Podcasts about phosphodiesterase

In this episode, we dive into the early therapies and how our understanding of vascular physiology drastically changed the management of pulmonary hypertension. Intro 0:12 In this episode 0:18 Recap of part 1 & 2 0:31 What part 3 is about 2:31 WHO conference in 1975: Treating pulmonary hypertension 3:48 The Discovery of Non-Steroidal Anti-inflammatory Drugs (NSAIDs), Part 1 5:20 Epoprostenol 6:18 Prostacyclin 10:37 Endothelin antagonists 11:41 Phosphodiesterase type 5 (PDE5) inhibitors 14:08 Interaction of nerves and blood vessels 15:06 The Soups VS the Sparks 17:36 A dreamed experiment 19:06 Acetylcholine 23:23  Enter “the calabar bean” 24:45 Acetylcholine and vasodilation: 1976 26:01 Rabbit aorta 27:45 Nitric oxide 29:38 Why are we using nitric oxide to treat pulmonary hypertension? 31:31 Tachyphylaxis 33:48 TNT factories 35:09 Nitrous oxide and tachyphylaxis 36:52 Pfizer in the 1980s 38:06 Understanding the trigger of pulmonary hypertension 40:53 PDE5 and nitric oxide and pulmonary hypertension 43:07 The end of the ripping yarns 44:20 Coming up in part 4 46:17 Thanks for listening 47:29 We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Bernard C. C R Soc Biol. 1851;3:163-164. Furchgott RF, et al. Nature. 1980;doi:10.1038/288373a0. Galiè N, et al. N Engl J Med. 2005;doi:10.1056/NEJMoa050010. Ghofrani HA, et al. Nat Rev Drug Discov. 2006;doi:10.1038/nrd2030. Giordano D, et al. Biochim Biophys Acta. 2001;doi:10.1016/s0167-4889(01)00086-6. Guthrie F. Q J Chem Soc. 1859;doi:10.1039/QJ8591100245. Higenbottam T, et al. Lancet. 1984;doi:10.1016/s0140-6736(84)91452-1. Marsh N, et al. Clin Exp Pharmacol Physiol. 2000;doi:10.1046/j.1440-1681.2000.03240.x. Montastruc JL, et al. Clin Auton Res. 1996;doi:10.1007/BF02281906. Nejad SH, et al. Future Cardiol. 2024;doi:10.1080/14796678.2024.2367390. Tansey EM. C R Biol. 2006;doi:10.10116/j.crvi.2006.03.012. Warren JV. Trans Am Clin Climatol Assoc. 1988;99:10-6. Disclosures: Brown reports no relevant financial disclosures.

In dieser Episode sprechen Hans-Dieter Höltje und Bernd Rupp über Cardenolide aus Fingerhut und synthetische Phosphodiesterase-Hemmer zur Behandlung von Herzinsuffizienz sowie über NO-Donatoren, die zur Therapie von Angina Pectoris eingesetzt werden.

Join us as we go through the JEADV Editor's Picks of May 2024:   (1) Non-Invasive Differentiation of Nail Disorders (2) Phosphodiesterase-4 (Pde4) Inhibition in Hidradenitis Suppurativa (3) Beware of Computer-Guided Melanoma Detection? (4) Exploring the Mind-Skin Connection   Read the Editor's Picks here: https://onlinelibrary.wiley.com/doi/10.1111/jdv.19953   Link to video version: https://www.youtube.com/playlist?list=PL2DbuyADMP5mFx4sZqS_vQtdTGOGIbwb1   You are invited to participate in our survey to improve the show. Your feedback is valued and appreciated to allow us to better serve our audience: https://eadv.org/eadv-podcast-survey/

Commentary by Dr. Valentin Fuster

Treatment Options for BPHMen with moderate to severe BPH symptoms, meaning those significantly bothered by their symptoms, should discuss the benefits, risks, and costs of various treatments with their doctors. Here are some common treatment options:Watchful Waiting:For men with mild symptoms or those not too bothered by their symptoms, doctors may suggest waiting and monitoring the condition. Annual check-ups and lifestyle changes, like adjustments in diet and exercise, can be helpful during this period.Medication:Various medications can manage BPH symptoms:Alpha-Blockers:These medicines, such as Alfuzosin and Tamsulosin, are commonly used and can help by relaxing the muscles in the prostate. They can cause side effects like dizziness and ejaculation problems. 5-alpha Reductase Inhibitors:Drugs like Finasteride and Dutasteride can reduce the size of the prostate. However, they may cause sexual side effects, such as lowered sexual desire or erectile problems. Combination Therapy: Combining an alpha-blocker with a 5-alpha reductase inhibitor may be more effective in some cases.Phosphodiesterase-5 Inhibitors:Medicines like Tadalafil can be used to treat BPH symptoms and may also enhance sexual function.Minimally Invasive Procedures:There are non-surgical procedures, like transurethral needle ablation and microwave thermotherapy, that can improve symptoms. They may not be as effective as surgery but are less invasive.Surgery:Surgical procedures are recommended for more severe cases. Different surgical options are available based on the patient's needs and the doctor's recommendations.Making a Decision:Doctors will consider the severity of symptoms, the size of the prostate, and the patient's overall health when suggesting a treatment option. It's crucial to discuss and understand the potential benefits and risks of each choice to make a decision that's best suited to the individual's needs and lifestyle. Hosted on Acast. See acast.com/privacy for more information.

