Podcasts about cyp3a4

Contributor: Jorge Chalit-Hernandez, OMS3 Educational Pearls: CYP enzymes are responsible for the metabolism of many medications, drugs, and other substances CYP3A4 is responsible for the majority Other common ones include CYP2D6 (antidepressants), CYP2E1 (alcohol), and CYP1A2 (cigarettes) CYP inducers lead to reduced concentrations of a particular medication CYP inhibitors effectively increase concentrations of certain medications in the body Examples of CYP inducers Phenobarbital Rifampin  Cigarettes St. John's Wort Examples of CYP inhibitors -azole antifungals like itraconazole and ketoconazole Bactrim (trimethoprim-sulfamethoxazole) Ritonavir (found in Paxlovid) Grapefruit juice Clinical relevance Drug-drug interactions happen frequently and often go unrecognized or underrecognized in patients with significant polypharmacy A study conducted on patients receiving Bactrim and other antibiotics found increased rates of anticoagulation in patients receiving Bactrim Currently, Paxlovid is prescribed to patients with COVID-19, many of whom have multiple comorbidities and are on multiple medications Paxlovid contains ritonavir, a powerful CYP inhibitor that can increase concentrations of many other medications A complete list of clinically relevant CYP inhibitors can be found on the FDA website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers  References Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20(7):653-656. doi:10.1111/j.1525-1497.2005.0136.x Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396. PAXLOVID™. Drug interactions. PAXLOVIDHCP. Accessed March 16, 2025. https://www.paxlovidhcp.com/drug-interactions Summarized & Edited by Jorge Chalit, OMS3 Donate: https://emergencymedicalminute.org/donate/  

Modafinil (Provigil) is a CNS stimulant medication. I cover modafinil pharmacology, adverse effects, drug interactions, and much more on this podcast episode. You should be aware that modafinil is a Schedule 4 controlled substance so it does carry a risk of dependence and addiction. Modafinil can cause CYP3A4 induction and lead to lowering the concentrations of many medications. This includes antiepileptic agents and oral contraceptives. The most common adverse effects of modafinil include ramping up the body and causing symptoms such as anxiety and insomnia. Cardiovascular changes are a risk with modafinil as this medication can contribute to hypertension and tachycardia.

This episode is sponsored by Meded101.com/store - Go check out their resources, books, and review courses! They will help you prepare to pass your pharmacology classes and board exams! Lansoprazole is a PPI that can be used for GERD, ulcers, and other GI conditions. B12 and magnesium deficiency are possible long-term mineral and vitamin effects. Augmentin is a combination medication of amoxicillin and clavulanate. It is an antibiotic for infection. Diarrhea is the most common adverse effect. Lovastatin is a cholesterol-lowering medication. It is often not a preferred statin due to CYP3A4 interaction and it is less potent than other medications. Valacyclovir is a prodrug that gets converted to acyclovir. It is an antiviral medication and can treat herpes zoster and herpes simplex infections. Chlorpromazine is a dopamine antagonist that has anticholinergic activity as well. It is a first-generation antipsychotic medication.

Le pamplemousse est un fruit aux multiples bienfaits, riche en vitamine C et en antioxydants. Pourtant, il peut devenir dangereux lorsqu'il est consommé avec certains médicaments. Ce phénomène est bien documenté en pharmacologie et repose sur son interaction avec une enzyme clé du métabolisme des médicaments.Un effet sur le métabolisme des médicamentsLe principal problème du pamplemousse vient de sa capacité à inhiber une enzyme du foie et de l'intestin, appelée cytochrome P450 3A4 (CYP3A4). Cette enzyme joue un rôle majeur dans la dégradation de nombreux médicaments avant leur passage dans la circulation sanguine. En bloquant son action, le pamplemousse empêche le métabolisme normal de ces substances, ce qui peut entraîner une accumulation excessive du médicament dans l'organisme et augmenter le risque d'effets secondaires graves.Quels médicaments sont concernés ?De nombreuses classes de médicaments sont affectées, notamment :- Les statines (anti-cholestérol) : Une étude publiée dans The American Journal of Medicine (1998) a montré que la consommation de jus de pamplemousse pouvait augmenter jusqu'à 15 fois la concentration de certaines statines (simvastatine, atorvastatine). Cela accroît le risque d'effets secondaires comme des douleurs musculaires, voire des atteintes musculaires sévères (rhabdomyolyse).- Les antihypertenseurs : Une recherche menée en 2012 dans The Canadian Medical Association Journal a démontré que le pamplemousse augmentait la concentration de certains inhibiteurs calciques (comme l'amlodipine et le félodipine), entraînant une chute excessive de la pression artérielle et des risques de vertiges ou de syncope.- Les immunosuppresseurs (utilisés après une greffe) et certains anxiolytiques (comme le triazolam) sont également impactés, avec un risque de toxicité accru.Combien de temps dure l'effet du pamplemousse ?L'effet inhibiteur du pamplemousse sur le CYP3A4 peut durer jusqu'à 72 heures après ingestion. Cela signifie qu'il ne suffit pas d'espacer la prise du médicament et la consommation du fruit ; il est préférable de l'éviter complètement si votre traitement est concerné.ConclusionLe pamplemousse peut perturber le métabolisme de nombreux médicaments en augmentant leur concentration sanguine, ce qui accroît les effets secondaires et la toxicité. Il est donc essentiel de lire les notices et de demander conseil à un professionnel de santé avant de consommer ce fruit si vous prenez un traitement. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.

Welcome back to the Real Life Pharmacology podcast! We are on the home stretch of the top 200 medications. This is meant to be a quicker refresher of some of the most important drugs you'll come across in practice. Please be sure to go search the archives at RealLifePharmacology.com if you are looking for more information on one specific medication. We have over 300 individual episodes on specific drugs! On this episode of the Top 200 medications, we've covered the medications below. Niaspan (niacin) is vitamin B3 and may be used in patients who fail other therapies for triglyceride management. Uroxatral (alfuzosin) is a selective alpha-blocker that can be helpful in relieving urinary retention symptoms in BPH. Biaxin (clarithromycin) is a macrolide antibiotic that is notorious for many drug interactions because it inhibits CYP3A4. Zomig (zolmitriptan) is a "triptan" medication that can be used for the acute relief of migraine headaches. Invokana (canagliflozin) was one of the first SGLT2 inhibitors invented that can be used to lower blood sugar in type 2 diabetes.

Today's sponsor is Freed AI! Freed's AI medical scribe listens, transcribes, and writes notes for you. Over 15,000 healthcare professionals use Freed and you should too! Learn more here! On this episode of the Top 200 Drugs Podcast, I cover medications 151-155. This podcast includes; cefuroxime, ketoconazole, pregabalin, esomeprazole, and ipratropium/albuterol. Cefuroxime is a 2nd generation cephalosporin that has a very similar bacterial coverage profile to amoxicillin. It has significant gram positive coverage. Ketoconazole is an azole antifungal medication. It is well known for causing hepatotoxicity as well as interactions via CYP3A4. Pregabalin has a lot of similarities with gabapentin. It can be used fo various pain syndromes such as neuropathy and fibromyalgia. Esomeprazole is a PPI and has a similar profile to omeprazole. It inhibits CYP2C19 and has a few notable interactions that I cover in this episode. Ipratropium and albuterol is a combination of a short acting anticholinergic and short acting beta agonist.

N Engl J Med 2019;381:1524-1534Background Dual antiplatelet therapy after percutaneous coronary intervention had become a standard of care. Both prasugrel and ticagrelor had been shown to provide more rapid and consistent platelet inhibition than clopidogrel. Randomized controlled trials had shown both drugs were superior to clopidogrel in patients with acute coronary syndromes. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The two drugs have different loading strategies in patients who have acute coronary syndromes without ST-segment elevation. In these patients, ticagrelor is usually administered as pretreatment before diagnostic angiography, but prasugrel is administered only after the coronary anatomy has been assessed by means of diagnostic angiography since no advantage has been observed when prasugrel is used as pretreatment.Before ISAR-REACT 5, there had been no direct comparisons of the two antiplatelet drugs. ISAR-REACT 5 was an investigator-initiated multicenter, non-industry funded RCT to compare the efficacy and safety of the two treatments in patients with acute coronary syndrome. Patients The trial enrolled 4013 patients from 23 centers. Patients were eligible with either STEMI, NSTEMI or unstable angina for which intervention was planned. Exclusion criteria included intolerance of either drugs, history of stroke or intracranial bleeding or any condition that increased the risk of bleeding. Patients could not be on concomitant oral or i.v. therapy with drugs affecting CYP3A4 system. Baseline Characteristics There were 2012 patients assigned to ticagrelor and 2006 patients assigned to prasugrel. The suspected diagnosis at admission was STEMI in 41%, NSTEMI in 46%, and unstable angina in 13% of the patients. The average age was 64 years. Female sex was 24%. Average systolic blood pressure and heart rate was 144 mmHg and 77 bpm. All factors were well balanced. Trial Procedures Therapy with ticagrelor was started at a loading dose of 180 mg and continued at a maintenance dose of 90 mg twice daily. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization. Therapy with prasugrel was started at a loading dose of 60 mg and continued at a maintenance dose of 10 mg once per day. A reduced maintenance dose of 5 mg daily was recommended in patients who were 75 years of age or older and in those who had a body weight of less than 60 kg. Prasugrel therapy turned on presentation. STEMI patients were given prasugrel as soon as possible after randomization. In those without STEMI, the loading dose was delayed until knowledge of the coronary anatomy. Prasugrel loading was given before crossing the lesion. In patients with a coronary angiography–confirmed acute coronary syndrome who were not considered to be candidates for PCI but who were considered to be candidates for conservative therapy, dual antiplatelet therapy (aspirin and the randomly assigned trial medication) was recommended. About 83% of patients received PCI, 2% CABG and 13-14% were managed conservatively. Clinical follow-up was scheduled at 30 days, 6 and 12 months.Endpoints The primary end point was a composite of death, MI, or stroke at 1 year after randomization. Secondary end points included the safety end point, which was the incidence of bleeding at 1 year (type 3, 4, or 5 on the Bleeding Academic Research Consortium [BARC] scale, which ranges from 0 to 5, with higher values indicating more severe bleeding), the incidence of the individual components of the primary end point at 1 year, and the incidence of definite or probable stent thrombosis at 1 year.The sample-size calculation assumed a primary endpoint would occur in 10% in the ticagrelor group vs 12.9% in the prasugrel group. This led to an estimate of 1900 patients in each group and 80% power to detect a relative risk reduction of 22% in the ticagrelor group. All analyses, including the analysis of the primary end point, were performed according to the intention-to-treat principle Only the safety end point was analyzed in a modified intention-to-treat population, which included all patients who received at least one dose of the randomly assigned trial drug and were assessed for bleeding events up to 7 days after discontinuation of the trial drug.Results At discharge, 81% of patients in both groups received the randomly assigned trial drug. Slightly more patients in the ticagrelor group stopped taking the study drug by one year (15.2 vs 12.5%). One-year follow-up was complete in all but 90 patients (41 patients in the ticagrelor group and 49 patients in the prasugrel group).A primary end-point event (death, MI, stroke) occurred in 184 of 2012 patients (9.1%) in the ticagrelor group and 137 of 2006 patients (6.8%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P=0.006). The composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 161 of 2012 patients (8.1%) in the ticagrelor group and 124 of 2006 patients (6.3%) in the prasugrel group (hazard ratio, 1.32; 95% CI, 1.04 to 1.66).The rates of death, stroke and stent thrombosis did not statistically differ in the two groups. But the risk of MI was 63% higher in the ticagrelor group (4.8% vs 3.0%; HR 1.63; 95% CI, 1.18 to 2.25).Major bleeding was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).No heterogenous treatment effects were obvious from the subgroup analyses. Discussion For patients with acute coronary syndrome who were considered for intervention, prasugrel was superior to ticagrelor for the reduction of the primary endpoint. The effect size was large (ticagrelor 36% worse compared to prasugrel), and this was statistically robust. The reduction was obtained without an increase in bleeding. The trialists noted that this was not simply a comparison of drugs, but a comparison of treatment strategies. Authors had assumed that pre-treatment of ticagrelor would be superior. But this trial showed that a prasugrel-based strategy with deferred loading (after knowing the coronary anatomy) was superior. The primary endpoint finding was bolstered by the composite of cardiovascular death, MI and stroke also being 32% higher in the ticagrelor arm. This was an investigator-initiated non-industry funded study with an event rate in the ticagrelor arm similar to expected findings. We find this compelling evidence for the superiority of prasugrel in this patient population. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

On this episode, I discuss the new medication vonoprazan and where it will likely be used in practice. Vonoprazan is from a brand new class of medication called "PCAB". I discuss this medication and its pharmacology in this podcast episode. Drug interactions and cost are the two major downsides of this medication that will likely limit its use compared to the PPIs. CYP3A4 inducers like rifampin, carbamazepine, and phenytoin should not be used with vonoprazan. They will reduce the effectiveness of vonoprazan.

On this episode of the Real Life Pharmacology podcast, I take a dive into the most common mechanisms of drug interactions. Below I list some of the common drug interactions seen in practice and how they work! Opposing Effects Many drugs will work on various receptors throughout the body. To use as an educational point, there is no better example to point to than the beta receptor. Beta-blockers are frequently used in clinical practice for their ability to lower blood pressure and slow the heart rate. Both of these beneficial actions are primarily achieved by blocking the effects of beta-1 receptors. Some beta-blockers have action on alternative beta receptors. Propranolol is one such beta-blocker that is classified as a non-selective beta-blockers. This means that in addition to the positive effects on beta-1 receptors, it can also have blocking effects on beta-2 receptors. The blockade of the beta-2 receptor by propranolol can also be life-changing. It can directly oppose beta-2 agonists like albuterol from having their beneficial effects of opening up the airway. Enzyme Inhibition Medication metabolism is arguably the largest and most clinically significant source for drug interactions. Medications that are primarily metabolized by enzymes in the liver can be greatly affected if we affect how those enzymes work. CYP3A4 is one of the most well studied and well-known enzymes that can impact hundreds to maybe even thousands of drugs. Apixaban is an oral anticoagulant that is broken down at least in part by CYP3A4. By using a CYP3A4 inhibitor like erythromycin, there is the potential to raise concentrations of apixaban. This could lead to a higher risk of bleeding. Enzyme Induction Carbamazepine is a drug that you must know. This drug is a potent enzyme inducer. This differs significantly from an enzyme inhibitor and will have the exact opposite clinical effect. Drugs that are inactivated by liver enzymes will be inactivated more quickly in a patient taking an enzyme inducer. Going back to our prior apixaban example above, carbamazepine can induce CYP3A4 and facilitate a more efficient and swifter breakdown of the drug. Bleeding will be less likely. The risk for treatment failure, usually in the form of a blot clot, will be more likely.  Here's more information from the past on carbamazepine. Alteration in Absorption Binding interactions can be consequential and are one of the most common types of drug interactions. Many medications have the potential to bind one another in the gut. This can lead to lower concentrations of a specific medication. Calcium and iron are two of the most common examples of medications that can bind other drugs. Alteration in Protein Binding By remembering that unbound drug is an active drug, you should appreciate the risk for protein binding alterations. A significant number of medications can bind proteins in the bloodstream. As this occurs, that drug is not freely available to create physiologic effects. When another medication is added that can also bind these proteins, this can displace other medications and increase the quantity of free drug in the bloodstream. This essentially allows for enhanced physiologic effects. Warfarin is a medication that is highly protein-bound. When another drug is added that can kick warfarin off of those protein binding sites, it can free up warfarin which will increase the likelihood of elevating the patient's INR and increase their bleed risk. Alteration in Renal Elimination Some drugs can alter the way other medications are eliminated through the kidney. Chlorthalidone, like all thiazide diuretics, has the potential to block the excretion of lithium from the kidney. This can lead to lithium toxicity. This type of interaction, while significant, is much less common than drug interactions involve the liver and CYP enzyme pathways.   Effects on Transporters One of the last types of drug interactions is the effe...

On this podcast episode, I discuss darifenacin pharmacology, adverse effects, drug interactions and much more. CYP3A4 and CYP2D6 are important enzymes in relation to darifenacin. I breakdown the importance of these enzymes and how they can impact drug therapy. Darifenacin has anticholinergic activity but affects the central nervous system less than other agents in its class such as oxybutynin and tolterodine. Darifenacin's pharmacology is selective for the Muscarinic-3 (M3) receptor in bladder tissue which helps reduce the risk for CNS adverse effects.

On this podcast episode, I discuss alfuzosin pharmacology, adverse effects, drug interactions, and much more! Alfuzosin is an alpha blocker used to help relieve the symptoms of BPH. Low blood pressure is a possible adverse effect of alfuzosin and is more likely when combined with PDE-5 inhibitors like sildenafil. CYP3A4 is an important enzyme in the metabolism of alfuzosin. Inhibitors of CYP3A4 can raise concentrations and increase the chance of alfuzosin toxicity.

On this podcast episode, I discuss meperidine pharmacology, adverse effects, pharmacokinetics, drug interactions, and much more! Meperidine is an opioid that is seldom used due to neurotoxicity. I describe how this can happen in this podcast episode. Meperidine has numerous drug interactions and using a CYP3A4 inhibitor may increase the risk for toxicity. Seizures are a risk with meperidine due to its neurotoxic metabolite normeperidine. I discuss this further in this podcast episode.

On this episode of the Real Life Pharmacology Podcast, I cover phenobarbital pharmacology, adverse effects, important drug interactions and much more. Phenobarbital is an enzyme inducer. It is an inducer at CYP3A4 so this can lead to numerous drug interactions. Phenobarbital can exacerbate the risk for opioid overdose and increase the risk for respiratory depression and death. Phenobarbital can deplete numerous vitamins such as vitamin D, folic acid, and vitamin B12. Monitoring of these is important.

This week on ReInvent Healthcare, I emphasize the importance of understanding certain genetic variants and their impact on detoxification pathways. As well as certain tests you can suggest to your clients and foods that can help their detoxification pathways so they live a balanced lifestyle.IN THIS EPISODE:Defining Detoxification PathwaysDetoxification is a critical function, especially in today's world filled with environmental toxins, pesticides, and pollutants. The liver plays a crucial role in detoxification, and there are two phases of detoxification - Phase 1 and Phase 2. Understanding genetic SNPs (single nucleotide polymorphisms) and their role in the body's detox pathways give us valuable insights into individual variations and susceptibilities.Some Detoxification SNPs - There are several genetic SNPs related to detoxification pathways, such as CYP1A1, CYP1A2, CYP1B1, CYP3A4, CYP2C9, and others. These SNPs influence the detoxification of environmental toxins, caffeine, estrogen, prescription drugs, aflatoxin, and more. Understanding these SNPs allows us to identify potential imbalances in detox pathways and helps us make informed decisions for personalized wellness strategies.Importance of TestingTesting is essential to determine whether the detoxification SNPs are active and causing imbalances in the detox pathways. Organic acid tests and blood tests, such as liver function tests and methylation markers, can help identify potential issues. By combining genetic information with lab testing, we gain a comprehensive view of a person's detoxification capabilities. Understanding genetic SNPs and lab results helps us guide patients toward avoiding toxic exposures, environmental pollutants, and food additives that may burden their detox pathways.How To Support DetoxificationOnce genetic SNPs and active detox pathways are identified, our clients can be educated on avoiding toxic substances and making lifestyle changes. These changes may include using non-toxic household products, choosing organic food, avoiding food additives, and reducing exposure to common allergens. Additionally, incorporating certain detox-supporting herbs like artichoke leaf, burdock root, dandelion, and Hawthorn berry can be beneficial.References:Get our FREE Guide to Taking a Detailed Health History that gets you to root causes Access Additional Resources for Practitioners ready to improve clinical outcomes through our Nutritional Endocrinology Practitioner Training. Check out our other episodes about Functional Food Facts here.

On this episode of the Real Life Pharmacology Podcast, I discuss lovastatin pharmacology, adverse effect, drug interactions, and more! Lovastatin is broken down by CYP3A4 so drugs like clarithromycin, diltiazem, and others may increase concentrations. Lovastatin is a lipophilic statin and I discuss the importance of this on the podcast. Lovastatin has a very short half-life which means that it is ideal to dose this medication at night for maximal efficacy.

On this episode of the Real Life Pharmacology Podcast, I discuss amlodipine pharmacology, adverse effects, and important drug interactions. I break down why edema occurs with amlodipine on this episode of the Real Life Pharmacology podcast. While beta-blockers are typically the first-line agent for the prevention of chronic angina symptoms, CCBs like amlodipine can be used as an alternative. There are some potential CYP3A4 interactions with amlodipine. I discuss the severity of these interactions and how to monitor patients.

