Podcasts about pde4

Visit learnAMAstyle.com for free downloads in writing in medicine and the life sciences.    The FDA has approved blinatumomab (Blincyto) for treating adult and pediatric patients one month or older with CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) in the consolidation phase. This bispecific T-cell engager (BiTE®) therapy targets CD19 surface antigens on B cells, allowing T cells to recognize and eliminate malignant B cells. The approval was based on the Phase 3 E1910 trial showing improved overall survival with blinatumomab plus chemotherapy compared to chemotherapy alone.   The FDA has approved roflumilast cream 0.15% (Zorvye) for treating mild to moderate atopic dermatitis (AD) in patients aged 6 years and older. This steroid-free, once-daily topical treatment is a selective, highly potent phosphodiesterase 4 (PDE4) inhibitor designed for long-term disease control. The approval was based on phase 3 studies showing significant improvements in disease clearance, itch reduction, and overall skin condition compared to the vehicle group.   The FDA has approved a new 6mg single-dose prefilled syringe for faricimab-svoa (Vabysmo), facilitating easier administration for neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO). Faricimab-svoa is a VEGF and Ang-2 inhibitor, now available in a ready-to-use format. This approval provides an alternative to the existing single-dose vial and is granted to Genentech.   The FDA is set to decide on OX124, a high-dose naloxone nasal rescue medication designed to reverse opioid overdoses, with the PDUFA date set for July 15, 2024. Developed by Orexo, OX124 offers rapid absorption, high bioavailability, and enhanced stability, addressing the critical need for potent rescue medications due to the high rate of synthetic opioid overdoses. If approved, OX124's launch is anticipated later in 2024.   The FDA accepted an NDA for vonoprazan (Voquezna) tablets for treating heartburn associated with Non-Erosive gastroesophageal reflux disease (GERD) in adults, with the PDUFA date set for July 19, 2024. Vonoprazan is a potassium-competitive acid blocker (PCAB) offering an alternative to traditional proton pump inhibitors (PPIs). Non-Erosive GERD, affecting 38 million U.S. adults, is characterized by reflux-related symptoms without esophageal mucosal erosions, impacting quality of life with symptoms like heartburn and chest pain.  

Jillian who is living with plaque psoriasis, and board-certified nurse practitioner, Melodie Young, discuss disease management with topicals. This episode is sponsored by Arcutis Biotherapeutics, Inc. Please see Important Safety Information and full Prescribing Information including Patient Information for Zoryve (roflumilast) indicated for use on the skin (topical), including in areas with skin folds, to treat plaque psoriasis in people six years of age and older. 

In episode 57 of Derms and Conditions, our host, James Q. Del Rosso, DO, sits down with Christopher Bunick, MD, PHD, an associate professor of dermatology at Yale University School of Medicine who performs specialized dermatologic research utilizing x-ray crystallography and other novel techniques. The 2 discuss research findings surrounding new information on properties that differentiate the activity of antibiotics, with specific data on how narrow spectrum activity with sarecycline differs from the broad-spectrum tetracyclines we use in dermatology. There are new data described by Dr Bunick and his team on how the unique molecular structure of sarecycline targets Cutibacterium acnes (C. acnes) through multiple mechanisms of action, making it less vulnerable to antibiotic resistance.    Dr Del Rosso begins by introducing sarecycline, a major new antibiotic in dermatology, and has Dr Bunick discuss some of his research on the medication. Dr Bunick explains how the recent scientific findings on the biochemistry of sarecycline translate clinically and have allowed us to not only advance our understanding of sarecycline but also other tetracyclines, including minocycline and doxycycline. Drs Del Rosso and Bunick follow this up by agreeing on the importance of dermatologists having a strong understanding of tetracyclines given their prevalence and frequency of use in clinical practice.   Next, they switch focus to C. acnes, and Dr Bunick discusses his new findings on the ribosomal structure of C. acnes through the use of cryo-electron microscopy and how tetracyclines interact with it. Dr Bunick's research group found that sarecycline binds C. acnes at both the 30S ribosomal subunit and a new additional ribosomal binding site, which had not previously been discovered. In addition, Dr Bunick notes how these variations in the mechanism of action can explain why tetracycline antibiotics have different properties, such as side effect profiles, despite being in the same chemical class. Drs Bunick and Del Rosso further solidify this point by explaining how similar research has established differences between PDE4 inhibitors such as roflumilast.   Finally, they discuss antibiotic resistance in acne and how clinicians can better select therapies. Dr Bunick explains that sarecycline has the lowest rate of antibiotic resistance amongst tetracyclines because it targets C. acnes through 2 ribosomal binding sites and has an mRNA interfering carbon side chain that no other tetracycline possesses. Overall, Drs Bunick and Del Rosso agree that there is substantial scientific evidence on the effectiveness of sarecycline that supports its use by clinicians. Tune in to this episode to learn more about the new developments on antibiotics being discovered at a molecular level in the treatment of acne!