In part 2 of this 2 part episode Buck discusses male sexual health with Justin Houman, MD from Tower Urology in Los Angeles. Over half of American men over the age of 40 suffer from erectile dysfunction and other sexual disorders.  00:00:42 - Male Refractory Period 00:01:44 - Erections are going to be weaker as you age 00:02:15 - Medication like Phosphodiesterase that help lower one's refractory period 00:02:50 - Hormone called Prolactin that can cause increased refractory time 00:07:36 - Dealing with Premature Ejaculation 00:10:24 - Paxil and Tramadol For Premature Ejaculation 00:12:10 - Prostate issues 00:12:37 - Benefits of Cialis and Flomax 00:14:49 - Testosterone Replacement 00:16:17 - Clomid for Hypogonadism and Low Testosterone 00:18:31 - Human Chorionic Gonadotropin (hCG) 00:24:08 - Preserving Fertility 00:26:39 - Testosterone Blood Testing 00:27:44 - Masturbation Effects on Testosterone Levels 00:30:30 - Supplements like Tongkat Ali and Fadogia Agrestis

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.07.531588v1?rss=1 Authors: Sharp, B. M., Jiang, Q., Kim, P., Chen, H. Abstract: Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we inactivated PDE4B in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats These rats then were given 23-hour chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the mutant group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5 ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5 dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These studies provide insight into the motivational effects of NAcs PDE4B that may impact the smoking behaviors mapped in human GWAS. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.01.530659v1?rss=1 Authors: Anticevic, I., Otten, C., Vinkovic, L., Jukic, L., Popovic, M. Abstract: DNA-protein crosslinks (DPCs) are very frequent and damaging DNA lesions that affect all DNA transactions, which in turn can lead to the formation of DSBs, genomic instability and cell death. At the organismal level, impaired DPC repair (DPCR) is associated with cancer, aging, and neurodegenerative phenotypes. Despite the severe consequences of DPCs, the mechanisms of the DPCR pathway at the organism level are still largely unknown. SPRTN is a protease that removes most cellular DPCs during replication, whereas tyrosyl-DNA phosphodiesterase 1 repairs one of the most abundant enzymatic DPCs, topoisomerase 1-DPC (TOP1-DPC). How these two enzymes repair DPCs at the organism level is currently unknown. Using the zebrafish animal model and human cells, we demonstrate that TDP1 and SPRTN repair endogenous, camptothecin- and formaldehyde-induced DPCs, including histone H3- and TOP1-DPCs. We show that resolution of H3-DNA crosslinks depends on upstream proteolysis by SPRTN and subsequent peptide removal by TDP1 in RPE1 cells and zebrafish embryos, whereas SPRTN and TDP1 function in different pathways in the repair of endogenous TOP1-DPCs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

https://psychiatry.dev/wp-content/uploads/speaker/post-11087.mp3?cb=1670008136.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: Positron Emission Tomography Assessments of Phosphodiesterase 10A in Patients With Schizophrenia – Manabu Kubota et al. Schizophrenia Bulletin. 2022. Phosphodiesterase 10A (PDE10A)Full EntryPositron Emission Tomography Assessments of Phosphodiesterase 10A in Patients With Schizophrenia –

For all things Dr Ardis: https://theDrArdisShow.comSupport Ba'al Busters: https://tipeeestream.com/baal-busters/donationand https://GiveSendGo.com/BaalBustersToday's Show is a MUST SEE! Ophirex is a company created by Moderna founder Derrick Rossi. Moderna was best known as the world's largest venom supplier ever before putting a lethal vaccine on the market. Ophirex is being heavily funded by the DoD, the WELLCOME TRUST (WEF), and the WHO. They claim their work in preventing death by snake bites is directly related to helping prevent COVID-19!! How's that? How's PLA2 found in snake bite victims in the highest concentration ever found in humans in the autopsied bodies of dead COVID patients and fatalities after the mRNA shots? Dr Ardis also discusses a new documentary in the works with Badass Dr Tau Braun. Did a University in Utah in 2018 synthesize snake venom phosphodiesterase? Phospholipase A2? How and why did they use E Coli to propagate it?

  Vidcast:  https://youtu.be/b5IJjsOEf-s   The FDA and the My Stellar Lifestyle company are recalling the Wonder Pill with lot numbers 20210912 and 31853-501 with an expiration date of 9/24.  These pills are tainted with tadalafil, a phosphosdiestase inhibitor drug marketed as the prescription erectile dysfunction drug Cialis.  This contaminant makes this over-the-counter supplement an unapproved drug with unproven safety and efficiency.  Using it could be dangerous for those taking nitrate-containing drugs including nitroglycerin due to the lowering of blood pressure to dangerous levels.  These pills were marketed by amazon.com and walmart.com.    If you bought Wonder Pills, contact the outlet from which you made the purchase to arrange for a return and refund.  For additional information, contact Proper Trade LLC at 1-732-242-4711 or via the email propertradingllc@gmail.com.   https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/proper-trade-llcmy-stellar-lifestyle-issues-voluntary-nationwide-recall-wonder-pill-capsules-due   #wonderpill #tadalafil #ed #phosphodiesterase #hypotension #recall  