In this episode, we review clinical pearls and common pitfalls of immunosuppression regimens for organ transplantation with a particular focus on tacrolimus and mycophenolate. Key Concepts Most recipients of an organ transplantation will be on a two or three drug regimen. The most common regimen is tacrolimus and mycophenolate with/without a corticosteroid. Tacrolimus is hepatically eliminated and susceptible to CYP3A4 and PGP drug interactions. Particularly at higher drug concentrations, it is associated with nephrotoxicity and neurotoxicity (among several other adverse effects). Mycophenolate is unstable in the acidic environment of the stomach. The two formulations on the market are CellCept (which uses a prodrug, mycophenolate mofetil, that is converted in the liver to an active compound) and Myfortic (an enteric-coated formulation of mycophenolic acid, which releases after exiting the stomach). The intensity of an immunosuppression regimen is determined by numerous factors, including the type of organ, how long ago the organ was transplanted, if acute rejection has occurred in the past, patient-specific risk factors, and more. Additional Resources Register to be a donor at Donate Life America (https://donatelife.net) or at the HRSA OrganDonor.gov site (https://www.organdonor.gov) Learn more about stem cell donation and transplant at https://bethematch.org

Dutasteride (Avodart) is a 5-alpha-reductase inhibitor. I discuss the pharmacology, adverse effects, and drug interactions on this podcast. Dutasteride reduces the size of the prostate over time. It takes a significant amount of time to provide symptom relief (usually at least 3-6 months). Dutasteride is broken down by CYP3A4 to a minor extent which means that strong CYP3A4 inhibitors may increase drug concentrations. When using dutasteride for BPH, remember to review the medication list for drugs that can cause urinary retention such as anticholintiercs and alpha-agonists.

A drug interaction that should be at the front of our minds.    Check out the Medsafe Data sheet here. https://www.medsafe.govt.nz/profs/PUArticles/March2014StatinsAndCYPInteractions.htm   Check out this paper on a case of rhabdomyolysis.  Fallah, A., Deep, M., Smallwood, D., & Hughes, P. (2013). Life-threatening rhabdomyolysis following the interaction of two commonly prescribed medications. The Australasian Medical Journal, 6(3), 112-114.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626026/#!po=83.3333   www.rnzcuc.org.nz podcast@rnzcuc.org.nz https://www.facebook.com/rnzcuc https://twitter.com/rnzcuc   Music licensed from www.premiumbeat.com Full Grip by Score Squad   This podcast is intended to assist in ongoing medical education and peer discussion for qualified health professionals.  Please ensure you work within your scope of practice at all times.  For personal medical advice always consult your usual doctor  

Brexpiprazole (Rexulti) is a second generation antipsychotic. I discuss its pharmacology, adverse effects, drug interactions, and more in this podcast episode. I like to associate brexpiprazole with aripiprazole. They have a lot of overlapping characteristics, particularly in relation to the adverse effect profile. Brexpiprazole tends to have a low incidence of metabolic adverse effects which makes it a nice selection for patients who have diabetes, hypercholesterolemia, or who are overweight. CYP3A4 and CYP2D6 are the two primary enzymes that break down brexpiprazole. I discuss the pharmacogenomic considerations associated with this medication.

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Follow up to medical miracle, published by Elizabeth on November 4, 2022 on LessWrong. The response to my medical miracle post has been really gratifying. Before I published I was quite afraid to talk about my emotional response to the problem, and worried that people would strong arm in the comments. The former didn't happen and the latter did but was overwhelmed by the number of people writing to share their stories, or how the post helped them, or just to tell me I was a good writer. Some of my friends hadn't heard about the magic pills or realized what a big deal it was, so I got some very nice messages about how happy they were for me. However, it also became clear I missed a few things in the original post. Conditions to make luck-based medicine work In trying to convey the concept of luck-based medicine at all, I lost sight of traits I have that made my slot machine pulls relatively safe. Here is a non-exhaustive list of traits I've since recognized are prerequisites for luck based medicine: I can reliably identify which things carry noticeable risks and need to be assessed more carefully. I feel like I'm YOLOing supplements, but that's because it's a free action to me to avoid combining respiratory depressants, and I know to monitor CYP3A4 enzyme effects. A comment on LessWrong that casually suggested throwing activated charcoal into the toolkit reminded me that not everyone does this as a free action, and the failure modes of not doing so are very bad (activated charcoal is typically given to treat poison consumption. Evidence about its efficacy is surprisingly equivocal, but to the extent it works, it's not capable of distinguishing poison, nutrients, and medications). This suggests to me that an easy lever might be a guide to obvious failure modes of supplements and medications, to lower the barrier to supplement roulette. I am not likely to have the time to do a thorough job of this myself, but if you would like to collaborate please e-mail me (elizabeth@acesounderglass.com). A functioning liver. A lot of substances that would otherwise be terribly dangerous are rendered harmless by the human liver. It is a marvel. But if your liver is impaired by alcohol abuse or medical issues, this stops being true. And even a healthy liver will get overwhelmed if you pile the load high enough, so you need to incorporate liver capacity into your plans. A sufficiently friendly epistemic environment. If it becomes common and known that everyone will take anything once, the bar for what gets released will become very low. I'm not convinced this can get much worse than it already has, but it is nonetheless the major reason I don't buy the random health crap facebook advertises to me. The expected value of whatever it is probably is high enough to justify the purchase price, but I don't want to further corrupt the system. Ability to weather small bumps. I'm self-employed and have already arranged my work to trade money for flexibility so this is not a big concern for me, but a few days off your game can be a big deal if your life is inflexible enough. Somehow I feel obliged to say this even though I've lost work due to side effects exactly once from a supplement (not even one I picked out; a doctor prescribed it) and at least three times from prescription medications. A system for recognizing when things are helping and hurting, and phasing treatments out if they don't justify the mental load. It's good to get in the habit of asking what benefits you should see when, and pinning your doctor down on when they will give a medication up as useless. Although again, I've had a bigger problem with insidious side effects from doctor-initiated prescription meds than I ever have with self-chosen supplements. Probably there are other things I do without realizing how critical they ar...

Link to original articleWelcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Follow up to medical miracle, published by Elizabeth on November 4, 2022 on LessWrong. The response to my medical miracle post has been really gratifying. Before I published I was quite afraid to talk about my emotional response to the problem, and worried that people would strong arm in the comments. The former didn't happen and the latter did but was overwhelmed by the number of people writing to share their stories, or how the post helped them, or just to tell me I was a good writer. Some of my friends hadn't heard about the magic pills or realized what a big deal it was, so I got some very nice messages about how happy they were for me. However, it also became clear I missed a few things in the original post. Conditions to make luck-based medicine work In trying to convey the concept of luck-based medicine at all, I lost sight of traits I have that made my slot machine pulls relatively safe. Here is a non-exhaustive list of traits I've since recognized are prerequisites for luck based medicine: I can reliably identify which things carry noticeable risks and need to be assessed more carefully. I feel like I'm YOLOing supplements, but that's because it's a free action to me to avoid combining respiratory depressants, and I know to monitor CYP3A4 enzyme effects. A comment on LessWrong that casually suggested throwing activated charcoal into the toolkit reminded me that not everyone does this as a free action, and the failure modes of not doing so are very bad (activated charcoal is typically given to treat poison consumption. Evidence about its efficacy is surprisingly equivocal, but to the extent it works, it's not capable of distinguishing poison, nutrients, and medications). This suggests to me that an easy lever might be a guide to obvious failure modes of supplements and medications, to lower the barrier to supplement roulette. I am not likely to have the time to do a thorough job of this myself, but if you would like to collaborate please e-mail me (elizabeth@acesounderglass.com). A functioning liver. A lot of substances that would otherwise be terribly dangerous are rendered harmless by the human liver. It is a marvel. But if your liver is impaired by alcohol abuse or medical issues, this stops being true. And even a healthy liver will get overwhelmed if you pile the load high enough, so you need to incorporate liver capacity into your plans. A sufficiently friendly epistemic environment. If it becomes common and known that everyone will take anything once, the bar for what gets released will become very low. I'm not convinced this can get much worse than it already has, but it is nonetheless the major reason I don't buy the random health crap facebook advertises to me. The expected value of whatever it is probably is high enough to justify the purchase price, but I don't want to further corrupt the system. Ability to weather small bumps. I'm self-employed and have already arranged my work to trade money for flexibility so this is not a big concern for me, but a few days off your game can be a big deal if your life is inflexible enough. Somehow I feel obliged to say this even though I've lost work due to side effects exactly once from a supplement (not even one I picked out; a doctor prescribed it) and at least three times from prescription medications. A system for recognizing when things are helping and hurting, and phasing treatments out if they don't justify the mental load. It's good to get in the habit of asking what benefits you should see when, and pinning your doctor down on when they will give a medication up as useless. Although again, I've had a bigger problem with insidious side effects from doctor-initiated prescription meds than I ever have with self-chosen supplements. Probably there are other things I do without realizing how critical they ar...

Ranolazine is primarily used for chronic angina management. I discuss pharmacology, drug interactions, adverse effects, and more in this podcast episode. Ranolazine is well known to have drug interactions. CYP3A4 is of major importance but there are other subtle drug interactions that are important. QTc prolongation has been reported with ranolazine so it is important to recognize risk factors and other medications that may contribute to this concern. Enzyme inducers like carbamazepine, phenytoin, and St. John's wort are all associated with reducing the concentrations of ranolazine.

Seguimos con las interacciones fármaco-alimento: - Cefuroxima axetilo (Zinnat)Los alimentos favorecen la absorción de la cefuroxima axetilo. Se desconoce a través de qué mecanismo.Para aumentar la biodisponibilidad del antibiótico se recomienda administrarlo juntamente con alimentos. - EtanolLa ingesta continuada o puntual de alcohol, habitual durante las comidas de la cultura occidental, puede provocar también la inhibición o la inducción de ciertos fármacos, especialmente de la mayoría de los que actúan sobre el sistema nervioso central. De hecho, el alcohol interacciona con casi el 50% de los medicamentos más dispensados en la oficina de farmacia (psicofármacos, analgésicos, anticoagulantes, antihipertensivos, antihistamínicos). Muchos de estos fármacos son EFP (p. ej., los antigripales).Es importante desaconsejar la administración conjunta de alcohol mientras dure el tratamiento, así como tener un mayor cuidado en el manejo de maquinaria o vehículos. - Fenilpropanolamina (presente en algunos preparados antigripales)El efecto hipertensor de la fenilpropanolamina puede resultar potenciado por el efecto de la cafeína. La fenilpropanolamina puede también aumentar significativamente las concentraciones plasmáticas de la cafeína. Existe el peligro de crisis hipertensivas y hemorragias intracraneales.Deben evitar el uso de este fármaco los pacientes vulnerables, como los hipertensos (atención a los antigripales EFP como Aspirina Complex y Vincigrip) y evitar la cafeína. - Furosemida (Seguril, Salidur)No se conoce el mecanismo de acción, pero la administración de furosemida conjuntamente con alimentos disminuye su biodisponibilidad.En caso de inicio del tratamiento, hay que recomendar la toma de furosemida en ayunas. Si no es así, no modificar la pauta de administración. - IMAO (Inhibidor de la monoaminoxidasa o un tipo de antidepresivos)Cuando hay interacción de cierto grupo de alimentos con los inhibidores de la monoaminooxidasa (IMAO) se trata de una interacción farmacodinámica.Los fármacos IMAO son un grupo de sustancias que tienen en común su capacidad de bloquear la desaminación oxidativa de aminas endógenas como la noradrenalina y la adrenalina y también la serotonina y la dopamina. También inhiben la metabolización de la tiramina, histamina, betafeniletilamina y triptamina tanto de origen endógeno como ingeridas a través de la alimentación. Podría ocasionarse una crisis hipertensiva a causa de la interacción entre aminas biógenas contenidas en ciertos alimentos (tabla 1) en el caso de una administración conjunta con alguno de estos fármacos.Como consecuencia de la interacción pueden aparecer crisis hipertensivas que pueden ser graves e incluso provocar la muerte por hemorragias intracraneales. Otros posibles síntomas son midriasis, dolor de cabeza, diaforesis, palpitaciones, y nauseas.La medida más adecuada es restringir la ingesta de ciertos alimentos que pueden aportar una concentración variable de estas aminas. - Quinolonas más derivados lácteosCiprofloxacina (Baycip) y norfloxacina (Noroxin) forman quelatos con el calcio si se administran conjuntamente con lácteos. Se interfiere en su absorción y la biodisponibilidad será también mucho menor.Se recomienda no administrar estas quinolonas con derivados lácteos ni ingerir lácteos hasta 2 horas después de la administración del medicamento. Con ello se respetará la eficacia antibacteriana de los fármacos. - TetraciclinasLa administración conjunta de tetraciclinas (Bristaciclina dental) con leche o derivados lácteos es una interacción ampliamente conocida. A causa de la formación de quelatos con el calcio la absorción del fármaco es mucho menor con estos alimentos. Dicha interacción se produce también con otros alimentos que contengan calcio. La doxiciclina (Vibracina) y la minociclina (Minocin), mucho más actuales, interaccionan mucho menos con estos alimentos (se reduce su biodisponibidad en tan sólo un 25-30%).Se deben evitar los lácteos al administrar tetraciclinas. Las tetraciclinas de acción prolonagada (minociclina y doxiciclina) son, además, de elección por ser tratamientos largos. Es preferible la administración del fármaco en ayunas, ya que la quelación puede ser también con otros cationes divalentes distintos del calcio y que se hallen presentes en la comida.- Zumo de pomelo más fármacosLa administración conjunta de ciertos fármacos con zumo de pomelo provoca un incremento significativo en la concentración plasmática de muchos de ellos. Ello es debido a la supresión de la enzima CYP3A4 del citocromo P450 en la pared del intestino delgado, lo que provoca una disminución del metabolismo de primer paso. Ello implica un aumento en la biodisponibilidad y concentraciones plasmáticas más elevadas de los sustratos de esta enzima. En algunos fármacos se pueden encontrar incrementos en el área bajo la curva y la concentración máxima de más del 70%. Hay que añadir a esto que la administración a largo plazo del zumo de pomelo no disminuye la magnitud de la interacción ni se desarrolla tolerancia.Los componentes que tienen una mayor probabilidad de ser los responsables de la interacción son los flavonoides y los derivados cumarínicos.Son muchos los fármacos que interaccionan con el zumo de pomelo y pertenecen a distintas estructuras farmacológicas.Los primeros fármacos que se estudiaron fueron antagonistas de los canales del calcio como felodipina (Perfudal), nifedipina, nitrendipina (Tensogradal), nisoldipina (Syscor) y amlodipina (Norvas); también en otros como diltiazem (Masdil) y verapamilo (Manidon).En algunos casos, al aumentar la concentración del principio activo en sangre se puede aumentar la frecuencia de ciertos efectos secundarios que son dosisdependientes como, por ejemplo, un antiarrítmico como la amiodarona (Trangorex).El incremento de las concentraciones plasmáticas tras la administración conjunta de un fármaco con zumo de pomelo puede ser una ventaja o un inconveniente. Sería una ventaja en fármacos en los que es difícil alcanzar la biodisponibilidad deseada, que son caros y que la pauta posológica requiere mucha frecuencia. Pero, por otro lado, no todos los pacientes reaccionan igual (amplia variabilidad interindividual). La administración conjunta con zumo de pomelo demandaría una complicada monitorización del fármaco o efectos adversos importantes en alguno de los fármacos. Por ello, se recomienda evitar tanto el pomelo como su zumo si se está llevando a cabo un tratamiento con algún fármaco de los antes mencionados. Con otros principios activos que sean extensamente metabolizados hay que evitar esta fruta, a menos que se haya demostrado para los fármacos una ausencia total de interacciones con el pomelo.*

On this episode, I discuss ticagrelor pharmacology, adverse effects, and important drug interactions. Ticagrelor has a warning with regards to the use of aspirin. Higher doses of aspirin can impair the effectiveness of ticagrelor and I discuss this further on this episode. Bleeding is the major adverse effect from ticagrelor and naturally, hematocrit and hemoglobin are important monitoring parameters. I discuss CYP3A4 drug interactions on this episode and how it may affect ticagrelor.

On this podcast episode, I discuss lurasidone pharmacology, adverse effects, and drug interactions. CYP3A4 is an important enzyme in the breakdown of lurasidone. I discuss this further on this episode. Lurasidone is best taken with food as this enhances absorption and helps improve drug concentrations. Lurasidone tends to have a lower risk for metabolic syndrome compared to other antipsychotics which is a nice advantage.

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists. I'm Pradip Kamat coming to you from Children's Healthcare of Atlanta/Emory University School of Medicine. I'm Rahul Damania from Cleveland Clinic Children's Hospital and we are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let's get into our episode: Here's the case presented by Rahul: A 21-month-old girl was brought to an OSH ED for somnolence and difficulty breathing, which developed after she accidentally ingested an unknown amount of liquid medicine that was used by her grandfather. Per the mother, the patient's grandfather was given the liquid medication for the treatment of his opioid addiction. The patient took some unknown amount from the open bottle that was left on the counter by the grandfather. Immediately after ingestion of the medicine, the patient initially became irritable and had some generalized pruritus. The patient subsequently became sleepy followed by difficulty breathing and her lips turned grey. The patient was rushed to an outside hospital ED for evaluation. OSH ED: The patient arrived unresponsive and blue, she was noted to be sleepy and difficult to arouse on arrival, with pinpoint pupils and hypoxic to 88%. , but After receiving Naloxone, however, she became awake and interactive. Her glucose on presentation was 58 mg/dL and Her initial VBG resulted 7.3/49.6/+2. She continued to have intermittent episodes of somnolence without apnea. Poison control called and recommend starting a naloxone infusion; she was also given dextrose bolus. The patient was admitted to the PICU. To summarize key elements from this case, this patient has: Accidental ingestion of an unknown medication Altered mental status Difficulty breathing—with grey lips suggestive of hypoventilation/hypoxia All of which brings up a concern for a toxidrome which is our topic of discussion for today The typical symptoms seen in our patient of pinpoint pupils, respiratory depression, and a decreased level of consciousness is known as the “opioid overdose triad” Given the history of opioid addiction in the grandfather, the liquid medicine given to him is most likely methadone.In fact, in this case, the mother brought the bottle of medicine, which was subsequently confirmed to be prescription methadone given to prevent opioid withdrawal in the grandfather.   To dive deeper into this episode, let's start with a multiple choice question: Which of the following opioids carries the greatest risk of QTc prolongation? A. Methadone B. Morphine C. Fentanyl D. Dilaudid The correct answer is methadone. Methadone prolongs QT interval due to its interactions with the cardiac potassium channel (KCNH2) and increases the risk for Torsades in a dose-dependent manner. Besides the effect on cardiac repolarization, methadone is also associated with the development of bradycardia mediated via its anticholinesterase properties and through its action as a calcium channel antagonist. Hypokalemia, hypocalcemia, hypomagnesemia, and concomitant use of other drugs belonging to the family of CYP3A4 system inhibitors such as erythromycin can prolong Qtc. Even in absence of these risk factors, methadone alone can prolong QTc.   Thanks for that, I think it is very important to involve your Pediatric Pharmacy team to also help with management as children may be concurrent qt prolonging meds. Rahul, what are some of the pharmacological and clinical features of methadone poisoning? Methadone is a synthetic opioid analgesic made of a racemic mixture of two enantiomers d-methadone and l-methadone. besides its action on mu and kappa receptors, it is also an NMDA receptor antagonist. Due to its long action, methadone is useful as an analgesic and to suppress opioid withdrawal symptoms (hence used for opioid...

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I mentioned prednisolone to prednisone conversion in this podcast. Please go check out Pyrls.com for a free steroid conversion downloadable PDF with a free account! On this episode, I discuss prednisolone (Orapred, Pediapred) pharmacology, adverse effects, practice pearls, and drug interactions. Prednisolone is a systemic corticosteroid that can cause insomnia, elevations in blood sugars, and numerous effects if used long-term. CYP3A4 is an important enzyme in the breakdown of prednisolone. Inhibitors or inducers may raise or lower drug levels respectively.

On this episode of the podcast, I cover budesonide (Pulmicort) pharmacology. Our sponsor (Pyrls.com/rlp) for this episode is providing a FREE PDF of their inhaled corticosteroid categorizations chart (i.e. low/medium/high dose ICS) when you sign up for a free account! The onset of action of inhaled budesonide is several hours up to a few days. Patient education is critical to ensure that patients stick with its use. Budesonide does have a nebulized formulation that is often used in pediatrics and geriatrics. There aren't a ton of critical drug interactions, but you should think about medications that inhibit CYP3A4 and may have additive immunosuppressive effects.

On this episode, I discuss verapamil pharmacology, adverse effects, and important drug interactions. There are numerous drug interactions to be aware of with verapamil as it inhibits the enzyme CYP3A4. Verapamil is a calcium channel blocker (non-dihydropyridine) that blocks calcium channels in the heart and vessels. In addition to hypotension and bradycardia, verapamil can cause constipation which may be more prominent in our geriatric patients.

On this episode I discuss roflumilast (Daliresp) pharmacology, adverse effects, and important drug interactions. Roflumilast is indicated to reduce the incidence of COPD exacerbations. Roflumilast is significantly broken down by CYP3A4 so there are numerous drug interactions that we have to take into account. Psychiatric issues, GI upset, and weight loss are all potential adverse effects due to roflumilast.

