are mostly native to Australia, although people in other parts of the world grow them as ornamentals, although they need warm climates to survive. Koalas eat the leaves of many different types of eucalyptus trees, but they prefer about 30 species, typically ones whose leaves contain higher levels of protein. But eucalyptus leaves contain toxins that make other animals avoid them—toxins that can poison even large animals like horses and cattle if they eat any. Even handling eucalyptus leaves with your bare hands can irritate your skin. The koala’s liver produces a type of protein called cytochrome P450, which breaks down the toxins and stops them from making the koala sick. Still, researchers have observed that the koala does avoid certain leaves or parts of leaves that contain higher concentrations of the toxins. Researchers recently sequenced the koala genome, which gives us new genetic understanding of its biology. One thing the genome reveals is the koala genes associated with taste receptors. For most mammals, a bitter taste is a warning that something you’re eating might be toxic. That’s why things like coffee and strong tea are acquired tastes, because they contain compounds that can make the drink taste bitter, especially if it’s not prepared properly. That’s why I put a whole bunch of sugar and milk into my coffee. The koala has more bitter taste receptors than almost any other animal studied, which means it can probably taste the level of toxins in every leaf. This helps it choose the least toxic leaves. Interestingly,
Pharmacogenetics is an emerging field and is defined as the variability in drug response due to genetics. Genetic differences can be divided into pharmacokinetic (what the body does to the drug) and pharmacodynamic (what the drug does to the body) biomarkers. Pharmacokinetic biomarkers include cytochrome P450 enzymes, drug transporters, and more. Examples of pharmacodynamic biomarkers important to pain therapeutics include opioid mu receptor 1 (OPRM 1), catechol-o-methyltransferase (COMT), and methylenetetrahydrofolate reductase (MTHFR). Ultimately, polymorphic variations in these biomarkers may lead to alterations in effectiveness, safety, and tolerability of medications. In this comprehensive interactive forum, led by Dr. Jeffrey Fudin, the next generation of clinical pharmacy specialists in pain management will focus on patient case based pharmacogenetic profiles used to discuss relevant biomarkers with genetic variations and the role these play to enlist actionable outcomes for optimizing medication regimens. These genetic variations may impact a person’s response to a medication including safety and effectiveness, potentially supporting supratherapeutic or presumed subtherapeutic opioid dosing (PAINWeek 2017)
Genetics aside, what else influences our individual biochemistry? Put Dr Mark Donohoe and Andrew in a room together and you can expect thought-provoking discussion, fascinating tangents and humour sprinkled amongst valuable clinical pearls. In this episode, Andrew and Dr Donohoe deliver just that, as they dive into a number of the nuances influencing the practice of personalised medicine including our microbes, our cytochrome P450 pathways as well as drug, food and environmental exposures. You can find today's transcript and show notes here: https://www.fxmedicine.com.au/content/one-size-does-not-fit-all-dr-mark-donohoe *****DISCLAIMER: The information provided on FX Medicine is for educational and informational purposes only. The information provided is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you learn here raises questions or concerns regarding your health.*****
In this video interview, Christopher Shade, PhD, describes the diverse clinical applications of cannabidiol (CBD) oil. Also included is information about safety, dosage, and other issues associated with this somewhat controversial natural substance. About the Expert Christopher W. Shade, PhD, founder and CEO of Quicksilver Scientific, specializes in the biological, environmental, and analytical chemistry of mercury in all its forms and their interactions with sulfur compounds, particularly glutathione and its enzyme system. He has patented analytical systems for mercury speciation (separation of different forms of mercury), founded the only clinical lab in the world offering mercury speciation in human samples, and has designed cutting edge systems of nutraceuticals for detoxification and antioxidant protection, including advanced phospholipid delivery systems for both water- and fat-soluble compounds. Quicksilver Scientific is recognized globally for innovating on behalf of the pharmaceutical and nutraceutical industries. Dr. Shade is regularly sought out to speak as an educator on the topics of mercury, environmental toxicities, neuroinflammation, immune dysregulation, and the human detoxification system for practitioners and patients in the United States and internationally. About the Sponsor Quicksilver Scientific is a leading manufacturer of advanced nutritional systems with a focus on detoxification. We specialize in superior liposomal delivery systems and heavy metal testing to support optimal health. Our advanced liposomal supplements are highly absorbable, and support the body in the elimination of ubiquitous toxins, enabling you to achieve your genetic potential. At Quicksilver Scientific, we are passionate about health and well-being, and are committed to improving the lives of everyone we touch. To purchase Quicksilver Colorado Hemp Oil as a Practitioner, please access www.THRTech.com. Consumers, please access www.VitaExpress.com. Transcript Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today we have a fascinating and somewhat controversial topic to talk about. We're going to be talking about the therapeutic effects of CBD oil from cannabis. Before we begin, I'd like to thank the sponsor of this podcast, who is Quicksilver Scientific. My guest today is Dr. Christopher Shade. Dr. Shade, it's always a pleasure. Christopher Shade, PhD: Always a pleasure. Gazella: And I have to ask you first of all, is there a reason that CBD oil would be controversial? Am I right in that? Shade: Much ado about nothing. Gazella: Maybe. Shade: You know, is there a reason for controversy? Controversy's built out of us evolving as a society in which we had instituted cannabis prohibition, and we all had this reefer madness fear around the THC side of cannabis, the psychoactive high-inducing side. But CBD is coming from industrial hemp, which is the THC is bred out of it, and you're left with another component that is big in the resins of cannabis, and it's called cannabidiol. It's chemically different than THC, and its physiological effects are vastly different, and they seem almost magical when you look at so many ... At the variety of things that they do for you, but they don't get you high. They have an effect of balancing and calming the mind, but they have so many different therapeutic benefits, and it's really just getting people out of the fear of the evil weed, into this wonderful, medicinal plant and all the uses it has. Gazella: I want to get into the mechanisms of action and all the science associated, but first, and I know that you're not a legal expert, but is it available freely? Is CBD oil available for purchase, or are there limitations because cannabis is not legal in many states? Shade: Yeah. The entrance of CBD into use in the US was made possible by the 2014 Farm Bill, which was allowing the use of industrial hemp for various uses in trade in the US. In those uses came the use of the extracts. Now, by some interpretations, well, that's still cannabis, and that's still scheduled as a drug. Certain parts of the government are saying, "Hey." Like the DEA. "Hey, that should still be scheduled. We didn't say that's okay." Whereas other parts of the government are saying, "Hey, that's all right. That comes underneath the Farm Bill." Most of the states have rolled with this being under the Farm Bill, and being an allowed substance. It's gained so much widespread use, and a lot of that use is from very impaired people that rely on it heavily for their health. Most places are reluctant to step in and go against the Farm Bill. Certain states, however, Indiana notably, recently the Attorney General said, "No. We're not doing this, except for under certain exemptions. If you have a certain type of a ..." It was probably a seizure disorder, "Then you can get a permit to use this." Missouri, I don't know the extent of their laws, but they're kind of difficult. Most people don't sell it in Missouri. Then other states are taking a tack of trying to adopt it into a state cannabis law. Making it like THC, where it's regulated by the state, just like Colorado regulates THC. It does not regulate CBD independently, but for instance, the State of Florida is trying to bring CBD into their medical marijuana world. We'll see how it rolls in Florida, but right now the places to stay out of are Indiana and Missouri. This is such a moving target that this might change in a month. Gazella: Right. Now, just to clarify, though, CBD oil or hemp oil does not have THC in it. Dr. Shade: No. In most of the extracts of industrial hemp ... Industrial hemp is defined in the Farm Bill as a plant that, on a whole plant basis, has less than 0.3% THC. When the Colorado Department of Agriculture goes and certifies a crop here for being harvested and processed, it will take representative plants and analyze them for this threshold of THC. Now, these plants usually have, oh, 7% to 9% to 10%, upwards to peak around 15% CBD as well. There's some residual THC along with the CBD. One of the concerns originally was, "Well, when we concentrate that up, will there be enough THC for people to get high?" Now, processors who are trying to stay very clean with the law will use extraction technologies and post-extraction purification technologies that minimize the THC. For instance, in our CBD oil, there's virtually indetectable THC. Whereas some oils will have a 20-to-1 CBD to THC ratio, ours is around 500-to-1. It's super clean, and that's nice because a lot of people that want to use the oil have THC testing programs that they're in, if they're firefighters, or policemen, or airline pilots. A lot of the commercial extracts have enough THC that if you're using large amounts to be really therapeutic against something like pain, you will probably have enough THC to tip the scales on some of the analytical techniques looking for THC. Gazella: Got it. Thanks for that clarification. Now, let's get into the science, which is your area of expertise. What's going on from a mechanism of action standpoint? How does CBD oil work inside the human body? Dr. Shade: Well, it works on a number of different levels, and when we were describing this, we used to chase after one thing or another. We'd say, "Oh, it's antiinflammatory." Or, "Oh, it helps GABA-glutamate balance." As we go forward, we look at it more and more in this symphony, and this symphony, I call neuro-endo-immune poise, or balance. Neuro means neurotransmitters. Endo is endocrine or hormone, and immune is obvious. It's the immune system. Neurologically is how we used it the most, for damping neuro-inflammation. When I lecture to doctors, I say, "This is the most exciting supplement for us in the last 30 years in functional and integrative medicine." Because we're treating a lot of people with [mole 00:07:45] toxicity, Lyme disease, mercury toxicity, and all these have as part of their symptomology neuro-inflammation, where you become ... Your autonomic nervous system becomes sympathetically dominant, you've got overactivity of glutamate receptors, there's activation of the immune system in the brain called the microglia, and they're sort of at war with the glutamate receptors. That's causing anxiety first, then brain fog, then a disruption with the autonomic nervous system. You're moving resources and blood in wrong ways throughout the body, and this acts to just stabilize all of that. It will block the excitation of the microglia. It