Kanna is a PDE4 inhibitor and it has very similar effects to SSRI, serotonin reuptake inhibitor. It works really well on a biochemical level to keep those good hormones flowing around but it's gentle enough so you don't have to worry about serotonin syndrome. - Bandit French Are You Stressed Out Lately? Take a deep breath with the M21™ wellness guide: a simple yet powerful 21 minute morning system that melts stress and gives you more energy through 6 science-backed practices and breathwork. Click HERE to download for free. Is Your Energy Low? Get more superfoods to improve your energy, digestion, gut health plus also reduce inflammation and blood sugar. Click HERE to try Paleovalley's Apple Cider Vinegar Complex + Save 15% with the code 'JOSH' *Review The WF Podcast & WIN $150 in wellness prizes! *Join The Facebook Group Wellness + Wisdom Episode 500 In this episode, Lead Product Developer at LiftMode, Bandit French joins our host, Josh Trent, to talk about a plant that has been used for centuries by indigenous people in South Africa, its influence on our cognitive functions, and how it can sustainably boost our serotonin level. Are you ready to uncover the secrets of a South African plant, Kanna, and learn about its positive effects on the human brain? Join Bandit and Josh as they discuss why Kanna is nature's MDMA, its effects on the brain and amygdala, and why it's safer than pharmaceutical drugs.     LiftMode LiftMode offers quality & innovative nootropics for cognition enhancement, mental and physical health, and energy boost. *Save 20% With The Code "JOSH20"   LiftMode's Kanna Extract Powder LiftMode Kanna Extract powder is a powerful mood-support supplement derived from the African succulent, Sceletium tortusum. It grows naturally in South Africa and has been used for millennia by the Khoisan bushmen. This extract contains very high concentrations of the alkaloids Mesembrine and Mesembrenone. Kanna extracts are reputed to produce tranquil yet cheerful states of mind while acting as a mild

Featuring articles on chronic traumatic encephalopathy in military personnel, a PDE4 inhibitor for idiopathic pulmonary fibrosis, a monoclonal-antibody combination to prevent Covid-19, natural and hybrid immunity to SARS-CoV-2, and emerging technologies in health and medicine; a review article on the diagnosis and treatment of frostbite; a case report of a boy with chest pain; and Perspective articles on a radical treatment for insulin pricing, on the tobacco wars' lessons for the vaccination wars, on physicians as political pawns, and on the high cost of cancer drugs under Medicare Part D.

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

Join us for our new Psound Bytes Journal Club series discussing noteworthy publications in psoriatic disease. In this first episode we discuss three recent trial results for therapeutics in the pipeline with dermatologists Dr. Mark Lebwohl, Professor and Chairman, Dept. of Dermatology, Icahn School of Medicine, Mt. Sinai Health System in New York, and Dr. Andrew Blauvelt, President, Oregon Medical Research Center in Portland, OR. For disclosures and to claim .5 CME credits go to cme.psoriasis.org. For publication links: https://bitly.31a6a7s 

Join us for our new Psound Bytes Journal Club series discussing noteworthy publications in psoriatic disease. In this first episode we discuss three recent trial results for therapeutics in the pipeline with dermatologists Dr. Mark Lebwohl, Professor and Chairman, Dept. of Dermatology, Icahn School of Medicine, Mt. Sinai Health System in New York, and Dr. Andrew Blauvelt, President, Oregon Medical Research Center in Portland, OR. For disclosures and to claim .5 CME credits go to cme.psoriasis.org. For publication links: https://bitly.31a6a7s 