Fluticasone (Flonase) is a nasal corticosteroid that is used in the management of allergic rhinitis. A primary adverse effect that I have seen in practice with fluticasone is the risk for nose bleeds. Flonase can have some interactions via CYP3A4. Inhibitors of CYP3A4 like clarithromycin can increase concentrations. While the risk for systemic exposure is low with nasal fluticasone, long-term, high dose, and frequent use should be monitored appropriately.

How do you talk to patients about medicinal cannabis? Dr. Ashley Glode (University of Colorado) moderates a discussion on effectiveness and safety, misconceptions and more. Featuring Drs. Ilana Braun (Dana-Farber Cancer Institute), Daniel Bowles (University of Colorado), and Kent Hutchison (University of Colorado). Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 1/19/22   TRANSCRIPT ASHLEY GLODE: Hello, and welcome to ASCO Education's podcast on medical cannabis, also referred to as medical marijuana. My name is Ashley Glode, and I am an associate professor with the University of Colorado School of Pharmacy. It's my pleasure to introduce our three guest speakers Dr. Ilana Braun is chief of the division of adult psychosocial oncology at Dana-Farber Cancer Institute, and an assistant professor of psychiatry at Harvard Medical School. Dr. Daniel Bowles is an associate professor of Medical Oncology at the University of Colorado. We're also joined by Dr. Kent Hutchison, a professor of psychology and neuroscience at the University of Colorado Institute of Cognitive Science. Let's start with a simple but fundamental question. What is medical cannabis or medical marijuana? ILANA BRAUN: So Ashley, I think that's such a great first question. I think of medicinal cannabis as herbal nonpharmaceutical cannabis products that patients use for medicinal purposes. And typically they're recommended by a physician in compliance with state law. DANIEL BOWLES: Dr. Braun makes a really good point. And I think it's important to know when patients are referring to medical cannabis, there's a wide variety of different things they could be referring to. Sometimes they would be referring to smoked herbal products, but there are also edibles, tinctures, ointments, creams, all sorts of herbal-based products that people use and call medical cannabis. And then there are also the components that make up medical cannabis-- largely, the cannabinoids. And I think the big ones people think about are THC and CBD. And sometimes those are used in their own special way. So I think that it's important for us as providers to be able to ask our patients, what is it that you mean when you say, I'm using medical cannabis? ILANA BRAUN: I think that's such a great point. And I will add I think it's also important to remember that when you offer a medicinal cannabis card to a patient, you're giving them license in most states to access any number of products. It's not an insurmountable challenge, but it's a whole new world for traditional prescribers who are used to writing a prescription and defining what is the active ingredient, how often a patient will take the medicine, by what means. DANIEL BOWLES: I think the other thing we need to be very aware of, as hopefully people are listening to this across the country and elsewhere, is the laws vary wildly from jurisdiction to jurisdiction about what consists of medical cannabis, who is allowed to use it, and in what quantities. So I think it's really important that as we learn about these and we think about these, we think about how they apply to any of our specific situations in which we live in practice. KENT HUTCHISON: So it's interesting-- just follow up on what Dr. Braun and Dr. Bowles, what they're saying, those two words-- right-- medical and cannabis. I think the medical part is somewhat easier because it can refer to the reason the person is using. Are they using for medical reasons are they using for recreational reasons, even though that's a blur? But the cannabis part I think is what's really complicated. And this is what Dan was getting at. All the different products, all the different cannabinoids, I mean all the different bioactive terpenes and everything else in the material, all different forms of administration. That is where it gets super complicated to really define what that is. And then of course, there's so little research we don't really know what all those constituents do. ASHLEY GLODE: Now that we kind of have a little bit of familiarity with medical cannabis, can you comment on adult use cannabis and what that might mean for a patient? ILANA BRAUN: Ashley, I think it's a really good question. And in some of the early research I did to try to understand where medicinal ended and adult use began, or adult use ended and medicinal began, I began to discover a theme that emerged, which is they sort of blend into each other often. In other words, some of the oncologists that I spoke to believed that it was not such a bad thing for a patient with serious illness, and pain, and many other symptoms to have a sense of high or well-being. And conversely, when I spoke to patients using cannabis, sometimes a cancer patient used medicinal cannabis for enjoyment, and sometimes they used it for symptom management, and sometimes they used it for both. And so I think it is somewhat of a slippery slope between the two. Would you agree? DANIEL BOWLES: I think there are definitely blurred lines between the two. I think that the advantages of what most states would recognize as medicinal cannabis is usually they're less expensive, patients can use them in larger quantities. There are certain advantages. But there's also paperwork that goes along with medicinal cannabis that some patients don't feel comfortable with. Or particularly I think when you have a patient who's interested in trying cannabis or a cannabinoid for the first time, they might not want to go through all the extra steps required getting that medical marijuana card, whereas adult use, I think people feel more comfortable, at least in my state, sometimes walking into a dispensary to discuss the options with people who work at the dispensary and then get it from more of an adult use or recreational cannabis initially. And then if that's something that they find helpful for their symptom management, to then take those extra steps and try to get a medicinal card. ILANA BRAUN: I agree with Dr. Bowles that the target symptoms or the target effect is often similar and access can differ. KENT HUTCHISON: Yeah. Just to chime in, I agree. I agree also. It's definitely-- the lines get blurred. The recreational user might also appreciate-- for example, college students, I hear them say a lot of times that they appreciate some of the anxiety-reducing aspects-- right-- even though they're not necessarily a person who has an anxiety disorder. And then of course, patients appreciate a slight increase in euphoria or positive affect, and what does that mean? Is I mean they're also using for recreational reasons? Or is that completely, I guess, legitimate? On the other hand, there are sometimes I feel like when-- especially on the recreational side-- when people are using for the more psychological effects, the sort of psychotropic effects, I know sometimes the medical patients refer to that as being a little bit loopy as a side effect. So I feel like there's definitely some blurred lines. And maybe there are some places where we can think about in perhaps in a less blurred kind of way. ASHLEY GLODE: How often do you guys have a patient ask you about medical cannabis? And what are the most common questions they might have for you? ILANA BRAUN: In my psycho-oncology practice, patients frequently tell me they're using cannabis, often with good effect and minimal side effects for polysymptom management-- for instance to address nausea, or pain, or poor appetite, or sleep, or mood, or quality of life. But they don't ask me a lot of questions. For instance, one of my longest-standing patients. A man with metastatic cancer and gastroparesis. Vaporizes cannabis before meals to keep his weight up. And many of my patients also use cannabis as cancer-directed therapy. And for these patients, side effects can sometimes be more pronounced. For instance, I have a lovely patient with metastatic cancer who follows a Rick Simpson protocol. So what is that? That's an online recipe marketed with an antineoplastic claim. And so this patient targets hundreds milligrams of cannabinoids daily. And with such high cannabinoid doses, she sometimes feels spicy, or out of it, as she describes it. And then I had another patient who targeted high daily doses and developed a debilitating nausea and vomiting that was initially diagnosed as chemotherapy-induced nausea vomiting because it was so hard to tease out in the setting of so many medicinal agents, what was what. But the symptoms resolved completely within weeks of the cannabinoids being halted. And so as I mentioned, what's notable about all three of these patients, and many of the others I see, is that they are quite open with their oncology teams and me about their medicinal cannabis use. But they don't seem to rely me or other members of their oncology team for their therapeutic advice . We insert ourselves when we see potential harm, but much of the decision-making seems to be made-- I don't know in the naturopath's office, at the dispensary counter, or by trial and error. And this anecdotal experience in my practice is borne out in my research findings as well. Patients are just not getting the bulk of their cannabis therapeutics information from their medical teams. DANIEL BOWLES: In my clinical practice, I am asked about cannabis or cannabinoids a fair, amount often in the context that Dr. Braun is describing, where a patient is coming in and they're already using a cannabinoid or they are planning on doing it and they just want my opinion. And I think unlike talking about more conventional cancer-directed therapies where they really rely, I think, on their medical team for information and guidance, we are often more a supplement I think in terms of information. In terms of the patients who come to ask me about cannabis or let me know that they're using cannabis, it's a very wide selection of people. I see young people, old people talking about it, men, women, a variety of different malignancies. So there really is a lot of usage or are thought about usage of cannabis or cannabinoids amongst our cancer patients. I think if you look at the studies, they'll tell us that depending on where we're working, anywhere between 20% to 60% of patients have used cannabis in the last year to help manage some sort of cancer-related symptoms. And I think the other thing that is notable is you'll find people asking about cannabis or cannabinoids who I think we might not have otherwise expected. So for instance, Just this past week, I had a patient with anaplastic thyroid cancer in his 70s, and his daughter was wondering whether he could try CBD to help with his sleep and anxiety. She wanted to make sure that it wasn't going to interact with this cancer therapies. And I appreciated her bringing it up, and we could have a frank discussion about the pluses and minuses of it, just like we might any other therapeutic intervention. So I think that particularly as the laws have changed across the country, more and more people are willing to tell us that they're trying cannabinoids and cannabis than maybe would have even 10 or 15 years ago. KENT HUTCHISON: I think in an ideal world, patients would be talking a lot more with their physicians about this topic. And I think unfortunately that a lot of people do get their information from dispensaries. From the media, from social media, from their kids, and from whoever. And I think that's something that I hope will change in the future. DANIEL BOWLES: In terms of questions that I'm often asked, I'll be asked if it's going to interact with their cancer treatments, in terms of making their medications more or less effective. I do get questions about how I think their cannabis use might affect some of their symptoms. I get questions about other drug-drug interactions-- let's say, interactions with opiates, or benzodiazepines, or some of these other medications that a lot of our patients are on. ASHLEY GLODE: In a recent survey 80% of medical oncologists who discussed medical cannabis with their patients, 50% recommended it in the past year, but only 30% felt knowledgeable enough to make recommendations. What do you guys think needs to be done to address this knowledge gap? And what resources do clinicians have to get and stay informed? DANIEL BOWLES: So I'm a big fan of the NCI's PDQ as a great resource. It has a fairly objective information about cannabis and cancer specifically. So I think that's a nice reference for people who are interested in getting an initial overview on the topic. I think there are also a number of different educational programs. I know the University of Colorado, for instance, has a Cannabis Science Master's and also a certificate program. So there are courses available for people who want to educate themselves more on this topic. ILANA BRAUN: Yeah. I guess when I think about what needs to be done, I think that cannabis needs to become a routine part of medical training curricula and CME programs. I think that a federal funding for high-quality clinical trials and a loosening of federal restrictions on accessing study drug were to occur, that would be really a big boon for the medical community. And my colleagues on this podcast I know are doing some very creative pragmatic clinical trials naturalistic studying what is happening in the field. And I am doing clinical trials using an FDA-approved version of cannabinoids. But it's still very hard to study whole-plant cannabis in a form that is sort of a standardized trial drug in a cancer patient. And then when I think about where I would begin to read, I don't think there is a single source, unfortunately. But a great place to start reading is actually a project that Dr. Hutchinson was a part of, which was an expert panel that was assembled by the National Institute of Science Engineering and Medicine in 2017. And they produced a monograph on the health effects of cannabis and cannabinoids. And it's several hundred pages long, including sections devoted just to oncology. So in other words, there is scientific evidence to evaluate, and it's sizable. DANIEL BOWLES: The Austrian Center for Cannabinoid Clinical and Research Excellence also is a helpful resource. One of the nice things about that is they actually give some dosing suggestions or ideas for people who really don't quite know where to start. Right now, there aren't a lot of people in that position to say, here's how it should be done. Here's how it gets dosed. Here are the data to support those decisions. And so the folks in the next level of training don't learn it in the same way that we have learned how to prescribe other medications. And they can't then lay it down. So because the data are scant, in some respects, and particularly for herbal products that So. Many of our patients are using, I think it falls outside the medical model that we've all become so used to using to learn how to take care of patients. And I think that's one reason that so many oncology providers feel interested in learning more about this topic, but don't feel comfortable giving patients guidance on how to use them. KENT HUTCHISON: So both Dr. Braun and Dr. Bowles identified some of the key resources out there. And certainly the training issues that Dr. Bowles just talked about are important. And I do want to emphasize the one thing that Dr. Braun mentioned, which is basically that we do-- we lack research and we lack data on some key important issues, like dosing, for example. What dose is effective? So cannabidiol has been out there for a long time, but what dose is effective for what? We don't know, right? So we definitely lack research. And there are definitely obstacles to doing that research. ASHLEY GLODE: So you guys brought up some good points about there being a lack of data, but also there is some evidence. So what is the current research and evidence on the efficacy of medical cannabis for management of cancer symptoms and cancer pain, specifically? DANIEL BOWLES: So there was a really nice review article that just came out in the BMJ looking at cannabis and cannabinoids, not specific to cancer pain, but including cancer pain. And what they found-- they looked at different preparations from herbal products-- smoked herbal products, oral agents-- cannabinoids, more specifically. They found there is a modest, but a real improvement in pain in patients or research subjects treated with cannabinoids versus those usually typically treated with placebo. In particular, the data are supported in neuropathic pain, I'd say more so than the other pains. I think the data are less compelling with regards to many of the other symptoms that people often use cannabinoids for, such as sleep, anxiety, appetite, things along those lines. ILANA BRAUN: So I'll tell you a little bit about how I think about the evidence base in oncology for cannabis use. So I'll preface this with two points. The first is that, as I mentioned, cannabis products tend not to be one active ingredient, but hundreds of active ingredients-- cannabinoids, phenols, terpenes, they all have bioactivity. And they don't work individually, they work through complicated synergistic and inhibitory interactions that have been termed entourage effects. So I don't think one can easily extrapolate from clinical trials of, say, purified THC, to understand whole-plant cannabis' activity in the body and how it might perform in humans. And then the other point I'll make is that when I think about the types of clinical evidence that we as clinicians hold dearest, it's clinical trials of our agent of interest in our population of interest. So cancer patients using whole-plant full-spectrum cannabis that they would access at a dispensary or grow in their own home. With this in mind, I believe the strongest evidence, randomized double-blind placebo controlled trials of whole-plant cannabis and oncology populations begins to support its utility for chemotherapy-induced nausea and vomiting. So there have been a few studies that have looked at this. But just in 2020, the most recent is a study by Grimison, et al. It was a multicenter randomized double-blind placebo controlled crossover trial comparing cannabis extract. And I think the extract they use was a 1 to 1 THC to CBD ratio versus a placebo in patients with refractory chemotherapy-induced nausea and vomiting. And what they found was that with active drug, there was a complete response in 25% of participants versus only 14% with the placebo. And although a third of participants experienced additional side effects with the active drug-- so remember, this was a crossover trial, so they saw both arms-- 80% preferred cannabis to the placebo medication. So that's clinical trials of cannabis and cancer. But if we expand the base of the pyramid of acceptable evidence to include high-quality clinical trials for health conditions other than cancer and extrapolate back, then I agree fully with Dr. Bowles that there's a growing body of evidence that cannabis may be beneficial in pain management. And there have been many clinical trials done in this arena, and they span myriad pain syndromes, including diabetic neuropathy, post-surgical pain, MS pain, sickle cell pain. And so it does seem like cannabis works for pain management in several other illness models, so we could extrapolate back and hope that it works in cancer pain. And then there is a small body of evidence with nabiximols, which is a pharmaceutical that has a 1 to 1 THC to CBD ratio. And it's a sublingual metered dose spray. And it has been trialed for opioid-resistant cancer pain. And this is not as a single agent, but as an adjuvant to opioids. In early trials, two times as many participants in the active arm as compared to the placebo arm demonstrated a 30% pain reduction. And for the pain specialists who are listening, they will know that is a substantial pain reduction. But then, additional studies fail to meet primary endpoints. I think there were three clinical trials that followed. Nabiximols was found to be safe and effective by some secondary measures, but the FDA opted not to approve nabiximols for cancer pain. So I think there's some suggestion of effect, but there's some smoke, but no fire-- no pun intended. DANIEL BOWLES: I think many of the studies that have been done looking at cannabis-- or cannabinoids-- have been compared to placebo or they've been crossover. And I would say fairly consistently, there is some improvement in pain scores with the cannabis products versus placebo kind of across a wide variety of disease spectrums with regards to pain. I think one of the other questions that a lot of people have asked is, can you decrease people's opiate usage using cannabis? As we know, there's a huge epidemic of opiate misuse in the United States of America right now. And I think many people are looking for ways to decrease opiate usage. There was a nice study done from Minnesota in conjunction with the Minnesota dispensaries-- or state marijuana program-- where some researchers randomized people to starting kind of herbal cannabis products early in their study or three months into their study. So it was kind of a built-in control. And they looked at opiate usage rates, pain scores, quality of life scores, et cetera. What they found is there, again, was some improvement in pain control overall in the cannabis users. However, it did not equate to a decrease in opiate usage. So I think that it's an open question that I think a lot of people want to know the answers to before they start recommending or incorporating cannabis or cannabinoids more widely into their practice. KENT HUTCHISON: It's certainly a complicated issue, in some ways, right? Because the research which is summarized very nicely by both Dr. Braun and Dr. Bowles, it is suggested, but not overwhelming, by any stretch, right? It's not clear-cut. And I think that one of the big issues here we talked about the very beginning is how complicated this cannabis thing is. and Dr. Braun alluded to this also, that there are obviously many different formulations, many potentially active constituents in cannabis. And so what has mostly been studied so far is either synthetic versions of THC or nabiximols, which is probably the closest thing to what some people are using. So I think the jury's still out, for sure. And I think hopefully at some point, what will happen is that some of the products that are actually being used by people-- because most people aren't using nabiximols, most people are not using THC only, hopefully there'll be some trials of the things that people are actually using out there in the real world that will tell us something more about whether it's effective or not. And maybe even more specifically, which constituents-- which parts, together are most effective with respect to pain. DANIEL BOWLES: I think one of the other topics that some of my colleagues have alluded to already is not just cannabis' role in symptom management. I think pain is often what people think of, and people are using it for chemo-induced nausea and vomiting, anxiety, sleep, appetite, but a fair number of patients are also using cannabis or cannabinoids with the hopes that it is going to treat their cancer like a chemotherapy or an immunotherapy may. And oftentimes, patients will point to preclinical studies looking at oftentimes very high doses of THC or CBD that might show tumor cell death or tumor reduction in test tubes. And I spent a fair amount of time-- and I know some of my colleagues spent a fair amount of time-- talking with patients about how it's a big step between cannabis or cannabinoids working to slow cancer growth in a test tube, to working in an animal system, to working in people. ASHLEY GLODE: So what are the most important considerations clinicians should keep in mind before recommending medical cannabis to patients with cancer? DANIEL BOWLES: We should be asking why they want to use cannabinoids. I think just like we might any other medication that people are thinking about trying-- or herbal product that people are thinking about trying-- I think we need to ask why they're interested in using these products. So is it for symptom management? Is it for some of the ancillary side effects of cannabinoids or cannabis? Why are they wanting to use it? And I think trying to incorporate that more than into the medical model, I ask my patients, hey, if you're using this particular product, do you feel like it's doing what you intended it for it to do? If it is and it's legal in your state, great. Do it as you feel fit. If it's not meeting your goals, if it's not helping with the pain, or if it's not helping with the anxiety, or it's not helping with the nausea and vomiting, maybe we should rethink whether we would use it. Just as if I was prescribing more conventional anti-nausea medication and you didn't think it was working, we wouldn't keep using it. So I think that's a really important thing to keep in mind. I think the other thing to know from a safety standpoint is, who else is in the household? We have a psychiatrist on the call with us today. I think there is an ample amount of data that cannabis is not safe for young people. It's not safe for growing brains. And I think we need to make sure, just as we would want people's opiates to be secured, that their cannabinoids and cannabis products are secured as well, from those who do not want to use them. ILANA BRAUN: And the thing I would keep in mind is that in most states, giving patients a medicinal cannabis card is allowing them to access any number of products with different ratios of active ingredients, delivery mechanisms, onset of action, potencies. And if you don't discuss all of these issues with your patients, these are things that they will decide at the dispensary counter, or by discussing with friends and family, or by trial and error. And I think it's really important that we clinicians guide this narrative. ASHLEY GLODE: So what kinds of patients are not good candidates for medical cannabis? DANIEL BOWLES: I would not recommend medical cannabis for people who can't meet some of the criteria we already discussed. So people who can't keep it safe in their households or have concerns about diversion in their own households. Those are people who I think would not be great candidates for medicinal cannabis or cannabinoids. ILANA BRAUN: As the psychiatrist on the call, I would add that I worry for people with a strong history of psychosis, or currently psychotic, or with a strong family history of psychosis. And perhaps those severely immunocompromised, since there is evidence of fungal and mold contamination in some cannabis products. DANIEL BOWLES: The other group of people I discussed this with are patients on immunotherapies. One of the ways that cannabis may be effective in some of the symptoms we discussed is it's an anti-inflammatory agent. One of the ways it could be detrimental for patients on immunotherapies is that it's an anti-inflammatory agent. There is one small study that suggested that patients might have worse responses to immunotherapy who are cannabis users versus those who are not. So that is a conversation I like to have, just so patients feel like they can be informed. I think lastly, cannabis even for people with medical cards, is not free. So there can be a financial burden for people who are using it. So that's something that I'll often bring up with people as well. KENT HUTCHISON: One thing I would add to this would be history of a substance use disorder might also be a consideration here as well. Mainly because you don't know what the person is going to get, and it could be something that lends itself to relapse or encourages a problem. So I would add that to list. ILANA BRAUN: And I would second what Dr. Bowles said about the financial challenges of using cannabis regularly medicinally. It's not something that's covered by insurance, either. So these are out-of-pocket expenses, and they can add up fast, particularly for patients in the oncology space using it for antineoplastic therapy. ASHLEY GLODE: So is there a concern about drug-drug interactions for patients currently undergoing active cancer treatment? DANIEL BOWLES: There are some data that there can be drug-drug interactions with cannabis and certain agents. In particular, cannabidiol, or CBD, is a CYP3A4 inhibitor. And there are a lot of drugs that are metabolized through that particular system. So I think that that's the clinical relevance of those interactions, I think, is sometimes unknown. But that is another topic that I do think we need to make sure we bring up with our patients. ASHLEY GLODE: Thank you. Yeah. So a lot of what we'll do is from a drug interaction perspective, use the FDA-approved products that we have available to run through a drug interaction checker, like Dr. Bowles mentioned. So we'll use dronabinol as the THC-based product and epidiolex as the CBD-based product. There's also some resources, such as natural Medicines Database. And some of the pharmacy programs that we use, you can actually put in marijuana or cannabis as a drug and run drug interaction checks. So there's multiple potential interactions, like he mentioned, through the immune system. But through the cytochrome P450 pathway, cannabis has been shown in some instances to be an inhibitor, sometimes an inducer of certain enzymes, as well as a substrate. So it's really important to work with your pharmacy colleagues to run through different potential interactions that may be present. ILANA BRAUN: I'll just add one thing, just in case that's helpful. I mentioned earlier in the episode that I had a patient who used cannabis as an antineoplastic drug, and targeted very high doses and developed a terrible nausea and vomiting. And when she stopped, so did the nausea and vomiting, even though her chemotherapeutic continued. And I, to this day, don't know if that was a cyclic nausea and vomiting syndrome, which has been known to plague some heavy cannabis users, or whether drug-drug interactions led to her high-dose cannabis triggering high blood concentrations of her cancer-directed therapy at the time. And so I think that drug-drug interactions do need to be carefully weighed. ASHLEY GLODE: So wrapping up, has the medical community stance on medical marijuana shifted in recent years with legalization in many states? ILANA BRAUN: I don't think we know the answer to this, about how sentiment has shifted because there aren't longitudinal studies that I know of examining this question. But we need some. And one could imagine that as medicinal cannabis becomes are commonplace, providers are increasingly confronted with questions about how to guide care and the desire for high-quality clinical trials and in-depth cannabis therapeutics trainings increases-- and as one piece of evidence for this, at the end of 2020 the National Cancer Institute held a first-in-kind four-day conference at the intersection of cannabis and cancer. And so I'm hopeful that grant opportunities will follow from that. DANIEL BOWLES: I think overall there has been more willingness to discuss cannabis in the context of patient care in the last decade. A couple of ways that I see this is I much more frequently see cannabis use described not necessarily in the drug history, or in the social history, but in the medical history, or in their medications, if they're using it for medical or therapeutic purposes. I think the other place that I've noticed cannabis usage become a bit more mainstream is in the clinical trial setting-- not in clinical trials of cannabis, but one of the things that many of us do is clinical trials of new drugs. And very frequently, 10 years ago we ran into trouble trying to get our patients who were using cannabis products for cancer symptom control onto these clinical trials because of potential drug-drug interactions, or just the fear of the unknown. And I feel like we run into that less commonly now. KENT HUTCHISON: I think it's also worth pointing out that there have been more and more podcasts like this one, right? So to the credit of this organization, I think we are seeing some change. I just wanted to highlight that. And I compliment everyone here for putting us together and putting it out there. ASHLEY GLODE: All right. Well, thank you. That is all we have for today. And thank you very much Drs. Braun, Bowles, and Hutchison for a delightful conversation. Thank you so much to all the listeners tuning into this episode of the ASCO Education Podcast. [MUSIC PLAYING]   SPEAKER: Thank you for listening to this week's episode to make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit elearning.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