will stabilize the glutamate receptor. That will result in a neuro-stabilization. Your neurotransmitter balance between glutamate and GABA gets balanced. Your autonomic nervous system balance between parasympathetic and sympathetic gets balanced. But that starts cascading down even farther into the body, and we start to look at really what homeostasis or balance of the biology is, and it's a set of reactions that all have these yin-yang poles, which you want to sit in the middle of and take forays in the yin or yang as needed to handle different perturbations, but you always want to come back to the poise of the center, and CBD is always bringing that back to the middle. In hormones, in women, the organ with the greatest amount of cannabinoid receptors? The uterus. I always pair CBD with bitters, and guess what's in the ovaries, but bitter receptors. We find such a stabilization of the female cycle by taking those things together. Then the immune system. You want inflammation when you need to kill things, but then when it gets stuck on, and it won't turn off, you get things like development of chronic inflammatory states. These can be cardiovascular complications. These can lead to cancer. These are problems, so where's the switch to bring it back? The CB-2 receptor, the cannabinoid number two receptor, and where's that located through the body but on the peripheral immune cells of the body. CBD lubricates your endo-cannabinoid system. Why would you have cannabinoid receptors if you didn't make cannabinoids. The two main cannabinoids you make are 2-Arachidonoylglycerol and anandamide, and the reason you make them is to zip together the neural system, the endocrine system, and the immune system have that neuro-endo-immune poise, and CBD helps you build more of those endo-cannabinoids and helps potentiate those CB-2 receptors. At the same time, it's up-regulating chemo-protective and antiinflammatory genes and down-regulating pro-inflammatory genes. There's really no one thing that helps you create that poise, that essential homeostasis. Nothing does it like CBD oil does, and that's why it seems like a panacea, because it helps so many things. Gazella: That was actually my next question, because when I was researching for this interview, I found such a diverse amount of conditions that it was being effective for, so because it works on these multiple pathways, that's why you're saying it works for such a variety of conditions. Do you give practitioners who say, "Wait a minute. That's a little bit too good to be true. How can it be that good for that many things?" Dr. Shade: Well, then I give them the neuro-endo-immune poise story. Gazella: Exactly. Dr. Shade: And as soon as you said neuro-endo-immune poise, they go, "Wow." Gazella: That's right. Shade: Because what are the disorders? There's some part of you in that yin-yang balance that's stuck over here, or stuck over there. Anything that helps you zip together so many fundamental processes, everything just starts to come back together again. I mean, it runs through all of our different protocols, because it's that X-factor for zipping it all up again. Gazella: Right. Now, there's got to be some conditions that bubble to the top, and that was the other thing that I was so impressed with, with the research, is the amount of research associated with CBD oil has grown dramatically. But what conditions? As you're looking through the research and you're kind of identifying the strength of the research, what conditions are bubbling to the top, to say, "Yup, that's really what it's going to work for"? Shade: Right. In our world, we deal with detoxification, and so we're dealing with people who have various problems that are associated with toxins. Autism is a really big one. That's always ... Unless they're just totally exhausted, autistics, always bringing CBD into that, because of that neurological stabilization. Then we're dealing with various mole toxicity, Lyme disease, and the neuro-inflammation that comes from that, the different metal toxins. All of our detoxification protocols, especially when they're neuro-detoxification protocols, involve the use of CBD. Then in distinct disease states, the big ones, MS, Parkinson's, any kind of tremor. Of course, everybody knows seizure disorders. Those are all crying out for some application of CBD. But then since I understood the endocrine side of it, women who are having endocrine destabilization or hormone imbalance, we're always recommending CBD along with the bitter herbs to them, and we get great ... You might not think, "Premenstrual syndrome: CBD." But it's fantastic for that. Those are the main ones that we use. Oh, any chronic inflammatory pain. That's a really big one. Cardiovascular complications. That's really big, too. We've seen some great data emerging on the use of CBD, including some doctors who have used ours to get preliminary data, on the health of the inside of the vascular system, and you'll see those cells on the inside of the vascular system all getting less stress, increased poise, and so we recommend it in those cases as well. Gazella: Now, what about mental health? You've now just listed some conditions that are related to our physical health, but what about some conditions associated with mental health? Shade: Anxiety's just hands down the biggest one, because anxiety results from over-excitation of the glutamate receptors, and boom. CBD stabilizes that immediately. It's very, very fast around that. Now, it's interesting, for much more complicated problems, like schizophrenia, here you've got one plant, two chemicals, THC, CBD. THC is like putting the fast forward button on schizophrenia. It's really bad for a schizophrenic, where CBD has fantastic data around stabilizing schizophrenics, so there it's useful as well. Even in depression. Depression, you think, "Okay, well anxiety, you're really stimulated, and that calms you down." But depression is also often cycling with anxiety, and so depressive disorders, there's been a lot of data around use of CBD too, and most of my favorite integrative psychiatrists like Kelly Brogan, they've showed very clearly that depression is a neuro-inflammatory disorder, and so you've got different reactions to antigens in your food, in your environment. You're having these constant allergic states and cytokines, these pro-inflammatory states that are contributing to depression, and CBD is working against all that, creating that balance again so it can be used in anxiety and depression. Gazella: Yeah. It's fascinating. Shade: Yeah. Gazella: I'd like to talk about safety, because I have to tell you that I've read some conflicting statements associated with safety. Based on your interpretation of the scientific literature, is it safe? Are there any interactions, contraindications that we need to be worried about? Shade: On its own, without you having to stick something else into your body like a heart pressure medication, CBD is inherently incredibly safe. We've found a couple of people here and there that seem to have an allergy to the plant, and they just feel unhappy on it, but the issue around CBD and safety is that it interacts with some of the cytochrome P450 system, which are metabolizing drugs. If you're taking a drug for blood pressure, CBD may either lower its breakdown, so increase its circulating levels, or increase its breakdown, and thereby decrease their circulating levels. If you're on a lot of pharmaceuticals, you usually have to do a little bit of research and see if there's some interaction between the CBD and the pharmaceutical that you're on. There's starting to be good lists online of the potential interactions. They've got to get a little bit better at where these are really relevant interactions, and where they're not relevant interactions. But this will be one of the things that we come up with in the future, is nice, clear guidelines on whether something's going to positively reinforce a drug, or work against the activity of the drug. Gazella: I mean, the case that I read was specific to antidepressants, and that's where it was very conflicting. Some reports were, "Yes, it will react," as you describe, and some were, "It will not." Shade: Because it's not antidepressants. It's, "This list of chemicals." Gazella: Exactly. Yeah. Shade: They just happen to be antidepressants to your body that get metabolized down different pathways according to their chemical nature. Your breakdown doesn't care whether it's an antidepressant or whether it's testosterone. It's got a chemical nature, and it's got to fit into the cytochrone that breaks it down. You get a list of antidepressants, they have different chemical natures, and they go into different cytochrome P450 enzymes to break down, and CBD interacts with two or three of those enzymes. If the antidepressant interacts with the same enzyme CBD does, then there could be an interaction, and if it doesn't, then there's no interaction. It's not about antidepressants. Gazella: Yes, and nothing is ever clearly black and white when we're talking about this type of chemistry. Shade: No. Gazella: I'd like to talk a little bit about the product that you specifically formulated, Colorado Hemp Oil. What makes your product unique or special compared to other CBD oil products that are on the market? Shade: Quicksilver Scientific specializes in delivery systems, ways to get the compounds into little, lipid-based carrier spheres that are so small that they passively diffuse through mucosal membranes, like your oral mucosa, the sublingual space, as you're swallowing, through the stomach, the upper GI. It's the rapid and complete absorption of these little nano-spheres which is what we do, and when we stick CBD in there, there's a very fast uptake, there's a high total uptake, and it's a very rapid uptake. One of the things that's a problem with CBD is there's only net about 10% uptake of all the CBD you swallow. That's a very expensive molecule, as you know, and so you're throwing away a lot of that and not getting a lot. The stuff you do absorb is absorbed over the whole transit time of the GI, so if we look at uptake versus time, you have a very gradual, slow movement into the blood. The blood levels, the peak blood levels never get very, very high. Now, a lot of what CBD does, it does through interacting with receptors, and gene triggers, like nuclear transcription factors, like NRF-2, which turns up all your glutathione genes. Now, the receptors and those transcription factors react to peak doses. Level versus time, here's a regular CBD oil. Here's ours. You get a very high transient peak dose. You saturate the system. You're able to work very well on the brain. You're able to hit all of those transcription factors. You're able to interact with all of those membranes, and everything happens very quickly, and you get a very strong effect. The total absorption is anywhere from four to sixfold higher than a regular pill, but even if you took four to six times as much, you don't get as much of an action, because you don't have that peak dose to really induce everything, ring the bell of those receptors. What happens when you hit receptors, you trigger a whole cascade of different proteins to be made, which is affecting the metabolism of the body. That transient peak dose really creates the effect that you're looking for. Gazella: Now, your label says that the patient needs to hold it in their mouth for 30 seconds. How important is that, and is that all a part of the enhanced absorption of the product? Shade: It is, because this is a nice space in the oral cavity. Interacting with the oral musoca is a space where your spheres that you've made have not had to interact with stomach acids or bile, so there's nothing modulating them or modifying them, changing their shape, their size. It's a nice, pure space where all the capillaries are very close to the surface, and you can get a whole bunch in. Now, that being said, for some of our products that are water-core, that are liposomes, those are a little bit more sensitive to the GI conditions, and a little bit