Summary   Hello and welcome to episode #19!   This is Ralph Sanchez and today I'll be talking the outcomes of two recent studies that investigated the potential use of Viagra and Cialis in the risk reduction for late-onset Alzheimer's disease (LOAD).   I was in part inspired to provide an overview on these two recent studies as they are cautionary tales on how many studies do not include the interrelated factors that are essential in arriving to an integrated assessment and analysis that serves their very premise— which is, does this or that work in a potential solution to something else?   Does Viagra or Cialis offer any proposed solution to the risk for LOAD and dementia?   Well today, I'll be adding a great deal of information—the missing pieces to the puzzle as it were—with regard the pathways by which Viagra and Cialis may or may not work, and many other complimentary or natural alternatives that play a similar role in maintaining and optimizing a healthy cardiovascular and cerebrovascular system.   First, let me provide a little insight as to the molecular pathways in which drugs like Viagra and Cialis function, and why they may be considered as repurposed drug candidates for the treatment or in the risk reduction for LOAD.   Viagra (sildenafil) and Cialis (tadalafil) are Phosphodiesterase-5 inhibitors (PDE5is) which fall into a class of drugs that are normally prescribed to men to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).   PDE5is can have a profound effect on cardiovascular health and PDE5is mediate their benefits by inhibiting the breakdown of a molecule, cyclic GMP (cyclic 3′,5′ guanosine monophosphate).   Cyclic GMP (cGMP) is an intracellular and second messenger molecule that modulates many downstream pathways, including significant effects in vasorelaxation—the ability of your blood vessels to dilate and expand as needed.   The vascular effect that is enabled by PDE5i-induced vasodilation is a pivotal pathway in vascular homeostasis and a healthy heart-brain axis.   And that vasodilation effect is how PDE5is improve and treat ED.   There is a lot more to that vasodilation benefit mediated by PDE5i therapy  which I'll get to here soon.   So on to a brief description of the two recent studies on Viagra and Cialis, and so much more that was not included in those studies that will provide a crucial insight into how you can improve your vascular health and reduce your risk for LOAD.   NIH Studies First, a recent (2021)National Institutes of Health (NIH) funded study reported a risk reduction benefit of 69% for Alzheimer's disease (AD) in users of Viagra (Sildenafil).   The analysis simply compared Viagra users to those who did not take it, and the study was focused on a screen of drugs that could potentially be repurposed in the risk reduction for AD in aging individuals.   In a similar and second NIH funded study published this year (2022) titled— Drug Repurposing for Effective Alzheimer's Medicines—(DREAM), the NIH analyzed data from Medicare beneficiaries that were treated with Viagra and Cialis.   The NIH team compared people with pulmonary arterial hypertension (PAH) treated with Viagra and Cialis over those with PAH on another class of drugs (endothelin receptor antagonists) used to treat pulmonary hypertension.   And note that PAH is a term that refers to high blood pressure in the blood vessels leading from the heart to the lungs   Yes, PDE5is are also prescribed to patients to reduce blood pressure in PAH, and off-label use of PDE5 inhibitors (PDE5is) is used to treat cardiovascular diseases, Raynaud's disease and women with female sexual arousal disorder.   The average age of patients included in the DREAM study “was 74 years (range 65–96 years), and 69% were women.”   Notably, studies have shown that in women, "PDE5 inhibitor efficacy is estrogen dependent in female heart disease."   The DREAM PDE5i study rationale for focusing on patients with PAH and treated with PDE5is, Viagra or Cialis, for the new study analysis over those individuals on another class of antihypertensive drugs was attributed to the odds that the two groups were  "more likely to have people with similar characteristics".   In comparing those two pulmonary hypertension groups in the DREAM study the research team concluded that they "observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors"—Viagra or Cialis.   Bottom line, two differences in the design and outcomes as the Viagra study was favorable while the DREAM study was not. Fair enough.   However, there is much more to this story that was not included in the two studies, which includes an important benefit for heart and brain health that is only in part mediated by PDE5i therapy.   And we begin with nitric oxide— a vital molecule produced in your body and brain that not only impacts many potential benefits to your health, it can also be a component in deleterious oxidative stress reactions that are very damaging to your body and brain.   Nitric Oxide Nitric oxide (NO) was first discovered in 1772 but it was not until 1987 that it was identified as an important signaling molecule that played a vital role in endothelium-dependent vasodilation in mammals.   A few years later, in 1992, the journal Science nominated nitric oxide as the “Molecule of the Year” due to its role as a fundamental signaling agent in cardiovascular health and function.   In the body and brain, NO can be synthesized by two distinct pathways.   First, endogenous nitric oxide (NO) can be synthesized from the amino acid L. arginine (L-arginine-NO-synthase pathway) which is the initial upstream driver of cGMP activation in vasodilation.   Remember that we started this overview by emphasizing the role of PDEis in blocking the degradation of cGMP.   However, NO signaling is where cGMP activation begins.   Additionally, another amino acid—L. citrulline—is metabolized from arginine and can be utilized in regeneration of arginine.   Both amino acids are at the center of many studies which showcases their metabolism in vasodilation pathways.   Nitric oxide may be also be derived from the intake and metabolism of foods rich in nitrate (nitrate–nitrite–nitric oxide pathway).   Vegetables such as beets, celery, arugula and spinach, and fruits (e.g., strawberries) supply approximately 80%—85% of dietary nitrates in individuals that consume such foods regularly.   Indeed, those foods are not only a terrific source of nitrate, they also are rich in many types of polyphenols which are key nutrients in protecting against oxidative stress pathways associated with nitric oxide metabolism.   Many of you listening in or reading the transcript have likely become familiar with supplements using beets, or arginine and citrulline and other synergistic ingredients that have been heavily marketed to athletes as performance enhancers.   In a clinical setting, these NO enhancing products are often used for ED and cardiovascular health support.   Drugs (organic nitrates) are also well-known NO donors (e.g., nitroglycerin, amyl nitrite).   Thus, NO can be produced from the precursors L. arginine and L. citrulline, or nitrates and nitrites that are either derived from foods, supplements and drugs.   Another important understanding in all of this is that oral and gut bacteria convert dietary nitrate (NO3) to nitrite (NO2), and in the acidic stomach nitrite is further reduced to nitric oxide.   NB, antiseptic mouthwashes inhibit nitrate to nitrite metabolism by eradicating oral bacteria, and proton pump inhibitors (PPIs) and antacids suppress stomach acid and nitrite to NO metabolism.   To recap NO is an essential signaling and vasodilatory molecule secreted by vascular endothelial cells, which stimulates the production of cGMP (NO/cGMP Pathway) via activation of the receptor for cGMP— soluble guanylate (guanylyl) cyclase (sGC).   Another important point about NO in women is that estrogen (E2) increases NO synthesis.   Thus, the estrogen-NO dynamic is vital in vascular relaxation and endothelial-dependent vasodilation in women and should be included in any risk assessment for cardiometabolic and dementia risk in perimenopause or the earliest stage of menopause.   In contrast, cardiovascular disease (CVD) risk factors such as excess belly fat, high blood pressure, insulin resistance and type 2 diabetes, glycation and chronic inflammation (inflammageing) disrupts endothelial function, promotes arterial stiffness, and blunts the synthesis of NO.   Studies have shown that ED occurs in approximatelym35% to 75% of men with type 2 diabetes, and related studies have concluded that ED predicts future cardiovascular events.   Additionally, CVD risk factors upregulate the formation of an arginine metabolite—ADMA (asymmetric dimethylarginine)—that inhibits vascular NO production (eNOS uncoupling).   ADMA impairs vascular endothelial function and increases vascular oxidative stress (NO-ONOO cycle), and elevated ADMA has been linked to CVD in many studies. See image below.   