On this episode, I discuss oxycodone pharmacology, adverse effect, pharmacokinetics, and drug interactions. Oxycodone is broken down by CYP3A4 and CYP2D6. I discuss this further on the podcast and how interactions may alter concentrations. When a patient stops taking oxycodone after being on it for some time, you must recognize common symptoms of withdrawal. Oxycodone comes as in an extended-release and immediate-release oral formulation.

On this episode, I discuss clarithromycin pharmacology, adverse effects, and drug interactions. Clarithromycin is a macrolide antibiotic that can be used for many similar indications as azithromycin. Clarithromycin has numerous drug interactions as it can inhibit CYP3A4. This limits its use in practice. Clarithromycin can be used in the treatment of H. pylori in combination with other antibiotics and a PPI.

On this episode of the podcast, I discuss my approach and strategies to handle grapefruit juice interactions. Grapefruit juice causes drug interactions by inhibiting the CYP enzyme system. More specifically, it inhibits CYP3A4 which is responsible for the breakdown of many medications. Quantity is always an important consideration when assessing grapefruit juice interactions. The more that is taken, typically, the more drug concentrations will be affected. It is important to assess the use of grapefruit juice when your patient has a history of cardiovascular disease, cardiac conditions, pain, mental health disease, or gout as some medications used to treat these diseases can interact with grapefruit juice. If you are looking for more content on drug food interactions, be sure to check out my book in the links below.

Tiotropium is a long acting muscarinic antagonist (LAMA) that is also known by the brand name Spiriva. It comes as an inhaled aerosol solution as well as an inhaled capsule. The main indications are for the treatment of COPD and Asthma. Tiotropium works through reversible competitive inhibition of acetylcholine at type 3 muscarinic receptors in bronchial smooth muscle which leads to bronchodilation. The medication is poorly absorbed in the GI and hepatically metabolized via the CYP2D6 and CYP3A4 pathways. The time to peak is between 5-7 minutes with the half-life elimination between 25-44 hours. Although the data in pregnancy and lactation is limited, the benefits for use likely outweighs the risk for a patient dealing with uncontrolled asthma. Some common side effects are cough, headache, GERD, rash and UTI. Some serious side effects are paradoxical bronchospasms and angle-closure glaucoma. It is important to note that tiotropium is not intended to be a quick-relief inhaler and should not be used for flare-ups or shortness of breath. It is recommended to clean the inhaler once monthly with water air dried. After usage the patient should rinse the mouth out; not due to the risk of thrush like with an ICS but to help prevent xerostomia and throat irritation. Go to DrugCardsDaily.com for episode show notes which consist of the drug summary, quiz, and link to the drug card for FREE! Please SUBSCRIBE, FOLLOW, and RATE on Spotify, Apple Podcasts, or wherever your favorite place to listen to podcasts are. The main goal is to go over the Top 200 Drugs with the occasional drug of interest. Also, if you'd like to say hello, suggest a drug, or leave some feedback I'd really appreciate hearing from you! Leave a voice message at anchor.fm/drugcardsdaily or find me on twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

On this episode, I discuss rosuvastatin pharmacology, adverse effects, drug interactions and pharmacokinetics. Rosuvastatin is a hydrophilic statin which differs from some of the most commonly used statins like simvastatin and atorvastatin. Rosuvastatin is minimally affected by CYP3A4 drug interactions so that is a small potential advantage over simvastatin and atorvastatin. At dosages of 20-40 mg, rosuvastatin is considered a high intensity statin and can bring down LDL by over 50%.

Meloxicam is a nonsteroidal anti-inflammatory non-opioid analgesic medication used to treat osteoarthritis and rheumatoid arthritis. A treatment range is often between 5-15 mg PO qd with a max of 15 mg/day. Meloxicam works through reversible COX1/COX2 enzyme inhibition decreasing thromboxane and prostaglandins leading to antipyretic, anti-inflammatory, and analgesic effects. It is metabolized via the CYP2C9 and CYP3A4 pathways. The time to peak for tablets is around 4-5 hours with a half-life elimination of 13-22 hours. It should not be used during pregnancy and close to conception. Black Box Warning for cardiovascular thrombotic events and GI bleed/ulcerations/perforation. To avoid and minimize GI related issues take with food. Go to DrugCardsDaily.com for episode show notes which consist of the drug summary, quiz, and link to the drug card for FREE! Please SUBSCRIBE, FOLLOW, and RATE on Spotify, Apple Podcasts, or wherever your favorite place to listen to podcasts are. The main goal is to go over the Top 200 Drugs with the occasional drug of interest. Also, if you'd like to say hello, suggest a drug, or leave some feedback I'd really appreciate hearing from you! Leave a voice message at anchor.fm/drugcardsdaily or find me on twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Find the Memorizing Pharmacology book here: https://adbl.co/3wAZEmN The body system we continue to cover is gastrointestinal and omeprazole, esomeprazole, lansoprazole, pantoprazole are all proton pump inhibitors PPIs.  TonyPharmD YouTube Channel here: https://www.youtube.com/c/tonypharmd Suffixes -sone, -son- (GI) Because we're working through the seven major body systems starting with gastrointestinal, I'm going to hold off on talking about steroids for asthma and other respiratory conditions, but there are respiratory and inhaled steroids available such as fluticasone, a component in Advair and budesonide which is a component in Symbicort, both longer acting steroids. First, let's talk about the difference between an official stem and a useful drug suffix. An official stem is on the big list I have at memorizingpharm.com/drugsuffix PDF as these 800 or so are the agreed upon stems for medications by the governing bodies that decide such things. However, there are common endings that are still useful like -sone, s-o-n-e and son, s-o-n. For example, you can see -sone at the end of fluticasone and prednisone. However, budesonide (Enterocort) and ciclesonide (Alvesco) have son, s-o-n, as an infix, in the middle of the word. There are very few infixes in common English. So, look for the letters as an ending or in the middle. However, if you look on the big drug suffix list, pred, p-r-e-d is on the list. That's because prednisone is actually the prodrug for prednisolone, p-r-e-d-n-i-s-o-l-o-n-e which has neither sone, s-o-n-e nor son, s-o-n, but we want to show they have a relationship. Officially pred is for prednisone and prednisolone derivatives. Prednisone can be used for a very powerful medicine for an acute flare up, but it's not one that a patient can use long-term without significant side effects, so we'll talk about that and budesonide (Enterocort) is a steroid for Crohn's disease and ulcerative colitis. Crohn's disease can throughout the small or large intestine and rectum. Ulcerative colitis (UC) typically is at the end of the GI tract and the colon. The letter “U” which starts “Ulcerative colitis” is almost at the end of the alphabet to help you remember the difference. Since UC is at the end of the GI tract, that's a good candidate for rectal formulations. The reason we use steroids is that they reduce prostaglandin and kinin action, which are important inflammation modulators. Our target therapy length for these conditions might be 4 to 8 weeks. Side Effects In the short term, you will see insomnia and stomach upset. That makes sense, the body releases cortisol when you are stressed putting blood glucose in the blood stream, all of that fight or flight action will keep you awake with too much steroid. That is also an important issue with long term use and the raising of diabetics blood sugar. For example, if there is a diabetic patient with UC we have the problem of needing steroid but raising blood glucose as a side effect. Other notable side effects include increased risk of osteoporosis, affecting the bone strength and immunosuppression. When the immune system is reduced, the chance of infection increases. The liver breaks down budesonide very quickly which is good for a localized condition, it doesn't stay in the body as long. However, prednisone, does not break down as quickly which is good for a condition that might affect the whole body like lupus erythematosus. Interactions Remember we want to try to put our interactions and drugs on the patient chart in the GMRINCE order, GI, musculoskeletal, respiratory, immune, neuro/psych and endocrine. So, when you look at a CYP3A4 inhibitor chart and see dozens of medicines, try to order and group them. Here are some examples: Immune - Antibiotics/Antifungals CYP3A4 inhibition can affect macrolide antibiotics such as azithromycin (Zithromax), clarithromycin (Biaxin), and erythromycin (E-Mycin).  Note their suffix is thromycin, t-h-r-o-m-y-c-i-n vs. just mycin, m-y-c-i-n. While we call azole antifungals, “azole antifungals,” the actual stem is -conazole, c-o-n-a-z-o-l-e. Remember we talked about differentiating fluconazole (Diflucan), ketoconazole (Nizoral), and itraconazole (Sporanox), with proton pump inhibitors esomeprazole and the -prazole ending and the antipsychotics, -piprazole such as aripiprazole. Cardio Verapamil (Calan) is a calcium channel blocker with the pamil, p-a-m-i-l ending. Endocrine We discussed the issue of diabetes and increased blood sugar earlier.    

Tramadol can be used to treat and manage moderate to severe acute and chronic pain. It is also known as Ultram. An off label use is for Restless Leg Syndrome (RLS). When treating acute or chronic pain initiate 25-50 mg every 4-6 hours as needed with a max dosing range of 50-100 mg every 4-6 hours. The max dose per day is 400 mg. Tramadol acts on the mu-opioid receptor by blocking the ascending pain pathway. It alters the pain response and perception along with blocking reuptake of both serotonin and norepinephrine. Tramadol is extensively metabolized hepatically via the CYP3A4 and CYP2D6 pathway creating the metabolite M1. There is concern in children that are ultra-rapid metabolizers of CYP2D6 and use should be avoided in children. There are numerous black box warnings such as for addiction/abuse/misuse, risk of medication errors, accidental ingestion, and contaminant use w/ benzodiazepines or other CNS depressants. Monitor patients for level of pain relief and EKG and HR in patients with a family history of heart conditions. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Welcome all to IS PHARMACOLOGY DIFFICULT Podcast! I am Dr Radhika Vijay.Wonder is the beginning of wisdom!! I'd rather open my mind with wonder than close it with belief!! That's the mantra for today as I start the topic of day which goes on like "Drug Metabolising Enzymes-1"I will start my convo by classifying metabolising  enzymes into Microsomal and Non microsomal. Then I will throw light on each of the characteristics, features, sub heads and examples of each type, their details though not in much depth will be conversed upon!!i will in detail cover variety of isoenzymes of superfamily cytochrome P450, their different isoenzymes, features, inducers, inhibitors, etc.I will be talking in detail about nomenclature, specificity and genetic variability.That is the time and moment not to give in or give up, rather listen to clock's command to call it for the day and pack it all in! For all the updates and latest episodes of my podcast, please visit www.ispharmacologydifficult.com where you can also sign up for a free monthly newsletter of mine. It actually contains lot of updates about the medical sciences, drug information and my podcast updates also. You can follow me on different social media handles like twitter, insta, facebook and linkedin. They all are with same name "IS PHARMACOLOGY DIFFICULT". If you are listening for the first time, do follow me here, whatever platform you are consuming this episode, stay tuned, do rate and review on ITunes, Apple podcasts, stay safe, stay happy, stay enlightened, Thank you!!You can access various links viahttps://linktr.ee/ispharmacologydifficult

Tamoxifen is a selective estrogen receptor modulator that comes in both a tablet and solution. The tablet comes in a 10 mg and 20 mg strength and the solution comes in a 10 mg/5 mL concentration. Tamoxifen, also known as the brand name Femara, when used in reducing the risk of Breast Cancer in high risk females the dosing is 20 mg once daily for 5 years. When used in treating Breast Cancer the dosing does vary at 20-40 mg once daily. When 40 mg is needed per day the daily dose is divided into separate doses. When tamoxifen is metabolized via the CYP2D6 and CYP3A4/5 pathways the metabolites are 30-100 times more potent than tamoxifen itself. There is a black box warning for Uterine Malignancies and Thromboembolic Events. The monitoring parameters are bone mineral density, lipid panel, CBC with platelets, ophthalmic exam, and for medication adherence. The medication can be taken with or without food. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

On this episode I discuss colchicine pharmacology, adverse effects, drug interactions, and pharmacokinetics. Colchicine ultimately works by reducing the activity of neutrophils that help contribute to pain and inflammation associated with gout. Colchicine does have some drug interactions with medications and grapefruit juice via CYP3A4. The most common dose limiting side effect of colchicine is diarrhea. Colchicine can be used as a potential alternative to NSAIDs or corticosteroids in the management of a gout flare.

Let's get on to Macrolides, Lincosamides. A little bit of stuff on protein biosynthesis won't hurt to help us understand the pharmacology of these class of drugs, macrolides and Lincosamides. Bacterial protein synthesis involves proteins required for reproduction, and is made possible by ribosomal RNA, mRNA and tRNA. To begin, the double stranded DNA first unwinds in an untwisting motion in the region which codes for the specific protein to be made and only that one strand of the DNA serves as a template for what is known as transcription. RNA polymerase makes a copy of this segment, which now stands as what is called mRNA. Once the strand of mRNA is complete, it detaches from that segment, and in turn become attached to ribosomes. Now it gets interesting. Bacterial ribosomes are made of two subunits, the small 30s and a bigger 50s ribosomal subunits, together makes up 70s ribosomal unit. The numbers don't add up right? Yes 30+50 is not 70. If you want to know why, download the Podroom app and join the discussion, there you can ask me and I'll explain. For now, we move. The ribosomal subunits attach to the mRNA strand like a zipper and begin the synthesis of the polypeptide chain, along that strand. Now the amino acids needed for this synthesis, is bound to tRNA, so tRNA + amino acids bind to the ribosome which is on the mRNA strand and begins to work its way from one end of the strand to the other, making the polypeptide chain in the process, until it hits a stop codon which makes it stop and release the full polypeptide chain it has been making. The 70s ribosome couples itself back and awaits further instruction. It's very easy, see, these are the steps 1.    Bacterial DNA unwinds to reveal a segment to be copied 2.    RNA polymerase makes a copy of this segment, a complete mirror image of the segment, detaches this new copy, which now stands alone as mRNA 3.    This mRNA attaches to 70s ribosome, which clasps the strands above and below with its two subunits 50s and 30s 4.    tRNA which contains amino acids is then bound to the ribosome and this moves along the mRNA strand to synthesize the polypeptide chain. 5.    Macrolides and Lincosamides inhibit this ribosome and do not allow it to move. If it cannot move, polypeptide and hence protein synthesis stops, and bacteria cannot grow, everything becomes static, that is why they say these drugs are bacteriostatic. So now, drugs that affect ribosomes in protein synthesis either affect the 50s or 30s subunits of the 70s ribosome. Don't worry, there is a mnemonic for that. Buy AT 30 and CELL @50 Aminoglycosides and tetracyclines inhibit protein synthesis by inhibiting the 30s ribosomal subunit. Chloramphenicol, Erythromycin (macrolides), Lincosamides and Linezolid all inhibit 50s ribosomal subunit. So macrolides – are a class of antibiotics that contain the following drugs 1.    Erythromycin – the oldest, strep, staph, pertusis, diphtheria, M. pnemonia 2.    Clarithromycin- strongly g +ve, used in eradication of H. pylori, renal toxicity 3.    Azithromycin – strong G -ve, RTI mainly As you go from erythromycin to azithromycin, you go from old to new, and also their half lives increases in that fashion, and hence their frequency of dosing reduces. *MOA* - just like I said, inhibits 50s, along with other counterparts in the mnemonic CELL @50 *Spectrum of activity* – G -ve and +ve, anaerobes (upper airway), atypical bacteria (legionella, chlamydia, mycoplasma etc), others like mycobacterium avium complex, campylobacter, treponema pallidum etc *Absorption* - food decreases it, why enteric coated ones are made. Clarithromycin is well absorbed irrespective of food. *Distribution-* all body fluids and placenta except CSF *and Elimination* - Hepatic: ALL, only clarithromycin is partially excreted by renals, why it needs renal adjustment at times. Cannot dialyze. Erythro t1/2- 1.5hrs, clarithromycin about 6hrs, Azithro – 68hrs *Resistance* - 80% is through the active efflux mechanism in which the mef gene encodes for an efflux pump that actively pumps macrolide out of the cell, away from the ribosome it is supposed to inhibit. Another mechanism is one in which a gene alters the binding site of the macrolide on the ribosome. Lastly, there is cross resistance which occurs between all macrolides. *Adverse Reactions* - M- Motility A: Arrythmias (prolonged qt interval) C: Cholestatic Hepatitis R: Rash 0: eosinophilia *Drug interaction* : it inhibits CYP3A4 enzyme leading to increased effects of carbamazepine, theophylline, warfarin, valproate. Enough of Macrolides. Let's talk about a close relative in mechanism of action. The Lincosamides Briefly! In this class is Clindamycin and Lincomycin They are active against staph, gram +ve and -ve anaerobes. Also against Bacteroides. Mechanism of action – You know this already, yes say it, of course if you Cell@ 50 you will know it binds to 50s ribosome and hence inhibits protein synthesis. It is absorbed well, penetrates well into most tissues including bone, but not CSF Excreted via the liver, bile and Urine. Resistance: mechanisms via drug inactivation, alteration of 50s ribosomal subunit by adenine methylation and mutation of the 50s ribosomal protein. *USES:* 1.    Anaerobic infections 2.    Osteomyelitis, arthritis 3.    AIDS related toxoplasmosis (combined with pyrimethamine) 4.    AIDS related pneumocystis carinii pneumonia. ADVERSE REACTIONS: 1.    Severe diarrhea- pseudomembranous enterocolitis caused by clostridium deficille 2.    High IV dose – neuromuscular blockade 3.    Neutropenia 4.    Impaired liver function 5.    Hypersensitivity And that's all fellas. Next, we talk about Sulphonamides in the next episode. This content is made for medical students, all pharmacology enthusiasts and medical practitioners who want to refresh their memory within the shortest possible time. This is meant to be used in conjunction with detailed pharmacology notes or texts, not sufficient as a standalone.