more important that you do that oral holding. The nano-emulsion that we make, like the CBD, you have an oil core with a membrane around it. These are more resistant against change in the GI tract, and they will make it through, and you'll get the absorption anyways, but it'll be a little bit slower, and a little bit less efficient. The more you can do the oral hold, the better, but it is not a game-breaker. That's important for a lot of the people that are very taste-sensitive, or if you're working with autistic children, and they won't do that, or you're giving it to your dog or something, goes right down. Gazella: I don't know. My dog is pretty smart. Shade: Yeah. You just say, "30 seconds." Gazella: That's right. Shade: "No. Five seconds more." Gazella: It's interesting. I would like to stay on dosing. Is it complicated to dose from a practitioner's standpoint? Because you do have such a diverse offering of conditions that it can help. Is the dosing- Shade: Yeah. It's really titration dosing. You start at a low amount. One of the doctors in town here, Joe Cohen, goes with two pumps three times a day as a sort of basis dosing for an adult, and then they'll add more as they need it. If you're not getting the effects, how about three pumps three times a day? Then four pumps three times a day? Titrate up until you get the required effect. You can even start down at one a day, like if you're dealing with kids and you want to start low and slow, but just keep titrating up until you get the effect you want, and often once you induce the effect and start training the body into the healthier state, you can bring the doses back down. Just start low and work up until you get what you need. Gazella: Great. Now, before I talk about the future, because you know I like to talk about the future, I'd like to have you predict the future, is there anything else that practitioners need to know about CBD oil when it comes to using it in their clinical practice? Shade: No. Don't be afraid to use it for a wide variety of conditions. Work your dosages up until you get the effects that you want. Let people know, especially if they've never had anything like this, the feeling that they have in the first couple of days may be more intense than it will be later, but it's not ... Most of the other supplements, there's more tricks around it and things to watch out for. Not so much with this. One thing, though, you will, if you're using it alone, you will start to generate detoxification reactions through two mechanisms. One is NRF-2 up-regulation, that nuclear transcription factor that's turning up the glutathione system, and the other is the autonomic balance, bringing yourself over to a parasympathetic state, and detoxification doesn't happen in sympathetic states, because it's a luxury, and you're trying to survive when you're in sympathetic autonomic dominance. This will bring you over to parasympathetic. It'll help turn up these genes, so some people will start to have detoxification reactions. If they start getting headachey, or a little lower back stress, or rashes, give them good quality bitters, like the BitterX that we make, and maybe a little bit of GI binder, like our ultra-binder, or charcoal clay capsules, and that will help them detoxify. Gazella: Oh, good. That's good to know. Now, the future. Shade: The future. Gazella: What excites you the most when it comes to CBD oil research? Shade: Yeah. It's CBD not being just a standalone, but being an integrated ingredient in formulas, where it's doing this part of it, maybe the autonomic balancing, or the brain balancing, where the other things are doing other parts, and finding which things are synergistic together, which things are antithetical together. We'll find out how to blend it with other things, and really make it work better. Even if we're just working within the cannabis plant itself, there's the essential oils of the plant called the terpenes, very strongly affect the modulation of how CBD and THC work within the body. The science on the terpenes will be worked out, then the science on other nutriceuticals playing in with those will be worked out, and we'll start to see some really beautiful formulas come. Gazella: What about when we began, we talked about the availability. Do you see things loosening up a little bit? Shade: That part of the future. It's funny. There seems to be two forces at work within the United States around CBD. There's a liberalization movement that is not necessarily ... It's not coming out of Boulder County in California. It's coming from within the government, where they want to focus on real issues, like narcotics use, prescription pain med addiction, real drugs, heroin, cocaine, and they want to get away from talking about this. On the other side, there's other people who are just ... Some part of them are just working out what's already been started, where they're just really going to want to try to enforce this. We're starting to hear much more sophisticated language from the state departments of health about CBD, and that's towards a contractive thing. And who knows where that's really coming from? I mean, you have pharmaceutical companies getting into this now, and that may be the long, dark arm of the pharmaceutical companies. There's two things now, contraction and expansion, happening at the same time. Hopefully the light wins and we expand out, and we're able to use this in a broad scale, and do all the research that's really necessary to put this to the best use. Gazella: I would agree. I think that the therapeutic efficacy of CBD oil is really ... We're shining a light on it in the scientific literature. Even though it seems that it's preliminary, uncertain cases, it just seems like it's growing more [inaudible 00:28:22], it really should be something that we look harder at. Shade: Oh, it absolutely is, and I can always gauge it by when I'm on a plane, when little old ladies start talking to me about it, or my aunt came over from Florida, and she had a bottle of it, and it's made its way out to the masses. They need it. They want it. We hope it's here to stay. Gazella: I do too, and you know, we haven't even touched on the pain aspects, because right now we are in the midst of an opioid crisis in this country. Shade: Oh, yeah. Gazella: Is there an application for [crosstalk 00:28:57]? Shade: Oh, absolutely. Maybe little smidges of opioids along with CBD. CBD, and what we'll find is what we can blend with it nutriceutically to increase its effect at stopping pain, but it's got all the right aspects for that, and for some pains, it's magic. For other ones, it doesn't work as well. Well, maybe we'll find certain blends, but it will always, if you're taking it with opioids, it will always lower how much you need of the opioids, and that's one of the most beautiful things to come out of the legalization of medical marijuana in various states. They've seen a lowering of opioid use. Gazella: Right. It sure seems like CBD oil, hemp oil, is a valuable tool that clinicians can use in their clinical practice. Shade: Absolutely. Gazella: Great. Well, Dr. Shade, as per usual, this has been very interesting. Thank you so much for joining me today, and I would also like to thank the sponsor of this interview, who is Quicksilver Scientific. Thank you everybody for joining us. Have a great day.
Dr Todd Gaines recently visited AHRI and took time out to explain the significance of AHRI Director Stephen Powles' award. Steve recently won the American Chemical Society International Award for Research in agrochemicals. He's the first Australian to win the award, which is given to a scientist who has made outstanding contributions to the field of agrochemicals at the international level, with their vision and sustained contribution having opened new horizons for investigators in their field and beyond. Steve was recognised for his long-standing research contribution to identifying the role of cytochrome P450 enzymes in endowing herbicide resistance in plants. Steve was nominated for the award by Todd Gaines. Todd previously was a postdoctoral student of Steve, who spent three years as a researcher at UWA before returning to the US. Todd discusses what he's been up to and also goes into some detail about what P450s are as well. Take a listen! Music: www.bensound.com
Designer drugs are structurally related to illegal psychoactive drugs and include cathinones (bath salts and flakka), synthetic cannabinoids (K2), piperazines (Molly), salvia, kratom, and desomorphine (krokodil). Often designer drugs are readily available on the Internet or in head shops and skirt regulation through the development of novel analogs and labeling the products "not for human consumption." These novel psychoactive substances are consumed typically by younger males via various routes and modes for their desirable effects; however, undesirable and even life-threatening reactions or death may occur. Additionally, designer drugs are often coingested with other psychoactive substances and may be metabolized through cytochrome P450 pathways leading to drug-drug interactions furthering the potential for harm. Management is normally with supportive measures and symptomatic care. Unfortunately, most of these agents are challenging to detect as they are not readily identified by immunoassay urine drug testing, though some may lead to false positives. More advanced testing with liquid or gas chromatography/mass spectroscopy is able to detect designer drugs but is limited due to its availability, cost, delay in results, and the ever-changing designer drug structures.
TODAY'S GUEST: Stephanie Seneff is a Senior Research Scientist at the MIT Computer Science and Artificial Intelligence Laboratory. She received the B.S. degree in Biophysics in 1968, the M.S. and E.E. degrees in Electrical Engineering in 1980, and the Ph.D degree in Electrical Engineering and Computer Science in 1985, all from MIT. For over three decades, her research interests have always been at the intersection of biology and computation: developing a computational model for the human auditory system, understanding human language so as to develop algorithms and systems for human computer interactions, as well as applying natural language processing (NLP) techniques to gene predictions. She has published over 170 refereed articles on these subjects, and has been invited to give keynote speeches at several international conferences. She has also supervised numerous Master's and PhD theses at MIT. In 2012, Dr. Seneff was elected Fellow of the International Speech and Communication Association (ISCA). In recent years, Dr. Seneff has focused her research interests back towards biology. She is concentrating mainly on the relationship between nutrition and health. Since 2011, she has published over two dozen papers in various medical and health-related journals on topics such as modern day diseases (e.g., Alzheimer, autism, cardiovascular diseases), analysis and search of databases of drug side effects using NLP techniques, and the impact of nutritional deficiencies and environmental toxins on human health. Connect With Today's guest: DR. STEPHANIE SENEFF Stephanie Seneff Rm G-438 MIT Stata Center 32 Vassar Street Cambridge, MA 02139 USA seneff(AT)csail.mit.edu IN THIS EPISODE: After last week's episode with Dr. Stephanie Seneff, I was more eager than ever to get the word out about the dangers of glyphosates. So we actually continued the conversation for this episode and you'll get to hear a lot more of what she's learned in her studies. She's uncovering some amazing data that suggests that glyphosate poisoning is connected to Autism, Parkinson's, ALS, and much more. Glyphosate and autism connections are becoming more and more obvious as the research continues but you don't hear about it because the companies that produce the chemicals that contain glyphosate are in the back pocket of powerful politicians. The same is true of the companies that supply many of the vaccines we routinely give our children - and you got it, those vaccines often contain glyphosates too. It makes