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure. Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B? Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines. Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study? Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties. Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events? Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results. Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS.  Dr Carolyn Lam: Wow. What did they find Greg? Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel. Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction. Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored.  Dr Carolyn Lam: Summarize that for us. Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors, Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score. Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19? Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper. Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly.  Dr Carolyn Lam: Wow. So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.  Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg? Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments. Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox. Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden. Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter? Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings? Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say. Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases? Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application. Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found? Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals. Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors.   Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very, very challenging, Carolyn. Dr Peipei Ping: The beauty of the study is it utilized already in clinical trial, existing human antibody inhibitor, interleukin alpha-one antibody. You said antibody. So the reagent is already bile approved. Then examine very carefully in a post-ischemic fashion to see how relevant that agent in a time window reasonable to rescue ischemic injury. You can already tell from Lucas introduction; the results are profound, and it has stimulated many discussions in the field. It's very relevant to clinical center piece, even though it's still at that translational stage. So we saw this as a beautiful representation of how clinicians and scientists capable of not only bring something from the bench to the clinic or the clinic or to the bench. This is something comes to a full circle. It went from clinic where the reagent was used and created for something to the bench, understanding mechanistic insight, have a beautiful animal of human disease stroke model to test them and then take it to the clinic again. Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I actually didn't see that Luc[a], till you put it that way. I do have a couple of questions for Luca though. I understand you made it very clear in your paper that the human monoclonal antibody is in clinical use, but in this experiment, you had to use the rodent equivalent because the human antibody doesn't block the rodent IL-1α, which is very reasonable. But then it brings the question, how closely does this rodent model recapitulate thrombotic ischemic, or a stroke in humans? I mean, what do you think? Dr Luca Liberale: Well, what we see when we use our usual approach, this is a model that we're using in our center for molecular cardiology here in Zurich, and this been used in that specific group of Professor Ameche for many years. And this is usually quite well accepted as a model. So that, that the timeframe is 45 minutes of ischemia and 48 hours of reperfusion. I'll got to quite mirror the acute phase of an acute ischemic stroke, which is actually where we think that the inflammatory pathways can play the major roles. Also. I mean, everybody of us know that the recent anti-inflammatory trials confirmed this, that reducing the inflammation and the inflammatory pathways is good but can also be harmful. Dr Luca Liberale: So in the case, we can use an approach, which is limited in the time, maybe really close to that acute phase, really during the acute rates goes to the acute event. Well, maybe this can be quite useful and quite a translationally relevant that prolongs inactivation of such pathways as result. They can ask some for, so the balance in between the benefits and the harms cannot be that clear, can, I mean, needs to be quite well addressed. Dr Carolyn Lam: And that actually brings me to the next question. You know, the word translational has been mentioned quite a number of times here. So can you give us a sneak-peak on what the translational plans that your team may have? What's the next steps? Dr Luca Liberale: The next steps now is back to the company. So our basic findings are here. They will be published soon, and now it's all about the clinical scientist, and how they want to implement these basic findings into the clinic. Dr Carolyn Lam: So target engagement and mechanistic information as well. Peipei, could I just give you the last word, if you don't mind, maybe a bit of a cheeky question. What would you have loved to see in this paper or in a subsequent paper that offers a step closer to translation? Dr Peipei Ping: I think this study has shown most necessary components as a basic science research paper. I think the next level closer to the translation as Luca has already alluded to, has to do with both efficacy studies, as well as safety studies, and those actually would need to be done in the clinic because the mouse model. I think it's a fantastic model to offer these lines of information. Ischemic-wise I think it's very strong and translational value is very high and that was the predominant reason we voted to accept the paper. As you know, the accept and raise of circulation is very, very low as our bar is very high. Dr Carolyn Lam:  Very nice. So target engagement and mechanistic information as well. Congratulations, Luca. Thank you so much Peipei for your great comments. Now, listeners, you heard it first time here on Circulation on the Run. Thank you for joining us today.  Dr Greg Hundley: This program is copyright at the American Heart Association, 2020.  

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This product contains Royal Jelly a milky secretion harvested.2 fluid ounces.https://holistichavenpharmacy.com/collections/anxiety-depression/products/anti-stress_dropsKLAIRE LABS TARGET GB-X MOOD BOOSTING PROBIOTICA specialty shelf-stable probiotic formulation targeted to provide robust gut-brain axis support*Clinically demonstrated to support positive mood.*5 billion CFU (9-strain) blend in 30 single-serving sachets, no refrigeration required. Protected by PROBIOACT Technology for optimal efficacy and shelf-stability.*Hypoallergenic* and non-GMO. Free of the following common allergens: milk/casein, eggs, fish, shellfish, tree nuts, peanuts, wheat, gluten, and soybeans. No artificial additives, colors, flavorings, preservatives, sugar, or salicylates are used. Contains corn.Trusted by healthcare practitioners since 1969, Klaire Labs products are developed closely with physicians and are intended to be used as directed by a healthcare practitioner.*Target gb-X is a specialty probiotic formulation targeted to provide robust gut-brain axis support. It is the first probiotic clinically demonstrated to reduce cognitive reactivity to sad mood, decrease rumination, and diminish aggressive thinking.https://holistichavenpharmacy.com/products/klaire-labs-target-gb-x-mood-boosting-probioticDIGESTIVE ENZYMES ULTRA 180 CAPSDigestive Enzymes Ultra contains a high-strength mixture of vegetarian enzymes supporting enhanced protein, carbohydrate, fat, fiber and dairy digestion and promoting optimal nutrient bioavailability and absorption.https://holistichavenpharmacy.com/products/digestiveenzymesLAZARUS NATURALS CBD TINCTUREMade with Full Spectrum Hemp ExtractChoose from 50mg of CBD per 1ml or 15mg per 1mLVegan and gluten-free with no artificial flavors, preservatives or sweetenersIngredients: Organic Hempseed Oil, Fractionated Coconut Oil, Hemp ExtractCONTAINS: Tree Nuts (Coconut)Hemp oil has < 0.3% THC and is not psychoactive, therefore you don't have to worry about any debilitating high.