On this episode, I discuss cyclosporine pharmacology. This medication is an immunosuppressant used to reduce the risk of transplant rejection. Cyclosporine has a long list of potential adverse effects such as hyperglycemia, renal impairment, GI toxicity, and hypertriglyceridemia. Important monitoring parameters for cyclosporine include drug levels, electrolytes, renal function, and blood sugars. CYP3A4 interactions are critical with cyclosporine. Inhibitors can raise concentrations and inducers can lower concentrations.

MerhabaBu yazımızın konusu kolşisin. Ülkemizde özellikle FMF tedavisinde sıkça kullanılmasıyla günlük pratiğimizde sık sık karşılaştığımız bu ilaç şimdi de farklı bir başlıkta, COVİD tedavisinde, karşımıza çıktı. Kolşisinin hem etkilerini hem toksisitesini gözden geçireceğimiz bu yazımızda kolşisinin COVİD tedavisindeki olası yerinden ve Ocak 2021 sonunda yayınlanan klinik çalışmalardan da bahsedeceğiz.İyi okumalar Kolşisin Nedir Ne Değildir? Kolşisin, zambak ailesinden Colchicum autumnale ve Gloriosa superba isimli bitkilerden elde edilebiliyor ve aslında antik dönemlerden beri bilinen bir molekül. İlk olarak M.Ö. 3. yüzyılda zehir olarak sınıflandırılıyor; M.S. 6. yüzyılda eklem ağrılarında kullanılmaya başlanıyor. 1800’lerin başındaki medikal kayıtlarda gut artriti tedavisinde kullanıldığını görüyoruz. Günümüzdeki endikasyonları da aslında benzer; FMF ve gut atak tedavisi ve profilaksisi. Ruhsatlandırıldığı bu endikasyonlar dışında Behçet hastalığı, skleroderma, psödogut, sarkoidoz, amiloidoz, psöriazis, primer bilier siroz gibi özellikle otoimmun hastalık gruplarında öneriliyor. Yine inflamasyonun kötüleştirdiği perikardit, postperikardiyotomi sendromu, stabil iskemik kalp hastalığı gibi durumlarda kullanımına yönelik öneriler mevcut. Kolşisin temel olarak intrasellüler tübüline bağlanıyor, mikrotübül polimerizasyonunu inhibe ediyor. Mikrotübüller, hatırlayacağımız gibi aslında hücre iskeletinin çok önemli parçaları ve hücreiçi işleyişte çok önemli yer taşıyorlar. Hücrenin şekli, intrasellüler maddelerin transferi, sitokin ve kemokin salınımı, hücre migrasyonu, iyon kanallarının aktivitesinin düzenlenmesi ve hücre bölünmesi süreçlerinde görevliler. Kolşisin mikrotübül inhibisyonu ile mitozu metafaz evresinde durduruyor. Mitokondriyal aktiviteyi sınırlıyor. İnflamatuar hücrelerin kemotaksisini ve endozom ve eksozom transportunu inhibe ediyor. İnflamazom aktivasyonunu engelleyerek Kaspaz 1 aktivasyonunu ve IL-1 ve IL-8 salınımını engelliyor. Önemli bir adhezyon molekülü olan E-selektin ekspresyonunu da azaltarak monosit ve nötrofillerin etkisini azaltıyor. Nötrofillerin serbest oksijen radikali üretimini azaltıyor. Özetle inflamasyonu pek çok aşamada baskılıyor.Farmakokinetiğinde özellikle bilmemiz gereken noktalar; ilaç etkileşimleri açısından önemli olan CYP3A4 ve p-glikoproteine bağlandığı; karaciğer ve böbrek üzerinden atıldığı, bu sebeple de karaciğer ve böbrek yetmezliği durumlarında dikkatli kullanılması ya da doz ayarlaması gerektiği. Kolşisin Toksisitesi Kolşisin intoksikasyonu, nadir görülmekle beraber, kolşisinin terapötik aralığının dar olması ve toksisitesi halinde gerek diyalizden fayda görmemesi gerekse antidotu olmaması sebebiyle mortalitesinin yüksekliği ile biz acilciler için ciddi önem taşımaktadır. Kolşisinin tedavide kullanılan dozları 0,5-1 mg/gün olup atak tedavilerinde saatlik dozlara bölünmüş olarak maksimum 6 mg/güne kadar çıkılabilir. Metabolizması; CYP3A4 ve böbrek fonksiyonlarına göre değişebildiği için, doz arttırımında özellikle gastrointestinal yan etkilerin başlaması toksik etki olarak görülür. Doz arttırımı bu etkilerin görülmesiyle sınırlandırılır. Genel olarak 0,8 mg/kg doz alımında toksik etkiler görülmeye başlanır, özellikle 1 mg/kg üstünde ciddi toksisite bildirilmiştir.  Toksisitesi, geniş sitotoksik etkisi sebebiyle, neredeyse tüm organ ve sistemleri etkiler. 4-12 saatlik latent periyot sonrası toksisite semptomları görülmeye başlar. Kliniğini temel olarak 3 faza ayırabiliriz (Tablo 1). İlk fazda bulantı kusma, ishal, karın ağrısı gibi gastrointestinal bulgular ortaya çıkar; resüsite edilmezse ciddi sıvı kaybı, elektrolit imbalansı ve hipovolemik şoka ilerleyebilir. 24-72 saat sonra hayatı tehdit edici komplikasyonların oluştuğu ikinci faz görülür. Bu dönemde miyokardiyal depresyon, aritmiler, kemik iliği depresyonu, böbrek yetmezliği, karaciğer yetmezliği, solunum yetmezliği (ARDS), koagülopati (DİK) ve nöromuskuler anormallikler (periferal nöropati, deliryum, nöbet,

On this episode, I discuss bromocriptine pharmacology. It is a dopamine agonist that can be used for hyperprolactinemia and Parkinson's symptoms. One of the major side effects of bromocriptine is nausea which stems from its dopamine agonist action. Because bromocriptine is a dopamine agonist, it can counteract the action of antipsychotics. Bromocriptine is broken down by CYP3A4, so drug interactions can be common. Erythromycin, some of the azole antifungals, verapamil, grapefruit juice, and diltiazem are all medications that can increase concentrations.

On this episode, I discuss tacrolimus pharmacology. This medication is an immunosuppressant used to reduce the risk of transplant rejection. Tacrolimus has a long list of potential adverse effects such as hyperglycemia, renal impairment, GI toxicity, and hypertriglyceridemia. Important monitoring parameters for tacrolimus include drug levels, electrolytes, renal function, and blood sugars. CYP3A4 interactions are critical with tacrolimus. Inhibitors can raise concentrations and inducers can lower concentrations.

Ubrogepant is currently brand only and known as Ubrelvy. This drug is a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist used to treat migraines. There are two tablet strengths being the 50 mg and 100 mg dose. Initiated begins between 50 - 100 mg po for one dose and may be repeated after 2 hours for one more dose. The max dose is 200 mg per day. Dose adjustments should be made in patients with renal and/or hepatic impairment. This drug is primarily metabolized hepatically through the CYP3A4 pathway. Strong inhibitors or inducers for CYP3A4 should be avoided or used with dose adjustments. Ubrelvy's time to peak is around 1.5 hours with a half-life of 5-7 hours. Patients should be aware of drowsiness, and nausea and should not use drugs or substances that may enhance drowsiness such as alcohol. Ubrelvy can be taken with or without food and for best results not taken with a high-fat meal. Go to DrugCardsDaily.com for episode show notes which consist of the drug summary, quiz, and link to the drug card for FREE! Please SUBSCRIBE, FOLLOW, and RATE on Spotify, Apple Podcasts, or wherever your favorite place to listen to podcasts are. The main goal is to go over the Top 200 Drugs with the occasional drug of interest. Also, if you'd like to say hello, suggest a drug, or leave some feedback I'd really appreciate hearing from you! Leave a voice message at anchor.fm/drugcardsdaily or find me on twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Aripiprazole is metabolized by CYP2D6 and CYP3A4. Because of this, drug interactions can happen. I discuss specific examples in this episode. Partial dopamine agonist activity and serotonergic activity make up a significant amount of aripiprazole's pharmacology. Aripiprazole is classified as an antipsychotic and can be used in schizophrenia, bipolar disorder, and depression augmentation. Aripiprazole can cause significant akathesia. I discuss this adverse effect on this episode.

What is it about grapefruit that makes it incompatible with so many prescription drugs? What is CYP3A4? What about other similar fruits? Why the name grapefruit if there's no relation to grapes?   ... We explain like i'm five!   Thank you to the r/explainlikeimfive community as always and in particular the following users whose questions and comments formed the basis of this discussion: z-freak, smitten430kittens, 2pam, mistmanx, unusually_awkward, zldfn101, iamlizzy1, capt_groomp, dooks4introvert, notyogrannysgrandkid, femifoodie & tgpineapple To the ELI5 community that has supported us so far, thanks for all your feedback and comments. Join us on Twitter: https://www.twitter.com/eli5ThePodcast/ or send us an e-mail: ELI5ThePodcast@gmail.com