me angry when I realize how ignorant the public is to the dangers of glyphosate - but it's not our fault. The truth has been kept from us because it's not profitable. The use of this dangerous chemical has been going on for so long it's hard to pull it in and make changes, so the powers that be just look the other way when research shows that it's a problem. What can you do to avoid the effects of glyphosate so it doesn't contribute to autism, ALS, or Parkinson's disease in your family? One of the most important things Dr. Seneff recommends is eating organic and whole foods as much as you can. That's the only way you can avoid the pesticides that contain glyphosate. Eating organic won't entirely prevent you from ingesting this harmful chemical, but it will take you a long way towards health. If you want to undo the impact of glyphosate damage that may have already happened to your body the best place to start (besides eating organic) is to get your gut health in optimized. On this episode, Dr. Seneff and I talk a lot about what it takes to get your gut healthy and give some very practical recommendations for how to do it. Outline Of This Great Episode [1:58] My introduction to part two of my conversation with Dr. Stephanie Seneff. [9:04] Additional ways we are exposed to Glyphosates (see last week's episode for the first things mentioned). [10:17] The main ways that people's health is affected by Glysophates. [12:19] How can you get glyphosate out of your body? [18:00] The importance of making sure your supplements are pure. [19:52] Why some feel that humans are naturally protected from glysophates. [23:28] The link between Parkinson's, ALS, and glyphosates. [26:11] What is the Gut Brain Axis and how you can improve gut health. [32:20] The connection between gut problems and Autism. [36:12] Vaccines that contain glyphosates. [40:47] Why does the public believe glyphosates are not dangerous? [44:59] Why toxins are a sure contributor to Autism. [46:07] Why do people believe they need to kill microbes and germs in everything? [50:23] 3 important steps to rid yourself of glysophates. [54:00] How the increased cost of buying organic will come back to you in savings. Articles On Glyphosates http://www.anh-usa.org/half-of-all-children-will-be-autistic-by-2025-warns-senior-research-scientist-at-mit/ http://www.momsacrossamerica.com/glyphosate_found_in_feeding_tube_liquid http://www.homeopathyforwomen.org/glyphosate.htm Link for allowable amounts of glyphosates in 160 foods: http://www.ecfr.gov/cgi-bin/text-idx?SID=195f8b224b4d7d5ab8cfff3bf0f92f68&node=se40.24.180_1364&rgn=div8 Resources Mentioned on This Episode BOOK: The Miracle of MSM PRODUCT: Detox Fiber by Garden of Life (affiliate link) A description of how glyphosate impacts the body from MIT PhD. scientist Stephanie Seneff: 1) Glyphosate is an antimicrobial agent (antibiotic) and it preferentially kills the good bacteria, which causes an overgrowth of pathogens in the gut. This leads to leaky gut syndrome and inflammatory issues. 2) Glyphosate chelates rare minerals like manganese, cobalt, molybdenum, copper, iron, sulfur, selenium, etc., and this disrupts the management of these very important nutrients throughout the body. The minerals end up piling up in the wrong places, causing both toxicity and deficiency at the same time. 3) Glyphosate disrupts cytochrome P450 enzymes in the liver, which are important for many things, two of which are activating vitamin D and detoxifying multiple toxic chemicals and drugs. Acetaminophen (tylenol), for example, becomes toxic when these enzymes aren't working. 4) Glyphosate works synergistically with the aluminum, mercury, and glutamate in vaccines to cause much greater harm than would be the case if there were no glyphosate present in the blood when the vaccine was administered. 5) Glyphosate interferes with the shikimate pathway, which is used by both microbes and plants to produce the essential aromatic amino acids. Our own cells don't have this pathway, and they depend upon food sources and synthesis by gut microbes to supply these nutrients. They are precursors to many biologically important molecules such as the neurotransmitters serotonin, melatonin, dopamine, and norepinephrine, melanin, vitamin E, vitamin K, etc. In my view, the core pathology in autism is insufficient sulfate in the cerebrospinal fluid in the brain. This causes a severe impairment in neurogenesis and an inability to "clear the trash." It's indirectly caused by sulfur deficiency, melatonin deficiency, impaired sulfate synthesis, impaired sulfate transport, and excess flushing of sulfate through the kidneys - all induced by glyphosate. There's also neuroexcitotoxicity from glutamate and glyphosate and aluminum working synergistically.
TODAY'S GUEST: Stephanie Seneff is a Senior Research Scientist at the MIT Computer Science and Artificial Intelligence Laboratory. She received the B.S. degree in Biophysics in 1968, the M.S. and E.E. degrees in Electrical Engineering in 1980, and the Ph.D degree in Electrical Engineering and Computer Science in 1985, all from MIT. For over three decades, her research interests have always been at the intersection of biology and computation: developing a computational model for the human auditory system, understanding human language so as to develop algorithms and systems for human computer interactions, as well as applying natural language processing (NLP) techniques to gene predictions. She has published over 170 refereed articles on these subjects, and has been invited to give keynote speeches at several international conferences. She has also supervised numerous Master's and PhD theses at MIT. In 2012, Dr. Seneff was elected Fellow of the International Speech and Communication Association (ISCA). In recent years, Dr. Seneff has focused her research interests back towards biology. She is concentrating mainly on the relationship between nutrition and health. Since 2011, she has published over two dozen papers in various medical and health-related journals on topics such as modern day diseases (e.g., Alzheimer, autism, cardiovascular diseases), analysis and search of databases of drug side effects using NLP techniques, and the impact of nutritional deficiencies and environmental toxins on human health. Connect With Today's guest: DR. STEPHANIE SENEFF Stephanie Seneff Rm G-438 MIT Stata Center 32 Vassar Street Cambridge, MA 02139 USA seneff(AT)csail.mit.edu IN THIS EPISODE: I don't like to be seen as a scare-monger by any means. There's too much to be hopeful about in the world. But I do want to bring you the information that you need to know to safeguard your health and live your best life. That's why I bring you shows like this one about the many ways glyphosate poisoning is impacting our society. Dr. Stephanie Seneff is my guest, and she's the leading expert on the subject. Do you know what a glyphosate is? It's a synthetic amino acid that is a primary component of most pesticides. But that's not all. It's also added to vaccines and other things we ingest or put into our bodies. Until recently we didn't know the impact it could have on us but great people like my guest on this episode, Dr. Stephanie Seneff have done the research to discover the many ways glyphosates poison our food and water supplies. I hope you listen so you can learn about this very serious problem. When I was on the PGA tour as a professional golfer I was exposed to all kinds of chemicals on the golf courses due to the way they groom and keep up the course. I've spent years detoxifying myself from the glyphosate I was exposed to and I'm still not done. Because of that, you can understand why I was excited to have Dr. Stephanie Seneff on the show to educate us about this dangerous chemical and teach us what we can do to cleanse ourselves from it. Glyphosates are in almost all food sources these days. Even if a farmer is organic in his practices the rainwater and groundwater he uses to water his crops will have at least trace amounts of the chemical in them. That's just an example of how terribly we've polluted the planet with this destructive compound. But on this episode you can learn the best ways to protect yourself from glyphosates, so be sure you listen. Infertility and Autism are being linked more and more to exposure to glyphosates. Dr. Stephanie Seneff has made the case for both quite strongly and on this episode she reveals why she believes that by 2023, 50% of children born will have autism - unless we do something to curb the damage glyphosates are having on our environment and food supplies. You can learn the truth about glyphosate poisoning, on this episode. Outline Of This Great Episode [1:58] My introduction of Dr. Stephanie Seneff and the polluting of our food supply. [5:30] The impact of Glyphosates on the body (to set the context for this conversation). [11:37] My background with glyphosates and my motivation to discover more about them. [13:08] How Dr. Seneff got started in biology and her current specializations. [15:20] What happens when too many antibodies are produced. [20:05] Why are the effects of vaccines different than contracting the actual disease? [24:36] Some of the most common mutations that happen. [27:42] Are there groups of people who can't take extra sulphur to help? [31:85] How glysophates are diminishing the mineral content of soils. [34:20] What IS glyphosate? [36:58] Why is this synthetic amino acid so dangerous? [43:36] Why organic foods are not safe from glyphosates. [45:02] How GMO foods are connected to glyphosates. [50:41] Dr. Seneff's prediction about the rise of autism and infertility. [54:11] My summary and goodbye. Articles On Glyphosates http://www.anh-usa.org/half-of-all-children-will-be-autistic-by-2025-warns-senior-research-scientist-at-mit/ http://www.momsacrossamerica.com/glyphosate_found_in_feeding_tube_liquid http://www.homeopathyforwomen.org/glyphosate.htm Link for allowable amounts of glyphosates in 160 foods: http://www.ecfr.gov/cgi-bin/text-idx?SID=195f8b224b4d7d5ab8cfff3bf0f92f68&node=se40.24.180_1364&rgn=div8 A description of how glyphosate impacts the body from MIT PhD. scientist Stephanie Seneff: 1) Glyphosate is an antimicrobial agent (antibiotic) and it preferentially kills the good bacteria, which causes an overgrowth of pathogens in the gut. This leads to leaky gut syndrome and inflammatory issues. 2) Glyphosate chelates rare minerals like manganese, cobalt, molybdenum, copper, iron, sulfur, selenium, etc., and this disrupts the management of these very important nutrients throughout the body. The minerals end up piling up in the wrong places, causing both toxicity and deficiency at the same time. 3) Glyphosate disrupts cytochrome P450 enzymes in the liver, which are important for many things, two of which are activating vitamin D and detoxifying multiple toxic chemicals and drugs. Acetaminophen (tylenol), for example, becomes toxic when these enzymes aren't working. 4) Glyphosate works synergistically with the aluminum, mercury, and glutamate in vaccines to cause much greater harm than would be the case if there were no glyphosate present in the blood when the vaccine was administered. 5) Glyphosate interferes with the shikimate pathway, which is used by both microbes and plants to produce the essential aromatic amino acids. Our own cells don't have this pathway, and they depend upon food sources and synthesis by gut microbes to supply these nutrients. They are precursors to many biologically important molecules such as the neurotransmitters serotonin, melatonin, dopamine, and norepinephrine, melanin, vitamin E, vitamin K, etc. In my view, the core pathology in autism is insufficient sulfate in the cerebrospinal fluid in the brain. This causes a severe impairment in neurogenesis and an inability to "clear the trash." It's indirectly caused by sulfur deficiency, melatonin deficiency, impaired sulfate synthesis, impaired sulfate transport, and excess flushing of sulfate through the kidneys - all induced by glyphosate. There's also neuroexcitotoxicity from glutamate and glyphosate and aluminum working synergistically.