A useful assessment in analyzing the underlying factors associated with cardiometabolic disease such as atherosclerosis is the serum arginine/ADMA ratio which provides information on arginine bioavailability for production of NO.   So, to summarize, the integrity of NO-sGC-cGMP Pathway is critical to signaling and vasodilation mechanisms that are essential to blood flow and vascular/endothelial homeostasis.   Healthy endothelial function and NO levels is critical in the normal function of many vital organ systems including the cardiovascular and cerebrovascular system (neurovascular system), and the respiratory and renal systems.   Indeed, a healthy endothelium is a fundamental cornerstone to living younger, longer.   For a more thorough overview of the neurovascular system, please listen in to episode #16 titled: “Brain Detoxification-Part 1-The Role of the Blood Brain Barrier and The Glymphatic System” here on this channel.   NO-PDE5i Brain Benefits But what about the role of PDE5is in all of this?   Is there a role for PDE5i therapy in preventing cognitive decline?   Would the PDE5i—sildenafil, or other PDE5 inhibitors, impart the same benefits on brain and cognitive health as healthy levels of NO does?   Previous studies have shown that low dose sildenafil activates signaling pathways which suppresses the processing and generation of beta-amyloid and tau protein aggregates.   Additionally, PDE5 inhibition mediated benefits include: induces cellular antioxidant levels, blunts neuroinflammation, and stimulates the production of new mitochondria (mitochondrial biogenesis) Now, is there a world where the combined therapy of NO and PDE5i therapy exists?   Only a handful of recent studies have shown that supplemental citrulline or arginine therapy in combination with a PDE5 inhibitors could be a synergistic and therapeutic alternative to PDE5i monotherapy for severe ED and pulmonary hypertension.   Overall, combination therapy was superior to monotherapies.   No such combination studies that investigated PDE5 inhibitors with citrulline or arginine therapy in the risk for late-onset Alzheimer's disease (LOAD) have been undertaken.   Bottom line, given the lack of research that includes the multiple pathways of NO metabolism and its role in endothelial function, the investigation into Viagra or any other PDE5i in the risk reduction for LOAD is grossly incomplete.   And that answers the unfinished Viagra and Cialis story as a viable treatment for cognitive impairment or Alzheimer's as the NIH studies on Viagra and Cialis just did not go deep enough into interrelated mechanisms that intersect with the PDE5 enzyme.   However, key nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors, and they also protect against the upregulation of NO and the pro-inflammatory pathways and oxidative stress cascades associated with excess NO production.   Without a doubt, dietary, nutrient and botanical/herbal extracts are vital interventions in an optimal heart-brain health protocol.   More on that below after this brief overview on the glycocalyx.   The Glycocalyx (preview) I must add that any overview on NO in vascular and endothelial health is incomplete without an overview on the glycocalyx—a gel-like thin protective layer covering present on endothelial cells which maintains the endothelial barrier.   In fact, almost every cell in the human body, including bacteria, are covered by a glycocalyx layer.   And yes, the role of a glycocalyx layer in bacteria is another story.   The degradation of the endothelial glycocalyx layer in aging and cardiovascular disease significantly reduces endothelial cell production of NO, and collectively these interactions are a major and underlying factor in cardiovascular AND neurovascular disease.   I have been closely following the emerging research with regard to the glycocalyx over the past 5 years, and the evidence that you cannot have a healthy-heart-brain axis without a vibrant endothelial glycocalyx is compelling.   Case in point, the recent studies that have demonstrated the importance of the glycocalyx in vascular/endothelial health have established a new and critical insight into the treatment and potential reversal of atherosclerosis.   Nutrition-Diet (preview) A host of nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors.   First, apart from arginine and citrulline, vitamin C, E and D are core nutrients in NO-mediated endothelium-dependent relaxation.   Recently, vitamin K2-MK-7 studies have also been linked to enhanced NO-dependent endothelial function.   Glutathione has been shown to be an essential and protective antioxidant in modulating NO reactivity and protecting against the damaging NO-ONOO cycle.   Glutathione and glutathione-based enzymes detoxifies peroxynitrite (ONOO)—a reactive nitrogen species, and improves nitric oxide bioavailability and endothelial function.   And, tetrahydrobiopterin (BH4) is a key enzymatic cofactor required for the synthesis of several neurochemicals—serotonin, dopamine and NO.   Additionally, polyphenols and in particular flavonoids, are the most the most frequently reviewed and studied phenolic NO precursors and PDE5 inhibitors, and they support the integrity of the glycocalyx structure and function.   So many nutrients  to make a case for including the phytoestrogenic benefits of many flavanoids, but here is an abbreviated list of the most cited plant/herbal derivatives and nutrients: Resveratrol Quercetin Catechins, epicatechin (e.g.,green tea) Pine bark (Pycnogenol®) and grape seed extracts (GPSE) Isoflavones (e.g. genistein) Hawthorne (Crataegus species) Icariin (Epimedium brevicornum) Aged garlic extracts Pomegranate extracts Gingko biloba Black ginger (kaempferia parviflora) Xanthones (Anaxagorea luzonensis) And, all the nitrate/flavanoid-rich foods including beets, spinach/leafy greens, and celery, pomegranate, berries, cherries, citrus, garlic, dark chocolate and many others.   Of course, a low-carbohydrate Mediterranean diet or Mind Diet lifestyle is rich in polyphenols and other heart and brain health nutrients.   In addition, exercise training and caloric restriction promotes NO activity and endothelium-dependent vasodilation through activation of eNOS.   Additional points covered in this episode's audio file…   NO Synthesis (preview) Now, I'll briefly describe how NO is synthesized as there are principal pathways that illustrate key and elemental features of NO metabolism—good and bad.   The NO-cGMP pathway is in part regulated by the activity of a family of enzymes—nitric oxide synthases that regulate nitric oxide (NO) synthesis.   There are three NOS enzyme synthases—neuronal (nNOS), endothelial (eNOS), and inducible (iNOS).   iNOS driven NO production is associated with immune system responses to various stimuli such as infections, and NO can either function as a regulator of such responses, or excessive production of NO by iNOS can upregulate those pathways in a destructive manner.   Nitric Oxide-S-nitrosylation (preview) I want to add another important feature of NO metabolism with regard to the risk for LOAD.   And that is the physiological and pathophysiological role of another NO reaction that takes place in the body and brain which is termed S-nitrosation, or S-nitrosylation.   I was not planning on adding this to this episode, but a recent research study just published reported that a S-nitrosylation pathway was a risk factor in Alzheimer's disease in women.   S- nitrosylation is the bonding of NO to sulfur compounds on amino acids such as cysteine.   In a recent study finding reported on just a few days ago—December 14, 2022, the elevated S-nitrosylation modification of an immune system protein known as complement component C3 (SNO C3) was present at much higher (six-fold) levels in the brains of women who had died of Alzheimer's, compared to men who had died with the disease.   The postmortem brain research that was conducted at Scripps Research and Massachusetts Institute of Technology (MIT) also reported that declines in estrogen, which normally serves as a neuroprotective hormone, was likely a strong factor in the generation of the SNO-C3 form of complement C3.   Cured Meats (preview) Another key factor to weigh into this overview with regard to diet, nitrates, nitrites and NO, are cured meats.   In fact, some of you may be anticipating this section of the  overview by now as there is considerable concern and media dissemination of the potentially deleterious role of nitrates and nitrites used in various types of processed meat products such as bacon, sausages and other “deli meats”.   In fact, many studies have explored the risk of nitrate and nitrite added to various foods as their metabolism under certain conditions can potentially convert into a toxic nitrosamines (N-nitroso compounds)   That's it for this summary and as always, thank you for listening in or taking the time to read the summary . Please do listen in to hear the rest of the story. God bless and goodbye.   BrainDefend® Ralph Sanchez, MTCM, CNS, D.Hom. https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez        