Paul J. Wang: Welcome to the monthly podcast! On the Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wang, Editor-in-Chief. With some of the key highlights from this month's issue. Paul J. Wang: In our first paper, Demilade Adedinsewo and associates assess the accuracy of an artificial intelligence-enabled electrocardiogram [AI-ECG] to identify patients presenting with dyspnea who have left ventricular LV systolic function (defined as LV ejection fraction ≤35%) in the emergency department [ED]. Patients were included if they had at least one standard 12-lead electrocardiogram [ECG] acquired on the date of the ED visit and an echocardiogram performed within 30 days of presentation. Patients with prior LV systolic dysfunction were excluded. A total of 1,606 patients were included. Meantime from ECG echocardiogram was one day. The AI-ECG algorithm identified LV systolic dysfunction with an area under the curve [AUC] of 0.89 and accuracy of 85.9%. Sensitivity was 74%, specificity 87%, negative predictive value 97%, and positive predictive value 40%. To identify an ejection fraction less than 50%, the AUC was 0.85, sensitivity 86%, sensitivity 63%, and specificity 91%. NT-proBNP alone with a cutoff greater than 800 identified LV systolic function with an AUC of 0.80 by comparison. Paul J. Wang: In our next paper, Mahmood Alhusseini and associates hypothesize that convolutional neural networks [CNN] may enable objective analysis of intracardiac activation in atrial fibrillation [AF]. They perform panoramic recording of bi-atrial electrical signals in AF and use the Hilbert-transform to produce 175,000 image grids in 35 patients labeled for a rotational activation by experts who showed consistency, but with variability (kappa [κ]=0.79). In each patient, ablation terminated atrial fibrillation. A CNN was developed and trained on 100,000 AF image grids validated on 25,000 grids, and then tested on a separate 50,000 grids. They found in a separate test cohort of 50,000 grids, CNN reproducibly classified AF image grids into those with or without rotational sites with 95.0% accuracy. This accuracy exceeded that of support vector machines, traditional linear discriminant, and k-nearest neighbor statistical analyses. To probe the CNN, they applied gradient weighted class activation mapping, which revealed that the decision logic closely mimicked rules used by experts (C statistic 0.96). The authors concluded that convolutional neural networks improve the classification of intercardiac AF maps compared to other analyses and agreed with expert evaluation. Paul J. Wang: In our next paper, Kenji Okubo and associates examined whether late potential LP, abolition and ventricular tachycardia [VT] non-inclusive ability predicted long-term outcomes in patients with non-ischemic cardiomyopathy [NICM] undergoing VT ablation. The total 403 patients with NICM (523 procedures) who underwent VT ablation from 2010 to 2016 were included. The underlying structural disease consists of dilated cardiomyopathy (DCM, 49%), arrhythmogenic right ventricular cardiomyopathy (ARVD 17%), postmyocarditis (14%), valvular heart disease (8%), congenital heart disease (2%), hypertrophic cardiomyopathy (2%), and others (5%). Epicardial access was performed in 57% of patients. At baseline, the LPs were present in 60% of patients, and a VT was either inducible or sustained/incessant in 85% of the cases. At the end of the procedure LP abolition was achieved in 79% of cases in VT noninducability in 80%. After a multivariate analysis, the combination of LP abolition and VT noninducibility was independently associated with free survival from VT (hazard ratio, 0.45, p = 0.0002) and cardiac death (hazard ratio 0.38, P = 0.005). The benefit of LP abolition of preventing the VT recurrence in ARVD and postmyocarditis appeared superior to that observed for DCM. Paul J. Wang: In our next paper, Domenico Corradi, Jeffrey Saffitz and associates hypothesize that structural molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict postoperative atrial fibrillation [POAF] may identify new molecular pathways and targets for prevention of this common morbid complication. Right atrial appendage [RAA] samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial. 35.2% of patients experienced POAF compared to the non-POAF group. They were significantly older and more likely to have chronic obstructive pulmonary disease or heart failure. They had a higher Euro score and more often underwent valve surgery. No differences in atrial size were observed between POAF and non-POAF patients. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen storage, or connection 43 distribution at the time of surgery, was not significantly associated with the incidents of POAF. None of these histopathological abnormalities were correlated with level of NT pro-BNP, hs-cTnT, CRP, or oxidative stress biomarkers. The authors concluded that in sinus rhythm patients undergoing cardiac surgery, histopathological changes in RAA do not predict POAF. They did not also correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Paul J. Wang: In our next paper, Mark McCauley, Liang Hong, Arvind Sridhar, and associates hypothesize that obesity decreases sodium channel NAF 1.5 expression via enhanced oxidative stress, thus reducing the sodium current and enhancing susceptibility to atrial fibrillation [AF]. They studied a diet induced obese [DIO] mouse model. Pacing induced AF in 100% of DIO mice versus 25% in controls (P 20 ms shorter than the other sites, and/or induction of AF/atrial tachycardia during measurements. LVA ablation was performed in the LA-LVA patients during the follow-up period of a mean of 62 weeks, the EP test-guided group had a significantly lower recurrence rate (19%,11/57 versus 41%, 22/54, P=0.012) and a higher Kaplan-Meier AF/AT-free survival curve compared with controls (P=0.01). No significant differences in the recurrence, and AF/AT-free survival curves between PWI (positive EP test) and non-PWI (negative EP test) subgroups were observed. Therefore, PWI for positive EP tests reduced the AF/AT recurrence in the EP test-guided group. A stepwise Cox proportional hazard analysis identified EP test-guided ablation as a factor, reducing recurrence rates. The recurrence rates in LA-LVA ablation group and EP test-guided group were similar. Paul J. Wang: In our next study, Jinxuan Lin and associates assess whether simultaneous pacing of the left and right bundle branch areas may achieve more synchronous ventricular activation than just bundle pacing alone. In symptomatic bradycardia patients, the distal electrode of the bipolar pacing lead was placed at the left bundle branch area via a transventricular-septal approach. This was used to pace the left bundle branch area, while the ring electrode was used to pace the right bundle branch area. Bilateral bundle branch area pacing [BBBP] was achieved by stimulating the cathode and anode in various configurations. BBBP was successfully performed in 22 out of 36 patients. Compared with LBBP, BBBP resulted in greater shortening of QRS duration (109.3 vs 118.4 ms, P < 0.001). LBBP resulted in paced RBBB configuration with a DRVAT of 115 ms and interventricular conduction delay of 34.0 ms. BBBP fully resolved the RBBB morphology in 18 patients. In the remaining 4 patients, RBBP pacing partially corrected the right bundle branch block. Paul J. Wang: In our next paper, Ramanathan Parameswaran, Jonathan Kalman, Geoffrey Lee and associates recorded 2-minute long segments of simultaneous inter-operative mapping of endo- and epicardial lateral right atrial [RA] wall in patients with persistent atrial fibrillation [AF] using 2 high-density grid catheters (16 electrodes, 3 mm spacing). Filtered unipolar and bipolar electrograms [EGMS] of continuous 2-minute AF recordings and electrodes locations were exported for phase analysis. They defined endocardial-epicardial dissociation [EED] as phase differences of ≥20 ms between paired endo- and epi electrodes. Wavefronts [WF] were classified as single rotations, that is single wavefront, focal waves, or disorganized activity as per standard criteria. Endo-Epi wave fronts were simultaneously compared on dynamic phase maps. Complex fractionated electrograms were defined as bipolar electrograms with directional changes occupying at least 70% of the sample area. 14 patients with persistent AF underwent cardiac surgery are included. EED was seen in 50.3% of phase maps with significant temporal heterogeneity. Disorganized activity (endo 41.3%, epi 46.8%, P = 0.0194) and single wave (endo 31.3 versus epi 28.1, P = 0.129) were the dominant patterns. Transient rotations (endo 22%, epi 19.2%, P = 0.169, mean duration 590 ms) and non-sustained focal waves (endo 1.2% and epi 1.6%, P = 0.669) were also observed. Apparent transmural migration of rotational activations (n=6) from the epi- to the endocardium was seen in 2 patients. EGM fractionation was significantly higher in the epicardium than endocardium (61.2% versus 51.6%, P < 0.0001). The authors concluded that simultaneous endo-epi phase mapping of prolonged human persistent AF recordings showed significant EED marked temporal heterogeneity, discordant and transitioning wavefronts patterns and complex fractionations. No sustained focal activity was observed. Such complex 3-dimensional interactions provide insights into why endocardial mapping alone may not fully characterize the AF mechanism and why endocardial ablation may not be sufficient. Paul J. Wang: In our next paper, Andrew Beaser and associates hypothesize that intravascular ultrasound [IVUS] could accurately visualize and quantify intravascular lead adherence and degree of intravascular lead adherence correlates with transvenous lead extraction difficulty. Serial imaging of leads occurred prior to transvenous lead extraction using IVUS. Intravascular lead adherence areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with intravascular lead adherence grade. Lead extraction difficulty was calculated for each patient and compared to IVUS findings. 158 vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low = 0 versus high grade 97 seconds, P < 0.001) and median laser pulsations delivered (low = zero versus high grade 5,852, P < 0.001) were significantly higher in the high-grade segments. Most patients with low lead extraction difficulty score had low intravascular lead adherence grades. 86% of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores. Paul J. Wang: In our next paper, András Bratincsák, and associates sought to create the foundation of normative ECG standards in the young using Z-scores. 102 ECG variables were collected from a retrospective cohort of 27,085 study subjects with no known heart conditions, age zero to 39 years. The cohort was divided into 16 age groups by gender. Median interquartile range and range were calculated for each variable adjusted to body surface area. Normative standards were developed for all 102 ECG variables, including heart rate; P, R, and T axis; R-T axis deviation; PR interval, QS duration, QT, and QTc interval; P, Q, R, S, and T amplitudes in 12 leads; as well as QRS and T wave integrals. Incremental Z-score values between negative 2.5 and 2.5 were calculated to establish the upper and lower limits of normal. Historical ECG interpretive concepts were reassessed and new concepts observed. The author summarized that electronically acquired ECG values based on the largest pediatric and young adult cohort ever compiled provide the first detailed, standardized, quantitative foundation of traditional and novel ECG variables. Paul J. Wang: In our next paper, Jungmin Hwang and associates hypothesize that suppressing the late sodium current may counterbalance the reduced repolarization reserve in long QT syndrome [LQTS] and prevent early depolarization [EAD] and polymorphic ventricular tachycardia [PVT]. They tested the effects of selective late sodium channel blocker GS967 on polymorphic ventricular tachycardia [PVT] induction in a transgenic rabbit model of type two using intact heart optical mapping, cellular electrophysiology, and confocal calcium imaging and computer modeling. They found that GS967 reduced ventricular fibrillation [VF] induction under a rapid pacing protocol (7 out of 14 hearts in control versus 1 out of 14 at 100 nanomolar) without altering action potential duration [APD] or restitution and dispersion. GS967 suppressed PVT incidents by reducing calcium mediated EADs and focal activity during isoproterenol perfusion (at 30 nanomolar, 7 out of 12 and a 100 nanomolar, 8 out of 12 without EADs and PVTs). Confocal calcium imaging of LQT myocytes revealed GS967 shortened calcium transient duration by accelerating sodium calcium exchanger mediated calcium efflux from cytosol, thereby reducing EADs. Computer modeling revealed the inward late sodium current potentiates EADs in the LQT setting through providing additional depolarizing currents through action potential plateau phase, and increasing intracellular sodium that decreases the depolarizing sodium calcium exchanger, thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier current, IKS. Suggesting important roles in the late sodium current in regulating intracellular sodium. Thus, the authors concluded that selective late sodium channel blockade by GS967 prevents EADs and abolishes PVT in LQT rabbits by counterbalancing the reduced repolarization reserve and normalizing intracellular sodium. Paul J. Wang: In our next paper, Pietro Lazzerini, Mohamed Boutjdir and associates, hypothesize that systemic inflammation per se can significantly prolong QTc during infection via cytokine-mediated changes in potassium channel expression. They found in patients with acute infections, regardless of concomitant QT-prolonging anti-microbial therapy, QTc was significantly prolonged but rapidly normalized in parallel to C-reactive protein [CRP] and cytokine level reduction. Consistently, in Torsades de Pointes cohort, concomitant acute infections were prevalent 30% despite only a minority (25%) of these cases were treated with QT-prolonging anti-microbials. KCN J2, potassium channel expression in peripheral blood mononuclear cells was strongly correlated to that in ventricles, inversely associated to CRP and interleukin one changes in acute infection patients. The authors concluded that acute infection, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless of concomitant antimicrobial therapy. Paul J. Wang: In a research letter, Christophe Beyls and associates examined the risk of bradycardia and critically ill COVID-19 patients treated with Lopinavir [LPV], a protease inhibitor of HIV-1, and Ritonavir [RTV], another protease inhibitor that strongly inhibits hepatic cytochrome P 450 [CYP3A4] activity in order to increase the Lopinavir plasma concentration. During the first month of the outbreak, patients admitted to the ICU with positive PCR for COVID-19 received LPV (200 mg)/RVT (50 mg) twice daily for 10 days. Bradycardia was defined as heart rate below 60 for a period of more than 24 hours. All patients were monitored 24 hours a day for all hemodynamic parameters, including heart rate with a five-lead ECG. Monitors were linked to a computerized system allowing to extract hemodynamic data. LPV/RTV plasma concentration was monitored using analytic method, combining high propensity performance, liquid chromatography and tandem mass spectrometry at 72 hours and every 72 hours. They prospectively included 41 COVID-19 patients who received LPV/RTV treatment. Nine or 22% patients experienced bradycardia. No patients had a pre-existing nodal pathology on the ECG on admission. Among the 9 patients with bradycardia, 8 or 88% were sinus bradycardia and one (12%) third-degree AV block. Causality may be considered as bradycardia occurred at least 48 hours after LPV/RTV initiation, bradycardia resolved after discontinuation or dose reduction and no alternative cause was found. Patients who presented with bradycardia were older, had a higher RTV plasma concentration and a lower lymphocyte count. In our study, no correlation was found between RTV plasma concentration, LPV plasma concentration, and mean heart rate at day three. No patient had bradycardia in the first 48 hours after LPV/RTV administration. For patients with LPV RTV plasma level overdose, the dose of LPV RTV was divided by two until the next dose. For the patient with third degree AV block LPV/RTV was stopped. None of the patients had any known cytochrome CYP3A4-inhibiting drugs. The authors concluded that the results suggest that RTV plasma overdose in elderly critical ill patients may increase the risk of bradycardia. Paul J. Wang: In a research letter, Emily Zeitler and associates surveyed cardiac implantable device [CID] patients. A total of 109 patients were approached to participate, nine declined. Most respondents were white (79%), male (60%) with a mean age of 73 years. The median number of correct responses to the 11 factual questions was six. Respondents held some common misconceptions. For example, 25% of respondents believe that FDA determines the cost of the device. Trust in the FDA was high; 67% of respondents agreed "I trust the FDA". Respondents mostly agreed "the FDA would not approve my device unless it was a hundred percent safe". Only 6% of respondents agreed, "we would be better off if there was no FDA," and a similarly small fraction disagreed with "when it comes to medical devices, the U.S. does the best job in the world at keeping people safe". Most respondents, 69% demonstrated fear of device recalls by agreeing with "if there was a recall of all are part of my device, I think I would be worried or scared." On average, respondents were comfortable sacrificing some privacy for device surveillance, 75% agreed with "once the device has been approved, the FDA should continue to monitor for signs that there are problems with the device even if it means that private health information about me is collected". Respondents seemed to believe that the FDA was risk averse; 56% believed that the FDA does not approve devices unless they're a hundred percent safe. This is in contrast to trends shifting the demonstration of safety to post-approval settings and expanding acceptable forms of data for regulatory approval. Paul J. Wang: In a research letter, Laura Rottner, Christoph Sinning and associates examined novel high resolution imaging system based on a wide band dielectric technology, and reports the first clinical experience of feasibility and reliability of cryoballoon [CB] occlusion tool as compared to fluoroscopic and 3D transesophogeal [TEE] assessment during pulmonary vein isolation [PVI]. In consecutive patients with symptomatic atrial fibrillation [AF], cryoballoon-based ablation was performed with a novel 3D wide-band dielectric imaging system. Pulmonary vein [PV] occlusion was assessed with fluoroscopy in 3D-TEE and concomitantly correlated with the novel CB occlusion tool. The endpoint was defined as persistent PV isolation verified by spiral mapping catheter recordings 30 minutes after the last CB application. A total of 36 (90%) of PVs in 10 patients with paroxysmal (40%) and persistent (60%) were analyzed. In all patients, a normal PV anatomy with four separate PVs was documented. Visualization via 3D-TEE was feasible in 80% septal PVs and 100% of lateral PVs. In 67% of PVs, total PV occlusion was confirmed by all 3 imaging modalities. In 17% of PVs, incomplete PV occlusion was initially demonstrated by TEE and 3D dielectric imaging, whereas fluoroscopy suggested complete occlusion in initial analysis. After repositioning of the CB at 3 PVs, complete PV occlusion was verified by all three modalities. In 3 out of 36 (8%), no occlusion was initially seen by any imaging modality, for which the CB was repositioned resulting in total PV occlusion as confirmed by all three modalities. Two out of 36 PVs (6%) were confirmed to be occluded via fluoroscopy in 3D-TEE, but not by the CB occlusion tool. There was only one out of 36 PVs (3%), which were confirmed to be included by the CB tool and 3D-TEE, but not by fluoroscopy. A negative and positive predictive value of 1.0 and 0.6 was seen when comparing PV occlusion by the novel occlusion tool compared to PV collusion, verified by fluoroscopy and 3D-TEE. Paul J. Wang: In a special report, Jun Hirokami, and associates aim to clarify the spatial correlations between fractionated potential detected by Lumipoint with non-PV trigger. They enrolled 30 symptomatic atrial fibrillation [AF] patients who underwent non pulmonary vein [PV] foci ablation. 4 patients underwent the first procedure, 17 underwent second procedure and eight underwent third procedure, and one underwent a fourth procedure. They highlighted the fractionated signal area in atrial muscle [FAAM] during sinus rhythm and atrial pacing, thereby producing a digital FAAM map. They retrospectively applied Lumipoint to 30 patients in order to clarify the relationship between FAAM and non-pulmonary vein [PV] foci. Non-PV foci were successfully identified in all patients. They identified four patients with multiple non-PV foci. Of these four patients, one had non-PV foci at the superior vena cava and left arterial anterior wall. One had non-PV foci at the SVC and LA bottom wall. And two had non-PV foci at the SVC and interatrial septum. They only analyze 30 non-PV foci unrelated to SVC because the SVC isolation was routinely performed for non-PVC foci at the SVC. In order to analyze the correlation between FAAM and location of non-PV triggers, they determined the cutoff points of peaks slider, which non-PV triggers were completely located within the FAAM in. The accuracy of predicting location of the non-PV triggers was summarized using area under the receiver operating curve, a UROC curve. The optimal cutoff point of peak sliders to predict the location of non-PV was determined by the Youden Index. The Youden Index established the optimal cutoff point of the maximum peaks slider was 7; sensitivity was 0.906 and specificity 0.770. The peaks slider 7 was the most accurate predictor fractionated signals location area to the location of non-PV triggers. (area under the curve 0.902). The mean area of peaks slider 7 was six centimeters squared or 4.3% of the atrium. The authors concluded that the proof-of-concept observational study demonstrated that novel visualization tool of FAAM map successfully identified non-PV triggers that did not induce atrial fibrillation and/or non-PV foci, which potentially serve as substrates for AF maintenance. Paul J. Wang: In a special report, Leslie Saxon and associates update their prior publication providing further detail on mitigation adoption rates for the entirety of the U.S. patient population with implanted cardiac rhythm management devices falling under FDA cyber security advisories from any device manufacturer. They also provided limited data on known cybersecurity mitigation adoption outside the U.S. They report a unique complication resulting for introducing firmware to already implanted devices. Discuss how evolving FDA policies towards firmware mitigation adoption may increasingly determine how and when updates occur. They found that patients under 50 years of age and those over 80 years were less likely to receive the software upgrades, and male versus females had greater rates of upgrades. The upgrade rates varied according to U.S. Region and date of implant. Resynchronization devices were less likely to receive the upgrade, as were pacemaker dependent patient. Those ICD patients initially falling under the battery advisers were upgraded more frequently. The number of advisory patients followed in clinic was a significant predictor for firmware upgrade adoption, particularly for pacemakers that were often upgraded in smaller size clinics. Overall, only 24% of devices for all groups, and 22% of devices not impacted by the battery advisory were upgraded. For Abbott devices, the home communicator cyber security vulnerabilities were mitigated with an automatic software patch that was updated using the Merlin network, and adoption rates were nearly a hundred percent. For the entire patient cohort with impacted pacemaker and ICDs, U.S. and global adoption rates remain low at 24 to 35% with a low rate of complications. Most reported complications for pacemakers and ICD were symptoms (transient palpitations, dizziness, or syncope) that resulted from the temporary change in mode to VVI or transient loss of programmer telemetry while performing the upgrade (pacemaker 0.05%; ICD 0.01%). Globally, a total of 9 pacemakers and 8 ICDs required replacement, as a result of performing the firmware upgrade due to irreversible reversion to a backup pacing mode and loss of defibrillation therapy (ICDs). Analysis of the returned ICD pulse generaotrs found at 7 cases, the cause related to a capacitor bond failure that was exposed only when extended telemetry as required by the upgrade. The failure mechanism was an isolated component failure in the remaining ICD. The programmer based test has recently been FDA approved and can be performed prior to firmware upgrade to identify ICD patients at risk for capacitor bond failure. A total of 256 ICDs were susceptible to loss of RF telemetry after receiving a firmware update, and this has since been mitigated with a software patch. For Medtronic programmers, the initial mitigation responses of cybersecurity advisory was to take the programmers off the network. The network connection was enhanced with one or more security protections provided to the programmers using a flash drive, so the programmers can now be secured from potential cyber intrusion when connected to the network. Medtronic ICDs are currently being upgraded. The upgrade is being provided to impacted patients automatically when the device is interrogated with the programmer during follow-up. Metronic is introducing upgrades in phased approach with all expected to be completed by the beginning of 2021. There are 9% or 55,000 ICDs under this advisory that cannot receive the update due to design or safety constraints. Since the 2017 Abbott advisories identify cybersecurity vulnerabilities in pacemakers and ICDs with the potential for exploits have been increased, including 2 additional FDA advisories issued for another manufacturer. Medtronic's connected communication product and implantable defibrillators in the past 12 months. The authors comment that a recent report and a smaller number of Abbott impacted pacemaker and ICD patients from Canada reported marked differences in mitigation adoption rates between pacemakers and ICDs. This was due to an increase incremental clinical familiarity and comfort with performing the updates as experience and education surrounding these issues evolve. The authors indicate that automating cybersecurity updates without process in place for determining safety, for alerting patients or clinicians that have been delivered, may also be associated with yet unknown risks. Newer generation devices and communication protocols may render cyber security, advisories less frequent as cybersecurity integration is considered an essential aspect of device design. Paul J. Wang: In a review article, Albert Feeny and associates discuss the use of artificial intelligence [AI] and machine learning [ML] in medicine, which are currently areas of intense exploration showing potential to automate human tasks or even perform tasks beyond human capabilities. The first objective of this review is to provide the novice reader with a literacy of AI/ML methods, and to provide a foundation of how one may conduct an ML study. The review provides a technical overview of some of the most commonly used terms, challenges in AI/ML studies with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from the recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology with emphasis on disease detection and diagnosis, prediction, and patient outcomes and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate variation, adoption, and deployment of AI technologies and practice. Paul J. Wang: That's it for this month! We hope that you will find the journal to be the go-to place for everyone interested in the field! See you next time! This program is copyright American Heart Association 2020. Thank you.  

On this episode of the RLP podcast, I discuss fluconazole pharmacology. Fluconazole prevents fungi from producing essential components for their cell membrane and thus inhibits their growth. Drug interactions are common with fluconazole. Fluconazole inhibits CYP3A4, 2C9, and 2C19 to varying degrees. I discuss an interaction between fluconazole and phenytoin in this podcast episode. Hepatitis has rarely been reported with the use of azole antifungals like fluconazole.

On this episode of the RLP podcast, I discuss tamsulosin pharmacology. Tamsulosin inhibits alpha receptors which helps improve urine flow in patients with BPH. As an off-label use, you may see tamsulosin used to try to aid in the passage of renal stones. Tamsulosin concentrations may be increased by CYP3A4 inhibitors and reduced by CYP3A4 inducers.

Conjugated estrogens (Premarin) are most often used in the management of menopausal symptoms. Estrogen therapy can increase the risk for breast cancer and the risk should be assessed before beginning therapy. Blood clots are a potential consequence from the use of Premarin. Premarin can oppose the benefit of anticoagulation. Conjugated estrogens are broken down by CYP3A4. Inhibitors may increase concentrations while inducers may reduce concentrations.

Simvastatin use has declined over time due to more potent statins being available and due to numerous drug interactions. Grapefruit juice can inhibit CYP3A4 which will increase the concentrations of simvastatin. Genetic variations in SLCO1B1 can lead to patients being more susceptible to simvastatin toxicity. Simvastatin is a lipophilic statin. I discuss why this is important and how it might impact clinical decisions.

Giriş Uzamış QT sendromu (UQS), elektrokardiyogramda (EKG) uzun bir QT aralığı ile karakterize miyokardiyal repolarizasyon bozukluğudur. Bu sendrom, torsades de pointes (TdP) olarak da bilinen karakteristik hayatı tehdit eden kalp aritmisi olan polimorfik ventriküler taşikardi riskinde artışla ilişkilidir. UQS'li hastalarda semptomlar çarpıntı, senkop, nöbetler ve ani kardiyak ölümdür. UQS konjenital veya edinsel olabilir. Edinilmiş UQS genellikle ilaç tedavisinden kaynaklanır, ancak hipokalemi, hipomagnezemi ve bradikardi ilaca bağlı UQS riskini artırabilir​1​. Semptomlar Aritmilerin yokluğunda, edinilmiş UQS'li hastalar asemptomatik olacaktır. Bir aritmi geliştiğinde, belirtilerin tipi ve yoğunluğu, varsa, TdP oranına, süresine ve önemli komorbid koşulların varlığına veya yokluğuna bağlı olarak değişecektir. Semptomları fark eden edinilmiş UQS'si olan hastalar tipik olarak aşağıdaki semptomlardan bir veya daha fazlası ile başvururlar: ÇarpıntıSenkop veya presenkopAni kardiyak arrest  İnsidans QT uzaması ile ilişkili birçok ilacın mutlak ve karşılaştırmalı riskini belirlemek zordur, çünkü mevcut verilerin çoğu olgu raporlarından veya küçük gözlem serilerinden gelir. Ek olarak, TdP olmadan QT uzaması insidansı muhtemelen TdP'nin insidansından çok daha yüksektir. Altı aylık süre içinde tek merkeze yapılan tüm hastaneye başvuruların geriye dönük gözden geçirilmesinde 41.649 hastanın 293'ünde (yüzde 0.7) QTc ≥ 500 milisaniye olduğu, ancak ciddi QT uzaması olanların yüzde 6'sından azında senkop veya hayatı tehdit eden bir aritminin yaşandığı kaydedilmiştir. Hollanda'da, dokuz yıldan biraz daha az bir sürede 775 ani kardiyak ölüm (AKÖ) tespit edilen 500.000 kişiyle yapılan gözlemsel bir çalışmada, AKÖ'lü 775 hastanın 24'ünde (% 3.1) halihazırda QT uzatan ilaç mevcuttu. Kardiyak olmayan QT uzatan herhangi bir ilacın halihazırda kullanımı belirgin şekilde artmış AKÖ riskiyle (OR: 2.7) ve en yüksek risk antipsikotik ilaçlarla (OR: 5.0) ilişkiliydi. Her ne kadar bu sonuçlar ilaca bağlı TdP'nin belgelenmiş vakalardan daha yaygın olabileceğini düşündürse de, mutlak olay sayısı hala düşüktür ve AKÖ olaylarının küçük bir kısmını temsil etmektedir (AKÖ'lü 775 hastanın 24'ü (%3.1) halihazırda bir QT uzatan ilaç kullanıyordu). Risk Faktörleri Birden fazla risk faktörü olan hastalar daha fazla riskle karşılaşabilir. Bu faktörler aşağıdaki gibi sınıflandırılabilir. İlaç rejimi ile ilgili olarak: Yüksek ilaç dozları veya QT uzatan ilaç konsantrasyonları diğer kardiyak risklerin varlığında daha da riskli olabilir.QT uzatıcı ilacın hızlı intravenöz infüzyonu.QT aralığını uzatabilen birden fazla ilacın eş zamanlı kullanımı, hepatik sitokrom P450 enzimlerinin inhibisyonu nedeniyle ilaç metabolizmasını yavaşlatan bir ilaç ile QT uzatan bir ilacın kullanımı, CYP3A4'ü inhibe eden greyfurt suyunun eşzamanlı alımı gibi olası mekanizmalar ile QT aralığı artabilir.Diüretik tedavisi, elektrolit anormallikleri ile ilişkisi veya bazı diüretiklerin potasyum akımını doğrudan bloke etmesinden dolayı bir risk faktörü olabilir. İlaçla ilişkili risk faktörlerinin dışında EKG anormallikleri, metabolik faktörler, genetik faktörler, altta yatan kalp hastalıkları ile ilgili risk faktörleri de vardır. Kadın cinsiyet, ileri yaş, hipomagnezemi, hipokalemi, bradikardi ve daha az olarak hipokalsemi de risk faktörleri arasındadır​2,3​. Çalışmalar ABD'de 1995-2009 yılları arasında acil servise başvurulardaki QT'yi uzatan ilaçları içeren reçetelemelerin yıllık oranlarının incelendiği bir çalışmada bu ilaçların reçetelenme sıklığı, risk faktörleri ortaya konmuştur. Sonuç olarak yılda yaklaşık 16.5 milyon muayene (%15.0) QT uzatan bir ilacın reçetelenmesini ve 1.7 milyon (% 1.6) birden fazla reçetelemeyi içeriyordu. QT'yi uzatan ilaçlarla ilişkili muayeneler, çalışma süresi boyunca iki kattan fazla artmıştır (% 10.4 ila % 22.2). Difenhidramin, azitromisin ve ondansetron en sık reçete edilen ilaçlar olmuştur (vakaların% 46...