I asked David Aiello, President BioAdvantex Pharma Inc.: of all the molecules, why study and productise N-acetylcysteine? “That makes me think of another question, why did you marry that woman? You become fascinated with something, and your mind sees forward. I saw this as a huge business and scientific project with such a broad scope to help people. We didn't even understand the scope way back then.” Paracetamol-induced acute liver failure. In the US and UK, paracetamol (acetaminophen) toxicity is the most common cause of acute liver failure. When taken in normal therapeutic doses, paracetamol is safe. The cytochrome P450 enzymes convert approximately 5% of paracetamol to a highly reactive intermediary metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of overdose, the pathways become saturated, leading to more NAPQI. Liver supplies of glutathione become depleted, and NAPQI remains in its toxic form in the liver, reacting with cellular membrane molecules, resulting in widespread damage and death of liver cells. Beyond Paracetamol Overdose. Paracetamol is not the only thing that can cause oxidative stress and cell death. Inflammation and oxidative stress are almost synonymous, and we measure both in the testing we do. Urinary P-Hydroxyphenyllactate on an organic acids test is a marker of cell turnover, and 8-Hydroxy-2’-deoxyguanosine (8-OHdG) is a marker of oxidative damage to the guanine of DNA. Enter N-acetylcysteine. The availability of the sulfur-containing amino acid cysteine is known to be the rate-limiting substrate for glutathione resynthesis. L-cysteine is not safe to take as a supplement in high doses, what you want is the N-acetylcysteine (NAC) form. NAC doesn’t encapsulate well because the minimum effective dose is too big to fit into a capsule, and even if it did fit, the molecule would oxidise and fall apart. David's team at BioAdvantex have solved these problems by creating PharmaNAC, a large effervescent tablet sealed into a nitrogen filled blister pack. It's important to understand that exercise is itself an antioxidant and athletes should proceed with caution before supplementing with antioxidants without testing. Context matters. Here’s the outline of this interview with David Aiello 0:00:35 David was trained in immunology at the Stanford Herzenberg Lab. 0:01:03 He wanted to create a product that was relevant, made the right way and given at the right dose. 0:01:34 BioAdvantex have done 12 or 13 clinical trials in breathing, immunity, oxidative stress and mental health. 0:02:46 NAC is the standard of care of acetaminophen toxicity. 0:03:19 80,000 people every year are affected. 0:03:54 NAPQI. 0:04:13 Making glutathione requires glycine, glutamate and cysteine. 0:04:28 Almost every protein is less than 2% cysteine by weight. 0:05:56 You don't want L-cysteine. 0:07:30 NAC is easily oxidised. 0:08:55 Hydrogen sulfide is one of the degradation products of NAC. 0:09:20 Humans can detect H2S at 6 ppb. 0:09:31 There are 7 other degradation pathways. 0:11:43 NAC placebo pills. 0:13:42 Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: a randomized controlled trial. 0:15:51 Taking NAC is NOT like pouring water on the fire. 0:18:56 There's about a three-hour gap between when you take cysteine, and when it shows up in your blood, then there's about another three-hour gap until an increase in glutathione. 0:20:07 The liver is main store of cysteine, and also there’s cysteinylglycine in the blood. 0:28:30 Logging food and supplement intake. 0:29:05 Grace Liu. 0:29:10 GAD1 mutation. 0:29:47 The cystine-glutamate antiporter (xCT). 0:35:18 Depression, ruminations and PTSD.
Nathan Adams investigates some of the most important molecular machines within our cells, the cytochrome p450 enzymes
Dr. Frances Arnold is a professor of Chemical Engineering and Biochemistry at the California Institute of Technology (most of us know it as Caltech). Dr. Arnold’s research focuses on evolutionary design of biological systems, an approach she is currently applying to engineer cellulases and cellulolytic enzymes for manufacturing biofuels. This country’s energy security can look pretty bleak when you think about it: the need to address global warming, strife in oil-rich nations, and depletion of fossil fuels combine to paint an uncertain future, and although ethanol has a lot of friends in Iowa and D.C., ethanol isn’t going to end our energy woes. In the future, our energy supply will probably be cobbled together from a number of different fuels and sources. Dr. Arnold is interested in engineering microbes that can grant us a biofuel that packs more of a caloric punch than ethanol. She likes isobutanol, which can be converted into a fuel that’s more like the hydrocarbons we currently put into our fuel tanks. To develop proteins that make the comounds she wants the way she wants, Arnold and her team take a gene that needs tweaking to do the job, introduce directed mutations into it, and select the mutant proteins that do the job best. In this interview, I talked with Dr. Arnold about how she got into alternative energy during the Carter administration (and got out again during the Reagan administration), what she sees in the P450 enzyme, and how she explains her work to people outside her field.
Download Link: Right Click and Save As to download directly (VBR MP3 - 69 MB) or click on the Play button to listen.Danag Episode 10 Part 2The podcast is also available in other formats and file sizes here.Remember that you don't need an iPod to listen to the podcast. Just download the file above, and play it using Windows Media Player or your favorite MP3 player.You can also subscribe to us via the iTunes Store, thanks to Anansi Girl for her invaluable help! Click here to subscribe (clicking this will open iTunes).---SHOW NOTES | Danag: The Filipino Twilight Saga PodcastEpisode 10 Part 2 - What Do You Mean Edward Can't Have A Jamaican Accent, Man?In which:- We turn back time and recap the Twilight Highlights of 2008!- There is a lot of laughing, sorry.- You get to know more about the beginnings of TCP.- There is even more laughing. Really sorry.Running Time: 1 hour 12 minutesRecording Date: 24 January 2009This week’s panel: Daene, Mabelle, Clair de Lune, MinamiLinks and Notes:The Twilight Highlights of 2008APRIL1 - The birth of Twilight Coven Philippines (funnily enough on April Fool's Day) with the launch of the Twilight Coven Philippines blog. Early reports posted on the blog were on stock availability of the Twilight books in different bookstores in the Philippines.21 - MTV airs its first Twilight video feature, to the delight of fans. More features from MTV soon followed. 27 - Twilight Coven Philippines is listed on Stephenie Meyer's fansites page. - The Host becomes available in the Philippines.MAY2 - Summit releases a promotional picture for Twilight (the overly Photoshopped one. :p)6 - MTV launches "Twilight Tuesday" with the unveiling of Twilight's movie poster. The trailer was also announced to air with Speed Racer screenings in the US. - First "Twilight" teaser trailer is released online16 - TCP reaches # 52 in TwilightTopsites!JUNE1 - The MTV Movie Awards features Rob Pattinson and Kristen Stewart at the pre-show and unveils an exclusive clip (the ballet scene) from the movie.4 - The TCP forum obtains 50 members, with illuminatist becoming our 50th member. Hooray! - Stephenie Meyer confirms "Midnight Sun" as her next project10 - The four Twilight Coven Philippines administrators all meet in person for the first time, in preparation for the "Before Dawn" book discussion!12 - TCP confirms the August 4 release of Breaking Dawn in the Philippines, two days after its launch in the US.14 - "Before Dawn", a Twilight book discussion by TCP, takes place in Fully Booked, Bonifacio High Street.18 - MTV's "Twilight Tuesday" reveals the Cullen Crest and the "Greenhouse" scene27 - TCP and Powerbooks announce the Breaking Dawn Pre-Launch Party to be held on 2 August 2008 at Powerbooks Live! in Greenbelt.JULY3 – TCP announces the Twilight Fan Challenge consisting of the Fan Art and Fan Photo Contests in celebration of the upcoming release of Breaking Dawn.10 – We catch a first glimpse at the horrendous romance novel-ish cover of Entertainment Weekly's first attempt at a Twilight issue.23 – Inkworks gives a press release on their Twilight Movie Trading Card set.26 – We are treated to the San Diego Comic Convention's treasure trove of clips, interviews, and features on everything Twilight. - Twilighters are featured on Manila Bulletin, including the TCP admins. :P30 – Breaking Dawn spoilers begin coming out of the woodwork!AUGUST2 – It's the Breaking Dawn Pre-Launch Party in Powerbooks, Greenbelt 3! - The Twilight Saga's fourth and final chapter, Breaking Dawn, is released with much aplomb in the U.S.4 – Philippine release date of Breaking Dawn. - Hachette Book Group announces that Breaking Dawn sold 1.3 million copies in its first day in the U.S. - Little Brown Books for Young Readers also confirms publication of The Twilight Saga: The Official Guide as being on December 30, 2008.8 – Stephenie Meyer reacts to fan complaints on MTV.com saying – "It hurts."9 – The Canadian Press reports that with the widespread disappointment in Breaking Dawn, fans started a book return campaign. D'oh.16 – Powerbooks and TCP host the Twilight Restrospective Book Discussion in Greenbelt 3. - Twilight movie's official release date is bumped up from December 12 to November 21.24 – Viva International confirms that the local release date of the Twilight movie will be on November 20. Chaos ensues.25 – MTV reports that Twilight cast heads back to set to shoot new scenes for the movie. - Midnight Sun drafts start leaking online.29 – Stephenie Meyer posts a message about Midnight Sun on her website, shocking her fans with the statement that it will be on hold indefinitely. She also makes the 12 chapter draft available on her site.31 – TCP launches the Twilight ImPrints ContestSEPTEMBER1 – Support Stephenie campaigns launched by international fangroups in the wake of the Midnight Sun controversy8 – Reports regarding the Twilight cast appearance at the VMAs and the infamous Robert cut-off13 – Bella Swan-Cullen's birthday and