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https://holistichavenpharmacy.com/products/high-potency-cbd-tinctureFor any questions, feel free to email Nancy@holistichaven.com. Be sure to join Holistic Haven's newsletter by signing up on at holistichaven.org. And to purchase holistic and homeopathic remedies visit holistichavenpharmacy.com

Fragile X Syndrome is a rare developmental disorder and the most common cause of inherited intellectual disability. Tetra Discovery Partners, building on research about the role the enzyme PDE4 plays in the disease, is developing an experimental drug to inhibit its activity. We spoke to Mark Gurney, chairman and CEO of Tetra Discovery Partners, about Fragile X, the potential of its PDE4 inhibitor, and why this drug may have therapeutic benefit in a range of neurodegenerative diseases.

In the past two weeks for the Keto Summit, I interviewed Dave Asprey, Mark Sisson and Professors Tim Noakes, Kieran Clarke and Tom Seyfried. These are just five of the 33 expert interview I have lined up. Each interview is around one hour or 10,000 words long. So much wisdom, sometimes decades in the making, is there anything I can do to help retain some of it in my long term memory? Quite possibly: nootropics are are drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. I’m completely new to the idea, and if you are too you’ll find this podcast both helpful and intriguing. My expert guest is Ryan Munsey. Ryan is a former fitness model and gym owner turned writer, speaker, and biohacker. He's a mental and physical performance specialist with a degree in Food Science & Human Nutrition from Clemson University. An avid hunter, you'll often find him in the woods. Here’s the outline of this interview with Ryan Munsey: 0:00:12    Optimal Performance Podcast. 0:01:12    Book: Primal Endurance: Escape chronic cardio and carbohydrate dependency and become a fat burning beast! By Mark Sisson and Brad Kearns. 0:01:17    Keto Summit. 0:05:50    House of Strength gym. 0:05:57    Ryan has written for EliteFts, T-Nation, Men's Fitness. 0:06:06    Natural Stacks. 0:06:07    Joe Rogan Podcast. 0:06:08    Dave Asprey of the Bulletproof Radio Podcast. 0:11:36    Mental and physical performance stacks. 0:12:25    CILTEP (use the discount code CILTEPNBT). 0:13:04    My transcriptions are done by the wonderful people at Cabbage Tree. 0:16:14    Eat to Perform podcast. 0:17:37    Modafinil. 0:18:20    Racetam family. 0:19:30    Smart caffeine. 0:19:46    Abelard Lindsay. 0:20:19    Phosphodiesterase type 4 (PDE4) inhibitor. 0:20:24    Khan Academy video: G Protein Coupled Receptors and cAMP. 0:21:44    Book: The Edge Effect: Achieve Total Health and Longevity with the Balanced Brain Advantage by Eric R. Braverman. 0:22:15    L-Alpha glycerylphosphorylcholine (alpha-GPC). 0:22:18    Choline. 0:22:22    ONNIT Alpha Brain. 0:22:28    Bulletproof Choline Force. 0:23:35    Dopamine Brain Food and Serotonin Brain Food. 0:26:19    CILTEP (use the discount code CILTEPNBT). 0:28:17    Grand master of memory Mattias Ribbing. 0:40:14    NAC podcast.