Gorilla Mind Smooth is the most potent and comprehensive stimulant-free Nootropic formula on the market. If you don't already know what Nootropics are, they are a category of compounds that can improve cognitive function. This can extend into many different specific benefits, but the main draw of Nootropics is their impact on productivity, concentration, creativity and information retention. Gorilla Mind Smooth is our stimulant-free version of Gorilla Mind that provides a smoother, much less extreme level of energy, but still maximizes mental clarity, memory, creativity and focus. Regardless if you're currently using stimulant-based products (coffee, energy drinks, pre-workouts, etc.), cycling off of stimulants, or just never use stimulants, Gorilla Mind Smooth is the most potent Nootropic formula you can add into your life to enhance cognitive function. https://youtu.be/Hcj8CinGG6s Reviews These are some of the reviews we've received from customers using Gorilla Mind Smooth: Gorilla Mind Smooth Supplement Facts Per Full Daily Dose: L-Tyrosine - 1000 mg Organic Lion's Mane Mushroom (Hericium Erinaceus) (standardized to 25% β-glucans) - 1000 mg DMAE (Dimethylaminoethanol) - 750 mg Alpha GPC 50% (L-alpha-glycerylphosphorylcholine) - 600 mg Kanna (Sceletium Tortuosum) - 500 mg Bacopa Monnieri (standardized to 45% Bacosides) - 400 mg L-Theanine - 200 mg Bioperine® (Black Pepper Fruit Extract) (standardized to 95% Piperine) - 10 mg Huperzine A (Huperzia serrata leaf standardized extract) - 400 mcg The original Gorilla Mind Smooth formula had PEA, Hordenine and Teacrine in it. Originally, I was trying to chase a stimulant-free energy boost in Smooth, which is why I had those ingredients in it. However, over the past year I've started to really lean towards reformulating Smooth to create an entirely Nootropic comprised formula that is 100% geared towards maxing out cognitive function, rather than chase a relatively weak level of energy that we already destroy with Gorilla Mind Rush. Anyone buying Gorilla Mind that is using it for the laser focus and massive boost in energy and productivity is buying RUSH anyways, not SMOOTH. Instead of wasting precious capsule space with things that achieve a subpar level of energy, I decided that space would be far better utilized with other Nootropics. This is what led to me creating the current Gorilla Mind Smooth formula, which now has 1000 mg of Lion's Mane mushroom and 500 mg of Kanna in it. These compounds are far more conducive to enhancing the SMOOTH formula by supporting actual brain health, creativity, mental clarity and memory formation. If you want ridiculous amounts of energy and drive, get RUSH. For those who want a true stimulant-free Nootropic formula, SMOOTH is even better now and I highly recommend you give it a try. Gorilla Mind Smooth Vs. Other Nootropics On The Market This is the most maxed out stim-free Nootropic formula on the market. The full daily dose is 6 capsules. Even a half dose (3 capsules) is still far more potent than the majority of other Nootropic formulas out there at their max dosages. I formulated Gorilla Mind Smooth the exact same way I formulate any other product. I put in exactly what I would buy myself if I were shopping for each Nootropic separately. If you thought the pre-workout market was bad for underdosed products, your jaw will drop when you see some of the top selling Nootropic formulas. This industry is even worse because it is so niche and new. Preying on unsuspecting customers with garbage formulas sprinkled with vitamins and completely useless dosages of Nootropics is even more common in this industry. Because Nootropics are relatively new and uncharted waters for many, the prices get pretty aggressive on these watered down formulas as well that promise the world, and deliver nothing more than placebo. What's baffling to me is how many people eat up the marketing and blindly buy products priced at $60, $70, even $100 that probably cost $4-5 max to make. When the cost of bottles, lids, and labels costs more than the Nootropics in your formula, there's a f*cking problem. Fortunately, my audience is comprised of intelligent individuals who actually know how to spot value. It would be so easy to make a formula with a couple hundred milligrams of cheap choline that doesn't even cross the blood brain barrier, 100-200 mg of Bacopa Monnieri, throw a bit of caffeine in there for a kick, put some exotic sounding ayurvedic herbs in there, maybe sprinkle a couple low dosed Adaptogens in there, add a useless pinch of vitamins to make my label look more impressive and confusing, and then slap a label on it like every other company and then aggressively smash people with ads and market a high priced subscription model to the masses, or put it up on Amazon to compete with all the other loss leader cheap and ineffective Nootropics on there. The fact that the hypothetical piece of sh*t formula I just made up as an example of what not to do is actually still better than most of the Nootropic formulas on the market just goes to show how much some companies are deceiving their customers. If the majority of a company's budget goes into ads and sponsorships instead of product formulation, or they have a high ranking product on amazon, you can almost guarantee without even looking at the product that it sucks. Unlike what most companies will lead you to believe, there is no Nootropic formula that will lock you in like Bradley Cooper from Limitless (great movie by the way). https://youtu.be/4TLppsfzQH8 Just like our other products, it is me making the formula, and I put in what I would want to use as a customer. I used to spend time every day in University measuring out all my different Nootropics that were in my "stack", and toss and washing random powders. Obviously it makes things much easier to just have it in ready to go capsules that are actually dosed properly. With my products, everything is turnkey. How To Dose Gorilla Mind Smooth Take 3-6 capsules in the morning, or spread throughout the day. Start with 3 capsules to evaluate your tolerance. While Gorilla Mind Rush requires more of a tolerance assessment and slow dosage titration over time due to the heavy hitting stimulants, you will more than likely be fine jumping head first into Gorilla Mind Smooth and tapering up to the maximum recommended dose relatively quickly. Gorilla Mind Smooth Vs. Gorilla Mind Rush While the foundation of Nootropics in both Gorilla Mind products are mostly the same, there are some key differences between the two formulas. The main difference is that RUSH has a handful of potent stimulants that completely change how the product feels. RUSH is best stimulant-based Nootropic formula on the market for really waking you up and giving you tunnel vision focus and productivity. The strong backbone of Nootropics in RUSH are the portion that can actually enhance information recall, creativity, etc. But, the stimulants in RUSH are the driving force of the product, and can really be a game changer in productivity. SMOOTH on the other hand is stimulant-free and has the same Nootropics as RUSH, but also has 1000 mg of Lion's Mane mushroom and 500 mg of Kanna. Lion's Mane is amazing for supporting cognitive health, memory formation and mental clarity, while Kanna is a potent mood booster and can also support improved focus and energy levels. Gorilla Mind Smooth is significantly toned down in the energy department, so if you have too high of a sensitivity to stimulants or simply want a smoother level of focus, this would be more ideal for you. How To Combine Gorilla Mind Rush And Gorilla Mind Smooth If you don’t want to pick between either having the giant burst of energy and laser focus that RUSH provides, or the cognitive enhancing benefits of the Lion's Mane and Kanna in SMOOTH, you can combine the products. By taking 6 capsules of either, you will be getting a top end dose of Nootropics. Even with 3 capsules of either product you will still get an effective dose of Nootropics, and with RUSH, many won't even be able to exceed 3 capsules because the stimulant blend is extremely strong. If you are not a stim junkie who needs 6 capsules of RUSH I would recommend getting both so you can strategically tweak how much energy you want to get from the Rush to not over-stimulate yourself, but also reach the maxed out mental benefit you would get out of the Nootropics in each respective version of the product. Rotating Gorilla Mind Smooth and Gorilla Mind Rush Use Gorilla Mind Rush on days that require the most focus, productivity and energy. By rotating RUSH and SMOOTH, you can keep yourself sensitive to the stimulants in Gorilla Mind Rush, and reap the maximum benefit from each product during each use. Do You Need To Cycle Off Of Gorilla Mind Smooth? While SMOOTH will not cause tolerance build up like RUSH, I would still advise cycling off of everything for a week every month or so. Alternatively, allocate a couple days each week to days you do not take anything, including RUSH. Gorilla Mind Smooth Ingredients Breakdown L-Tyrosine - 1000 mg L-Tyrosine is an amazing cognitive enhancing amino acid that acts by balancing neurotransmitter levels in the brain. Its primary role is as the direct precursor to thyroxine and to the neurotransmitters dopamine, epinephrine, and norepinephrine. L-Tyrosine shines in its ability to improve mental sharpness, focus, energy levels, and cause mood elevation [R, R]. L-Tyrosine Vs N-Acetyl L-Tyrosine L-Tyrosine is the most bioavailable form of Tyrosine. In short, N-Acetyl L-Tyrosine is very inefficiently converted by the body to Tyrosine [R]. Even IV’ing N-Acetyl L-Tyrosine can’t elevate plasma Tyrosine levels to a significant degree, let alone via oral ingestion. Claims of increased water solubility and bioavailability are all marketing hype and were disproved easily by showing just how poorly N-Acetyl L-Tyrosine is at converting to Tyrosine in the body. The graph above depicts arterial concentrations of N-Acetyl-L-Tyrosine (NAT) and Tyrosine (Tyr) during intravenous infusion of N-Acetyl-L-Tyrosine. As you can see, Tyrosine levels barely even budge. This is the same kind of tactic used to try and market new and “improved” forms of creatine that at the end of the day do not yield any additional benefit, and just feature an inflated price tag. In our first batch of Gorilla Mind, we actually had N-Acetyl-L-Tyrosine in the formulas based on these claims of improved water solubility and bioavailability by our manufacturer at the time. After delving into the data further, I realized the massive difference in bioavailability and swapped out the N-Acetyl-L-Tyrosine for straight L-Tyrosine, found a better manufacturing facility, and all batches of Gorilla Mind products since then have featured L-Tyrosine instead. Organic Lion's Mane Mushroom (Hericium Erinaceus) (standardized to 25% β-glucans) - 1000 mg Lion’s Mane is a Nootropic and cognitive-enhancing mushroom that has been used for thousands of years by Buddhist Monks who believed that it enhanced brain power and improved their focus. The main reason it is so promising as a Nootropic is the effect it has shown to have on the synthesis of nerve growth factor (NGF) and neurogenesis. By enhancing neurogenesis and potentially even attenuating the negative effects of cognitive decline, Lion’s Mane may significantly improve mental acuity, information retention, and decrease mental fatigue. Most products on the market contain 250 - 500 mg of Lion’s Mane. We have a full gram (1000 mg) in Gorilla Mind Smooth to ensure you are actually getting an efficacious dose of Lion’s Mane in when you use it. Effect On Cognitive Function A double-blind, placebo-controlled trial was conducted on 50-80 year old adults with mild cognitive impairment to evaluate the efficacy of Lion's Mane as a cognitive aid. The Lion's Mane treated group showed significantly increased scores on the cognitive function scale compared with the placebo group [R]. Enhanced Nerve Growth Factor (NGF) Synthesis Results from animal studies support that Lion's Mane can enhance the synthesis of Nerve Growth Factor (NGF) [R, R]. NGF is required by neurons in order to survive and appears to play a major role in cognitive function. When NGF decreases in the brain, memory formation and information recall becomes greatly impaired. By maintaining optimal levels of NGF one may be able to support brain plasticity for improved information retention, memorization, as well as general cognitive health. Effect On Beta Amyloid Levels And Cognitive Decline In a rodent model, Lion's Mane was shown to attenuate the negative cognitive effects of beta amyloid in the brain (what is believed to be the main cause of Alzheimer's) [R]. It was also shown to ameliorate Alzheimer’s disease-related pathologies in several other rodent models of Alzheimer’s disease [R, R]. Mood Elevation And Stress Reduction Lion’s Mane also contains erinacine and other bioactive compounds that may increase dopamine production and improve state of well-being. One study showed that Lion's Mane supplementation reduced depression and anxiety after 4 weeks of use [R]. DMAE (Dimethylaminoethanol) - 750 mg DMAE's mechanism of action isn't fully understood, but it appears to work primarily by stimulating cholinergic receptors and has shown to improve cognitive function, energy levels, focus, and act as a neuroprotectant [R]. DMAE users consistently report improved memory, attention to detail, focus and mental clarity. DMAE Vs. Ritalin Study One double-blind, placebo-controlled study conducted on 74 children with learning problems compared the efficacy of DMAE to Ritalin for treating ADHD [R]. The children were either given 40 mg of Ritalin, 500 mg of DMAE, or a placebo every day for 3 months. Behavior rating forms, reaction time, and an array of other psychometric tests were given before and after treatment. DMAE showed improvements in these metrics of approximately the same magnitude as Ritalin. No major side effects were noted with either treatment with exception of 6 of the children on Ritalin noting appetite suppression. Alpha GPC 50% (L-alpha-glycerylphosphorylcholine) - 600 mg Alpha-glycerylphosphorylcholine (Alpha-GPC) is the highest quality and most bioavailable form of Choline. Taking massive dosages of straight Choline has shown to have no cognitive effect in humans [R]. Alpha-GPC on the other hand has shown to cross the blood brain barrier and provide the brain with a rapidly absorbed form of choline. This then supports the synthesis and release of acetylcholine. The surge of quickly absorbed choline in conjunction with the release of acetylcholine helps support an array of cognitive functions including but not limited to memory, HGH production, physical performance, concentration, focus, and information absorption/recall [R, R, R]. Alpha-GPC has also shown to significantly increase strength and may be an effective ergogenic aid [R]. How Much Choline Do You Need Per Day? The Adequate Intake (AI), as established by the Food and Nutrition Board of the National Institute of Medicine, for adults is 550 mg per day for men and 425 mg per day for women. We all know how brutally underestimated some of the AI's have proved to be in the past couple decades, and there is evidence suggesting that the AI for Choline is also far too low. One study showed that 2200 mg per day of Choline protected against the DNA damage that otherwise occurred in people consuming only 550 mg [R]. There are not enough studies on Choline, and it is a severely lacking area of research considering how important it is for brain health. I would shoot for at least 900-1200 mg of Choline per day. A big chunk of that can be achieved through regular liver and egg yolk consumption, but supplementation will help you hit that number with much greater ease. I eat 1 ounce of beef liver, 4 large eggs, and supplement with 600 mg of Alpha-GPC every day via Gorilla Mind. I also take extra precautions to support methylation, which I will delve into later in the methylation subsection. Alpha-GPC's Effect On Alzheimer's Dementia In a double-blind, randomized, placebo-controlled trial, patients with Alzheimer's dementia were treated with Alpha-GPC (400-mg capsules) or placebo capsules, 3 times daily, for 180 days [R]. In the Alpha-GPC group, assessed parameters consistently improved after 90 and 180 days versus baseline, whereas in the placebo group those same parameters remained unchanged or worsened. The results suggest that Alpha-GPC is a promising intervention for attenuating the cognitive decline that occurs from neurodegenerative disease. Alpha-GPC's Effect On Methylation And Health Status The MTHFR gene codes for an enzyme called methylenetetrahydrofolate reductase, or MTHFR. This enzyme is needed for the production of DNA and supporting methylation pathways that are essential for all bodily functions. Genetic variations in this gene results in reduced activity of the enzyme and has been associated with cardiovascular disease, neurological defects, some forms of cancer, and a myriad of other diseases and disorders [R, R]. Personally, I am homozygous for C677T of MTHFR, which results in a 80-90% decrease in my efficiency in processing folic acid. The direct reflection of that in blood biomarkers can be high homocysteine and low B12 and folate levels. I determined this via a simple 23andMe genetics test. Normally your body creates methyl groups by recycling Homocysteine to Methionine, as well as by converting Choline to Betaine. When nutrient intake needs are sufficiently met, the body depends on these two mechanisms equally. However, if you are deprived of methyl groups or have poor MTHFR activity because of a polymorphism, you can change that and start to create a disproportional ratio of dependency on the Choline to Betaine pathway. If you can't create enough Methylfolate, your body will ramp up the use of Betaine and Choline for methyl groups. By ramping up Choline to Betaine conversion to support methylation, your body can become depleted of the Choline it needs to create Acetylcholine. Downstream, the depletion of Choline can eventually lead to impaired cognitive function, DNA damage, and can be deleterious to overall health. The prevalence of MTHFR polymorphisms and micronutrient deficient diets is so common nowadays that almost everyone could benefit from Alpha-GPC supplementation to maintain higher levels of Choline. I take 600 mg of Alpha-GPC every day on top of the Betaine and Creatine I get from Gorilla Mode (or Gorilla Mode Nitric when I am not taking stimulants) to support methylation, improve my health, and optimize my performance. Alpha-GPC Vs. CDP Choline Alpha-GPC raises choline blood levels much more than CDP-Choline. While there is some speculation around the fringe benefits that may come with the Cytidine component of CDP-Choline, in general, the main reason we would use either Alpha-GPC or CDP-Choline is to supplement our diet and raise our Choline levels. Alpha-GPC accomplishes this better than CDP-Choline. Our Alpha-GPC is 50% Choline by weight, whereas CDP-Choline is only about 18% Choline by weight. That means that you would need to use almost three times as much CDP-Choline to get the same amount of Choline as Alpha-GPC. Are any of the companies out there with CDP-Choline in their formulas putting 1600-1700 mg of CDP-Choline per daily dose in their products? Not even close. Many companies still use Citicoline (CDP Choline) in their Nootropic formulas, despite the fact that Alpha-GPC has shown time and time again to be more effective both anecdotally, as well as clinically [R]. From what I've seen, the most reputable anti-aging "biohackers" in the industry also prefer Alpha-GPC over CDP-Choline. I have personally tried CDP-Choline and never really noticed any enhancing effect like I seemed to with Alpha GPC. - Rhonda Patrick (Ph.D in biomedical science/expert on nutritional health, brain & aging) Kanna (Sceletium tortuosum) - 500 mg Kanna supplementation has been found to effectively lower stress, elevate mood and increase focus. Personally, I notice a huge boost in my mood and I lock in a little bit more on whatever I am trying to concentrate on when I supplement with Kanna. Kanna was a huge success in our pre-workout formula because it also complements stimulants very well, which you have probably found out first hand if you have tried Gorilla Mode. Kanna works mainly via increasing the amount of serotonin available in the brain, and is typically utilized for its anti-anxiety and mood elevating effects [R]. This is an ingredient you will really feel, and can be especially useful for those days you need something effective that isn’t stimulant based. Anecdotally, a dose between 200-500 mg of Kanna has shown to be ideal for oral ingestion. Higher dosages between 1-2 grams have been associated with unwanted side effects like dizziness. Kanna has no addictive properties, and it is not hallucinogenic [R, R]. One thing to keep in mind with Kanna use is that it has a high affinity for the serotonin transporter. Therefore, it is plausible that Kanna can interfere with SSRI pharmaceuticals. Bacopa Monnieri (standardized to 45% Bacosides) - 400 mg Bacopa Monnieri is typically used as a memory enhancing Nootropic. There is a growing body of evidence suggesting that Bacopa Monnieri can protect neurons in the brain from accumulative damage, reduce β-amyloid levels in the brain, and improve cognitive performance by modulating neurotransmitters [R]. The efficacy of Bacopa Monnieri has been reinforced in six high-quality randomized, double-blind, placebo-controlled human trials. The results suggest that Bacopa Monnieri not only has the potential to attenuate neurodegenerative disease progression, but it may also be a potent memory enhancing agent in otherwise healthy individuals. Improved Verbal Recall - Bacopa Monnieri Vs. Modafinil Study In a meta-analysis, long-term Bacopa Monnieri supplementation produced more consistent and noticeable positive effects than Modafinil [R]. Primarily, Bacopa Monnieri was shown to be very effective at improving verbal recall. This suggests that Bacopa Monnieri would be especially useful for memorizing long speeches, business presentations, songs, scripts, etc. Apparently Bacopa Monnieri was used by ancient Vedic scholars to memorize lengthy hymns and scriptures, which would reinforce the clinical findings. Improved Information Retention And Memory Consolidation A randomized double-blind placebo-controlled study conducted on 46 healthy adults assessed the efficacy of supplementing 300 mg per day of Bacopa Monnieri for 12 weeks [R]. 23 subjects received Bacopa Monnieri, and 23 subjects received placebo. A battery of well-validated neuropsychological tests were used to assess Bacopa's efficacy as a Nootropic. The Bacopa Monnieri treated group had significantly improved speed of visual information processing, learning rate, memory consolidation, and state anxiety compared to placebo, with maximal effects evident after 12 weeks. In another study conducted on 76 healthy adults aged 40-65, Bacopa Monnieri showed significant improvements in information retention [R]. Another study conducted on 81 elderly Australians found that a Bacopa Monnieri extract produced significant improvements in verbal learning, memory acquisition and delayed recall [R]. L-Theanine - 200 mg L-Theanine is most commonly used for its calming and relaxing effects. I find that it also promotes a high level of mental clarity as well. L-Theanine primarily works by targeting the neurotransmitters GABA, Serotonin, Dopamine, Epinephrine and Norepinephrine. These neurotransmitters are responsible for feelings of attention, stress, arousal, relaxation and pleasure. By mitigating the over-activity of excitable neurotransmitters and enhancing the calming neurotransmitters, L-Theanine seems to help calm down the brain, reduce stress, and curb anxiety. This is why L-Theanine complements stimulants like caffeine so tremendously too, as it takes the edge off of stimulants that can cause jitters and over-stimulation. Stacking Caffeine With L-Theanine To Help You Get To Sleep And Smooth Out The Jitters If you get jitters even with low doses of caffeine, the L-Theanine in Gorilla Mind Smooth will really help curb that. The caffeine + L-Theanine stack is one of the most basic and effective Nootropic stacks to date. This is one of the main reasons why Gorilla Mind Rush won't send you off the rails despite having a very potent combination of stimulants in it (it also has a big dose of L-Theanine in it). If you love your coffee, green tea, or energy drinks and don't want the aggressive stimulant blend in Gorilla Mind Rush, Gorilla Mind Smooth will stack with your caffeinated drink of choice exceptionally well. One notable rodent model even showed that L-Theanine can partially counteract caffeine-induced sleep disturbances [R]. Improved Memory And Attention In a randomized, double-blind, placebo-controlled study conducted on 91 people with minor brain damage, a combination of L-Theanine and green tea extract improved memory, attention span, and alertness during a memory test [R]. Improved Verbal Fluency And Executive Function In another randomized controlled trial, 30 healthy adults were given 200 mg of L-Theanine per day, or placebo. Verbal fluency and executive function scores improved after L-Theanine administration [R]. Stress levels also went down, and sleep quality also increased after L-Theanine administration. Improved Reaction Time In another study conducted on 18 healthy University student volunteers, 200 mg of L-Theanine improved attention performance and reaction time response [R]. Neuroprotection In a study conducted on elderly volunteers with normal or minor cognitive dysfunction, volunteers who ingested powdered green tea containing 47.5 mg of theanine per day showed significantly lower decline in cognitive function compared with that of the placebo group [R]. BioPerine® (Black Pepper Fruit Extract) (standardized to 95% Piperine) - 10 mg Bioperine is a trademarked form of black pepper extract standardized to 95% Piperine. Black pepper extract is a very effective CYP3A4 and P-glycoprotein inhibitor [R]. These enzymes break down molecules like epinephrine and norepinephrine in the body. By prolonging the breakdown of the cognitive enhancing ingredients in this formula, Bioperine extends how long they work for, and can also significantly increase their bioavailability. Huperzine A - 400 mcg Huperzine A works by inhibiting acetylcholinesterase in the brain, which is an enzyme that breaks down the neurotransmitter acetylcholine. Acetylcholine is not only a major regulator of cognitive performance, but it is also an important neurotransmitter needed for optimal muscular contractions during exercise. Huperzine A has shown to promote neurogenesis (the birth of new neurons in the brain) and act as a neuroprotective agent for existing neurons in the brain. In turn, Huperzine A has shown to enhance memory, focus and overall cognitive function [R, R]. Huperzine A is one of the most potent Nootropics that you can really “feel” and it complements the other Nootropics in this formula perfectly. Other Notable Compounds I Didn’t Include In The Formula And Why Noopept, Racetams, Other Synthetic Nootropics And Prodrugs Although they are effective Nootropics, Noopept, Racetams (class of drugs all named with the suffix "racetam"), prodrugs like Adrafinil,  and other synthetic compounds that cannot be found in nature or in the food supply are not DSHEA compliant and cannot be legally sold as dietary supplements, so we did not include any. If this wasn't the case, I probably would have included 30 mg of Noopept in the formula. I also like Phenylpiracetam. Vitamins Vitamins are often included in Nootropic formulas to make a supplement facts panel look more impressive. If a company is willing to sacrifice room in their capsules to inflate their ingredient profile with stuff you very likely already get from diet or a multivitamin, that is a major red flag. More often than not, the dosages included are next to useless and are just there to make a product look more comprehensive. The main issue with this is that you only have so much room in a capsule. Most Nootropic products use a "00" capsule size in their bottles. Each "00" sized capsule can fit about 735 mg in it. That is precious space, and including a useful amount of vitamins in a product can easily take up several capsules of space. If a company is wasting space with vitamins and only has a serving size of around 6 capsules, they are probably just trying to hide the fact that the actual Nootropics portion of their formula is watered down garbage. Conclusion - What To Expect From Gorilla Mind Smooth In general, you can expect clear headed mental clarity, as well as improved information retention, creativity, productivity and concentration. Gorilla Mind Smooth is not designed to jack your brain into high gear, as that is a stimulant driven mechanism. Rather, it is purely meant to enhance cognitive function and overall mental performance. Try Gorilla Mind Smooth for yourself here.