Forks, Washington announced this day as Stephenie Meyer's Day16 – Twilight teaser trailer started being spotted in local theaters; Viva announces the local play date to be November 2117 – Meyer appears on the Ellen DeGeneres show20 – Paramore announced to contribute 2 songs in the movie OST; Hayley Williams explains Decode21 – Perry Farrell announced his soundtrack contribution, Going All the Way (into the Twilight)22 – NECA reported to make Twilight action figures, a spy photo of Edward is spotted24 – Tonner Doll Company announced licensee for Twilight dolls25 – Twilight poster spotted locally in major cinemas30 – Jack's Mannequin "Resolution" music video, in which Stephenie Meyer was creative consultant and co-director, debuts in MTV – TCP's Postcards for Stephenie campaign launchOCTOBER2 – Paramore's Decode debuts in Stephenie Meyer's site3 – Twilight character standees spotted in major local cinema lobbies6 – First episode of Danag: the Filipino Twilight Saga Podcast available online14 – TCP can also be accessed in Plurk16 – Twilight Movie Tie-In available locally22 – Local play date moved again to November 2622 - Twilight Illustrated Movie Companion available locally27 – TCP on TMF29 – A Taste of Twilight launched by Haagen-Dazs30 – Catherine Hardwicke, Robert Pattinson, and Kristen Stewart appeared at Rome International Film Festival to promote the Twilight filmNOVEMBER3 - Start of Haagen-Dazs' A Taste of Twilight promo - Danag Episode 04 - Too-Much-Information Alert is released - "Decode" Music Video debuts on MTV.com14 - Twilight Takes Back The Night15 - Summit announces the acquisition of rights to film the sequels17-19 - Twilight Mall Invasion at SM Megamall17 - Release of the Soundtrack - Danag Podcast Episode 5 - "What the Hale? This is what happens when we don't have a script... we talk about hair." - (US Time) - Twilight World Premiere in California20 - Danag Episode 6 - "Good thing we have a strong stomach"22 - TCP launches its series of Twilight Movie Contests23 - Summit announces it will make New Moon26 - Twilight premieres in the PhilippinesDECEMBER5 - Twilight Gay 016 - Twilight Soundtrack Launch Party7 - Summit announces the search for a new director for New Moon13 - Danag Episode 7 - "You know something's wrong when you think that the best actor is the Volvo"14 - Summit announces Chris Weitz as New Moon director, casts doubt on Taylor as Jacob19 - Twilight Gay 02 - Sparkly sex sells, also Val Sotto20 - TCP's Happy Cullen Christmas Party21 - Release of Wave 3 Pins23 - Danag Episode 8 - Who the hell are you and what have you done to the admins?24 - An announcement about Takipsilim appears on yehey.com and ABS-CBNNews.com - Happy 36th Birthday, Steph!25 - The news on the ABS-CBN site disappears28 - Yehey.com says Takipsilim is a hoax29 - ABS-CBN says Takipsilim is a hoaxWhat are the listeners' most memorable Twilight moments in 2008?Alyssa - Being able to watch the movie obviously made it to the top of my list along with the concert in glorietta. Because who wouldn't have enjoyed watching TWILIGHT, having a snapshot with edward&bella lookalikes, listening to urbandub and the other bands, and getting a nice twilight memorabilia (poster)?Sheri - When I saw the word TWILIGHT during the movie. Time froze and I started to hyperventilate. I can't believe that I'm watching the movie until that specific moment. It was surreal.Anna Nicolette - When I was eating dinner with my family and my dad suddenly asked me why the hale would I want to buy contacts. *real conversation*Dad: Bakit mo ba gustong bumili ng contacts?Me: *quiet*Mom: Para pumorma.Me: *still quiet*Dad: Gusto mo lang magmukhang Twilight (character) eh! Anung kulayba gusto mo?Me: *in a very hushed tone* Yellow(while I was speaking my mom spoke as well)Mom: Red!See? I have very supportive parents when it comes to my addiction to Twilight! My dad even bought me a Team Edward shirt from Hot Topic!Alex Jo - When I found out that my Edward Cullen is already by my side..XD( I realized that every person has its own Edward Cullen, and every person can BE someone's Edward Cullen.)Riyah - For me the most memorable Twilight-related moment is being literally going/visiting bookstores in malls (QC, makati, taguig, mandaluyong) looking and asking for the twilight saga books if it's available, going ga-ga over the internet on acquiring Twilight-related stuffs (shirts, pins, calendar, poster etc...).I've never been this obssessed about anything but there really is a charm that Edward Cullen has that makes girls drawn tohim although he is a fictional character. Jacq - Well, what do you know? I can consider myself as the Luckiest Pinay Twilighter of 2008 because of my Rome experience. I know anybody would give anything to have my place when I met them. However, the most memorable that happened is that I found a couple of friends from this Twilight craze and right now I can say we get along really well and I will forever treasure them for being part of existence.. No, we not only share Twilight FYI. =)Rome - I cannot think of any specific moment as there are far too-many. I'll just share the top of mind things.Becoming a member of TCP - It's my 2008 challenge for myself, doing something for the first time. Despite being a fan girl at heart, I never joined any local fandom groups aside from TCP. Having found new friends as a result of it is made of awesome.Discovering the Twilight Saga last June 2008 - without it, it wouldn't have led to thisWatching the movie 9 times which includes an advanced screening and a private viewing at PodiumReceiving a package of special editions of the Twilight books from my cousin in AustraliaPrezeuz - my ninang asked me what i want for christmas. since i still don't have the books, i asked na twilight na lang. indi ko na inexpect na mabibigay nya yun kasi kuripot yun! but when we saw each other again, she told me "uy, wala nang stock, gusto mo yung soundtrack na lang? haha! magkano yun?" "P450 siguro," i answered" "wag na lang! ang mahal! bigyan na lang kita ng pera tapos ballpen. haha! samahan ko na rin ng notebook" (its because, i love to write!) at that time, i was actually saving money for the cd... then when went to their house for Christmas. we exchanged gifts. you know what she got me? the soundtrack! i really didn't expect her to give something that expensive. because of the shock and too much happiness, i actually cried! and it is the first time i cried in front of all my relatives. they even recorded it. dang! i just wish they wont put the freaking vid in youtube. haha! ang babaw ko talagang tao! :]Melissa - I have LOTS so, just choosefrom them, hirap kasi pumili kasi 2008 was jampacked with loads of Twilight related activities.1. When I purchased my copy of New Moon in Fully Booked The Fort - I had no idea how to get there so I had to commute on a Sunday (which is my only rest day) and I had my period so I struggled to walk in DARK HIGH NOON (wink wink) despite my cramps - all for the love of Twilight.2. When I attended the book discussion in August at Makati because that was the 1st official TCP event I've been to where I met all the admins (nandun pa c Daene, buti nalang :) ) and Shane and Beth (both TCP members) and I had to render undertime (my boss had no idea that the reason I wrote in the leave form is false, hahaha).3. When I watched the movie premiere with no less than the TCP admins and members (thanks ulit to you guys for the free tickets) at Robinsons because I had just been from Laguna where we had our teambuilding seminar a few days ago. I even had my backpack with all my stuff in it! I didn't mind that Jam and her seatmate were likerecording a podcast because of all their talking, it was certainly a night to remember. Ang saya saya!4. Finally, the TCP Christmas Party because that was like the culmination of all the Twilight-related activities for the year, and because I've gained new friends (TCP members and admins narin, wink wink. sorry for the asskissing, hehehe), and even though I didn't win anything, it was a fun time for all. Oh, and I was able to claim my prize for the Postcard for Stephenie porject AND again, I had to render undertime again for work (bummer talaga when you have work on Saturdays :( )Kai - To steer away from the "fandom" my answer would probably be so random...First, Twilgiht and the rest of Meyer's books received so many recognition.Like she said, she never would have imagined that this would be SO BIG.For her to accomplish so much and letting us in on the "world" that she created. -- I guess we owe it to her or something.Second, of course everybody reads Twilgiht. But you would never expect Barack Obama "know about it".You know? For a Twilight fan (and a Obama supporter) it's exciting to hear those kinda things.I don't really know if he actually reads it to his daughters or whatnot but what I know is Malia, his oldest, read it.He said to Ryan Seacrest, "Apparently, it's big time". Liam - My most memorable Twilight-related moment in 2008 was, I think, when I bought several dozens of ChocoMucho to get a free Twilight movie premiere invite. My sibs and I literally ate all those ChocoMuchos just to get 1 ticket. I think it's one of the reasons why I gained so much weight harharhar.Elizabeth - The local release date of Breaking dawn would definitely top my list. Prior to the 4th i was convinced (I believe with all my heart and soul) that the local release is on the same day as the international release date (which is August 2) so I had my reservation in the nearest NBS branch from home (thinking that i cannot waste even an hour or so of waiting 'til i come home to start reading...) come, Saturday (August 2), before going to the bookstore I decided to check the internet (check on mails, blah blah) and was surprised to see that the local release date is on the 4th. August 4 is a monday, the most hectic time of the week at the office and it is my 23rd Birth Anniversary. I pretended to be sick, requested for a half day emergency leave...just to get my copy. all of my ka-opisina knew what i have been doing, except my boss. I spend half of my day at the office staring at my copy of Breaking Dawn, feeling guilty of tricking my boss, rushing all the things so i can get home early and start reading... almost forgetting that it is my day.Music Used This Week:Opening Credits - Immortalize Me by SalientSegment Transitions - Excerpt from Dinner With His Family by Carter Burwell from Twilight: The Score | Buy AlbumEnd Credits - Excerpt from Memory by Sugarcult | Buy AlbumEpisode Edited by: Clair de LuneDanag Logo Artwork: Paul MendozaThank You: Rome, Echo, and all the listeners who sent in their answers for this episode's questions.If you want to participate in our discussions or if you have topic suggestions, comments, and questions, please send them to:twilightcoven(at)gmail(dot)comFor the latest news in the Twilight Saga, visit our blog:twilightcovenph.blogspot.com