Axel Bolte, MSc, MBA, Co-Founder, President, and Chief Executive Officer, Inozyme Pharmaceuticals, gives an overview of ENPP1 deficiency.The ENPP1 gene produces a critical enzyme called ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1), which regulates inorganic pyrophosphate (PPi) levels in plasma. PPi is essential for preventing harmful soft tissue calcification and for regulating normal bone mineralization. Individuals who present in utero or in infancy are typically diagnosed with generalized arterial calcification of infancy (GACI), which is characterized by extensive vascular calcification and neointimal proliferation, resulting in myocardial infarction, stroke, or cardiac or multiorgan failure. Approximately 45% to 50% of infants with ENPP1 deficiency die within six months of birth. Children and adults with ENPP1 deficiency typically experience rickets and osteomalacia, a condition also known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). These patients can also exhibit a range of signs and symptoms that include hearing loss, arterial calcification, and cardiac and/or neurological involvement. There are currently no approved therapies for ENPP1 deficiency. Recently, however, Inozyme announced positive preliminary biomarker, safety, and pharmacokinetic data from the first 3 patients treated in the phase 1 portion of its ongoing phase 1/2 clinical trial of INZ-701 in adult patients with ENPP1 deficiency.

  Vidcast:  https://youtu.be/JPbLKTP9mD8   The FDA and Alpha Male Plus now recall Alpha Male Plus Male Enhancer Fruit Chew.  This dietary supplement is laced with tadalafil, a prescription medication for erectile dysfunction branded as cialis, that makes this over-the-counter product an unapproved drug with unproven safety and effectiveness.  The contaminating phosphodiesterase is a risk for those taking nitrates such as nitroglycerin as it potentiates this drug's blood pressure lowering to unsafe levels.  This drug has been compounded by a Dr. Manuel Mascarenas in Arizona who operates Alpha Male Plus.  If you have this supplement, stop using it and contact the company at 1-520-955-2015 to arrange for a refund.   https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/alpha-male-plus-issues-voluntary-nationwide-recall-alpha-male-plus-male-enhancer-due-presence   #alphamaleplus #tadalafil #cialis #phosphodiesterase #hypotension #recall  

Commentary by Dr. Valentin Fuster

Pulmonary HypertensionSpecial Guest: Brian Murray, PharmD, BCCCP Reference List: https://pharmacytodose.files.wordpress.com/2020/09/ph-references.pdf 03:38 – Recent changes in PH management; 05:05 – PH classification; 10:22 – PH functional classification; 13:15 – PH diagnosis; 16:00 – Vasoreactivity challenge; 18:51 – Drug-induced PH; 21:08 – Short- and long-term PAH treatment goals; 23:50 – PH risk factors; 26:00 – Modifying outpatient PH medications/medication regimens; 33:03 – Fluid management in PH; 35:37 – VTE prophylaxis/treatment in PAH; 38:32 – Management of arrhythmias in PAH; 41:35 – CCB for PH treatment; 46:24 – Comparative studies in PH; 47:37 – Prostacyclins; 71:30 – Endothelin receptor antagonists; 76:04 – Phosphodiesterase inhibitors; 77:00 – sGC stimulator; 80:00 – Preferred treatment of PAH?; 84:53 – Vasopressors in patients with PH; 88:50 – Acute RV decompensation; 92:32 – Effect of positive pressure ventilation on PH; 94:55 – Management of outpatient PH infusion pumps; 97:22 – Take-home points PharmacyToDose.Com@PharmacyToDose on Twitter/InstagramPharmacyToDose@Gmail.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.10.290825v1?rss=1 Authors: Baillie, G. S., Tibbo, A., Dobi, S., McFall, A., Tejeda, G. S., Blair, C., MacLeod, R., MacQuaide, N., Gok, C., Fuller, W., Smith, B., Smith, G., Brand, T. Abstract: Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that Popeye proteins exist in complexes with members of the PDE4 family in cardiac myocytes thus restricting cAMP signaling. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 is essential to maintain action potential duration in beating cardiac myocytes. Copy rights belong to original authors. Visit the link for more info

Phosphodiesterase 3

Nels and Vincent reveal a new choanoflagellate that forms multicellular cup shaped colonies that respond to light to alternate between feeding and swimming behavior. Hosts: Nels Elde and Vincent Racaniello Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiEVO Microbial accomplices in multicellularity (TWiEVO 11) Light regulated collective contractility (Science) Image credit Letters read on TWiEVO 48 Time stamps by Jolene. Thanks! Science Picks Nels - How to write a great science paper by Cormac McCarthy Vincent - Natural Selection Store Music on TWiEVO is performed by Trampled by Turtles Send your evolution questions and comments to twievo@microbe.tv