Alebard Lindsay aka Justin, is a friend of mine from LongeCity, a longevity forum. Justin's background has been doing professional software development for 17 years and has been interested in nootropics and researching the brain for more than 10 years. He started out on LongeCity reading and discussing nootropics with people and getting deeper into the research, learning more about the subjects. His family has a history of neurodegenerative illness in their 70s so he was always concerned about protecting and optimizing the brain. He's followed this hobby with a passion. After doing a lot of research over the years he happened upon these studies concerning PDE4 inhibitors and their synergistic interaction with forskolin, and talking and sharing it with people on LongeCity. Many people had a strong positive reaction to the stack he built. He then released it and it grew into a phenomenon called Natural Stacks, which really took off and grew beyond his wildest dreams. He's been working with natural stacks on developing supplement stacks for cognitive enhancement ever since. Justin can be found here: http://www.abelardresearch.com/ You can read about and purchase Justin's natural stacks here: http://www.naturalstacks.com/pages/the-history-of-ciltep

**Summary:** In Episode #180 Ari – joined by special guest hosts Nick Sonnenberg, founder of [Calvin App](http://www.calvinapp.com/) and co-founder of [Less Doing Virtual Assistants](http://www.lessdoing.com/VA) – interviews Abelard Lindsay, the creator of CilTep, a powerful, over-the-counter nootropic. Listen as Ari and Abelard talk brain chemistry, memory development, and cognitive function. **Special Announcements:** ## [Rockefeller Roundtable](http://helmsociety.com/ari-meisel-ceo-roundtable-nc/) Come watch Ari regale a roundtable of avid [Helm Society](http://helmsociety.com/) listeners with the lessons of Less Doing on September 9th from 10AM to 2PM in New York City. ## [Freeing Finland](http://www.biohackersummit.com) Come watch Ari and a collection of other well-renowned biohackers free the people of Finland from their bodily limitations at the 2015 Biohacker Summit being held in Helsinki, Finland from September 23rd through September 24th. Those interested in attending can [buy tickets here](http://biohackersummit.com/#pl_areauf9k2sm). ## [Leave Us a Review!](https://geo.itunes.apple.com/us/podcast/ari-meisel-less-doing/id605938952?mt=2&uo=6) Hey Less Doing Podcast Listeners, we want to hear from YOU! Visit us on iTunes and leave a review or subscribe to the podcast if you're not already a dedicated follower. **Time Stamped Show Notes:** - 18:34 – Introduction of Abelard Lindsay—Director of Research Development for Natural Stacks - 20:40 – Talking about CilTep - 21:20 – Coming up with the foundational ingredients - 21:53 – PDE4 inhibitors - 22:26 – There's a long cascade from short-term memory to long-term memory - 24:50 – Abelard basically conducted self-study with supplements to find the basis of CilTep - 26:20 – CilTep prolongs a state of wonder—it makes studying pleasurably addictive - 27:28 – When dopamine receptors are activated, they release CAMP into the neuron which causes memory encoding to increase - 29:08 – PDE5 is closely related to PDE4 but it drives sexual rather than mental arousal - 30:30 – Developing the pathway to improvement and problem solving - 33:10 – What Abelard takes regularly - 34:25 – Can you overdo it on nootropics? - 35:58 – Hard to clearly say because everyone is different - 36:45 – Nexus, CilTep, and Mitogen all work on different systems - 38:35 – None of Abelard's stacks feature caffeine - 39:10 – Abelard's _Top 3 Tips to be More Effective_ - 39:18 – Get to know your brain - 39:54 – Try to argue without using logical fallacies - 40:28 – Write down ideas - 41:38 – [www.AbelardResearch.com](http://www.AbelardResearch.com) and [www.NaturalStacks.com](http://www.NaturalStacks.com) and [www.axonlabs.io](http://www.axonlabs.io) and @CilTep **5 Key Points:** 1. Memory isn't a singular concept—there are different kinds of memory 2. Keep a written log of your ideas 3. Don't necessarily be opposed to self-experimentation. 4. Become close friends with your brain—get to know it. 5. Nootropic can help you create and prolong a natural state of wonder. **Resources Mentioned:** - [The MiFold](https://www.indiegogo.com/projects/mifold-the-grab-and-go-booster-seat#/story?utm_source=mifold.com&utm_medium=mifold.com&utm_term=hero_cta&utm_content=pre-order_now&utm_campaign=click-thru%20from%20mifold%20website) – A grab and go Car booster seat - [Drones for Blood Testing](http://www.vocativ.com/news/216434/bloody-good-drones-actually/) – Exploring the use of drones for blood transfer, testing, etc. - [The Slack Post](https://theslackpost.com/?ref=producthunt) – A simple online newspaper for the posting of all Slack integrations - [Chronic Inflammation and Behavior](http://www.medicaldaily.com/chronic-inflammatory-diseases-sometimes-cause-behavioral-problems-probiotics-might-345092) – From Medical Daily, an article highlighting how probiotics can help with mental illness - [Make a Game Out of Eating](http://www.yumit.io/?ref=producth --- Send in a voice message: https://anchor.fm/lessdoing/message

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.