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 09/19
Fri, 21 Nov 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9531/ https://edoc.ub.uni-muenchen.de/9531/1/Schmid_Dagmar.pdf Schmid, Dagmar ddc:610, ddc:600, Medizinische Fa
Advances in Membrane Proteomics, Self-assembling protein microarrays, The PROTEOMICS podcast is 2 years old this month, Quantifying cytochrome P450 protein concentrations using mass spectrometry
Advances in Membrane Proteomics, Self-assembling protein microarrays, The PROTEOMICS podcast is 2 years old this month, Quantifying cytochrome P450 protein concentrations using mass spectrometry
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 08/19
Im Rahmen dieser Dissertation wurde der potentielle Einfluss des endothelialen hyperpolarisierenden Faktors (EDHF) auf Thrombozyten untersucht und geprüft, ob die EDHF Wirkungen durch eine (oder mehrere) Epoxyeicosatriensäuren (Produkte der endothelialen CYP450 Monooxygenase) ausgelöst sein könnten. EDHF wurde bisher hauptsächlich, neben NO und Prostazyklin, als dritter funktionell bedeutender vom Endothel gebildeter vasodilatierender Faktor charakterisiert. Für NO und Prostazyklin ist vielfach eine Freisetzung in das Gefäßlumen und damit neben der lokalen dilatierenden Wirkung auch eine Beeinflussung zirkulierender Blutbestandteile, wie Thrombozyten beschrieben. Beide können die thrombozytäre Aktivierung und Aggregation effektiv hemmen und dadurch gefäßprotektive Wirkungen ausüben. Ob EDHF ebenfalls Blutbestandteile wie Thrombozyten beein-flussen kann, war die Hauptfragestellung dieser Arbeit. Wir konnten erstmals im Bioassay zeigen, dass kultivierte menschliche Endothelzellen (HUVEC) nach entsprechender Stimulation einen EDHF freisetzen, der Thrombozyten hyperpolarisiert. Weiterhin konnten wir nachweisen, dass dieser Faktor die thrombozytäre Adhäsion an Endothelzellen sowie die thrombozytäre Aktivierung (P-Selektin Expression) hemmte. Diese Effekte waren - analog zu den hyper-polarisierenden Effekten - vermittelt durch Aktivierung von Calcium aktivierbaren Kalium-Kanälen (KCa-Kanäle) mit großer (BKCa) und mittlerer (IKCa) Leitfähigkeit, nicht jedoch von denen mit geringerer (SKCa) Leitfähigkeit. Die beobachteten Hemmeffekte waren durch die EDHF Wirkungen auf das thrombozytäre Membranpotential erklärbar, ein zusätzlicher ergänzender membranpotentialunabhängiger Effekt konnte jedoch nicht ausgeschlossen werden. Der in unserem Bioassay nachweisbare EDHF zeigte ähnliche Eigenschaften wie exogen verabreichte Epoxyeicosatriensäuren (EETs) - Produkte, die durch die Cytochrom P450 2C8/9 Oxidase im Endothel aus Arachidonsäure gebildet werden. Erhärtet wurden diese Befunde durch eine CYP2C9 stabil überexprimierende Zellinie mit endothelialen Eigenschaften, welche verschiedene EETs in physiologischen Konzen-trationen freisetzte und deren Überstand ähnliche hyperpolarisierende und antiadhäsive Effekte auf Thrombozyten wie der EDHF hatte. EDHF stellte somit unter unseren experimentellen Bedingungen eine Epoxyeicosa-triensäure (oder eine Mischung verschiedener EETs) dar. Bei vielen Herz-Kreislauf Erkrankungen spielen thrombozytäre Aktivierung und Adhäsion eine wichtige Rolle. Insbesondere beim akuten Herzinfarkt, der Haupttodesursache in westlichen Industrieländern, kommt es in patho-physiologisch, z.B. durch Atherosklerose, vorgeschädigten Gefäßen, aufgrund einer arteriellen Thrombusbildung zum kompletten Gefäß-verschluss mit Myokardischämie. Daher könnte EDHF bzw. EET - infolge seiner thrombozytenhyperpolarisierenden und antiadhäsiven Effekte - von großer Bedeutung sein, vor allem, wenn er durch Risikofaktoren wie freie Sauerstoffradikale und Hyperlipidämie weniger stark beeinflusst würde als NO. Die Daten dieser Dissertation könnten somit zukünftiger Ansatzpunkt für weitere Untersuchungen sowie Basis für die Entwicklung potentiell gefäßprotektiver Medikamente zur effektiveren Therapie kardiovaskulärer Erkrankungen darstellen.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 04/19
Ursodeoxycholsäure ist kein klinisch relevanter Induktor der CYP3A-abhängigen Biotransformation
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 04/19
Widerstandsarterien spielen eine wichtige Rolle bei der Durchblutungsregulation. Bisher konnte der wichtigste endotheliale Dilatator in diesen Gefäßen, EDHF, nicht eindeutig identifiziert werden, da pharmakologische Inhibitoren unspezifische Nebenwirkungen aufwiesen. Die spezifische Inhibition von Enzymen mittels Antisensetechnik konnte in intakten Arterien nicht durchgeführt werden, da diese nur über einen kurzen Zeitraum funktionell intakt erhalten werden konnten. Im Rahmen dieser Dissertation wurde ein neues Organkulturmodell entwickelt, in dem erstmalig die endothelabhängigen EDHF- und NO-vermittelten Dilatationen über 48 h vollständig erhalten werden konnten. Zusätzlich entwickelten die kultivierten Arterien einen mit dem frisch isolierter Arterien vergleichbaren Spontantonus und zeigten eine myogene Reaktion, die sich in Kinetik und Ausmaß der Kontraktion nicht von den Kontrollarterien unterschied. Ebenso kontrahierten die chronisch perfundierten Arterien auf Stimulation mit Noradrenalin und dilatierten nach Applikation des NO-Donors SNP in vergleichbarem Ausmaß wie frisch isolierte Arterien. Um zu untersuchen, ob möglicherweise eine CytochromP450-Epoxygenase in der Signalkaskade des EDHF eine Rolle spielt, wurde zunächst die Expression von CYP2C8 in Widerstandsarterien mittels rtPCR und in-situ-Hybridisierung nachgewiesen. Da mit dem Organkulturmodell die Arterien funktionell vollständig intakt gehalten werden konnten, wurde die Wirkung von Antisense-Oligonucleotiden, die gegen CYP2C8 gerichtet waren, untersucht. Mittels konfokaler Mikroskopie konnte gezeigt werden, dass die FITC-markierten Oligonucleotide sich nur in der Intima befanden und die Transfektion des Endothels eine hohe Effizienz aufwies. Die Transfektion hatte keinen Effekt auf die NA-induzierte Kontraktion, auf die durch NS1619 (KCa-Kanalöffner)- oder die SNP- vermittelte Relaxation, was zeigt, dass die Funktion des glatten Muskels durch die Transfektion unbeeinträchtigt blieb. Die EDHF-vermittelten Dilatationen wurden durch die Transfektion mit den Antisense-Oligonucleotiden um 76% und die korrespondierenden Calciumabfälle um 58 % reduziert, während die Kontrolltransfektionen mit Scrambled- oder Senseoligonucleotiden keinen Einfluss auf die EDHF-mediierten Dilatationen hatten. Die endothelialen Calciumanstiege nach Stimulation mit ACh blieben in den Antisense-transfizierten Arterien unverändert. Das bedeutet, dass die Signaltransduktion der ACh-Rezeptoren durch die Transfektion funktionell nicht beeinträchtigt wurde. Auf diese Weise konnte mit einem spezifischen Inhibitor gezeigt werden, dass CYP2C8 eine EDHF-Synthase ist oder dessen Metabolit einen permissiven Faktor für einen anderen EDHF darstellt und ein elementarer Bestandteil der EDHF-Signalkaskade ist. Zusätzlich wurden mit diesem Organkulturmodell die Auswirkungen des kardiovaskulären Risikofaktors Hochdruck durch isolierte Erhöhung des transmuralen Drucks auf 120 und 160 mmHg (SMA120 bzw. SMA160) während einer Kulturperiode (48 h) untersucht. In den funktionellen Testungen zeigten sich nach 48 h geringere Außendurchmesserwerte in SMA120 und SMA160 im Sinne eines Remodelings. Der erhöhte Perfusionsdruck führte darüber hinaus zu einer Verstärkung der Noradrenalin-vermittelten Kontraktion. Dies ist jedoch nicht durch eine Erhöhung der Calciumsensitivität der Myofilamente zu erklären, da diese im Vergleich zur Kontrolle unverändert war, sondern durch eine Verstärkung der NA-induzierten Calciumanstiege. Neben den Veränderungen in der glatten Muskulatur zeigte sich insbesondere auch eine Beeinträchtigung der Endothel-vermittelten Relaxationen. Die NO-mediierte Dilatation wurde durch die chronische Perfusion bei 120 mmHg um 38% reduziert und bei SMA160 vollständig aufgehoben. Ebenso wurde die EDHF-vermittelte Relaxation bei SMA120 um 20 % und bei SMA160 um 47% verringert und der korrespondierende Calciumabfall um 41 % reduziert. Diese Reduktion der endothelialen Dilatationen wurde nicht durch eine Erhöhung der Elastance der Arterienwand hervorgerufen, da die dosisabhängige SNP-mediierte Relaxation unbeeinträchtigt war. Zusätzlich scheint eine strukturelle Schädigung des Endothels durch den erhöhten Druck unwahrscheinlich, da mittels Rasterelektronenmikroskopie keine Schäden an der Intima dargestellt werden konnten. Die Expression des ACh-Rezeptors scheint auch nicht in dem Maße verringert zu sein, dass sich daraus die verringerten NO- und EDHF-mediierten Relaxationen erklären ließen, da der endotheliale Calciumanstieg in SMA120 im Vergleich zu SMA45 unverändert war. Daher wird die Beeinträchtigung durch den erhöhten Druck in einem nachgeschalteten Signaltransduktionsweg vermutet. Erhöhter transmuraler Druck hat in diesem Modell innerhalb von 2 Tagen schon zu einer erheblichen Beeinträchtigung der endothelialen Funktionen und zu einer verstärkten Reaktivität des glatten Muskels in Widerstandsarterien geführt. Zwar ist eine Erhöhung des transmuralen Drucks für 48 h nicht mit einem jahrelang bestehenden Hypertonus vergleichbar, jedoch könnte man die so erhobenen Befunde als Hinweis werten, dass eine frühzeitige konsequente antihypertensive Therapie sinnvoll ist, um die druckinduzierte Verstärkung der glattmuskulären Reaktivität und die Einschränkung der Endothelfunktion zu verringern und eine daraus resultierende weitere Erhöhung des Blutdruckes zu verhindern.
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 02/07
The advantages of non-viral gene transfer systems are safety and low immunogenicity, therefore they are well suited for use as vectors in gene therapy. The main disadvantage, namely their low gene-transfer-efficiency, can be improved through the development of systemic gene transfer systems using targeted vectors with high specificity and gene transfer efficiency. The intravenous application of PEI22lin/DNS complexes leads to a high gene expression in the lung, but with high toxicity. This observation can be explained by the positive surface charge of the DNS complexes and the uncomplexed free PEI, which leads to aggregation of erythrocytes. DNS complexes can be isolated from free uncomplexed PEI by gel filtration. The systemic application of gel filtrated PEI22lin complexes to non-tumor bearing mice resulted in reduced toxicity however there was a decreased in gene expression compared to non-filtrated complexes. The same experiment was performed on tumor bearing mice and again reduced toxicity was observed and interestingly slightly higher gene expression found in the tumor compared to the non-filtrated complexes. Shielding the positive surface charge of the PEI22lin complexes by transferrin led to increased gene expression in the tumor with reduced expression in the lung and other organs. The improved tumor targeted gene expression was associated with reduced systemic toxicity. Tumor targeted gene expression appears to be dependent on the tumor model as this observation was only found in neuro2A neuroblastoma tumor model in A/J mice and not in B16F10 melanoma tumor models of C57BL/6 mice and CT26 colon carcinoma tumor models of BALB/c mice. To enhance the intracellular efficiency of the vectors, the endosomolytic active peptide melittin was incorporated into the transferrin targeted complexes. This led to a further increase in gene expression in the Neuro2A tumor models in A/J mice. For the local gene transfer, electroporation proved to be an easy to handle method to obtain a high gene expression in tissue. The non-invasive kaliper electrode was suitable for gene transfer to both muscle and tumor. The applied voltage showed to be the most important parameter in expression. The use of electroporation for intratumoral transfer of the therapeutic gene encoding for the cytokine TNF was unsuccessful. However, systemic application of the TNF-α gene in transferrin targeted complexes in combination with the intraperitoneal application of the chemotherapeutic Doxil® showed a clear synergistic effect. A significant delay in the tumor growth and in some cases a complete regression of the tumor was observed. The enzyme cytochrome P450 metabolizes the non toxic prodrug cyclophosphamide (CPA) into the cytotoxic drug. Electroporation of the cytochrome P450 gene into the tumor lead to its localized protein expression. When followed by the intraperitoneal application of CPA, a significant delay in the tumor growth of the human hepatocellular carcinoma Huh7 was observed in SCID mice. When applied to the Neuro2A tumor model in A/J mice, this application scheme showed a complete tumor regression in two animals. Furthermore the systemic application of the P450 gene in transferrin targeted complexes containing melittin in combination with CPA led to a strong delay in the tumor growth. In summary, this work describes a new anti-cancer strategy using the combination of chemotherapeutics and non-viral gene delivery resulting in a synergistic therapeutic effect in vivo. This promising strategy will be more effective with the improvement of non-viral gene delivery systems which have better targeted gene expression with lower toxicity.
Objective: Hepatocytes are increasingly used as functional units in bioartificial liver devices. The objective of the present study was to investigate the feasibility of culturing porcine hepatocytes in high density on a novel polyurethane-based nonwoven three-dimensional matrix. We investigated (1) the optimal cell density within this culture configuration, (2) the maintenance of liver-specific morphology and cell functions over long-term periods and (3) the necessity to apply an additional extracellular matrix component (collagen gel). Methods: Nonwoven polyurethane matrices were manufactured by a specially developed fiber extrusion technology. Pig hepatocytes were cultured at various cell densities of 0.1, 0.25, 0.5, 0.75, 1 and 2 x 10(6) cells/cm(2) on three-dimensional networks of nonwoven polyurethane matrices and cell adhesion as well as functional parameters (DNA of nonattached/attached cells, lactate dehydrogenase release and cytochrome P450 activity) were determined. To assess the performance of cells within this configuration albumin and urea excretion was measured over 8 days. The potentially beneficial effect of an additional extracellular matrix configuration was evaluated by comparing the average albumin synthesis in groups of identical cell numbers. Results: The optimal cell density in this three-dimensional culture configuration was 1 x 10(6) cells/cm(2). The functional capacity of hepatocytes was stable for 8 days at an average level of 53.7 +/- 5.6 ng/h/mug DNA and of 1.8 +/- 0.14 mug/h/mug DNA for albumin and urea excretion, respectively. The supplementation of an extracellular matrix configuration did not improve functional activity of cells. Average albumin synthesis was 35.6 ng/h/mug DNA (28.7, 42.8) and 32.7 ng/h/mug DNA (23.4, 49.2) for collagen-immobilized and control cultures, respectively, Conclusion: The results of the study indicate that nonwoven polyurethane sheets supply a biocompatible support structure for functionally active high density cultures. Thus, nonwoven polyurethane matrices should be further investigated on with respect to their role in the development, optimization and design of bioartificial liver systems. Copyright (C) 2001 S.Karger AG, Basel.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 01/06
Trotz ständiger Verbesserung der konventionellen Therapiemöglichkeiten zur Behandlung des humanen Pankreaskarzinoms rangiert diese relativ seltene Erkrankung auf Platz vier der Krebs verursachtenTodesfälle. Bisherige Behandlungsmöglichkeiten sind die Resektion, die allerdings nur bei ca 10 % der Patienten möglich ist, eine Strahlen- oder Chemotherapie. Bei einer konventionellen Chemotherapie mit Ifosfamid wird dieses Cytostatikum fast ausschließlich in der Leber aktiviert und muß damit über den Blutkreislauf an den Wirkort (Tumor) gelangen. Während dieses Transports reagiert ein Teil des kurzlebigen aktivierten IFOs mit gesundem Gewebe, wodurch die antitumorigene Wirkung verringert wird und Nebenwirkungen auftreten können. Daher wäre es sinnvoll eine direkte Aktivierung von IFO im Tumorgewebe zu bewirken um damit die antitumorigen Wirkung zu steigern bzw. die Nebenwirkungen zu reduzieren. Die zellvermittelte IFO-Aktivierung durch das hepatische Enzym Cytochrom P450 2B1 (CYP2B1) wurde in Klone verschiedener Zelllinien, die stabil die CYP2B1-cDNA von einem nicht-viralen Vektor exprimieren, untersucht. Die Präsenz und Funktion des CYP2B1-Proteins konnte mittels Western-Blot und eines enzymatischen Nachweissystems demonstriert werden. Durch Zugabe von IFO konnte eine Population CYP2B1-exprimierender Zellen in ihrem Wachstum in vitro stark gehemmt werden. Diese cytotoxische Wirkung betraf auch umgebenden nicht CYP2B1-exprimierende Zellen (bystander effect). Unter Vermeidung eines direkten Zell- Zell-Kontakts konnten als Ursache für die toxische Wirkung frei diffundierbare Metaboliten nachgewiesen werden. Ein Teil der Zellen, die von der toxischen Wirkung betroffen waren, zeigten im späteren Verlauf morphologische Veränderungen, die sich deutlich von denen apoptotischer Zellen unterschieden und damit der Nekrose zuzuordnen sind. In Zusammenarbeit mit der Universität Rostock wurden CYP2B1-exprimierende Zellen, die zuvor in Zellulosesulfatkapseln verpackt wurden, in humane Pankreastumoren von Nacktmäusen implantiert und dadurch eine deutliche Verstärkung eines antitumoralen Effekts nach systemischer Chemotherapie mit IFO im Vergleich zur konventionellen Chemotherapie nachgewiesen. Zusammen mit der Universität Rostock und dem Allgemeinen Krankenhaus Wien wurde eine Methode zur mikroinvasiven intraarteriellen Instillation verkapselter Zellen in das humane Pankreas an einem porcinen Modell etabliert. Diese Ergebnisse waren Basis für eine klinische Studie der Phase I, in der verkapselte CYP2B1-exprimierende Zellen in das humane Pankreas implantiert wurden und anschließend die Patienten systemisch mit IFO behandelt wurden. Dabei konnte die mittlere Überlebensrate im Vergleich zu retrospektiven Daten einer vergleichbaren Kontrollgruppe fast verdoppelt werden. Gleichzeitig wurde die Einjahresüberlebensrate im Vergleich mit unbehandelten Patienten verdreifacht bzw. gegenüber Patienten, die das derzeit wirkungsvollste Chemotherapeutikum für pankreatische Karzinome - Gemzar - erhielten, verdoppelt. Zur Verbesserung der intratumoralen IFO-Aktivierung wurden CYP2B1-transduzierende retrovirale Vektoren basierend auf dem murinen Leukämievirus (MLV), hergestellt. Pankreatische Tumorzellen zeigten nach Infektion mit diesen Viren im Vergleich zu leicht infizierbaren Mausfibroblasten eine geringere Infektionseffizienz und eine niedrigere Aktivität des MLV-Promotors. Denoch konnte für CYP2B1-transduzierte pankreatische Tumorzellpopulationen, eine CYP2B1-vermittelte erhöhte Sensitivität gegenüber IFO nachgewiesen werden. Um die Wirkung dieser schwachen intrazellulären IFO-Aktivierung in Tumorzellen in vivo untersuchen zu können, wurden mehrere murine Pankreastumormodelle etabliert. In einem syngenem Tumormodell wurden schließlich parentale oder CYP2B1- transduzierte pankreatische Tumorzellen in immunkompetente Mäuse injiziert und daraus subkutane Tumoren etabliert. Bei der anschließenden IFO-Behandlung wuchsen CYP2B1- transduzierte Tumoren langsamer als Tumoren, die aus nicht-CYP2B1-exprimierenden Zellen entstanden. Es wurde somit ein System für eine zellvermittelte Gentherapie für pankreatische Tumoren etabliert und in vitro, in vivo und in einer klinischen Studie in Zusammenarbeit mit anderen Gruppen untersucht. Um die Wirksamkeit weiter zu verbessern wurde die Möglichkeit einer Gentherapie mittels einer zusätzlichen Übertragung des Suizidgens durch retrovirale Vektoren getestet. Obwohl dieser Ansatz durch eine bessere Suizidgenexpression in pankreatischen Tumoren mittels geeigneter Promotoren noch weiter optimiert werden muss, konnte das ?proof of concept” mit dieser Arbeit etabliert werden.
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