Commentary by Dr. Valentin Fuster

This week we narrow in on the enlarging prostate and decipher the common issue of benign prostatic hyperplasia with Adam C. Reese MD, Associate Professor of Urology at the Lewis Katz School of Medicine at Temple University and Chief of Urologic Oncology at Temple University Hospital. Learn how to interpret the symptom profile for patients presenting with common urinary issues, what to feel for in the digital rectal exam, how to treat BPH, and when to refer. ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST). See you at SGIM 2019! Find us in our red Curbsider’s t-shirts handing out Curbsiders and Kashlak stickers/patches at SGIM 2019 in Washington DC! We’ll be recording full length shows and daily recaps! Credits Written and produced by: Paul Williams MD Hosts: Paul Williams MD, Matthew Watto MD Images and infographics: Elena Gibson, Beth Garbitelli Show Notes: Elena Gibson, Beth Garbitelli Edited by: Matthew Watto MD, Chris Chiu MD Guest: Adam Reese MD Time Stamps 00:00 SGIM announcement 00:30 Disclaimer, intro and guest bio 03:20 Guest one liner, book recommendation, favorite failure and surgical M&M 10:56 Case of benign prostatic hyperplasia, defining terms and obstructive/voiding versus storage/irritative symptoms 16:11 IPSS score and evaluating symptoms 22:10 Digital rectal exam. Will this give any useful information? 26:55 Taking a history about BPH and some lifestyle modifications 29:20 Lab studies for urinary tract symptoms and interpreting PSA and free PSA 36:20 Initial therapy for BPH and managing patient expectations, alpha blocker side effects 39:25 Choice of agent and monitoring symptoms on therapy 42:25 Nonpharmacologic management of bladder complaints 45:10 Who and when to refer to urology 47:33 Counseling about use of 5 alpha reductase inhibitors, their side effects and is there a risk for high grade cancer? 52:35 Phosphodiesterase inhibitors for BPH symptoms 53:50 Urethral milking. NOT prostate milking 54:55 Desmopressin for nocturia 56:20 Take home points 59:03 Prostate volume and PSA 61:10 Outro Full show notes available at http://thecurbsiders.com/episode-list. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler The TWiVniks consider the role of a cell enzyme that removes a protein linked to the 5'-end of the picornavirus genome, and the connection between malaria, Epstein-Barr virus, and endemic Burkitt's lymphoma.   Links for this episode Divergent requirements for removing VPg (mBio) Bond, covalent bond (TWiV 210) Link between malaria and endemic Burkitt's lymphoma (PLoS Path) Multifactorial role of malaria in Burkitt's lymphoma (PLoS Path) Plasmodium infection promotes AID-dependent B cell lymphoma (Cell) Children's cancer dependent on climatic factors (Nature) Denis Burkitt (Wikipedia) Request for PACE trial data (virology blog) Letters read on TWiV 374 This episode is sponsored by 32nd Clinical Virology Symposium and ASM Grant Writing Webinar Weekly Science Picks Alan - Indoor skydivingVincent - Cancer Virus by Crawford, Johannessen, and RickinsonRich - WitKathy - The Only Woman in the Room by Eileen PollackDickson - Show everyone your clinical data Send your virology questions and comments to twiv@microbe.tv

Vincent, Dickson, and Daniel review how Viagra might be used to block transmission of Plasmodium falciparum, and introduce a new case study. Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin Links for this episode: Malaria life cycle (jpg) cAMP regulates gametocyte infected erythrocyte deformability (PLoS Path) P. falciparum in bone marrow (Blood) Image credit Letters read on TWiP 91 Contact Send your questions and comments (email or mp3 file) to twip@twiv.tv Subscribe Subscribe to TWiP (free) in iTunes, by the RSS feed or by email

The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

Hosts: Vincent Racaniello, Rich Condit, Dickson Despommier, Alan Dove, and Kathy Spindler The complete TWiV team reviews identification of the cell receptor for hepatitis B and D viruses, and the cell enzyme that cleaves the genome-linked protein from picornaviral RNA. Links for this episode: HBV and HDV cell receptor (eLIFE) Getting to grips with hepatitis (eLIFE) Sodium taurocholate Poliovirus hijacks DNA repair enzyme (PNAS) Letters read on TWiV 210 Weekly Science Picks Rich - Vendée GlobeDickson - Earth at nightAlan - Trophée Jules VerneKathy - Science cookiesVincent - Trilobite Glassworks Listener Pick of the Week Ken - Spanish flu pandemic model (teacher's guide)Jim - Santa Cruz Science Communication Program (also see SHERP) Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv

Background: Idiopathic Pulmonary Fibrosis (IPF) is an unresolved clinical issue. Phosphodiesterases (PDEs) are known therapeutic targets for various proliferative lung diseases. Lung PDE6 expression and function has received little or no attention. The present study aimed to characterize (i) PDE6 subunits expression in human lung, (ii) PDE6 subunits expression and alteration in IPF and (iii) functionality of the specific PDE6D subunit in alveolar epithelial cells (AECs). Methodology/Principal Findings: PDE6 subunits expression in transplant donor (n = 6) and IPF (n = 6) lungs was demonstrated by real-time quantitative (q)RT-PCR and immunoblotting analysis. PDE6D mRNA and protein levels and PDE6G/H protein levels were significantly down-regulated in the IPF lungs. Immunohistochemical analysis showed alveolar epithelial localization of the PDE6 subunits. This was confirmed by qRT-PCR from human primary alveolar type (AT)II cells, demonstrating the down-regulation pattern of PDE6D in IPF-derived ATII cells. In vitro, PDE6D protein depletion was provoked by transforming growth factor (TGF)-beta 1 in A549 AECs. PDE6D siRNA-mediated knockdown and an ectopic expression of PDE6D modified the proliferation rate of A549 AECs. These effects were mediated by increased intracellular cGMP levels and decreased ERK phosphorylation. Conclusions/Significance: Collectively, we report previously unrecognized PDE6 expression in human lungs, significant alterations of the PDE6D and PDE6G/H subunits in IPF lungs and characterize the functional role of PDE6D in AEC proliferation.

Abstract This study examined new strategies for pharmacological treatment in a mouse model of chronic inflammatory bowel disease. As clinical parameters we determined the lethality and clinical score which consisted of weight loss, presence or absence of diarrhea and blood in the faeces. Further, pathoanatomical and histological data were examined. To determine the effect of pharmacological treatment on the level of cytokines, the respective concentrations were measured in the colon. The aim of this study was to determine the effect of the ICE-inhibitor Pralnacasan and the PDE-4-inhibitor Rolipram on reducing colitis. We also assessed whether a combination of both drugs might have a synergistic effect. The results showed a clear therapeutic effect of Pralnacasan, whereas Rolipram was neither effective in the clinical outcome nor in changing cytokine levels. In contrast the combination of both drugs showed a synergistic effect which prevented both occurrence of colitis in clinical measurements and increase of cytokine levels. In summary, this study provides the first evidence that a combination of two drugs which act on different pathways provide a strong synergistic effect which can completely prevent the occurrence of colitis in a mouse model

Thu, 14 Oct 2004 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/2863/ https://edoc.ub.uni-muenchen.de/2863/1/Welsch_Julia.pdf Welsch, Julia

Die Suppression von Tumor-Nekrose-Faktor-a durch die spezifische Hemmung der Phosphodiesterase konnte bisher sowohl in vitro als auch in verschiedenen Tiermodellen für chronisch entzündliche Erkrankungen gezeigt werden (Torphy 1998; Schudt et al. 1999; Bundschuh et. al. 2001; Hatzelmann und Schudt 2001). In der vorliegenden Arbeit wurde die Wirkung des spezifischen Phosphodiesterase Typ 4-Inhibitors Roflumilast und des dualselektiven Phosphodiesterase Typ 3/4-Inhibitors Pumafentrine im Mausmodell der Dextran-Sodium-Sulfat induzierten Kolitis getestet. Hierbei handelt es sich nach unserer Kenntnis um die erste Prüfung dieser Substanzen in diesem Tiermodell und um die erste Untersuchung eines Phosphodiesterase Typ 3/4-Inhibitors in einem Kolitismodell überhaupt. Die Kolitis wurde durch orale Gabe von Dextran-Sodium-Sulfat im Trinkwasser über 11 Tage induziert. Die Entzündung des Kolons war mit geringer Variation gut reproduzierbar. Die Phosphodiesterase-Inhibitoren wurden mit Beginn der Dextran-Sodium-Sulfat-Gabe einmal täglich p. o. über den gesamten Versuchs-verlauf appliziert. 109 weibliche Balb/c Mäuse wurden in den Versuchsreihen eingesetzt. Roflumilast zeigte eine dosisabhängige Wirksamkeit. Die 5 mg/kg KG Dosis zeigte einen deutlichen therapeutischen Effekt auf den klinischen Verlauf, die Kolonlänge, die Produktion von Tumor-Nekrose-Faktor-a im Kolon sowie das Milzgewicht. Diese Verbesserung korrelierte mit einer geringeren Ausprägung der histopathologischen Veränderungen im Kolon. Bei der 1 mg/kg KG Dosis wurden nur der klinische Score, die Kolonlänge und das Milzgewicht signifikant verbessert. Pumafentrine bewirkte in der mittleren eingesetzten Dosierung (5 mg/kg KG) eine Besserung des klinischen Scores, der Kolonlänge und der Tumor-Nekrose-Faktor-a-Produktion im Kolongewebe. Es konnte keine Beeinflussung der systemischen Entzündungsreaktion anhand einer Verringerung des Milzgewichtes beobachtet werden, jedoch zeigte sich bei ex vivo stimulierten Splenozyten eine signifikant geringere Aktivierbarkeit und Zytokinsynthese. Die 20 mg/kg KG Dosis verbesserte als einzigen Endpunkt die Tumor-Nekrose-Faktor-a-Produktion im Kolon, während die 1,5 mg/kg KG Dosis in keinem der untersuchten Parameter zu einer signifikanten Wirksamkeit führte. Die Ergebnisse dieser Arbeit zeigen, dass die Phosphodiesterase-Inhibitoren Roflumilast und Pumafentrine dosisabhängig zu einer Verbesserung der Dextran-Sodium-Sulfat-induzierten Kolitis - als einem Modell für chronisch entzündliche Darmerkrankungen - führen. Die spezifische Hemmung der Phosphodiesterase Typ 4 und die duale Hemmung der Phosphodiesterase Typ 3/4 stellen deshalb viel versprechende Ansätze in der Therapie chronisch entzündlicher Darmerkrankungen dar. Beide Substanzen befinden sich in fortgeschrittenen klinischen Studien für die chronisch obstruktive Lungenerkrankung und für Asthma bronchiale. Deshalb sollten diese Präparate in anderen Tiermodellen für chronisch entzündliche Darmerkrankungen oder klinischen Studien weiter untersucht werden.

Sat, 1 Oct 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9517/1/stief_christian_9517.pdf Jonas, Udo; Stief, Christian Georg; Forssmann, W. G.; Truss, Michael C.; Meyer, M. F.; Schulz-Knappe, P.; Taher, A.

Tue, 1 Jan 1991 12:00:00 +0100 https://epub.ub.uni-muenchen.de/6111/1/6111.pdf Ten Bruggencate, Gerrit; Sutor, Bernd

The actions of the phosphodiesterase inhibitor denbufylline on the excitability of hippocampal neurons were investigated by means of extracellular and intracellular recordings. Denbufylline, which has been shown to selectively inhibit a low KM, Ca2+/calmodulin-independent phosphodiesterase isozyme, concentration-dependently increased the amplitude of the extracellularly recorded CAI population spike evoked by electrical stimulation of the Schaffer collateral/commissural pathway. Concentration-response-curves yielded an EC50 for denbufylline of 0.76 M. In comparison, the nonselective phosphodiesterase inhibitor 3-isobutyl-lmethylxanthine (IBMX) also produced an increase in the amplitude of the population spike. From the concentration-response-curve, which was steeper than that of denbufylline, an EC50 for IBMX of 1.04 M was obtained. However, despite their similar EC50 values, denbufylline was found to be significantly more potent at lower concentrations (