Diazepam has numerous dosage forms. There are rectal, injectable, and oral formulations of the drug that are commonly used in clinical practice. Diazepam has 2 major metabolic pathways. It is broken down primarily by CYP3A4 and CYP2C19, leaving open the potential for numerous drug interactions. I discuss this further in the podcast. Diazepam is on the Beers list because it has a tendency to accumulate in the geriatric patient population and cause adverse effects like sedation, confusion, and falls. Respiratory depression, coma, and death are significantly more likely in overdose situations where opioids are used in combination with benzodiazepines like diazepam.

Diltiazem is a non-dihydropyridine calcium channel blocker that can be used in atrial fibrillation as well as hypertension. One big downside to diltiazem is that it does have a few drug interactions via CYP3A4. Aripiprazole, apixaban, and certain statins are all examples of medication that can have concentrations increased by adding diltiazem to a patient's regimen. Diltiazem works a little differently from dihydropyridine calcium channel blockers (like amlodipine) as it works on the heart AND the vessels.

Zolpidem enhances the action of GABA which is an inhibitor neurotransmitter. Zolpidem metabolism can be impacted by the use of CYP3A4 inhibitors. Concentrations can rise on account of this potential interaction. It is important to remember to go slowly when tapering off zolpidem. Particularly in patients who have been on the drug for a long time or those who are on higher doses. Abnormal sleeping behaviors like sleep-walking, eating, or driving have been reported with zolpidem. Remember that CNS depressant drug interactions can happen with zolpidem. Take note of any other sedating medications prior to starting zolpidem.

Episode 3: James Horowitz interviews Rachel Rosovsky on DOACs. Dr. Rosovsky is the Director of Thrombosis Research in the Division of Hematology at Mass General Hospital. She is also an Assistant Professor at Harvard and a member of the Board of Directors of the PERT Consortium.  Dr. Horowitz is the Director of the CCU at NYU Langone Health and the Co-Chair of the Interdisciplinary Resuscitation Committee. He is also an Assistant Professor or Medicine and a member of the Board of Directors of the PERT Consortium. Directly acting oral anticoagulants.   FDA approved DOACS: Xarelto (rivaroxaban), Eliquis (apixaban), Savasya (edoxaban), Pradaxa (dabigatran). All DOACs have similar efficacy in terms of VTE occurrence and better safety profile compared compared to Coumadin. MOA: Dabigatran: directthrombin inhibitor.   Rest of the DOACs: factor X inhibitors. DOACS usually do not need monitoring. Most common interaction noted with drugs like ketoconazole (CYP3A4). Dosing: Dabigatran and Edoxaban: Overlap with parenteral enoxaparin for 5 to 10 days is needed. Apixaban and Rivoraxaban: Need loading dose. For apixaban it is 10 mg 2 times a day for 7 days followed by 5 mg 2 times a day.  Rivaroxaban: 15 mg 2 times a day for 21 days followed by 20 mg once a day. (Xarelto need to be taken with food) Only 55% of the patients with Coumadin remain in therapeutic range. Drug reversal agents for DOACs Dabigatran reversal: Idarucizumab Xarelto and Eliquis reversal: Andexenat Alpha. Factors in deciding candidacy for DOACs: DOACs in patients with Child-Pugh score B/C cirrhosis should not be used. Renal failure with CrCl 120 kg, based on ISTH guidelines. (higher the BMI may have increased risk of bleeding with better efficacy, potentially due to absorption issues-- levels can fluctuate) Drug monitoring for DOACs: No standardized methods. Not routinely done. It should be considered in patients with extremes of weight and patients who have gone gastric/bariatric surgeries, because all DOACs are absorbed get into upper GI tract. Pregnancy and Venous thromboembolism: No DOACs in pregnancy. Enoxaparin is the treatment of choice -1 mg/kg every 12 hours up to week 36 followed by changing them to unfractionated heparin. (subcutaneous calculated dose). Patients who had prior DVTs/PEs and become pregnant may need prophylactic dose of enoxaparin (40 mg subcutaneous once a day) Cancer and VTE: VTE is a second leading cause of death in cancer patients. Drug of choice was enoxaparin over warfarin. Edoxaban Vs Enoxaparin: Edoxaban with less recurrent VTE, but worse bleeding profile (most bleeds in gastric cancer patients) Rivaroxaban Vs Enoxaparin: Rivaroxaban with less recurrent VTE, but worse bleeding profile (most bleeds in gastric cancer) Cancer patients who may not be good candidate: a) GI cancer b) needing many procedures c) liver/renal failure d)brain mets.  Provoked vs Unprovoked and extended a/c: Unprovoked PE: Two-year risk of recurrence 25% or higher. Provoked by surgery [mainly orthopedic surgery, pregnancy, long hospital stay]: risk of recurrence 1% at one year, 3% at 5 years. Flying is a weak risk factor to be considered as provoked. Amplify-Ext trial: 70% decrease risk of recurrence with low dose apixaban without an increased risk of bleeding in unprovoked VTE. Einstein Choice trial: 70% decrease risk of recurrence with low dose rivaroxaban without an increased risk of bleeding. 60% of patients had provoked VTE with ongoing risk factors. (i.e. Obese patients, patients who are immobile, and are still immobile). Cancer screening following PE: 5-10% of patients with VTE would be diagnosed with malignancy in next 5 years. Recommendation is to do age appropriate cancer screening. Valves and DOACS: (increase risk of ischemic events)   Reference: Rali P, Gangemi A Moores A et al. Direct-Acting Oral Anticoagulants in Critically Ill Patients. Chest. 2019 Sep;156(3):604-618.

Cilostazol has antiplatelet and vasodilatory effects. Because of this, it can manage symptoms of intermittent claudication. GI upset, headache, and edema are common adverse effects associated with the use of cilostazol. Cilostazol is recommended to be given on an empty stomach. In patients with heart failure, cilostazol use is contraindicated. CYP3A4 interactions are prevalent with cilostazol. Inhibitors of CYP3A4 can increase the concentrations of cilostazol.

Erythromycin uniquely has some potential benefit in the setting of gastroparesis. Azithromycin you will likely not see used for this indication. Erythromycin binds the 50s subunit and ultimately prevents protein synthesis which is necessary for bacteria to grow and replicate. QTc prolongation is a risk with all macrolide antibiotics (erythromycin included). By inhibiting CYP3A4, erythromycin can be responsible for numerous drug interactions.

Buspirone is an anti-anxiety medication that has the potential of having some serotonin agonist activity. Buspirone has a very high first-pass metabolism. This means that the body breaks much of the medication down prior to it getting into the systemic circulation. Buspirone is broken down by CYP3A4, so concomitant use with inhibitors or inducers can alter its concentrations Buspirone should not be used as needed as this medication takes a while to start to show benefit.

Budesonide is a corticosteroid that can be given orally or rectally for management of Crohn's disease or ulcerative colitis. Because budesonide has a high first pass metabolism, the relative impact of systemic effects may be less than other steroids like prednisone. Remember that CYP3A4 inhibitors can increase the concentrations of budesonide. I discuss this further on the podcast. Different dosage forms of budesonide (oral versus rectal) can be used for different reasons. The site of the inflammation in Ulcerative colitis can determine which dosage form is most appropriate.

Be Prepared for Patients to Ask About CBD Cannabidiol (CBD) products are moving into some pharmacies and mainstream retailers...not just smoke shops, dispensaries, etc. CBD and THC are cannabinoids found in two varieties of the cannabis plant...marijuana and hemp. CBD doesn't cause a "high" like THC. Hemp with 0.3% THC or less is no longer a federally controlled substance and is a legal source of CBD...after last year's Farm Bill. But cannabis STATE laws vary. For example, cannabis is fully legal in California...but all forms are illegal in Idaho. FDA regulations add to the confusion. They say CBD can't be sold as a supplement...since it was first approved as an Rx drug (Epidiolex). But CBD is allowed in hemp-derived "cosmetics"...creams, lotions, etc. This leaves a lot of murkiness with CBD...especially with orals, tinctures, foods, etc...and enforcement is spotty. So far, the most conclusive evidence is with Epidiolex...a purified CBD solution approved for two rare and severe seizure disorders. Emphasize that there's not good evidence yet to support popular CBD claims...such as relieving chronic pain, anxiety, or insomnia. And the variety of CBD products leaves many unknowns about their safety, quality, dosing, etc. In general, recommend avoiding CBD in pregnant or breastfeeding women...and lean away from it in patients taking multiple meds. Educate that CBD may cause drowsiness, diarrhea, etc...and using it with CNS depressants (benzos, opioids, etc) may worsen sedation. Be aware of many potential interactions. For example, CBD inhibits CYP2C8, 2C9, and 2C19...and might raise levels of meds such as amitriptyline, valproic acid, and warfarin. Or CBD levels might be increased by CYP3A4 inhibitors, such as clarithromycin. Plus high CBD doses are linked to elevated liver function tests. Explain most urine drug tests check for THC...not CBD. But high CBD doses with trace amounts of THC...or impure products...could lead to a positive THC test. If patients plan to try CBD, suggest checking the product for a "certificate of analysis" from an independent lab. This doesn't confirm safety or efficacy...but shows levels of CBD, THC, and contaminants. Dive deeper with our chart, Comparison of Cannabinoids...and access our Natural Medicines for more on efficacy, safety, and interactions. Key References: -www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#othercbdapproved (05-16-19) -Health Effects of Cannabis and Cannabinoids: National Academies Press (US); 2017 -Can Fam Physician 2018;64(2):111-20 Pharmacist's Letter. June 2019, No. 350604 See omnystudio.com/listener for privacy information.

Rivaroxaban is a factor 10a inhibitor that inhibits clot formation and thins the blood. Rivaroxaban needs to be monitored for bleed risk. Checking periodic CBC can help us assess if hemoglobin and hematocrit are remaining stable. Enzyme inducers like rifampin, St. John's Wort, and carbamazepine can reduce concentrations and increase the risk of treatment failure. NSAIDs and antiplatelet medications can significantly increase the risk of bleed with rivaroxaban. Rivaroxaban should not be used with dual P-glycoprotein and CYP3A4 inhibitors. Examples include ketoconazole, itraconazole, and ritonavir.

Trazodone pharmacology is complex. It can inhibit serotonin reuptake, block histamine receptors, and possibly have alpha-blocking activity. Side effects of trazodone include sedation, dizziness, and dry mouth. Rarely, priapism may occur. I've seen this nugget come up on pharmacology exams! While trazodone is classified as antidepressant, it is often used to help manage insomnia. Trazodone can possibly prolong the QT interval. Risk of other medications and patient specific parameters should be considered. Trazodone concentrations can be increased with the use of CYP3A4 inhibitors and reduced with 3A4 inducers.

Dr. Perl gives guidance on providing optimal patient therapy when prescribing midostaurin with a strong CYP3A4 inhibitor.

Fentanyl er den foretrukne opioid i de danske regioners ambulancetjenester. Fentanyl er et syntetisk opioid som er 100 gange mere potent end morfin, faktisk var det fentanyl man bedøvede patienter med når man lavede bypass tidligere, og når vi siger bedøvede med så mener vi det, for de fik ikke andet end det, til gengæld fik det massere af det. I FOAMmedicPHARMA gennemgår vi de medikamenter vi bruger til daglig og denne gang er det Fentanyl vi skulle lære lidt om. Det er ikke kun læring at lytte på, men bestemt en kæmpe læring for os at lave research til episoderne. Vi er selv blevet mere ydmyg over for dette kraftige og afhængighedsskabene morfin ligende produkt. Vi håber i kan lide det i hører. Kom gerne med indspark, tanker og forslag til de næste episoder i kommentarfeltet længere nede. Og der er en ny spænende quiz så lyt med. Abonner eller hent via iTunes for iOS og for android via Stitcher.  Nu også via TUNE IN Støt FOAMmedics arbejde med 5 eller 10 kr pr. podcast Hvis du har lyst til at støtte vores arbejde med at lave lækker lyd og skrift så klik ind på 10er.dk og støt os med 5,10 eller 15 pr. podcast episode, så bliver vi så sindsygt stolte og glade. Eller klik på 10'er logo her under og en pop-up løsning kommer frem. DISCLAIMER Det her er vores fortolkning af det pågældende medikament, det er ikke den endegyldige sandhed og vi opfordre som altid til at være kritisk over for den viden man hører og selv tjekke op på relevant viden og fakta. Du vil muligvis høre information eller om tilstande vedr. et medikament, hvor du ikke har delegation til at benytte medikamentet. men som udelukkende bliver omtalt, for at vi kan blive klogere i processen. Denne podcast er ikke en erstatning for pro.medicin.dk eller vores lokale retningslinjer. Hermed links og info fra denne episode   Lean body weight  Hvad betyder det egentlig. I episoden taler vi om at vi skal udvise forsigtighed ved svært overvægtige når vi dosere fentanyl. Vi nævner udtrykket Lean body weight som det man skal tage udgangspunkt i. Det betyder at man skal tage den normale vægt for en person af den størrelse, og ligge 20% til. Så har man et estimeret niveau som passer og uden man er i øget risiko for at overdosere. Vi taler også om hæmmer og fremme i forbindelse med metaboliseringen, her er lidt information om det og de mediciner vi skal være opmærksom på.  Cytochrome P450 3A4 (CYP3A4) inducere Antiepileptika som carbamazepin, phenytoin og primidon er stærke enzym-inducerende lægemidler, som øger fentanylmetabolismen i leveren, således at fentanyl udskilles hurtigere fra kroppen. En betydelig forøgelse af behovet for fentanyl må forventes hos enhver patient i langtidsbehandling med disse antiepileptika, men ikke med natriumvalproat. CYP3A4-hæmmere (cytochrom P450 3A4) Fentanyl metaboliseres hovedsageligt via CYP3A4. Det har en høj clearance og metaboliseres hurtigt samt i stor grad. Når Haldid anvendes, kan samtidig anvendelse af en CYP3A4-hæmmer reducere clearance af fentanyl. Når der anvendes enkeltdoser af Haldid, kan perioden med risiko for respirationsdepression være forlænget, og det kan kræve særlig pleje af patienten, en længere observationstid og muligvis overvågning af respirationsfrekvensen på opvågningsenheden. Når der anvendes flere doser Haldid, kan der være en øget risiko for akut og/eller forsinket respirationsdepression, og det kan være nødvendigt at reducere dosen af Haldid for at undgå akkumulering af fentanyl. Oral ritonavir (en stærk CYP3A4-hæmmer) reducerede clearance af en enkeltdosis intravenøs Haldid med 2/3, men den maksimale plasmakoncentration af fentanyl blev ikke påvirket. Itraconazol (en anden stærk CYP34A-hæmmer) 200 mg/dag oralt i 4 dage havde dog ingen signifikant effekt på farmakokinetikken af en enkeltdosis intravenøs Haldid. Co-administration af andre CYP3A4-hæmmere, såsom voriconazol eller ketoconazol (stærke CYP3A4-hæmmere),

Hormetism is the application of progressive, intermittent stress to overcome challenges and grow stronger physically, mentally and emotionally. As athletes, we intuitively understand the hormetic effect of exercise but did you know that cold, altitude, plant toxins and even straining slightly to read can all be used to help us get stronger? My guest is for this interview is Todd Becker, a freelance blogger based in the San Francisco Bay Area, where he lives with his wife and two children. He has degrees in Chemical Engineering and Philosophy from Stanford University and Brown University.  Todd currently works as a staff scientist for a biotechnology company in Palo Alto, where he leads project teams and holds more than 20 patents.   Not everyone will have access to all of the hormetic stressors we talk about in this episode. The important takeaway message is that there's more than one way to get stronger. Take advantage in whatever way you see fit. Here’s the outline of this interview with Todd Becker: [00:00:24] Myopia: A Modern Yet Reversible Disease. [00:00:53] AHS16 - Todd Becker - Living High and Healthy. [00:01:48] Hormesis. [00:02:35] Low-carb and intermittent fasting. [00:03:58] Going on holiday and forgetting glasses. [00:04:40] Print pushing. [00:05:02] Exercise. [00:05:29] Immune system. [00:06:07] UV. [00:06:13] Overcompensation. [00:07:28] Lactose tolerance. [00:08:35] Unnecessarily avoiding the sun. [00:10:05] Finding the perfect amount of stress. [00:12:15] Learning to fast blog post. [00:13:00] Heart rate variability or even just resting HR. [00:14:02] Cold showers. [00:14:43] Alcohol. [00:15:53] Metabolic flexibility. [00:16:08] Allostasis. [00:17:07] Wood smoke. [00:17:25] Evolutionary mismatches. [00:17:41] Is charred meat bad for you? [00:18:29] Catching Fire: How Cooking Made Us Human. [00:19:02] Phases of detoxification. [00:19:17] CYP3A4. [00:19:42] Superoxide dismutase. [00:20:01] Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More. [00:21:28] Low-dose dioxins. [00:21:53] Hormone analogues. [00:22:14] Gluten. [00:22:40] IgE emergency response. [00:22:50] An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. [00:23:36] Peanut allergies [00:23:56] Karelia (historical province of Finland). [00:25:00] Reversing peanut allergies. [00:25:22] Poison ivy and oak. [00:26:49] Peanut oil in diaper cream. [00:27:06] Oral vs topical exposure. [00:27:23] Epstein–Barr virus infection at certain ages. [00:28:09] Altitude. [00:28:24] Boulder has the lowest obesity rate in the US. [00:29:28] PGC1-a via hypoxia. [00:30:16] Barry Murray on my podcast. [00:31:36] Altitude masks. [00:32:02] Train high race low. [00:32:24] Jeremy Powers on this podcast. [00:34:43] gettingstronger.org

Dr Levis talks to ecancertv at ASH 2013 about novel agents for FLT3-ITD positive acute myeloid leukaemia (AML) The relapse rate for FLT3-ITD positive AML is worse than normal AML, and when relapse does occur cure is near to impossible. Activating mutations in the receptor tyrosine kinase FLT3 occur in roughly 30% of acute myeloid leukemia patients, implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin (PKC412) shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Besides its mere presence, the allelic ratio as well as ITD insertion site within the FLT3 gene had been reported as prognostic factors in FLT3-ITD positive AML. Pharmacokinetic analyses revealed clinically important interactions between potent CYP3A4 inhibitors, such as azoles, and midostaurin. Allogeneic transplant remains the best option.

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects.