Podcasts about qtc

In this episode, we explore lamotrigine's cardiac side effects, focusing on QTc prolongation and QRS widening. How concerned should psychiatrists be about the FDA warning regarding lamotrigine's cardiac effects? We examine the evidence behind these concerns and discuss practical implications for clinical practice. Faculty: Scott Beach, M.D. Host: Richard Seeber, M.D. Learn more about our memberships here Earn 0.5 CME: Lamotrigine: From Current Indications to Cardiac Side Effects Lamotrigine Effect on QTc Prolongation and QRS Widening

Show notes at pharmacyjoe.com/episode996. In this episode, I’ll discuss whether the Tisdale Risk Score can be used to identify ICU patients at risk of QTc prolongation. The post 996: Tisdale Risk Score For Identifying ICU Patients at Risk of QTc Prolongation appeared first on Pharmacy Joe.

Show notes at pharmacyjoe.com/episode989. In this episode, I'll discuss delayed QTc prolongation in overdose patients. The post 989: How to Identify an ED Toxicology Patient at Risk of Delayed QTc Prolongation appeared first on Pharmacy Joe.

This is Allan VK4HIT with news from Ipswich and District Radio Club. Ron has been calling in the Ipswich morning net since July 1986. For Ron, it has been a labour of love and for the rest of us listening or taking part in the net, he has been a constant – the voice of reassurance in a world of change. Sadly, Monday, November 25 was the last time Ron made the regular call for stations owing to a change of home address which doesn't permit a base station setup. VK4RG was first licensed in 1956 and he is hopeful his trusty handheld will enable him to call in occasionally. VK4RG, we salute you and thank you for your service to the club and amateur radio. Reporting from Ipswich this is Allan, VK4HIT. I'm John VK4JPM Darling Downs Radio Club Secretary with the club update for Sunday 8th of December. Before I remind you about the tech meeting tomorrow night - yes, tomorrow night. John VK4JBE is coming up from Brisbane to give us all the good stuff about Software Defined Radios. If you're just catching up to the topic, check out the Wikipedia article online, because that's a good introduction to the introduction. All the info on the meeting is on the website at www.ddrci.org.au Hello, I'm Geoff Emery, VK4ZPP, and I've been thinking. During the past week, the postman handed me the latest edition of Amateur Radio magazine and it prompted me to think about what we used to have. Once there was a state-based newsletter aptly called QTC. This was a great addition to the shack in that reminders of events were in tangible form rather than just committed to memory. When the weekly news went out on packet radio, it was an easy task to print it out and these days we are very likely to have a printer on our home network which can do the same job with the news bulletins. You see, QTC went into a column in AR magazine before it went SK. Largely club notes have been lost to the printed medium and this makes our broadcast news all the more important in getting the messages out to fellow amateur operators. This is especially true with the magazine now bi-monthly having gone from monthly to 11 issues a year and now every 2 months. I don't know how many clubs are running nets these days as there isn't a quickly accessible list for me to check. I know that not a lot can be heard from my location and without receiving reminders or newsletters I would bet that most of us are just as much in the dark as I am. So here we are engaged in a communications activity and we seem to be confounded by poor communications. I don't know how many missives are sent via the WIA Memnet service but I receive advice of the release of the digital issue of the magazine so that amounts to only 1 every 2 months. Periodically the text edition of the national news drops off until I send a plea for help and that makes me wonder how effective our IT systems are working for the WIA. To place a little context on the subject, I live in a house with people not only getting older but also living with chronic health issues. There are many times that I think of things that I would like to see done by me or others but circumstances don't give the luxury of acting on those thoughts. For me, getting updates in my email is a welcome piece of assistance as I don't have to devote time to searching them out. It also provides a point of connection to the wider community in a way that is accessed at convenient times. You see these ways of sharing are important on a personal level as much as they support club activity and growth. Once it was the cartoonist's jibe that you had to lick the tip of a pencil or bash the heck from a typewriter to get the news out. These days we can achieve things much more sedately and just as effectively with our mobile devices or shack computers. I look forward to getting your news in electronic or broadcast. I'm Geoff Emery VK4ZPP and that's what I think….how about you?

In this episode of the Top 200 Drugs Podcast, I cover glyburide, citalopram, olmesratan, carvedilol, and tiotropium. Glyburide is a sulfonylurea that is well known to cause hypoglycemia and weight gain because it stimulates the pancreas to increase insulin release. Citalopram is an SSRI most well known for its potential to increase the risk for QTc prolongation. It has a notorious drug interaction with omeprazole Olmesartan is an ARB that can be used for hypertension. Hyperkalemia is an electrolyte imbalance that can be caused by its use. Carvedilol is one of the few beta-blockers with significant alpha-blocking and beta-blocking activity. I discuss what this means in this Top 200 drugs podcast. Tiotropium is an anticholinergic medication that can open the airway. It is most commonly used for COPD.

On this episode of the Real Life Pharmacology podcast, I cover medications 51-55. They are eszopiclone, celecoxib, estrogen, moxifloxacin, and donepezil. Eszopiclone is a "Z" drug used for insomnia. Its adverse effect profile is very similar to benzodiazepines. Celecoxib is a COX-2 Inhibitor used for pain and inflammation. I discuss how this medication differs from traditional NSAIDs. Estrogen therapy is used for menopausal symptoms but carries a risk of cancer and blood clots. Moxifloxacin is a quinolone antibiotic. Binding drug interactions, boxed warnings, and QTc prolongation are potential concerns. Donepezil is a medication used for dementia. I discuss its mechanism of action and common adverse effects.

Lamotrigine is an antiseizure medication and also may be used for bipolar disorder. A rash is a major side effect to remember with this medication. Valganciclovir is an antiviral medication that can be used to prevent cytomegalovirus (CMV) in patients with a suppressed immune system. Fluconazole is an azole antifungal that can be used to treat candidiasis, blastomycosis, and tinea infections. Drug interactions, QTc prolongation, and hepatotoxicity are potential risks. Atenolol is a beta-blocker used to treat atrial fibrillation and hypertension. It is relatively selective for beta-1 receptors meaning that it doesn't affect the lungs as much as non-selective agents. Montelukast is a medication that blocks the actions of leukotrienes. This can be beneficial for the management of allergies and asthma.

The Deep End with Dan Sweetman explores the complex tension between faith, doubt and what a deep life truly looks like today.  In this edition of The Deep End, Dan speaks to Dr Andrew Bain who is the Vice Principal at QTC, a writer, philosopher and historian. Andrew unpacks some of the doubts he's faced when reading the Bible and how we are to go about understanding the most confronting and disturbing sections of God's word.  The Deep End is a production of 96five Brisbane and Lifepoint Church Rothwell. Find more 96five podcasts here!See omnystudio.com/listener for privacy information.

Introduction A new creation! I'm Malcolm Cox. Welcome to this series on ‘A new creation'. Today, another model that may help us understand how God changes us. This week we take a look at a model of spiritual growth put forward by Trevor Hudson. His model is a variation on the model developed by Dallas Willard we explored in QTC 521. See a picture of the model here. Hudson's take is very similar to Willard's. We will focus on the key difference - community. However, first a brief comment on what he calls the "Divine friendship with the Trinity". "Redeemed people are redeemed to God and to his community. God is Community, and so are his people. We need to recover a proper appreciation for the Trinitarian doctrine of God, and noting how it affects thinking about community." 'A Particular People -- Toward a faithful and effective Ecclesiology' -- Inagrace T. Dietterich Bear in mind that this model is no formula. In community with individuals Our closest relationships are the litmus test of our growth. We love each other by telling each other the truth -- in a loving way. Ephesians 4.14-16 “Then we will no longer be infants, tossed back and forth by the waves, and blown here and there by every wind of teaching and by the cunning and craftiness of people in their deceitful scheming. Instead, speaking the truth in love, we will grow to become in every respect the mature body of him who is the head, that is, Christ. From him the whole body, joined and held together by every supporting ligament, grows and builds itself up in love, as each part does its work.” "As members of God's kingdom community, each of us is given a manifestation of the Spirit in our lives for the purpose of the common good. We all have something to offer because of what the Spirit gives to us (1 Corinthians 12.7)." Forgotten God. Francis Chan and Danae Yankoski 1 Corinthians 12.7  “Now to each one the manifestation of the Spirit is given for the common good.” 2. In community with the group The church is a catalyst for change. A place where it is safe enough to be ourselves and allow one another to influence us to stretch towards Christ. Regular collective worship is vital to our spiritual formation because it reshapes us by reconnecting us to the community of faith. Hebrews 10.24-25 “And let us consider how we may spur one another on toward love and good deeds, not giving up meeting together, as some are in the habit of doing, but encouraging one another—and all the more as you see the Day approaching.” Conclusion "God measures our spiritual health or spiritual dysfunction by the relationships and community and the people around us. (Location 2244)" Wide Awake, Erwin Raphael McManus For reflection What does it mean to you to have healthy spiritual friendships? How do you know they are spiritually enriching? What hesitations do you have regarding devoting yourself to spiritual community, and why? What do you see as the key ways community can aid your spiritual growth? What do you believe you have to offer your spiritual community to help other people grow? Next time we will go on to look at James Bryan Smith's model of spiritual transformation. Your brother, Malcolm Please add your comments on this week's topic. We learn best when we learn in community. Do you have a question about teaching the Bible? Is it theological, technical, or practical? Could you send me your questions or suggestions? Here's the email: malcolm@malcolmcox.org. If you'd like a copy of my free eBook on spiritual disciplines, “How God Grows His People”, sign up at my website: http://www.malcolmcox.org. Please pass the link on, subscribe, and leave a review. "Carpe Diem" Kevin MacLeod (incompetech.com) Licensed under Creative Commons: By Attribution 4.0 License  http://creativecommons.org/licenses/by/4.0/

In this episode, we say Hi to all our new listeners after SHM, we are glad you are joining us and hope you stick around! Make sure to follow on your platform of choice. Today we are broadcasting part 1 of an interview with Dr. Marlene Martin, an addiction medicine specialist who works at the SF General. We talk to her about methadone initiation issues including faster initiation, QTc checks, and pain management during an admission. Note: this episode is provided for informational purposes only. We do not directly endorse the use of these discussions, including CAM2038, without proper input from your local addiction medicine consultants. | 00.00 - Episode open: HELLO TO OUR NEW LISTENERS! | | 00.48 -Intro to Dr. Marlene Martin | | 01.53 - Latine v Latinx - ask people how they want to be referred to! | | 03.08- Methadone and checking the QTc | | 09.34 - What happens outpatient with the EKG and the QTc? | | 10.04 - Discussing needs with other groups. Its a team effort! | | 11.14 - Methadone changes and EKG followup | | 12.07 - COMING SOON: FASTER METHADONE TITRATION (spoiler, don't do it yet without addiction medicine guidance) | CAM2038 as a possible depot option. Studies are currently being done | 17.15 - What to do with pain on top of methadone or Buprenorphine | Rapid Clinical Updates: Inpatient Management of Opioids [SHM 2023] Marlene's paper “Inhospital substance use policies” [JAM 2023] | 24.53 - Closing | [The appearance of external hyperlinks does not constitute endorsements by UCSF of the linked websites, or the information, products, or services contained therein. UCSF does not exercise any editorial control over the information found therein, nor does UCSF make any representation of their accuracy or completeness. All information contained in this episode are the opinions of the respective speakers and not necessarily the views their respective institutions or UCSF, and is only provided for information purposes, not to diagnose or treat.] Music by Amit Apte. Cover art organized by Neal Tambe.  

On this episode, I discuss the pharmacology surrounding QTc prolongation and drug interactions. I discuss which medications are more likely to cause QTc prolongation and which patient populations we should be more concerned about. Antiarrhythmics are a common class of medication that can exacerbate QTc prolongation when used with other interacting medications. 500 ms is a common value utilized to help identify patients at risk for QTc prolongation and ultimately torsades de pointes.

Show notes at pharmacyjoe.com/episode897. In this episode, I’ll discuss whether ICU patients benefit from daily QTc interval monitoring during antipsychotic use for delirium. The post 897: Is It Necessary To Monitor QTc of ICU Patients Receiving Antipsychotics for Delirium? appeared first on Pharmacy Joe.

Show notes at pharmacyjoe.com/episode897. In this episode, I’ll discuss whether ICU patients benefit from daily QTc interval monitoring during antipsychotic use for delirium. The post 897: Is It Necessary To Monitor QTc of ICU Patients Receiving Antipsychotics for Delirium? appeared first on Pharmacy Joe.

On this podcast episode, I discuss levofloxacin pharmacology, adverse effects, boxed warnings, interactions, and much more. Levofloxacin is well known to cause QTc prolongation and many drugs can increase this risk such as antiarrhythmics, citalopram, antipsychotics, and many more. Binding interactions are important when discussing levofloxacin pharmacology. Calcium, iron, magnesium, and many other cations can block the absorption of this medication. I discuss tendon rupture in relation to levofloxacin use and what factors may increase the risk of this rare adverse effect.

In this episode Dr. Gillian Beauchamp sits down with Dr. Stephanie Weiss to discuss HERG channel blockade, QTc prolongation and cardiotoxicity. 

In this podcast episode, I discuss methadone pharmacology, adverse effects, drug interactions, and pharmacokinetics. Methadone is a full opioid agonist that may be used for pain management and opioid use disorder. Transitioning from methadone to another opioid is complicated. I discuss conversion in this podcast episode. Methadone can increase the risk of QTc prolongation and also has a lot of drug interactions. I discuss them in detail in this podcast episode.

CardioNerds (Dr. Daniel Ambinder, Dr. Giselle Suero Abreu, Dr. Kahtan Fadah, and Dr. Colin Blumenthal) discuss arrhythmias in CardioOncology with Dr. Michael Fradley. In this episode, Dr. Michael Fradley joins us in the CardioNerds CardioOncology clinic where he uses his unique dual training in cardio-oncology and electrophysiology to walk us through the complex interplay and management of these disorders. We discuss the incidence and pathophysiology of these arrhythmias, including the link with various cancer treatments, screening and detection, and complex management including rate vs rhythm control in atrial fibrillation, need for anticoagulation, effects on the QTc and so much more. Given the unique challenges with this population we also delve into how this affects their oncology care and how to approach changes to their cancer treatment. Show notes were drafted by Dr. Kahtan Fadah and episode audio was edited by student Dr. Tina Reddy. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Arrhythmias in CardioOncology Arrhythmias are common in cancer patients due to shared risk factors and bi-directional risk between cardiac and oncologic disorders. Many cancer therapeutics can be directly arrhythmogenic or lead to cardiotoxicities that pre-dispose to arrhythmias. Though incidence of arrhythmia can be significant increased with some cancer therapeutics (e.g. ibrutinib), there is not specific data to support proactive ambulatory monitoring for arrhythmia without evidence of clear symptoms. Atrial fibrillation is the most common arrhythmia in cancer patients and management of atrial fibrillation, as well as other tachyarrhythmias, is unchanged from management in non-cancer patients. General principles of when to start anticoagulation or rate vs rhythm control are not significantly different (e.g. still use CHA2DS2-VAsC, monitor for symptoms etc), but providers should be more mindful of drug-drug interactions with cancer therapeutics. Cancer therapeutics as well as common medications used to treat side effects or complications (e.g. antiemetics, antibiotics, etc) can prolong the QT interval and increase risk of Torsades de pointes (TdP). The QTc should be monitored with an ECG for patients on these medications. If a patient does develop a serious arrhythmia like TdP, management is similar to that in non-cancer patients. The goal of arrhythmia management in cardio-oncology is to prevent cardiovascular disease from becoming a barrier to appropriate cancer therapy. Though cancer therapeutics should be temporarily or permanently discontinued in potentially fatal events (e.g TdP from QTc prolonging meds), the overall goal is to manage the arrhythmias appropriately to allow cancer therapeutics to be continued or restarted. Show notes - Arrhythmias in CardioOncology What is the prevalence of arrhythmias in patients with cancer? Arrhythmias are common in patients with cancer due to a multitude of factors. Atrial fibrillation is the most common arrhythmia in this population and occurs in approximately 5% of patients with cancer. The driving forces are multifactorial and include the direct arrhythmogenic effects of cancer therapeutics and cardiotoxicities of cancer therapeutics that make arrhythmogenesis more likely. Additionally, there is a bi-directional link between cancer and cardiac disorders. For example, not only is atrial fibrillation more common in patien...

La American Heart Association publicó un documento con recomendaciones específicas para el manejo del paciente en paro cardiaco por intoxicación. Este artículo repasará las principales recomendaciones. Este es el tercer episodio de una serie de episodios relacionados al manejo del paro cardiaco por envenenamientos. En este episodio discutimos el manejo de la intoxicación por cocaína. Toxíndrome clásico de intoxicación por cocaína El toxíndome clásico de la intoxicación por cocaína está basado en la sobre-estimulación simpatomimética. A pesar de que la cocaína hace daño aún en dosis bajas, muchas personas usan la cocaína ilegalmente con fines recreaciones debido a su efecto de estimulación alfa y beta. Por lo tanto, hay pacientes que tienen presencia de cocaína pero no necesariamente tienen una queja principal asociada al uso de la cocaína. Para efectos de esta discusión, vamos a dividir los pacientes que usan cocaína en tres escenarios: Los pacientes que tienen signos típicos asociados al consumo de cocaína, con o sin una queja principal que amenaze la vida. Los pacientes con efectos adversos severos Paro cardiaco La cocaína produce signos y síntomas típicos de la estimulación alfa y beta: Taquicardia Hipertermia Hipertensión Diaforesis Agitación Dejando a un lado temporalmente la discusión de los efectos adversos a la salud, dos personas pudieran percibir estos signos de forma diferente: uno pudiera desearlo al punto de que la usa para obtener esta estimulación, y otra persona pudiera percibirlo como efectos no deseados. Es posible que las palpitaciones, sudoración y agitación sean percibidas como un signo desagradable. No obstante, es parte del efecto clásico de la cocaína y pudiera, o no, requerir atención médica de emergencia. En otros pacientes, la estimulación excesiva de los receptores beta y alfa pudiera producir una emergencia hipertensiva, vasoespasmo coronario, disección aórtica, y/o arritmias cardiacas que requieran atención médica de emergencia. Para efectos de esta discusión, voy a considerar el paciente en paro cardiaco como un escenario diferente porque el manejo es diferente. Manejo de emergencias asociadas al uso de cocaína Aunque los efectos anteriores, especialmente el potencial para producir infartos y arritmias, puede ser suficiente para llevar al paciente a un paro cardiaco, existe otro mecanismo por el cual el uso de cocaína está asociado a inestabilidad hemodinámica, arritmias y paro cardiaco: bloqueo de los canales de sodio y potasio. En el episodio anterior del ECCpodcast les mencionaba que el propranolol, a pesar de que puede producir inestabilidad puramente por el bloqueo de los canales beta, también actúa como bloqueador de canal de sodio y es este último mecanismo el que lo hace más peligroso que los demás betabloqueadores. De la misma manera, la cocaína puede producir efectos de bloqueo de canales de sodio y potasio que están asociados a emergencias médicas. Efectos debido al bloqueo de canales de sodio Prolongación del QRS Taquicardia de complejo ancho El manejo del bloqueo de canales de sodio puede incluir el uso de bicarbonato de sodio. Efectos debido al bloqueo de canales de potasio Prolongación del intervalo QTc La prolongación del intervalo QTc puede dar paso a una taquicardia ventricular polimórfica. El manejo de esta puede incluir el uso de magnesio. Otros efectos debido a sobre-estimulación alfa y beta En términos generales, el manejo de la sobre-estimulación por la cocaína está basado en el uso de benzodiazepinas para manejar los síntomas y jarabe de tiempo. Pueden haber algunas recomendaciones adicionales según el contexto clínico. Emergencias hipertensivas y síndrome coronario agudo La cocaína puede producir espasmo de las arterias coronarias, especialmente en personas que usan cocaína por primera vez. Es un mecanismo clásico de dolor de pecho y de síndrome coronario agudo en pacientes jóvenes. No obstante, el uso de cocaína, aún en dosis bajas, está asociado a eventos cardiovasculares mayores. La cocaína puede acelerar la producción de placas ateromatosas en las arterias coronarias, lo que puede inducir a enfermedad coronaria y síndrome coronario agudo. Las guías de la American Heart Association recomiendan que se usen vasodilatadores como los nitratos, la fentolamina y los bloqueadores de canales de calcio para pacientes con vasoespasmo coronario y/o emergencias hipertensivas. Arritmias ventriculares Al igual que con las arritmias ventriculares por propranolol, se recomienda el uso de lidocaína en vez de amiodarona o procainamida en pacientes con arritmias ventriculares, por el hecho del bloqueo de los canales de potasio. Taquicardias atriales La estimulación beta puede producir taquicardias atriales tales como taquicardia sinusal, fibrilación atrial o taquicardias nodales. Los betabloqueadores históricamente han estado prohibidos en los pacientes con taquicardias por cocaína. La estimulación simpática de la cocaína incluye efectos en los receptores alfa y beta (1 y 2). La estimulación alfa provoca vasoconstricción, pero la estimulación B2 provoca vasodilatación arterial. En otras palabras, la vasodilatación por B2 mantiene a raya la vasoconstricción por alfa. Si se elimina el efecto B2 (por el betabloqueador), ocurre una estimulación alfa sin oposición, lo que puede llevar a una crisis hipertensiva. Podemos argumentar que esto no se ve frecuentemente, y que algunos pacientes que son admitidos con síndrome coronario agudo y que han sido administrados betabloqueadores luego dan positivo a cocaína y nunca experimentaron una crisis hipertensiva. Aunque esto no ocurre en todos los pacientes, es una complicación potencial que puede ser evitada usando otro medicamento que no sea un betabloqueador. Paro cardiaco por intoxicación con cocaína Posiblemente lo único antes mencionado que aplique durante el manejo del paro cardiaco es la consideración del uso de bicarbonato y lidocaína. Resumen: Recomendaciones de la AHA para el manejo de pacientes con intoxicación por cocaína Recomendamos el enfriamiento rápido externo para pacientes con hipertermia que amenaza la vida por envenenamiento por cocaína. (Clase de recomendación 1, Nivel de evidencia: C-LD) Es razonable administrar bicarbonato de sodio para taquicardias de complejo ancho o paro cardiaco por envenenamiento por cocaína. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable administrar lidocaína para taquicardias de complejo ancho por envenenamiento por cocaína. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable administrar vasodilatadores (ej. nitratos, fentolamina, bloqueador de canal de calcio) para pacientes con vasoespasmo coronario o emergencias hipertensivas inducidas por cocaína. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Referencias Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR; on behalf of the American Heart Association. 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: an update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023;148:e•••–e•••. doi: 10.1161/ CIR.0000000000001161

La American Heart Association publicó un documento con recomendaciones específicas para el manejo del paciente en paro cardiaco por intoxicación. Este artículo repasará las principales recomendaciones. Este es el segundo episodio de una serie de episodios relacionados al manejo del paro cardiaco por envenenamientos. A pesar del efecto de bloqueo de los receptores beta 1 y beta 2, el propranlol y el sotalol pueden causar inestabilidad cardiaca por bloqueo de canales de sodio y bloqueo de canales de potasio, respectivamente. Por lo tanto, el manejo de estos dos β-bloqueadores requiere una discusión adicional. Bloqueadores de canales beta La presentación del paciente con intoxicación con betabloqueadores incluye: Hipotensión Bradicardia Hipoglicemia Hiperkalemia Coma, convulsiones Manejo de sobredosis con betabloqueadores Atropina Glucagón Calcio (debido a hiperkalemia por intoxicación) Vasopresores Insulina en altas dosis Dextrosa (hipoglucemia debido a intoxicación, y debido a la insulina) ILE Therapy Resumen de las recomendaciones de la AHA para intoxicaciones con betabloqueadores Recomendamos la administración de insulina en altas dosis para la hipotensión debido a envenenamiento con betabloqueadores refractario a, o en conjunto con, terapia con vasopresores. Clase de recomendación: 1, Nivel de evidencia: B, NR Recomendamos que se administren vasopresores para la hipotensión debido a envenenamiento con betabloqueadores. Clase de recomendación: 1, Nivel de evidencia: C-LD) Es razonable usar un bolo de glucagón, seguido de una infusión continua, para la bradicardia o hipotensión debido a envenenamiento por betabloqueadores. Clase de recomendación: 2a, Nivel de evidencia: C-LD Es razonable utilizar técnicas de soporte vital extracorpóreo como VA-ECMO para amenaza a la vida por sobredosis de betabloqueadores con shock cardiogénico refractario a intervenciones farmacológicas. Clase de recomendación: 2a, Nivel de evidencia: C-LD Puede ser razonable administrar atropina para bradicardia inducida por betabloqueadores. Nivel de recomendación: 2b, Clase de evidencia: C-LD Puede ser razonable intentar el uso de marcapasos eléctrico para bradicardia inducida por betabloqueadores. Nivel de recomendación: 2b, Clase de evidencia: C-LD Puede ser razonable usar hemodiálisis para amenazas a la vida por sobredosis con atenolol o sotalol. Clase de recomendación: 2b, Nivel de evidencia: C-LD La terapia de emulsión de lípidos intravenosos no es de beneficio para envenenamientos que amenazan la vida con betabloqueadores. Clase de recomendación: 3 no hay beneficio. Nivel de evidencia: C-LD Notas adicionales sobre el propranolol La sobredosis con propranolol puede producir un bloqueo en los canales de sodio. Los bloqueos de canales de sodio se manifiestan prolongación del complejo QRS y un complejo QRS predominantemente positivo en aVR. El manejo de los pacientes con intoxicaciones con bloqueadores de canales de sodio requiere la administración de bicarbonato de sodio. La amiodarona y la procainamida están contraindicadas en el manejo de los pacientes con intoxicación con bloqueadores de canales de sodio. Esta Guía de la AHA discute el tema de las intoxicaciones con bloqueadores de canales de sodio en otra sección, por lo que este tema no se expandió en esta sección de intoxicaciones con betabloqueadores. Notas adicionales sobre sotalol La sobredosis con sotalol puede producir prolongación del completo QTc, y como resultado el paciente puede tener torsada de punto.  Bloqueadores de canales de calcio Dos tipos de bloqueadores de canales de calcio: Dihidropiridinos (frecuencia) Nifedipina Amlodipina No-dihidropiridinos (vasodilatación) Diltiazem Verapamil Resumen de recomendaciones de la AHA para intoxicaciones con bloqueadores de canales de calcio Recomendamos la administración de vasopresores para la hipotensión por envenenamiento con bloqueadores de canales de calcio. (Clase de recomendación: 1, Nivel de evidencia: B-NR) Recomendamos la administración de insulina en dosis alta para hipotenso debido a envenenamiento con bloqueadores de canales de calcio. (Clase de recomendación: 1, Nivel de evidencia: B-NR) Es razonable administrar calcio para envenenamiento por bloqueadores de canales de calcio. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable administrar atropina para bradicardias hemodinámicamente significativas debido a envenenamiento por bloqueadores de canales de calcio. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable utilizar técnicas de soporte vital extracorpóreo tales como VA-ECMO para shock cardiogénico debido a envenenamiento por bloqueadores de canales de calcio que sea refractario a intervenciones farmacológicas. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Puede ser razonable tratar con marcapasos eléctrico para envenenamientos con bloqueadores de canales de calcio con bradicardia refractaria. (Clase de recomendación: 2b, Nivel de evidencia: C-LD). La utilidad de los bolos e infusión de glucagón para envenenamientos por bloqueadores de canales de calcio es incierta. (Clase de recomendación: 2b, Nivel de evidencia: C-LD) La utilidad de administrar azul de metileno para shock vasodilatorio refractario debido a envenenamiento por bloqueadores de canales de calcio es incierta. (Clase de recomendación: 2b, Nivel de evidencia: C-LD) El uso rutinario de terapia con emulsión de lípidos intravenosos para envenenamiento por bloqueadores de canales de calcio no está recomendado. (Clase de recomendación: 3, no hay beneficio, Nivel de evidencia: C-LD) Referencias Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR; on behalf of the American Heart Association. 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: an update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023;148:e•••–e•••. doi: 10.1161/ CIR.0000000000001161 https://litfl.com/beta-blocker-toxicity/  https://litfl.com/glucagon-as-an-antidote/ https://litfl.com/high-dose-insulin-euglycaemic-therapy/

La American Heart Association publicó un documento con recomendaciones específicas para el manejo del paciente en paro cardiaco por intoxicación. Este artículo repasará las principales recomendaciones. Este es el segundo episodio de una serie de episodios relacionados al manejo del paro cardiaco por envenenamientos. A pesar del efecto de bloqueo de los receptores beta 1 y beta 2, el propranlol y el sotalol pueden causar inestabilidad cardiaca por bloqueo de canales de sodio y bloqueo de canales de potasio, respectivamente. Por lo tanto, el manejo de estos dos β-bloqueadores requiere una discusión adicional. Bloqueadores de canales beta La presentación del paciente con intoxicación con betabloqueadores incluye: Hipotensión Bradicardia Hipoglicemia Hiperkalemia Coma, convulsiones Manejo de sobredosis con betabloqueadores Atropina Glucagón Calcio (debido a hiperkalemia por intoxicación) Vasopresores Insulina en altas dosis Dextrosa (hipoglucemia debido a intoxicación, y debido a la insulina) ILE Therapy Resumen de las recomendaciones de la AHA para intoxicaciones con betabloqueadores Recomendamos la administración de insulina en altas dosis para la hipotensión debido a envenenamiento con betabloqueadores refractario a, o en conjunto con, terapia con vasopresores. Clase de recomendación: 1, Nivel de evidencia: B, NR Recomendamos que se administren vasopresores para la hipotensión debido a envenenamiento con betabloqueadores. Clase de recomendación: 1, Nivel de evidencia: C-LD) Es razonable usar un bolo de glucagón, seguido de una infusión continua, para la bradicardia o hipotensión debido a envenenamiento por betabloqueadores. Clase de recomendación: 2a, Nivel de evidencia: C-LD Es razonable utilizar técnicas de soporte vital extracorpóreo como VA-ECMO para amenaza a la vida por sobredosis de betabloqueadores con shock cardiogénico refractario a intervenciones farmacológicas. Clase de recomendación: 2a, Nivel de evidencia: C-LD Puede ser razonable administrar atropina para bradicardia inducida por betabloqueadores. Nivel de recomendación: 2b, Clase de evidencia: C-LD Puede ser razonable intentar el uso de marcapasos eléctrico para bradicardia inducida por betabloqueadores. Nivel de recomendación: 2b, Clase de evidencia: C-LD Puede ser razonable usar hemodiálisis para amenazas a la vida por sobredosis con atenolol o sotalol. Clase de recomendación: 2b, Nivel de evidencia: C-LD La terapia de emulsión de lípidos intravenosos no es de beneficio para envenenamientos que amenazan la vida con betabloqueadores. Clase de recomendación: 3 no hay beneficio. Nivel de evidencia: C-LD Notas adicionales sobre el propranolol La sobredosis con propranolol puede producir un bloqueo en los canales de sodio. Los bloqueos de canales de sodio se manifiestan prolongación del complejo QRS y un complejo QRS predominantemente positivo en aVR. El manejo de los pacientes con intoxicaciones con bloqueadores de canales de sodio requiere la administración de bicarbonato de sodio. La amiodarona y la procainamida están contraindicadas en el manejo de los pacientes con intoxicación con bloqueadores de canales de sodio. Esta Guía de la AHA discute el tema de las intoxicaciones con bloqueadores de canales de sodio en otra sección, por lo que este tema no se expandió en esta sección de intoxicaciones con betabloqueadores. Notas adicionales sobre sotalol La sobredosis con sotalol puede producir prolongación del completo QTc, y como resultado el paciente puede tener torsada de punto.  Bloqueadores de canales de calcio Dos tipos de bloqueadores de canales de calcio: Dihidropiridinos (frecuencia) Nifedipina Amlodipina No-dihidropiridinos (vasodilatación) Diltiazem Verapamil Resumen de recomendaciones de la AHA para intoxicaciones con bloqueadores de canales de calcio Recomendamos la administración de vasopresores para la hipotensión por envenenamiento con bloqueadores de canales de calcio. (Clase de recomendación: 1, Nivel de evidencia: B-NR) Recomendamos la administración de insulina en dosis alta para hipotenso debido a envenenamiento con bloqueadores de canales de calcio. (Clase de recomendación: 1, Nivel de evidencia: B-NR) Es razonable administrar calcio para envenenamiento por bloqueadores de canales de calcio. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable administrar atropina para bradicardias hemodinámicamente significativas debido a envenenamiento por bloqueadores de canales de calcio. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Es razonable utilizar técnicas de soporte vital extracorpóreo tales como VA-ECMO para shock cardiogénico debido a envenenamiento por bloqueadores de canales de calcio que sea refractario a intervenciones farmacológicas. (Clase de recomendación: 2a, Nivel de evidencia: C-LD) Puede ser razonable tratar con marcapasos eléctrico para envenenamientos con bloqueadores de canales de calcio con bradicardia refractaria. (Clase de recomendación: 2b, Nivel de evidencia: C-LD). La utilidad de los bolos e infusión de glucagón para envenenamientos por bloqueadores de canales de calcio es incierta. (Clase de recomendación: 2b, Nivel de evidencia: C-LD) La utilidad de administrar azul de metileno para shock vasodilatorio refractario debido a envenenamiento por bloqueadores de canales de calcio es incierta. (Clase de recomendación: 2b, Nivel de evidencia: C-LD) El uso rutinario de terapia con emulsión de lípidos intravenosos para envenenamiento por bloqueadores de canales de calcio no está recomendado. (Clase de recomendación: 3, no hay beneficio, Nivel de evidencia: C-LD) Referencias Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR; on behalf of the American Heart Association. 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: an update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023;148:e•••–e•••. doi: 10.1161/ CIR.0000000000001161 https://litfl.com/beta-blocker-toxicity/  https://litfl.com/glucagon-as-an-antidote/ https://litfl.com/high-dose-insulin-euglycaemic-therapy/

In this episode, Joe interviews Deborah C. Mash, Ph.D.: neuroscientist; Professor Emerita of Neurology and Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine; and leading researcher in addiction and brain disorders for over 30 years. She is also the CEO and Founder of DemeRx Inc., a clinical stage drug development company working to advance ibogaine and its active metabolite, noribogaine, for the treatment of opioid use disorder. She talks about the Federal and state complications behind ibogaine research, the need for partnerships between clinics and researchers, what needs to be done to collect much needed Phase II and III ibogaine data, and why this all has to be in partnership with the FDA.  And she discusses much more: her story of how studying Cocaethylene led to her finding out about ibogaine; ibogaine and QTc-prolongation; deaths related to iboga and the amount of variables that aren't considered; how the French were essentially using noribogaine in the 1930s; and, as this was recorded at Psychedelic Science 2023, her thoughts on the event and Rick Doblin's opening statement. Click here to head to the show notes page.

In this enlightening episode, Ryan engages in a deep conversation with Dr. Paul Hutson, PharmD, a renowned researcher in the field of psilocybin and director of the Transdisciplinary Center for Research in Psychoactive Substances at the University of Wisconsin Madison. Dr. Hutson shares his extensive knowledge and insights into the promising role of psilocybin in the treatment of depression and substance use disorder.  Throughout the discussion, they delve into the research that supports the use of psilocybin in medical therapy, shedding light on the rigorous processes involved in conducting such studies. Dr. Hutson elucidates the efficacy and safety findings that have emerged from his and others research, offering listeners a glimpse into the potential future of psilocybin in mainstream medical practices. Listeners will gain a deeper understanding of the meticulous approach to research that ensures both safety and effectiveness. Dr. Hutson shares firsthand experiences and observations, providing a rich and detailed perspective on the current state of psilocybin research. Moreover, the conversation ventures into the practical aspects of integrating psilocybin into contemporary medical practices, discussing the potential frameworks and guidelines that would govern its use. They explore what the future might hold for patients and practitioners alike as they stand on the cusp of a revolutionary shift in mental health treatment.Whether you're a healthcare professional keen on the latest developments in medical research or someone interested in the evolving landscape of mental health treatment, this episode promises to be a rich source of information and insight. Tune in to be informed and to foster a deeper understanding of the promising horizon that psilocybin research is unveiling in the medical community.Biography for Dr. Paul Hutson PharmDTransdisciplinary Center for Research in Psychoactive SubstancesDr Hutson's PublicationsSingle Dose Psilocybin for Major Depression- JAMA 2023Psilocybin and QTc in healthy volunteersMeta-Analysis of research supporting Psilocybin use in anxiety and depressionPharmacokinetics of PsilocybinSubjective effects of high dose PsilocybinOther referenced studiesSingle dose psilocybin for treatment resistant depression Psilocybin for alcohol use disorderPsilocybin for For tobacco cessation

This episode is a discussion of the FDA and ICH guidance E14 titled “Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”. I start with background on the reason for these evaluations, then move to an overview of the key evaluations needed. I then discuss in some detail the thorough QT study and the concentration QT analysis. Then I provide some parting thoughts from my experiences with these analyses. Links discussed in the show: • ICH E14 Guidance (FDA website) • Scientific white paper on concentration – QTc modeling by Garnett et. al • Correction to publication • You can connect with me on LinkedIn and send me a message () • Send me a message • Sign up for my newsletter Copyright Teuscher Solutions LLC All Rights Reserved

You can also listen to this episode on Apple Podcasts or Spotify!Manish Agrawal MD and Paul Thambi MD are oncologists who have spent decades caring for patients with cancer. They realized early in their careers that chemotherapy could treat the cancer—but what about the emotional, psychological and spiritual impact of facing mortality? When they learned about the potential for medications like MDMA and psilocybin to help people gain access to parts of their minds they didn't know existed—and to address the human experience of suffering—they quit their day jobs as practicing cancer doctors to found Sunstone Therapies, the sole psychedelic-assisted therapy research and treatment center in the Washington, D.C. area.  The data are increasingly clear: these non-addictive substances hold the power to expand consciousness and improve quality of life.When guided by a trained therapist in the appropriate setting, even one experience with a psychedelic medication can help people unlock closed doors in their minds and to feel safe enough to explore its contents. They can be the catalyst for patients' ability re-route well-worn pathways of negative and maladaptive thoughts, feelings and behaviors.It turns out that science and spirituality aren't mutually exclusive.On this episode of Beyond the Prescription, Drs. McBride, Agrawal and Thambi discuss the inseparability of physical and mental health; the promise of psychedelic therapy to treat the psychological impact of cancer and other diseases such as PTSD, anxiety, and depression; and their shared excitement about the potential for these drugs to fundamentally expand the standard of care in medicine. Bios:Manish Agrawal, MDManish brings an extensive background and experience that spans medicine, engineering, philosophy, and ethics to his role as CEO of Sunstone Therapies. Driven by a deep interest in healing, Manish is particularly passionate about whole person healing and the transformative potential of psychedelic therapies. Manish previously held the position of Co-Director of Clinical Research at Maryland Oncology Hematology, where he dedicated 15 years to the care of cancer patients. He completed a fellowship at the National Cancer Institute, National Institutes of Health, and his residency at Georgetown University Medical Center.Paul Thambi, MDPaul brings deep experience in oncology care and clinical trial design to his role as Chief Medical Officer at Sunstone. He is a proponent of strong organizational culture and strives to create a compassionate, open and accepting workplace to advance whole person healing in medicine. As a medical oncologist, Paul developed important and meaningful relationships with patients, witnessessing their emotional and physical distress upon diagnosis and throughout treatment, leading him to explore psychedelic therapies to improve the emotional and mental health of patients fighting cancer. Paul completed his oncology fellowship at the National Cancer Institute and, prior to pursuing medicine, he began his professional career in engineering and consulting.Join Dr. McBride every Monday for a new episode of Beyond the Prescription.You can subscribe on Apple Podcasts, Spotify, or on her Substack at https://lucymcbride.substack.com/podcast. You can sign up for her free weekly newsletter at lucymcbride.substack.com/welcome.Please be sure to like, rate, and review the show!The transcript of the show is here![00:00:00] Dr. Lucy McBride: Hello, and welcome to my office. I'm Dr. Lucy McBride, and this is Beyond the Prescription, the show where I talk with my guests like I do my patients, pulling the curtain back on what it means to be healthy, health as more than the absence of disease. As a primary care doctor, I've realized that patients are more than their cholesterol and their weight. We are the integrated sum of complex parts. Our stories live in our bodies. I'm here to help people tell their story, and for you to imagine and potentially get healthier from the inside out. You can subscribe to my free weekly newsletter at lucymcbride.substack.com and to the show on Apple Podcasts, Spotify, or wherever you get your podcasts. So let's get into it and go Beyond The Brescription. [00:01:03] Buckle your seatbelt. Today we are going to talk about one of my favorite subjects, the re emerging field of psychedelic medicine. I truly believe it is going to change the landscape of modern mental health care in this country. I cannot wait to introduce you to my guests today, Dr. Manish Agarwal and Dr. Paul Thambi. They are oncologists who have spent decades caring for patients with cancer. They realized early in their careers that chemotherapy could treat the cancer, but what about the whole person? What about the emotional, psychological, and spiritual impact of facing a hard diagnosis and mortality? When they learned about the potential for psychedelic medicines like MDMA and psilocybin to address patients' whole health, to offer some acceptance and insight and access to the patient's interiority in ways that they had never seen before, Paul and Manish left their day jobs as practicing cancer doctors to found Sunstone Therapies. [00:02:13] This is where I am now sending some of my patients, not just to face cancer diagnoses, but also for anxiety, depression, and PTSD. Sunstone Therapies is the sole psychedelic assisted therapy research and treatment center in the Washington, D. C. area. The goal of Sunstone is to better treat the emotional and psychological impact of cancer and other disorders. Paul and Manish are contributing to the fundamental expansion of the standard of care in medicine and it is a wonderful thing to be part of and to watch. Paul and Manish, thank you so much for joining me today on the podcast.[00:02:53] Dr. Paul Thambi: It's a pleasure to be here. Thanks for having us.[00:02:55] Dr. Manish Agarwal: Yeah, it's great having you. Thank you. [00:02:57] LM:  The two of you together have backgrounds in medicine, engineering, philosophy, data science, and research, yet you landed in the field of psychedelics for a reason. Tell me why that is. What is so exciting about this field to you?[00:03:15] MA: Paul and I both have been practicing oncologists for almost 20 years, and over time we got really good at taking care of cancer patients, their physical symptoms, but their quality of life was not always directly proportional to how they physically felt. And over time it really starts eating away at you, that you're not able to take care of the emotional health of cancer patients.[00:03:35] When we saw this emerging field and started looking at the data, We visited and learned about it and then got training and explored to see is this real. And that's what sort of led us down this path is, for me personally I've always been into philosophy, that's why I have my masters in philosophy.[00:03:54] I've been interested in the human side of medicine not just the science side. Both have fascinated me and this really brought both of them together. The reason that Paul and I both went into medicine is to treat people and to make them feel better. And really, for the cancer patient, for any patient, you have to take care of everything, not just the physical symptoms.[00:04:14] PT: Everything that Manish said is echoed in my life and how I was drawn to this. And I think there were a few patients that really suffered emotionally that really hit home for me. And I carried that pain from what they went through with me. And when Manish showed me the data on psychedelic assistive therapy, it wasn't really the data, it was really more these YouTube videos where we saw how there were a couple of patients on the NYU trial and the Hopkins trial, and how they were before they went on that treatment and after. And there was a palpable change that you could feel through the video even, and it was just something that I wanted to be able to see if we can bring to our patients. [00:05:00] LM: Can you give me an example of a patient who has been served by this treatment, maybe a cancer patient? I'd love to hear an anecdote.[00:05:08] MA: There's a young patient with kids and a serious cancer, and had struggled with depression, didn't know anything about psychedelics, but really applied. And to see the change in his life, he's changed the relationship with his mother, who had a hard time with her son having cancer. And he was able to have a conversation with her afterwards, saying, I want my mom back.[00:05:29] And then he was bleeding, when he went home for something else, he got a cut. And his young boy sat up and said, “Dad, are you dying?” And he was able to sit and have a conversation with him. He said, I would never be able to do those things before. And he was able to really sense into that. And then the other group that's really, I've sort of been really blown away by is the military that we've been treating recently.[00:05:51] They have such complex things that they've seen, such complex trauma. And they've tried everything. I mean everything. For a military person to come and seek this care is not easy because the entire institution, it can affect their career if they talk about mental health. So they're desperate and to see the lives that are turned around, I literally wouldn't believe it if I didn't see it.[00:06:15] And it's been powerful to see them going from, thinking about suicide regularly, to really no meaning, to a sense of despair, to not where everything is great and perfect, but they're having a fundamental change, and they want to live, and they want to reconnect, and they're building their lives back together.[00:06:33] LM: I mean, that says everything that you need to know about why this is important. Acceptance, hope, peace, which isn't possible every day of the week, nor is it mutually exclusive with ongoing pain, as humans experience a myriad emotions on a day to day basis. But to think that there's something out there that could give people more agency and acceptance is pretty extraordinary given that we've had pretty poor tools to help people with emotional health and mental health. And so I guess my question to you is then, how do you see the psychedelics changing the way we think about mental health?[00:07:19] PT: One of the things that can help to do is just to shine a light on this is a part of our health that we need to focus on. There is now these tools that are being talked about that can be helpful, perhaps more helpful than the existing tools and that allows people to start talking about their emotional health more to their doctors, to their family.[00:07:44] And in terms of how these medicines can help, I think it's not just the medicine. I just want to talk a little bit more about that because the medicine does some things and would act on some of the same receptors that SSRIs act, but there's more to it than the medicine. You talked about it being an experience and it is that, and it's not always that it finds stories that are hidden, sometimes those stories are there and people feel them all the time, but they turn away from them. And what you need to do, what we're starting to learn with this is that you need to create an environment, a container as it's called in this space, that feels safe, that allows people to trust and be vulnerable in that space.[00:08:32] So that when they experience those fears, and some of those stories may be hidden, some of them may be ones that they've lived with their whole lives, but now they can look at those. They can be with that story that they've felt, and face it. Because they feel a sense of trust, and they're with therapists or people who care about them.[00:08:53] Who created a relationship with them that allow them to go deep into that story and find the pieces of that story that serve them and the, and the pieces of the story that don't and talk about that, integrate that into their lives, integrate that into their conversations with their families. It's that that does the healing more so than the medicine or as much as the medicine.[00:09:17] LM: It's such an important point because I see patients Who I will kind of raise this idea to—people who have complex PTSD or who are facing terminal diagnosis. And sometimes they'll say to me, well, I tried mushrooms in college and [it] didn't do much then. And I just had a bad experience. I remind them that that set and setting matters so much.[00:09:40] And I think it's such a good point that it's not just the medicine.It's the ability to feel vulnerable and safe, which is sort of this mystical aspect of the medications and then to face some things that you already did know you had and that weren't hidden. I think that's a great point.[00:09:57] MA: Yeah, I mean, I think it's actually pretty nuanced in all of that, because one thing I tell people is, I think psychedelics allow you to access psychic material like no other thing that I know of. But they're not a magic bullet. And if MDMA cured PTSD, I tell people that anyone that goes to a rave wouldn't have PTSD anymore.[00:10:22] But lots of people go to raves and still have PTSD. And so it must be more than the medicine. So it's not to take away from it, because I think you have access, but it is again, the context or, or how it's received. And so, it's like any medicine, the wrong dosage in the wrong context can be harmful or beneficial.[00:10:37] And what you talked about, I think, is really nuanced, and I think it's important. We actually call it sometimes therapy assisted by psychedelics. Because a relationship allows you to really trust, and to trust yourself, and to go deep. And if you have that sense of trust, you're able to access material that you may not otherwise be able to.[00:10:56] And a lot of times, sometimes injury or things occurred in a relationship and to have another wiring of your brain in a healthy relationship, to be witnessed when you were in pain or just to be held or to be supported is a different experience now than it might have been the time that it happened. And you're able to almost nurture that younger part of yourself.[00:11:18] And so that's, it's really, it is quite cutting edge and that's one of the things that fascinated us because it's not… people want medicine therapy. It's like, it's really this combination of the two and, and so you can emphasize one, emphasize the other, but without the two and done in concert and the right setting, it just is not as effective.[00:11:37] And so, you know, for us the therapists and the medicine are super important, but so is everything else. So the way the room is set up, the furniture, the music. The person that answers the phone, the way you're received, the way the follow up is. Because if you think about it, we all are sort of on alert, and you get a sense in your gut, can I trust this place? Can I trust this institution? Can I trust this store? We have relationships with people and institutions, and you start… some part of your psyche that's assessing for danger knows, how deep can I go? And so, you really have to build a place that tries to reassure even the unconscious part that it's okay to go deep here.[00:12:18] LM: I think it's such a good point. And because I was going to ask you how much… let's take psilocybin, for example, which is the active ingredient in mushrooms, how much of that feeling of safety and trust is the chemical itself, and how much is the therapist, the experience of, you know, calling the front desk, scheduling, seeing the lighting, seeing the room, because I have patients who are in therapy for 30 years, even, who trust their therapist, who feel safe, they have a comfortable experience, but they aren't actually making the kind of progress that you sometimes see in patients who have three experiences with psychedelics in the right setting.[00:13:08] MA: I don't think it's medicine that causes the trust. I think it's the environment. I think the medicine brings to the surface the issues that are there, and without the trust, you are not able to process them. And so, yeah, if they have a trusting relationship with their therapist, that's probably a really important piece, but then it's also deeper than that.[00:13:29] Can the therapist handle whatever material comes up? Are they able to be with that? Do they know how to navigate that? And so, if there's distress or anxiety or fear, what they don't necessarily need is reassurance or minimizing of it, and it's how to navigate those waters that's a different skill set than traditional therapy. I don't think the medicine in itself causes trust, it just amplifies what's there, but in a therapeutic relationship trust can be built, and trust is an intrinsic part of each one of us, but it's to rediscover that.[00:13:58] LM: Such a great point.[00:14:00] PT: I echo all of that. I think also, what the medicine does is when you feel that trust, the medicine is a catalyst for you to go into those crevices that you talked about within the story. It may be a story that you know about, but now there's going to be chapters of that story that were hidden to you. And if you feel the trust, it allows you to do that in a way that I think is hard to do on your own. So there is that catalyst that you get from the medicine around that.[00:14:30] LM: It's so gratifying to hear you talk about these sort of mystical and, and visible elements of the human experience because, again, I think that's what's missing in modern medicine, at least in the United States. We don't think about the 364 days a year you're not sitting with your doctor as health.[00:14:52] We don't think about the way we feel in our bodies, the way we think, our self perception, the way we approach stress or vulnerabilities as health. When actually there are direct physical impacts of chronic stress on our bodies. There's direct physical impact of what you described as a vigilance.[00:15:16] In fact, so many patients I see have been diagnosed with anxiety. And we'll use the word anxiety kind of casually, because it's so commonly used, people know the word, but, but actually when you dig deeper with a lot of these patients who have “anxiety” it's not necessarily that they worry excessively, or that they feel even anxious, they don't even often identify with that word, but that's the code in their charts: F41.9, but a more nuanced description of the way they feel, I think, is this vigilance, this sort of emotional, behavioral, and then sometimes medical reaction to feeling threatened that stems from an experience or set of experiences in their childhood. And we talk about adverse childhood experiences having physical and emotional mental health manifestations later in life.[00:16:06] But I see patients all the time who have been diagnosed with anxiety, but whose symptoms stem directly from some adverse childhood set of experiences or experience. And then they have hypertension, binge eating, cardiovascular disorder, cardiovascular disease, racing thoughts, sort of like a twitchiness physically and emotionally when they are faced with stress. And I think that those are the people, as far as I understand it, who have had PTSD who are being studied first and foremost with psychedelics. Is that right?[00:16:41] PT: Yeah, that's right. Right now, that's the indication that has shown the most benefit with MDMA.[00:16:45] MA: Yeah, and to piggyback on, I mean, you've made a couple of points, I guess, and we should probably just touch on them. I think just working backwards… the last point, I think that if people do have these feelings of anxiety or depression, and I think when, um, a disservice we've done is pathologize them, that somehow that's the problem.[00:17:05] And it actually is a sign of health because they're having a normal reaction to abnormal situations. And so, what trauma can sometimes be is that when you're very young you have a situation that was very difficult. But you responded normally, you would feel anxious or you'd feel depressed or sad. But then you didn't have support in that situation and so it got stuck.[00:17:27] And then, now you react when things arise, your body, your psyche has a visceral memory of that, of that lack of safety or that issue that occurred. And so, it's not that the person is a problem, it's not a pathology. They had a normal response to an abnormal situation, whether it was an abusive family member or neglect or abandonment, whatever it was.[00:17:50] It's just that, that situation isn't occurring now. And they need support to be able to work out of that. And what they do, what I've seen sometimes, is that actually becomes their superpower. So they get really sensitive. If you had power issues and somebody that powered over you wasn't, you get really sensitive to that.[00:18:07] And you know in your body when something might be happening even before your mind does. And so, it's turning that story to say it's not a problem as much as how you can move on with it. And then the only other comment I was going to make is on the first part you were saying around, medicine, not looking at these other aspects of our emotional health and I think it's a historical time, really. I think for much of history, the shamans were the physicians and there was a connection between the mind, body, and spirit. And then to great progress, we developed a great scientific understanding of the body and develop antibiotics and other things that help us live a lot longer.[00:18:47] And that's helped us, but then because your blood pressure is good and because your coronaries are clean and you don't have cancer, it doesn't mean you're happy. Now I think things are turning again, that the human is not just a biological entity, but it's also a spiritual, emotional, psychological… whatever you want to call it.[00:19:06] And until you have all of that together. You're just not going to feel fully human. And so before there was this science versus religion or science versus woo woo or whatever it is. But I think more and more you'll see really respected neurobiology labs that are starting to, to talk about that. And you're doing MRIs of monks of brains and you're seeing that meditation causes certain changes.[00:19:27] And then when we do MRIs of patients on psychedelics, going back to your point on vigilance, there is something called the default mode network. And that part of the brain is always looking for problems. It's the default mode. It's being vigilant. And that's the part that quiets down, other parts of the brain wake up, and they're able to start connecting.[00:19:49] And so science now is backing up what's happening. And so there's not so much this tension there, and people are wanting to both be physically and emotionally whole.[00:19:58] LM: It makes so much sense. I've heard Roland Griffiths talk about the experience that long term meditators can have as being the closest to the experience or benefits of psychedelic. Is that something you agree with?[00:20:18] PT: Yeah, I think that, that makes sense. I mean, I think deep meditation allows you to see or feel things that you're feeling with a little bit of removal from that. And that allows you to have a different perspective. So, there is a correlation that can be made.[00:20:36] LM: So, when people look at the New York Times and they see an article about psychedelic medicine, I think they automatically, in many cases, go to two thoughts. One, aren't these recreational drugs that are just for people in rock concerts in the 1960s? And two, that doesn't apply to me. This is for people who are really far gone. And so I'd love for you to speak to the sort of stigma around psychedelic medicine, where that comes from.[00:21:08] PT: Yeah, and Michael Pollan talks a lot about this in, in his book How to Change Your Mind and how there was social and maybe political pressure around creating stigma. So I think that's some of what happened and then also you get into the 1980s where, you know, this is your brain on drugs, those commercials that would come out that really heightened my sensitivity as a child growing up in the 80s around that.[00:21:34] And I think those are things that are hard to release. And now that we're starting to understand, and this is coming up again, psychedelics, realizing that these have been around for millennia. And they've been used by cultures as rites of passage for ways to solve the problems of a community. And I think now that those stories are coming back up and also the scientific data which provides people with a level of comfort, especially those people that have this fear of addiction and drugs and all of those things that I had when I was a kid, knowing that this is coming up in the medical institution. Along with the stories from the past are allowing for people to see this in a different way and to accept it more… I think one of the reasons that people feel safe doing this is that, especially like in the environments that we have at Sunstone, where it is in a sort of a medical environment, where our office, where we treat people, is on the campus of a hospital, and they can see the hospital out the window.[00:22:36] And we're clinicians that have treated patients before as doctors, and it's in a research setting. That allows them to overcome that stigma, to feel safe as they embark on this thing they were told never to do in the past.[00:22:51] LM: And so what do you make of this kind of... Emerging industry where people are taking the medicines off label with various healers and going on retreats in Costa Rica, because I worry, I don't know if you worry that if the set and setting are not appropriate, if the person who is supposed to be the guide isn't trained or perhaps worse, if the recipient of the therapeutic isn't aware of the potential risks and isn't guided in an appropriate way, then, then we might end up losing all the ground and getting these medications approved through the appropriate medical channels. Do you have that concern? [00:23:32] MA: For sure, to some degree I do. I mean, I think there are probably great practitioners around some of those settings, but there's just no way to filter through that. And what I worry about, and I get more worried about, is the longer we're doing this, because we're treating complex PTSD patients, they're complicated. And things that come up, if you're not trained and equipped to do that well, it actually... it causes more harm. In fact, I was speaking with a senior psychedelic therapist who's worked for MAPS in Colorado, and she does only things legally, but she does a lot of integration work, and it's integration work for people that did psychedelics underground.[00:24:17] And the biggest thing that she sees... As people got re-traumatized because they would have an experience and it was severe and the therapist wasn't able to be there. So then again, it felt like what I'm feeling is not okay, which is a feeling that they had the first time. And so she's having to rework through that.[00:24:35] So in that way there's legitimate concern. And the other thing that I worry about is, we've seen this, that you talk to people, they seem fine, or you have one assessment of their mental condition, but it gets more complex and even they're not aware of it fully. And so you have to be really prepared for that.[00:24:56] And the other point I was going to make is what you said, what you asked initially about the underground. But then you also said, people said, I'm not as sick, or how about that stigma? So I think there's a real stigma around mental health. There's a stigma around psychedelics and there's a stigma around mental health.[00:25:13] And so this is both. What it still surprises me time and time again is that people just under report their symptoms, but they still seek it out. So there's sort of this dance. They're like kind of… I'm really kind of okay because it's how they dealt with it. It's like we don't have an environment where you're able to be sad or anxious and there's not something wrong with you and so people play it down and… this is totally anecdotal, but I swear it's worse with men. We'll see, they'll come in, and they're like, I'm fine, I'm fine, and then you, well I drink a lot, and then, yeah, I guess I have feelings of sadness, and then you do the scale, and it's like, wow.[00:25:53] I think it's even harder for men to admit their emotional struggles and that's just a generality, but overall I think there's a collusion of denial around our emotional state and somehow you just have to be, present a certain way, and there's something wrong with you if you're struggling.[00:26:07] LM: I mean, I have a couple of thoughts about that. One is thank you for saying out loud that men are more walled off than women to a woman. No, I'm kidding. I think you're generalizing, but yes, let's just acknowledge that we are very self aware species, women, that is. Secondly, I think we all have a level of denial.[00:26:22] I think denial serves us sometimes, right. Denial is a way of partitioning off pain so that we can cope and function. But then when denial takes on a life of its own and the stuff that is in the denial closet is sort of seeping through the edges and like running out of the bottom of the closet and informing our health, that's when denial is no longer serving us. It's when it's actually in the driver's seat. So it strikes me that the experience, in an appropriate setting with a psychedelic, could help people pull that wall down or open that closet and, and take a look inside and maybe rethink how they approach that thing they didn't think they could approach.[00:27:08] And then secondly, yeah, mental health still has a bad rap when, as you both know, we all have mental health. It's not a feature you can kind of opt out of as like the human without the mental health. And as you said earlier as well, we tend to medicalize and pathologize mental health.[00:27:30] So in a way that's good because we are acknowledging that these have medical consequences, that an anxiety disorder is a medical condition, as opposed to just a personality flaw, which was what some people think of it as. But we also tend to label and sort and diagnose conditions that are just normal.[00:27:50] Like, of course, when someone has been raised by an alcoholic parent and they have been conditioned to sort of be a certain way, sort of invisible or good or not a problem, that is going to have an impact on their health such that when they get into a therapist's office or a doctor's office in their forties and their maybe that's not depression.[00:28:13] Maybe you had a response to an experience and sure the symptoms are that of depression, but it's actually something more complex, more nuanced. And so I'm not really asking you a question. I'm just making an observation that we're up against a lot as we market these medicines and therapeutics to people because of the stigma around mental health because of the stigma around drugs But I think if it's done well—which is why Sunstone and other research institutions exist—if it's done well, and we can actually help people understand that their interior lives their past their stories have relevance to their health. And that yes, having clean coronary arteries and nice blood pressure is great, but it's not sufficient for health, then it really, I do think is going to change the way we think about health.[00:29:04] It's already changed it for me. It's just that it's not legal yet in DC. And I haven't tried psychedelic medicine. I want to, it has changed the way I think about emotional health. I mean, I've been thinking about mental health and health in this way, my whole career, but I don't think modern medicine has given doctors really permission to do that.[00:29:20] And so I wonder what you think is in the pipeline. Are these things going to be FDA approved in the next five years, ten years? Are people going to be able to access these therapeutics? Are there going to be enough guides to appropriately shepherd people through the process? What are we looking at in the next year or five years.[00:29:41] MA: I just want to comment a little bit on what you said around the denial piece. I think that denial actually is quite healthy. And on where your neurological system was, when you experienced something, it might've been, it probably was overwhelming and the proper and healthy response would have been denial and to put it into a box.[00:30:00] It's just that now it's not necessary and it's not integrating back into your life. And so I'm very wary of pathologizing any of these things because they're usually healthy. It's just in the context now. And so I just make that one point and the other one around the mental health issue that, it's good that we're talking about it, but I think that we wouldn't want a life without emotions, right?[00:30:23] If you push down your anxiety and your fear, you also push down your joy and happiness and love, the things that we humans live for. And so they sort of go both hand in hand and you can't have both of those.[00:30:38] LM: Yeah, sort of like when we talk about alcohol when we're sort of self medicating, right? It blunts distress, but also blunts joy, libido, life. So you can't selectively numb. You also can't selectively be the human without an emotional life because that wouldn't be good. Then we'd all be like chat GPT or AI, right?[00:31:00] PT: Yeah, yeah, and it just, I'm just going to piggyback on that denial part of things too, because I think one of the things that's important to remember is that people have built up these ways of denial, of sort of pushing things away. Psychedelics, like we mentioned before, can be a catalyst to break through that denial.[00:31:17] That can be, you can lose your balance when that happens. So I just want to highlight again how important it is to have that integration and that container afterwards because you can't feel that way afterwards. You have to be with people that help you find that centeredness again. [00:31:35] And in terms of access and what's happening, we talked about how MDMA has been studied in PTSD for some time now. And there are two phase three trials. They're showing significantly positive results. And that might be the first medication that gets approved as a psychedelic for PTSD outside of esketamine, which has been approved for depression. And that might happen in the next year or two and we will hope for that.[00:32:01] And psilocybin is behind that in terms of how it's being used in various types of depression, and more and more information is coming out around that looks good, and perhaps if it continues to look good, that could be the next medication that gets approved. We'll see. So I think those are the things that are happening in terms of access and how we get this to people if they are approved, if they do show that they are effective, You're right, I don't think our healthcare system is built for this right now and there aren't enough therapists that are trained in this to treat everyone that has PTSD or even a half the people that have PTSD that might qualify for MDMA or for psilocybin in some sort of depression. And that's what we're thinking a lot about.[00:32:48] We have investigated how to do this in a group setting, with group preparation, taking the medicine as a group, and having integration as a group. We find it is not only a way that introduces efficiencies, but we also see therapeutic healing with that approach, too. To be able to be connected with another group of people that have something similar to what you have or what you're going through, whether that be cancer or PTSD or depression, and to develop this bond during the sessions that you have with each other around preparation and integration, we think that's probably going to be therapeutic, too.[00:33:29] That model also allows for more people to be trained on this. So, we're trying to think about how to do that from a group setting. We're trying to think about how digital tools can be used to improve or to give us efficiencies in this setting, but also remembering that there's compassion that's needed with this, so not to overuse digital processes. We're thinking about that as well. How do you do scheduling and other things? So, I think there's a number of problems to be solved around access, but they're solvable.[00:34:00] LM: And so if you're listening to this and you're thinking to yourself, wow, I've been in therapy for 10 years. I'm on Prozac, but I still feel anxious. I'm sure there's some parts of me I haven't really discovered. This sounds really interesting. Or if you're just listening and want to try psychedelics, where would you go?[00:34:18] Would you have to enroll in a clinical trial? Would you call Sunstone? Would you wait until MDMA is approved? What would you do if you were curious and wanted to participate in the research or the therapeutic elements here?[00:34:31] MA: I think the first thing you would do is look for a clinical trial. And so, there are many, many places now that are doing research throughout the country and internationally. And certainly at Sunstone, we have five studies open now, and we will have another three more open this year. We have them in depression and anxiety and PTSD and cancer and family members of cancer patients and so there's other places that have that. So I think that's sort of the most rigorous way to get that. And I do think that some medicines, as Paul said, will be approved next year. I think that, I cannot underemphasize the importance of the context and the safety. What you don't want is to do something and get worse and so you want to make sure that you have safety if you're not good on that road.[00:35:16] And I think we've talked a lot about the upsides of psychedelics and we're talking about that because so much of mental health right now, we don't have great treatments for, but we're still really in early days and we still have a lot to learn. Who's most going to benefit? Which people are completely contraindicated for?[00:35:36] How do you get people ready? And so I understand the hype because people are desperate. And at the same time, I want to be cautious in that I think we're still learning about how to use these powerful medicines.[00:35:50] LM: Yeah, I mean, I think one thing I am concerned about in particular, and I know this is out there in the public, is the potential risk for someone, particularly in their 20s who may be predisposed to schizophrenia. Is there a link between the use of psychedelic drugs and either the awakening or the schizophrenia or mental illness?[00:36:09] Plus, as you've already talked about, this idea of not having the right set and setting not having the appropriately trained guide or the feeling on the patient side of of safety and trust such that people get worse. So what are the absolute contraindications right now in your mind?[00:36:28] PT: Some of them are around people who have a tendency towards manic episodes. Like bipolar disorder with mania because that has been described where people had manic episodes after having a psychedelic experience, so I think that's one firm contraindication right now, at least in research trials. [00:36:49] The others are—there are some cardiac effects that people worry about with some of the psychedelic medicines, so if there's a history of abnormal heart rhythms or a potential tendency to have an abnormal heart rhythm, that's another contraindication. Some of them like MDMA have sympathomimetic effects, which means they can cause the heart rate to go up and the blood pressure to go up. So if someone doesn't have controlled high blood pressure, or if they have underlying heart disease, they may need to get evaluated with a stress test and things like that to show that things would be safe if those conditions happen.[00:37:27] LM: And what about, so many Americans are on SSRIs, so is there a contraindication? For people who are on SSRIs or who are on any other medications at all?[00:37:38] MA: In terms of the SSRIs, right now we taper people off of them, and it's less about safety as much as efficacy, that we think it might blunt the depth of the response of a psychedelic. Although there are ongoing studies that are bringing some of that into question, and so they probably do work maybe at a higher dose, and so it's not an absolute contraindication, it's certainly not a contraindication for safety, it's just a, you might limit its efficacy.[00:38:02] LM: Interesting.[00:38:03] MA: And some of the drugs that can prolong the QTC, there's some concern around that, and so we certainly do EKGs on all the patients.[00:38:11] LM: What is so great about the way you're describing the research is that you have a healthy level of respect for these medications. You have enthusiasm, but it is tempered with appropriate caution. So thank you guys for joining me. It's been so fun learning about Sunstone. I've been grateful to you guys for taking some of my patients into your clinical trials, and I can't wait to see what's next.[00:38:37] PT: Thanks for having us, Lucy.[00:38:39] MA: Yeah, it's just been great getting to know you.[00:39:03] LM: Thank you all for listening to Beyond the Prescription. Please don't forget to subscribe, like, download, and share the show on Apple Podcasts, Spotify, or wherever you catch your podcasts. be thrilled if you liked this episode to rate and review it. And if you have a comment or question, please drop us a line at info@lucymcbride.com. The views expressed on this show are entirely my own and do not constitute medical advice for individuals. That should be obtained from your personal physician. Get full access to Are You Okay? at lucymcbride.substack.com/subscribe

Drs. Allison Zibelli and Arielle Heeke discuss the NATALEE trial's novel approach to high-risk HR+ breast cancer, the potential of delaying CDK4/6 inhibitors in HR+, HER2-negative mBC to decrease toxicities and costs in the SONIA trial, and de-escalation strategies in HER2+ early-stage breast cancer. TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your guest host for the ASCO Daily News Podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center at Jefferson Health in Philadelphia. My guest today is Dr. Arielle Heeke, a breast medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina.  Today, we'll be discussing practice-changing studies and other key advances in breast cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.   Arielle, it's great to speak with you today.   Dr. Arielle Heeke: Thank you so much for having me.  Dr. Allison Zibelli: Let's start with LBA500. This was the NATALEE trial of ribociclib and endocrine therapy as adjuvant treatment in patients with hormone receptor-positive HER2-negative early breast cancer. What are your key takeaways from the study, and how do you think this changes our approach to high-risk ER-positive breast cancer?  Dr. Arielle Heeke: Yeah, this was definitely the study for which many of us were waiting to see the results. It was exciting to see the results come through so quickly. As you mentioned, the NATALEE trial was a phase 3 study that evaluated three years of adjuvant ribociclib at a dose of 400 milligrams, which is a little different than what we're used to in the metastatic space at 600 milligrams. But essentially, it randomized patients to receive this 400-milligram dose with their adjuvant aromatase inhibitor therapy versus just the standard of care adjuvant endocrine therapy in patients that are high risk with early-stage breast cancer.   What made NATALEE somewhat unique is they defined high risk a little bit more broadly than we've seen in previous studies, such as monarchE. So, what I mean by that is NATALEE enrolled patients with stage 2 and 3 early-stage breast cancer. And notably, they allowed for patients that were lymph node-negative but had some other high-risk features, such as a grade 3 tumor or a grade 2 tumor with high-risk genomics, such as oncotype or a high Ki-67. So, by broadening who was eligible, NATALEE captured more patients at risk for recurrence. Of course, we know that recurrence is not specific for patients with lymph node-positive disease. We can see recurrence even with stage 1, but certainly, we start to see more recurrence risk as patients drift into stage 2 and stage 3.   In the NATALEE study, the majority of these patients did receive prior chemotherapy, which I also think is interesting. We've kind of seen in the metastatic space that sometimes chemotherapy can augment patients' responsiveness to CDK4/6 inhibitors. But specifically in NATALEE, 88% of patients had received prior chemotherapy, and ultimately, about a third of the patients were lymph node-negative.   So, diving into some of the results with this first analysis that we saw at ASCO, with the median follow-up for invasive disease-free survival of just 27.7 months, they were able to show that the risk for invasive disease was reduced by 25.2% with the addition of ribociclib plus endocrine therapy compared to endocrine therapy alone. And this three-year invasive disease-free survival rate was 90.4% for the combination therapy compared to 87.1% for endocrine therapy alone, which is an absolute difference of 3.3%. Additionally, patients treated with ribociclib and endocrine therapy had a 26.1% reduced risk for distant disease-free survival compared with endocrine therapy alone, and this was a rate of 90.8% for ribociclib with endocrine therapy compared to 88.6% with endocrine therapy alone, which correlates to an absolute benefit of 2.2%.    They did show results for overall survival as well, but again, follow-up was just a median of 27.7 months. So, data was essentially immature to show any true overall survival benefit from this approach. And in fact, only 20% of patients had completed three years of ribociclib at this data cutoff. And as a reminder, again, NATALEE involved ribociclib for three years compared to two years, which we've seen with other studies in this space.   Also, what was encouraging from NATALEE were the readouts for toxicities. Neutropenia is definitely a concern with this class of medication, and they were able to show that rates of neutropenia were overall lower than what we've seen in the pooled data in the metastatic space. And also that problematic QTc prolongation for which we have to get EKGs baseline two weeks and four weeks. They also showed that the likelihood of having QTc prolongation on this therapy was significantly less at that 400-milligram dose compared to 600.   I think the key takeaway is yes, this drug is effective as adjuvant therapy, which is perhaps not surprising since we've seen such promising results in the metastatic space, but numerically not as striking as what we have at this point with adjuvant abemaciclib, but of course, this is a newer study. We hope to see that continued separation of the curves as we were fortunate enough to see with the abemaciclib data, but obviously we'll be looking for additional analyses from NATALEE.    And then how this will change practice, of course, we'll have to wait to see if the therapy is approved for use in the adjuvant setting for early-stage hormone receptor-positive breast cancer, but it certainly will be a nice option for patients that struggle with GI toxicity kind of at baseline. But also, if they were previously on abemaciclib and were not able to tolerate due to the GI toxicity, this would be an option for them. Also, as mentioned, it's a broader patient population, so we can consider this perhaps for a patient with lymph node-negative disease.   Although we will have to ask ourselves that just because someone meets eligibility for the NATALEE  study, and if the therapy is ultimately approved, is it appropriate to give it to all those patients? Or do we need to still kind of think of this in the setting of the highest-risk patient, not just any patient with stage 2 plus disease? There was a lot of talk at the meeting, certainly about biomarkers and potentially using ctDNA to try to find these predictors of benefit from CDK4/6 inhibitor therapy, but obviously, still a long way to go before we can use that type of technology in this space.  Dr. Allison Zibelli: Thank you. Staying on the topic of CDK4/6 inhibitors, everybody was excited about the SONIA trial, which was LBA1000, and this trial was asking if we can delay using CDK4/6 inhibitors for newly diagnosed ER-positive HER2-negative metastatic breast cancer as a way to decrease both toxicity and cost. Tell us about this study.  Dr. Arielle Heeke: The SONIA trial was such a cool study to see, and the presenter reported findings in such a thought-provoking way. Really great to see this sort of work being done because I think we all wonder deep down in our gut, if more is more, or if we do need to kind of be a little bit more thoughtful about how we introduce these therapies certainly from a patient perspective. Patients that participate at ASCO [meetings] have been saying for years how important it is to consider the toxicities in terms of side effects, but also, of course, financial toxicities. So, it was great to see the SONIA trial at center stage.   Essentially, as you mentioned, it was a study that randomized patients in the first-line setting with metastatic hormone receptor-positive breast cancer to receive either first-line CDK4/6 inhibitor therapy or second-line CDK4/6 inhibitor therapy. So basically, there was a mandated crossover, so patients that received the CDK4/6 inhibitor first-line did not receive a second line and vice versa. Patients that were randomized to receive their endocrine therapy as monotherapy first line went on to receive CDK4/6 inhibitor at second-line. And the second-line endocrine therapy was fulvestrant in both of those situations.    We kind of run into this problem with patients now where we have so many therapies available to us that we don't typically run out of treatment options, but rather we run up against treatment toxicity or ultimate failure of the human body to keep up with the demands of ongoing therapy. So, again, while it's maybe somewhat attractive to start treatments earlier using things first-line rather than second-line or longer, just kind of post-CDK4/6 inhibitor progression, you know using this CDK4/6 inhibitor again with a different endocrine therapy backbone is probably not offering a meaningful benefit to that many patients. So this type of study is so necessary to really try to help us frame who needs those therapies sooner and longer or perhaps is there a substantial portion of patients that we don't need to put them through that sort of toxicity.   So that's the SONIA trial. Some things to note about the patient population, these patients were a bit older than what we've seen in some of our metastatic CDK4/6 inhibitor trials. There was a median age of 64 and 87% were postmenopausal. Additionally, just 40% had received prior chemotherapy. And as is true for most of our studies, 91% have received palbociclib on study with just 8% receiving ribociclib. And the choice of the CDK4/6 inhibitor was per the treating provider, and at the time of the of study globally, palbociclib was the more commonly prescribed CDK4/6 inhibitor. But over the last year or so, data has certainly emerged favoring ribociclib in the metastatic setting.   On the SONIA trial, patients were monitored for a median of 37.3 months. And looking at the primary endpoint of the second progression-free survival, which is defined as the time for random assignment to the second objective disease progression or death, for those patients who received first-line CDK4/6 inhibition, had a PFS2 of 31 months compared to 26.8 months with second-line CDK4/6 inhibitor use. And this slight difference was non-statistically significant. So the conclusion was that time to second progression was not impacted by whether or not a patient received first-line CDK4/6  inhibition or second-line CDK4/6 inhibition. Additionally, there were no differences in overall survival between the 2 arms with a median overall survival of 45.9 months with first-line CDK4/6 inhibitor use versus 53.7 months in second-line CDK4/6 inhibitor use.  And that actually equates to significant differences in time on drug. The median duration of CDK4/6 inhibitor use with first-line therapy was 24.6 months compared to 8.1 months with second-line use. And by being on therapy for an additional 16.5 months if you use CDK4/6 inhibitor first-line, this, of course, leads to increased toxicity and certainly increased financial burden. And it was estimated that for each patient that receives this therapy first-line, there is an additional $200,000 spent on getting them the CDK4/6 inhibitor first-line, whereas the results from SONIA suggested that whether you use it first-line or second-line, the outcomes are essentially exactly the same.   And then specific for the SONIA trial, by conducting the study, they saved approximately €25 million on drug expenditure during the conduct of the trial. It's just amazing when you take it to that scale. And then lastly just to mention, they looked at quality of life assessments as well and there were no differences in the two arms whether they got first-line or second-line CDK4/6 inhibition.  Dr. Allison Zibelli: I thought this study was remarkable, and it got a long ovation when it was presented at the meeting. I'm certainly going to use this strategy and prioritize who needs upfront CDK4/6 inhibitor therapy.  I think that we have to think of not just drug toxicity for our patients, but financial toxicity. A lot of these drugs have very high copays and the number one cause of bankruptcy in the United States is medical costs. So that's something we really have to keep in mind. I also thought it was very interesting that the study was designed in cooperation with the patient advocacy group and patients themselves were very enthusiastic about this study and helped design it and helped recruit to it. So all in all, I thought this was a remarkable study.    So moving on, LBA1013 was the TORCHLIGHT study of toripalimab versus placebo in combination with nab-paclitaxel for patients with metastatic or recurrent triple-negative breast cancer. Many of us are not familiar with toripalimab. Can you tell us about the drug and how it was used in this study?  Dr. Arielle Heeke: Yes, toripalimab is essentially an immunotherapy agent. It's an IgG4K monoclonal antibody that targets PD-1. In this study, TORCHLIGHT, patients were randomized to receive toripalimab versus placebo in combination with nab-paclitaxel in newly metastatic triple-negative breast cancer. The patients on study were randomized two to one to receive drug or placebo. The drug is given on day 1 of a 3-week cycle at 240 milligrams and then patients of course also receive nab-paclitaxel on a day 1 and day 8 schedule of a 21-day cycle. They did look at outcomes on the study based on PD-L1 positivity status and they assessed for PD-L1 with an IHC assay JS311 antibody that ultimately generated a combined positive score. And PD-L1 positivity was defined as a CPS of greater than or equal to one based off of this assay. In the study population, about a third of patients were- patients' tumors were CPS negative, a third had a CPS of 1 to 10 and about a quarter had a CPS of greater than or equal to 10. And then approximately 7% of the tumors had an unknown status.   And then getting right into the results, we were provided results in the PD-L1 positive subgroup as well as the whole patient population. Looking at the primary endpoint of PFS, there were significant improvements seen in median PFS with the addition of toripalimab to nab-paclitaxel, again in the first line setting with a median PFS of 8.4 months with the addition of the immunotherapy agent versus 5.6 months with placebo. And this was statistically significant.  And then in the intent to treat population, there were some numeric improvements, in median, progression-free survival at 8.4 months with the addition of toripalimab versus 6.9 months with placebo.   We also got some results with overall survival that were quite intriguing, although this initial analysis was not designed to necessarily prove statistically significant differences in overall survival. But again, there were some promising trends. Looking first at the PD-L1 positive subgroup, the median overall survival was 32.8 months with the addition of toripalimab versus 19.5 months with placebo. Breaking it down a little bit further based on CPS values, for a CPS of 1 to 10, median overall survival was 32.8 months versus 19.5 months. And then for those very high CPS or greater than or equal to ten, median overall survival was not reached in this group versus 18.3 months with placebo. Also, looking in the intent-to-treat population, there were also improvements in overall survival with the addition of toripalimab with a median overall survival of 33.1 months with the addition of immunotherapy versus 23.5 months with nab-paclitaxel alone. So potentially, depending on next steps of this study, we would potentially have an option to add immunotherapy that is not biomarker specific, meaning we can potentially provide toripalimab to all patients regardless of their PD-L1 status.  Dr. Allison Zibelli: Very interesting new drug to look forward to. So, one of the major themes of this year's meeting was de-escalation strategies. For example, LBA506 reported the three-year invasive disease-free survival of the PHERGain trial, which looked at eliminating chemotherapy for HER2-positive patients getting neoadjuvant therapy. Tell us about the design of this study and how will it impact the care of these patients?   Dr. Arielle Heeke: The design was very complicated. I had to look at it a few times to really make sure I got my head around it. But I think once you do figure it out, you can see how there might be a path forward in clinical practice. Although I think for all of this work, it's maybe not ready yet for primetime, but certainly thought-provoking. But the PHERGain clinical trial, I feel like we've heard about this study for a little while and this concept of de-escalation really kind of started in the HER2-positive space. But this study was a randomized study of chemotherapy de-escalation and early HER2-positive breast cancer using PET/CT as a marker of response to therapies that don't involve chemotherapy.   Patients were eligible for the study if they had stage 1 to 3a HER2-positive breast cancer with no prior therapy for breast cancer, and ultimately 356 patients were enrolled in a 1 to 4 randomization scheme with the majority of patients ultimately enrolled into the experimental group, which is called Group B. So, to break down Group A and Group B, Group A essentially were patients that receive typical standard of care, which at this point is TCHP for six cycles, neoadjuvantly or prior to surgery. Once they complete those cycles they move into surgery and then Herceptin-PERJETA adjuvantly for additional twelve cycles.  I should also note that this study was conducted prior to results of the KATHERINE trial that showed benefit of switching to adjuvant T-DM1 if there's residual disease. So, patients in Group A as well as Group B did not receive T-DM1 at any point. So, again, Group A is kind of your standard of care. Group B was the “experimental arm.” And so, what they did in this arm to assess potential de-escalation strategies, patients first received Herceptin-PERJETA alone for two cycles with or without endocrine therapy, if they were also hormone receptor-positive. But after those two cycles, they underwent a PET/CT, and then if a response was garnered, they would continue with Herceptin-PERJETA and again plus or minus endocrine therapy to complete six cycles total before proceeding on with surgery. Then if they were fortunate enough to achieve complete response at the time of surgery, then they just continued with Herceptin-PERJETA maintenance, whereas if they did not achieve a complete response at the time of surgery, then they actually received TCHP 6 times adjuvantly. So, the chemotherapy was introduced after surgery.   And then going back to that PET/CT time point, if patients did not achieve a response at that check-in point, after 2 cycles of Herceptin-PERJETA, at that point they were transitioned to chemotherapy with TCHP, again, for six cycles. So, either they could kind of ride all the way through if they got that complete response at the time of surgery with Herceptin-PERJETA only, or if at surgery there was residual disease, they went on to receive TCHP after surgery, or if they did not have a response on that interim PET/CT after 2 cycles of HP then they would go on to receive TCHP neoadjuvantly.    So, looking at the results, they actually had 2 primary endpoints. The first primary endpoint was rates of a complete response at the time of surgery in patients that had a PET response. So, PET responses were actually seen in nearly 80% of all the patients treated with Herceptin-PERJETA without chemotherapy. And in those PET responders, a complete response rate at the time of surgery was seen in approximately 38% of patients. So, 37.9% of PET responders actually achieved a complete response when they went to surgery after receiving Herceptin-PERJETA alone, which is pretty amazing. I mean, we're used to seeing higher complete response rates with neoadjuvant therapy for HER2-positive disease, but again, this is a chemo-free regimen so that is encouraging for that 38% of patients that really didn't need chemotherapy.   And then the second primary endpoint, and this was what we saw basically for the first time with the 2023 ASCO Meeting, was results for the 3-year invasive disease-free survival in Group B or this experimental de-escalation group. And ultimately it was shown that the three-year invasive disease-free survival and the intent to treat group B population was 95.4%, which met its statistical endpoint, or, basically the null hypothesis was rejected. They just needed some sort of outcome that was not worse in terms of the 3-year invasive disease-free survival of 89%.   And then looking actually at the patients that kind of did the best. So, the patients that were PET responders and achieved a complete response at the time of surgery and therefore really only ever received Herceptin-PERJETA, their three-year invasive disease-free survival was 98.8%. So, really very good. Additional endpoints they looked at in Group A and Group B were favorable in terms of three-year invasive disease-free survival in Group A, and then three-year distant disease-free survival and three-year overall survival in both groups, all approximately 98%. So, very favorable.   So, ultimately, these findings reflect a potential role for a chemotherapy-free treatment approach for some patients with early-stage HER2-positive breast cancer. And this particular study, they used PET/CT to influence chemotherapy decision-making, which potentially identified 1 in 3 patients who can omit chemotherapy. With that, 80% of patients receiving the response with a PET/CT, and then of that, 80%, again, 38% actually having that complete response. And ongoing work is also being done to look at other mechanisms to assess for an opportunity to de-escalate with MRI imaging or HER2DX testing to again try to identify patients who can potentially defer chemotherapy in this setting. I did not see from the results what proportion of patients were hormone receptor-positive, which I think is also interesting when thinking about chemotherapy de-escalation, can you lean a little bit more heavily on endocrine therapy? Perhaps we'll get that data in the future.   Dr. Allison Zibelli: That's a very important point.  I would like to thank you, Dr. Heeke, for coming on the podcast today and sharing your valuable insights with us. We really appreciate it.  Dr. Arielle Heeke: Absolutely. It was a great meeting to dive into. It's always exciting to see what comes out of ASCO in the breast space. We're usually well represented there, and I hope that these studies will lead to further exploration.   Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find links to all abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:   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.  Follow today's speakers:   Dr. Allison Zibelli   Dr. Arielle Heeke  @HeekeMD     Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Allison Zibelli:    None Disclosed   Dr. Arielle Heeke:   Honoraria: Merck  Consulting or Advisory Role: Jazz Pharmaceuticals, Caris Life Sciences, Amgen, Daiichi Sankyo/Astra Zeneca, Pfizer, AstraZeneca, Menarini, Genome Insight  Speakers' Bureau: Daiichi Sankyo/Astra Zeneca      

Several psychiatric medications prolong the QTc interval and place patients at risk of the dreaded torsade de pointes. Some patients are particularly vulnerable to QTc prolongation: the elderly, patients with heart disease and electrolyte imbalances, and patients taking certain medications, like thioridazine and ziprasidone. In this podcast, we provide a step-by-step guide so that you can keep your patients safe from this cardiovascular side effect.CME: Take the CME Post-Test for this episodePublished On: 6/18/2023Duration: 15 minutes, 00 secondsVictoria Hendrick, MD, and Prabhjot Gill, BS, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Peter Carroll's distinguished career has spanned over 100 productions and 50 years. He continues to work in musical theatre, new Australian texts, and global classics. He has worked with the major theatre companies and commercial managements in Australia including, MTC, QTC, STC, STCSA, Belvoir, Bell Shakespeare, and Opera Australia.  Peter began his career as a teacher (English, History and Drama) while gaining experiences in theatre work. In 1968 he went to London to study at the Central School of Speech and Drama where he topped the course. He returned to Sydney in 1970 and for three years headed the Voice and Speech department at the National Institute of Dramatic Art. During this time, he produced many plays for the students and kept up his acting work with guest appearances. At the end of 1973 Peter decided to attempt a full-time acting career and his work since then has more than vindicated his choice. He was a founding member in the 1970's of the Nimrod Theatre Company, performing up to seven or eight major roles a year, ranging from Shakespeare and Restoration comedy to contemporary Australian drama. He has acted for the Sydney Theatre Company from its beginnings at the Sydney Opera House. Some of his early performances were as Benedick in John Bell's hilarious production of Much Ado About Nothing, the dual roles of Hotspur and Pistol in Richard Wherrett's production of Henry IV, Jesus in a Perth Festival production of The Mystery Plays of Wakefield and Thomas à Becket in a Perth Festival production of Murder in the Cathedral. As one of Australia's most admired and popular stage actors, he is particularly well remembered for his beautifully studied role of the Catholic priest in Ron Blair's one-character play, The Christian Brothers, which was performed to acclaim from leading critics and audiences in all Australian capitals, numerous country centres, NZ and Riverside studios in London. In a vast career some standout performances include, Money and Friends, The Cherry Orchard, The Blind Giant is Dancing, A Hard God, Happy Days and Night on Bald Mountain. His repertoire is extensive. His casting in the role of Juan Peron, in the musical Evita marked a return to the earliest days of his career when he sang Gilbert and Sullivan productions at Sydney University. A resume of iconic musical theatre roles have peppered his career - Sweeney Todd, Thenadier in Les Miserables, Gus the theatre cat in CATS, Bella Zangler in Crazy for You, Pilate in Jesus Christ Superstar and The Narrator in Into the Woods.His film and television career has been extensive here in Australia and internationally. TV credits include titles such as Aftertaste, The Letdown, Bloom, and Rake. Film credits include The Power of the Dog, Sleeping Beauty, The Chant of Jimmy Blacksmith, and Crazy Rich Asians.Peter has won many awards including Green Room Awards, a Helpmann Award, a Sydney Theatre Critics' Circle Award and an Honorary Doctorate of Creative Arts. He is the inaugural recipient of the Media Arts & Entertainment Alliance's Lifetime Achievement Award; and he continues to be a proud supporter of the union and was awarded an AM for services to the theatre in 2021. The STAGES podcast is available to access and subscribe from Spotify and Apple podcasts. Or from wherever you access your favourite podcasts. A conversation with creatives about craft and career. Recipient of Best New Podcast at 2019 Australian Podcast Awards. Follow socials on instagram (stagespodcast) and facebook (Stages).www.stagespodcast.com.au

Peter Carroll's distinguished career has spanned over 100 productions and 50 years. He continues to work in musical theatre, new Australian texts, and global classics. He has worked with the major theatre companies and commercial managements in Australia including, MTC, QTC, STC, STCSA, Belvoir, Bell Shakespeare, and Opera Australia.  Peter began his career as a teacher (English, History and Drama) while gaining experiences in theatre work. In 1968 he went to London to study at the Central School of Speech and Drama where he topped the course. He returned to Sydney in 1970 and for three years headed the Voice and Speech department at the National Institute of Dramatic Art. During this time, he produced many plays for the students and kept up his acting work with guest appearances. At the end of 1973 Peter decided to attempt a full-time acting career and his work since then has more than vindicated his choice. He was a founding member in the 1970's of the Nimrod Theatre Company, performing up to seven or eight major roles a year, ranging from Shakespeare and Restoration comedy to contemporary Australian drama. He has acted for the Sydney Theatre Company from its beginnings at the Sydney Opera House. Some of his early performances were as Benedick in John Bell's hilarious production of Much Ado About Nothing, the dual roles of Hotspur and Pistol in Richard Wherrett's production of Henry IV, Jesus in a Perth Festival production of The Mystery Plays of Wakefield and Thomas à Becket in a Perth Festival production of Murder in the Cathedral. As one of Australia's most admired and popular stage actors, he is particularly well remembered for his beautifully studied role of the Catholic priest in Ron Blair's one-character play, The Christian Brothers, which was performed to acclaim from leading critics and audiences in all Australian capitals, numerous country centres, NZ and Riverside studios in London. In a vast career some standout performances include, Money and Friends, The Cherry Orchard, The Blind Giant is Dancing, A Hard God, Happy Days and Night on Bald Mountain. His repertoire is extensive. His casting in the role of Juan Peron, in the musical Evita marked a return to the earliest days of his career when he sang Gilbert and Sullivan productions at Sydney University. A resume of iconic musical theatre roles have peppered his career - Sweeney Todd, Thenadier in Les Miserables, Gus the theatre cat in CATS, Bella Zangler in Crazy for You, Pilate in Jesus Christ Superstar and The Narrator in Into the Woods. His film and television career has been extensive here in Australia and internationally. TV credits include titles such as Aftertaste, The Letdown, Bloom, and Rake. Film credits include The Power of the Dog, Sleeping Beauty, The Chant of Jimmy Blacksmith, and Crazy Rich Asians.Peter has won many awards including Green Room Awards, a Helpmann Award, a Sydney Theatre Critics' Circle Award and an Honorary Doctorate of Creative Arts. He is the inaugural recipient of the Media Arts & Entertainment Alliance's Lifetime Achievement Award; and he continues to be a proud supporter of the union and was awarded an AM for services to the theatre in 2021. The STAGES podcast is available to access and subscribe from Spotify and Apple podcasts. Or from wherever you access your favourite podcasts. A conversation with creatives about craft and career. Recipient of Best New Podcast at 2019 Australian Podcast Awards. Follow socials on instagram (stagespodcast) and facebook (Stages).www.stagespodcast.com.au

On this episode, I discuss risperidone pharmacology, adverse effects, monitoring, and common indications. There are numerous drug interactions that I discuss in this podcast episode. CYP2D6 inhibitors may increase drug concentrations. Risperidone increases prolactin more than most 2nd generation antipsychotics. This can lead to sexual adverse effects. QTC prolongation is a concern with all antipsychotics like risperidone. We can monitor EKG to monitor for this risk.

In this episode, we discuss the concerns of QTc prolongation, which can cause a fatal arrhythmia called torsades de pointes (TdP). We cover the difference between QT and QTc, how to interpret a QTc (and when it is inaccurate), common medications that prolong QTc, and how pharmacists can evaluate the risk of QTc/TdP in patients who are receiving QTc-prolonging therapies. Key Concepts The QTc interval is the QT interval that has been “corrected” for heart rate. In nearly all cases, when describing a QT interval, it should be expressed as the QTc. Although a prolonged QTc is usually defined as a QTc exceeding 450-480 msec, the risk of torsades de pointes (TdP) begins to become concerning when the QTc is more than 500 msec, 15-20% longer than baseline, or if the QTc has increased by more than 60 msec. Vaughan-Williams Class III antiarrhythmics are most implicated in QTc prolongation and TdP risk. These therapies include sotalol, dofetilide, and dronedarone. Although amiodarone is a class III antiarrhythmic, its risk of TdP is quite low despite the fact that it often substantially prolongs the QTc. When pharmacists are assessing the risk of QTc prolongation and TdP, multiple factors (not just the QTc itself) should be considered. Risk scores, like the Tisdale Risk Score, as well as considering the risks/benefits of switching drug therapy, should be evaluated. References CredibleMeds.com. Arizona Center for Education and Research on Therapeutics. http://crediblemeds.org. Noel ZR, See VY, Flannery AH. Walk the Line-The Importance of Well-Informed Interpretation of QT Prolongation. Ann Pharmacother. 2021;55(1):123-126. doi:10.1177/1060028020934718 E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Food and Drug Administration (FDA). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-clinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic-potential-non-antiarrhythmic-0

Rick Body, University of Manchester and Manchester University NHS Foundation Trust, and Sarah Edwards, University Hospitals of Derby NHS Foundation Trust, cover the pick of the papers from EMJ's May 2023 issue. In this edition, we cover papers on shoulder dislocation, blunt chest trauma, uterine bleeding, medical errors, benign paroxysmal position vertigo, and calcium and QTc interval. Read the highlights: https://emj.bmj.com/content/40/5/317 You can subscribe to the EMJ podcast via all podcast platforms, including Apple Podcasts, Google Podcasts, Stitcher and Spotify, to get the latest podcast every month. If you enjoy our podcast, please consider leaving us a review or a comment on the EMJ Podcast iTunes page (https://podcasts.apple.com/us/podcast/emj-podcast/id445358244). Thank you for listening!

Show notes at pharmacyjoe.com/episode799. In this episode, I’ll discuss whether the Tisdale Risk Score can be used to identify ICU patients at risk of QTc prolongation. The post 799: Can the Tisdale Risk Score be used to identify ICU patients at risk of QTc prolongation? appeared first on Pharmacy Joe.

Show notes at pharmacyjoe.com/episode799. In this episode, I’ll discuss whether the Tisdale Risk Score can be used to identify ICU patients at risk of QTc prolongation. The post 799: Can the Tisdale Risk Score be used to identify ICU patients at risk of QTc prolongation? appeared first on Pharmacy Joe.

QTc x FA by Cardiopapers

“When I draw the interprofessional team for the management of cardio-oncology patients, I always place nurses in the center of it, besides the patient, because nurses are the eyes and ears of interprofessional care 24 hours a day,” ONS member Anecita Fadol, PhD, FNP-BC, FAANP, FAAN, FHKAN, associate professor at the University of Texas MD Anderson Cancer Center in Houston, told Jaime Weimer, MSN, RN, AGCNS-BC, AOCNS®, oncology clinical specialist at ONS, during a conversation about getting to “the heart of the matter” of symptom management for the cardiovascular complications of cancer therapies. You can earn free NCPD contact hours after listening to this episode and completing the evaluation linked below. This episode is part of a series about cancer symptom management basics. We'll add a link to future episodes in the episode notes after the next episode airs. Music Credit: “Fireflies and Stardust” by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0 Earn 1 contact hour of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at myoutcomes.ons.org by January 27, 2025. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of NCPD by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: The learner will report an increase in knowledge related to cardiovascular complications associated with today's cancer treatments. Episode Notes Complete this evaluation for free NCPD. Oncology Nursing Podcast Episode 193: How Social Determinants of Health Affect Cardio-Oncology Survivorship ONS Voice articles: Nursing Considerations for ICI-Related Myocarditis Advanced Practice Nurses Are at the Heart of Patient Care in Cardio-Oncology Cardio-Oncology Program Monitors Heart Toxicities Throughout Survivorship Further Research Can Help Nurses Balance Cardiovascular Conditions With Cancer Treatments Clinical Journal of Oncology Nursing articles: Immune Checkpoint Inhibitor–Related Myocarditis: Recognition, Surveillance, and Management Cardio-Oncology: A Continually Evolving Subspecialty in Oncology Nursing Cardio-Oncology Health Disparities: Social Determinants of Health and Care for Black Breast Cancer Survivors Oncology Nursing Forum article: Mitigating Cardiovascular Dysfunction Across the Cancer Continuum ONS book: Cancer Basics (Third Edition) ONS course: Cancer Basics Learn more about the 48th Annual ONS Congress®. Journal of the American Heart Association article: Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment Circulation articles: Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity Immune Checkpoint Inhibitor–Associated Myositis Cardio-Oncology: Vascular and Metabolic Perspectives: A Scientific Statement From the American Heart Association New England Journal of Medicine article: Fulminant Myocarditis With Combination Immune Checkpoint Blockade Lancet Oncology article: Cardiovascular Toxicities Associated With Immune Checkpoint Inhibitors: An Observational, Retrospective, Pharmacovigilance Study Journal of the American College of Cardiology article: Cardiovascular Disease Risk Among Cancer Survivors: The Atherosclerosis Risk In Communities (ARIC) Study American College of Cardiology Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes Advancing the Cardiovascular Care of the Oncology Patient Heart Failure Society of America 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guideline for the Management of Heart Failure International Cardio-Oncology Society European Society of Cardiology Guidelines on Cardio-Oncology Joint National Committee Guidelines for the Management of Hypertension in Adults Attend the Cardio-Oncology Multidisciplinary Practice Virtual Environment on February 13, 2023. To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From Today's Episode “The most commonly reported cardiovascular toxicities can be classified into five main categories: 1. Cancer treatment-induced hypertension; 2. Cardiomyopathy, left ventricular dysfunction, or heart failure; 3. Myocarditis; 4. Vascular toxicity; and 5. Arrhythmias and QTc prolongation. These cardiovascular toxicities can be caused by the different anti-cancer agents.” Timestamp (TS) 01:46 “Cardio-oncology is more complex than the straightforward cardiology practice. Because in terms of the cardiovascular complications, these symptoms can overlap. But on the other hand, it's a very interesting area of practice because, especially as a nurse, it's like you are a detective, looking into a case and trying to find out what is the main etiology.” TS 23:50 “Nurses have a critical role in identification, monitoring, and management of these treatment-related cardiovascular complications, both in the inpatient setting and the outpatient setting with our cancer survivors. So, a nurse should remember in nursing practice, before administering anticancer treatments. . . a comprehensive cardiovascular history and a full cardiovascular assessment should be performed.” TS 30:27 “When I have to draw the interprofessional team for the management of cardio-oncology patients, I always place nurses in the center of it, besides the patient. Because nurses are the eyes and the ears of the interprofessional care who is seeing the patient 24 hours a day. And early recognition—nurses can do it and monitor the response and all the other symptoms.” TS 36:42 “Nurses are very critical in the management of these patients. Nurses are the experts in terms of doing patient teaching because we have an intimate relationship with patients. In terms of the baseline cardiovascular disease in terms of patient teaching, it is very important for nurses to teach the patient aggressive management of the known cardiac risk factors. . . because these are the ones that could cause cardiovascular complications later on when patients are receiving anticancer treatments.” TS 39:05

Show notes at pharmacyjoe.com/episode780. In this episode, I'll discuss delayed QTc prolongation in overdose patients. The post 780: How to Identify an ED Toxicology Patient at Risk of Delayed QTc Prolongation appeared first on Pharmacy Joe.

Show notes at pharmacyjoe.com/episode780. In this episode, I ll discuss delayed QTc prolongation in overdose patients. The post 780: How to Identify an ED Toxicology Patient at Risk of Delayed QTc Prolongation appeared first on Pharmacy Joe.

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.

Take Home Points Severe hypocalcemia can cause hypotension and QTc prolongation leading to Torsades de Pointes.  Treat moderate to severe symptoms and any EKG changes with IV calcium salts Always search for and treat the underlying cause of hypocalcemia REBEL Core Cast 88.0 – Hypocalcemia Click here for Direct Download of the Podcast Definition: A ... Read more The post REBEL Core Cast 88.0 – Hypocalcemia appeared first on REBEL EM - Emergency Medicine Blog.

Como medir o intervalo QTc no paciente com FA? by Cardiopapers

Como medir o QTc na presença de bloqueio de ramo? by Cardiopapers

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...

Episode 105: Renal Cell Carcinoma. Manpreet and Jon-Ade explain how to diagnose renal cell carcinoma. Introduction about age and kidney transplant by Dr. Arreaza and Dr. Yomi. Introduction: Too old for a new kidney?By Hector Arreaza, MD. Discussed with  Timiiye Yomi, MD.Today we will be talking about the kidneys, those precious bean-shaped organs that detoxify your blood 24/7. Amazingly, we can live normal lives with one kidney, but when the kidney function is not good enough to meet the body's demands, patients need to start kidney replacement therapy. Modern medicine has made a lot of advances with dialysis, but the perfection of a kidney has not been outperformed by any machine yet. That's why kidney transplant is the hope for many of our patients with end-stage kidney disease.The need for a kidney transplant is growing, likely due to increasing chronic diseases such as diabetes and hypertension, and also because of an increase in elderly population. About 22% of patients on the kidney transplant waiting list are over age 65. A cut-off age to receive kidney transplant has not been established across the globe. Different countries use different criteria for the maximum age for transplant. The American Society of Transplantation's guidelines states “There should be no absolute upper age limit for excluding patients whose overall health and life situation suggest that transplantation will be beneficial.” So, if your patient is older than 65 and needs a kidney, they may qualify for a transplant, and age should not be an absolute contraindication to receive it. Actually, older patients may have lower risk of rejection due to a theoretically weaker immune system. A live donor is likely to be a better option for elderly patients. A condition that would make your elderly patient a poor candidate for kidney transplant would be frailty. Common contraindications to kidney transplant include active infections or malignancy, uncontrolled mental illness, ongoing addiction to substances, reversible kidney failure, and documented active and ongoing treatment nonadherence.So, remember to take these factors into consideration when deciding if you need to refer your elderly patients for a kidney transplant, there is no such thing as being too old for a new kidney if your patient meets all the criteria for a transplant.This is Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it's sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care physician for additional medical advice. Renal Cell Carcinoma. By Manpreet Singh, MS3, Ross University School of Medicine, and Jon-Ade Holter, MS3 Ross University School of Medicine. Moderated by Hector Arreaza, MD. Definition:Renal cell carcinoma is a primary neoplasm arising form the renal cortex. 80-85 percent of renal tumors are renal cell carcinomas followed closely by transitional cell renal cancer and Wilms tumor.  Epidemiology: In 2022, 79,000 new cases of kidney cancer were diagnosed with almost 14,000 mortalities. There is a 2:1 male to female ratio and the average age is 64 and normally 65-74. African Americans and American Indians have a higher prevalence rate compared to other racial groups. The lifetime risk for developing kidney cancer in men is about 1 in 46 (2.02%) and 1 in 80 (1.03%) in women.  Risk Factors associated with RCC: Anything that causes assault to the kidneys and affects its function would cause increased demand, injury, and inflammation. This assault can lead to cell derangement and lead to cancer. The risk factors that have been associated with RCC are smoking, obesity, HTN, family history of kidney cancer, Trichloroethylene (a metal degreaser used in large manufacturing factories), acetaminophen, and patients with advanced kidney disease needing dialysis. Patients with syndromes that cause multiple types of tumors: VHL (von Hippel-Lindau) deficiency, a tumor suppressor, gives rise to clear cell renal cell carcinoma. Familial inheritance of VHL deficiency is mostly found in patients that have RCC at a very young age, before 40 y/o. Other tumors can be found in the eye, brain, spinal cord, pancreas, and pheochromocytomas.Hereditary leiomyoma-renal cell carcinoma due to FH gene mutations causing women who have leiomyomas to have a higher risk of developing papillary RCC.Birt-Hogg-Dube (BHD) syndrome mutation in FLCN gene who develop various skin and renal tumors.Cowden syndrome is a mutation in the PTEN gene giving rise to cancers associated with breast, thyroid , and kidney cancers.Tuberous sclerosis causes benign tumors of the skin, brain, lungs, eyes, kidneys, and heart. Although kidney tumors are most often benign, occasionally they can be clear cell RCC. Screening For RCC:Screening is unnecessary because of the low prevalence of this cancer in the general population, though certain groups require annual repeat imaging via US, CT, or MRI. Inherited conditions that are associated with RCC such as VHL syndrome or Tuberous SclerosisESRD patients who have been on dialysis for 3-5 yearsFamily history of RCCPrior kidney irradiation Clinical Picture: Most patients with RCC are asymptomatic until cancer grows large enough to cause disruption of local organs, such as the kidney, bladder, or renal vein, and dysregulates other organs via metastasis. Therefore, it's important to look at other signs and symptoms caused by RCC.  The patient most likely will be an older male who presents with the classic triad of: Flank pain: caused by rapid expansion and stretching of the renal capsule.Hematuria: occurs from the invasion of the neoplasm into the collecting duct.Palpable abdominal mass: mass tends to be homogenous and mobile with respirations. Though this presents only in 9% of patients during the presentation, having physical symptoms is a sign of advanced disease and 25% of patients with these signs tend to have distant metastasis.  Anemia: normally associated with anemia of chronic disease. It precedes the disease by at least 8 months to 1 year. Males can develop varicoceles because of decreased emptying due to neoplasm obstruction. Patients normally develop varicoceles on the left due to the spermatic vein emptying in the higher resistance left renal vein, which causes backup of the blood in the pemphigus plexus. Though a right-sided varicocele should raise a higher suspicion of obstruction due to the spermatic vein draining directly into the IVC which is lower in resistance. A right-sided varicocele is seen in approximately 11 percent of patients. The paraneoplastic syndrome can also arise from RCCEpo: Erythrocytosis with symptoms of weakness, fatigue, headache, and joint pain.PTHrP: PTH-related peptide acts like PTH which gives rise to hypercalcemia with the prevalent symptoms of arthritis, osteolytic lesions, confusions, tetany, ventricular tachycardia, shortened QTc, and nausea and vomiting.Renin: overproduction from the juxtaglomerular cells can cause disarrangement of the RAAS system causing hypertension.Others also like ACTH and beta-HCG. Other disorders present include hepatic dysfunction, cachexia, secondary amyloidosis, and thrombocytosis. Workup If a patient comes in with painless hematuria, then the first test should be abdominal CT or abdominal ultrasound. A CT is more sensitive than the US but it can quickly indicate if the abdominal mass felt can be a cyst or a solid tumor.  US of kidneys should show if it's a simple cyst:-The cyst is round and sharply demarcated with smooth walls- It's anechoic – appears solid black-There is a strong posterior wall echo-Use the Bosniak classification to classify mass  Bosniak I: benign simple cyst with thin wall less than equal to 2mm, no septa or calcifications. No future workup is needed. Bosniak II: benign cyst, 3 cm diameter, requires f/u with US/CT/MRI at 6 months, 12 months, and annually for the next 5 years. Chance of malignancy: 5%.  Bosniak III: indeterminate cystic mass with thick, irregular or smooth walls. This requires nephrectomy or radiofrequency ablation. Chance of malignancy: 55%  Bosniak IV: Clearly a malignancy its grade III with enhancing soft tissue components that its independent from the wall or septum. Requires total or partial nephrectomy. Chance of malignancy 100%.  CT of the kidneys for a neoplasm should show:-Thickened irregular walls or septa -Enhancement after contrast injection are suggestive of malignancy-CT can also help detect invasion in local tissue areas such as renal vein and perinephric organs  MRI is used if the patient cannot use contrast or kidney function is poor. MRI can also evaluate the growth of the cancer. Other imaging studies:Other imaging studies that may be useful for assessing for distant metastases include bone scan, CT of the chest, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Treatment and staging Nephrectomy, partial or total, will be used as the initial tissue collection for pathology. If the patient is not a surgical candidate, you can also obtain a percutaneous biopsy. The nephrectomy is preferred because first, it serves as a definitive treatment option, but also it allows for definitive staging of the cancer with tumor and nodal staging. Regardless of the size, any solid mass may indicate malignancy and point towards RCC, requiring resection.   TNM staging Stage I: Tumor is 7cm across or smaller and only in the kidney with no lymph nodes or distant mets. T1N0M0 Stage IIa: Tumor size is larger than 7cm but still in the kidney but no invasion of lymph node or mets. T2N0M0 Stage IIb: Tumor is growing into the renal vein or IVC, but not into neighboring organs such as adrenals or Gerota's fascia and still lacks lymph node invasion and mets. T3N0M0.  Stage III: Tumor can be any size but has not invaded outside structures such as adrenals, though nearby lymph node invasion is present but not distant. There is no distant mets. T3N1M0. Stage IV:  The main tumor is beyond the Gerota's fascia and may grow into the adrenal gland . It may or may not spread to the lymph nodes or may not have distant mets. Stage IV also consists of any cancer that has any number of distant mets. T4 Adjuvant therapy can be done with immune therapy. Conclusion: Now we conclude our episode number 105 “Renal cell carcinoma.” This type of cancer may be asymptomatic until it is large enough to cause symptoms. Keep it on your list of differentials on patients with hematuria, flank pain, weight loss, and abnormal imaging. Keep in mind the features of simple kidney cysts vs complex cysts when assessing kidney ultrasounds. Your patient will be grateful for an early diagnosis of RCC and a prompt treatment. Even without trying, every night you go to bed being a little wiser.This week we thank Hector Arreaza, Timiiye Yomi, Manpreet Singh, Jon-Ade Holter. Thanks for listening to Rio Bravo qWeek Podcast. If you have any feedback, contact us by email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. Audio edition: Suraj Amrutia. See you next week!  Bibliography: Is There a Cut Off Age for Kidney Transplant?, Mayo Clinic Connect, Jul 18, 2017, https://connect.mayoclinic.org/blog/transplant/newsfeed-post/is-there-a-cut-off-age-for-kidney-transplant/ Atkins, Michael. “Clinical Manifestations, Evaluation, and Staging of Renal Cell Carcinoma.” UpToDate, January 21. https://www.uptodate.com/contents/clinical-manifestations-evaluation-and-staging-of-renal-cell-carcinoma American Cancer Society. “Key Statistics About Kidney Cancer”. Cancer.Org, 2022, https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html. Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, Grünwald V, Gillessen S, Horwich A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019 May 1;30(5):706-720. doi: 10.1093/annonc/mdz056. PMID: 30788497. https://pubmed.ncbi.nlm.nih.gov/30788497/. Gaillard, F., Bell, D. Bosniak classification system of renal cystic masses. Reference article, Radiopaedia.org. (accessed on 20 May 2022) https://doi.org/10.53347/rID-1006. Kopel J, Sharma P, Warriach I, Swarup S. Polycythemia with Renal Cell Carcinoma and Normal Erythropoietin Level. Case Rep Urol. 2019 Dec 11;2019:3792514. doi: 10.1155/2019/3792514. PMID: 31934488; PMCID: PMC6942735. https://pubmed.ncbi.nlm.nih.gov/31934488/. Leslie SW, Sajjad H, Siref LE. Varicocele. [Updated 2022 Feb 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448113/. Maguire, Claire. “Understanding Endoscopic Ultrasound and Fine Needle Aspiration.” Educational Dimension, Educational Dimensions, 1 Jan. 2007, educationaldimensions.com/eLearn/aspirationandbiopsy/eusterm.php. Maller, V., Hagir, M. Renal cell carcinoma (TNM staging). Reference article, Radiopaedia.org. (accessed on 20 May 2022) https://doi.org/10.53347/rID-4699. Palapattu GS, Kristo B, Rajfer J. Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma. Rev Urol. 2002 Fall;4(4):163-70. PMID: 16985675; PMCID: PMC1475999. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475999/.

QTc x FA by Cardiopapers

This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)." Dr. Greg Hundley: Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies. Dr. Greg Hundley: So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity. Dr. Greg Hundley: Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention. Dr. Greg Hundley: So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article. Dr. Greg Hundley: Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval. Dr. Greg Hundley: So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score. Dr. Greg Hundley: So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk. Dr. Greg Hundley: Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown. Dr. Greg Hundley: So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma. Dr. Greg Hundley: So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Andrew Stokes: Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period. Dr. Greg Hundley: Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct? Dr. Andrew Stokes: That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events. Dr. Greg Hundley: And so, can you describe for us your study population and your study design? Dr. Andrew Stokes: Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals. Dr. Greg Hundley: Very nice. And so, what were your study results? Dr. Andrew Stokes: So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group. Dr. Greg Hundley: Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older? Dr. Andrew Stokes: I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications. Dr. Greg Hundley: Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes? Dr. Andrew Stokes: Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions. Dr. Greg Hundley: And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research? Dr. Andrew Stokes: Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction. Dr. Greg Hundley: Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies? Dr. Andrew Stokes: That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health. Dr. Greg Hundley: Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward? Dr. Andrew Stokes: The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys. Dr. Greg Hundley: Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of? Dr. Andrew Stokes: Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Mandated by regulatory bodies the world over, the thorough and precise evaluation of a new drug's cardiac effects is a critical element of new chemical entity development. Sponsors must submit all new chemical entities with systemic exposure to a dedicated thorough QT study (also referred to as TQT study) to understand the drug's impact on ECG parameters and determine whether the compound prolongs the corrected QT (or, QTc) interval. In Issue 9, we discuss global regulations, design, and timing of QT assessment, including a case study from a first-in-human clinical trial. Click here to download a readable, PDF version of Issue 9: https://www.altasciences.com/sites/default/files/2022-04/The-Altascientist_issue9_TQT_2022.pdf CHAPTERS: - 0:08 — Section 1: Introduction - 1:50 — Section 2: Global Regulations - 3:49 — Section 3: QT/QTc Study Design - 7:01 — Section 4: Timing of Assessment - 9:36 — Section 5: Case Study — First-in-Human Clinical Trial Involving QT Assessment - 12:09 — Section 6: Cardiac Assessment Specializations Altasciences is an integrated drug development solution company offering pharmaceutical and biotechnology companies a proven, flexible approach to preclinical and clinical pharmacology studies, including formulation, manufacturing, and analytical services. For over 25 years, Altasciences has been partnering with sponsors to help support educated, faster, and more complete early drug development decisions. Altasciences' integrated, full-service solutions include preclinical safety testing, clinical pharmacology and proof of concept, bioanalysis, program management, medical writing, biostatistics, clinical monitoring, and data management, all customizable to specific sponsor requirements. Altasciences helps sponsors get better drugs to the people who need them, faster.

On this episode, I discuss esomeprazole (Nexium) pharmacology, adverse effects, tapering, kinetics, and drug interactions. I spend a good amount of time discussing the esomeprazole and clopidogrel interaction in this podcast episode. Esomeprazole inhibits CYP2C19. This can cause an increase in citalopram concentrations and raise the potential for QTc prolongation. It is critical to reassess the length of therapy and the dose of PPIs like esomeprazole.

"Wall Street doesn't believe in this target," by Dario Altieri. A scientist shares his 12-year journey that led to the discovery of a drug now in clinic.   TRANSCRIPT Narrator: Wall Street Doesn't Believe in This Target by Dario C. Altieri, MD (10.1200/JCO.22.00180) March 2, 2009. Just published in the Journal of Clinical Investigation.1 And we even got the cover. Twists and turns of heat shock protein-90 (Hsp90), the chaperone, the evolutionary capacitor. Great name and important cancer target. People smiled when I talked about this at the Hsp90 conference. No, no, really there is a lot of it in mitochondria, and only in mitochondria of tumor cells. And, I don't know why, but Hsp90 drugs don't touch it: somehow, they don't get to mitochondria. So, I made my own. Took an old Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin and attached it to triphenylphosphonium, a carrier that basically gets anything into the mitochondria. No, of course, I didn't do the synthesis in my laboratory. What do I know about medicinal chemistry? Outsourced it. Like sneakers and sweaters. And after three months, there it was: an Hsp90 inhibitor that only goes to the mitochondria, causes aggregation of a lot of proteins, and kills tumor cells in minutes. Makes sense, right? Mitochondria must control protein folding, especially in cancer, and they do it with chaperones. Inhibit the process and tumor cells can't cope. Normal cells don't seem to mind. So, strong preclinical activity, and against a lot of different tumor types. Better than any other Hsp90 inhibitor. Good safety. Totally different mechanism of action. And even a cool name, Gamitrinib. Tired of curing mice. What if this were to work in people? Ideas are made in academia; drugs are made in companies. Okay, fine, then I'll launch a startup, spinout, whatever they are called. The (former) doctor-turned scientist now turns entrepreneur, and then captain of industry. Problem is, I am not like that. More like an (aged) boy scout. The inner soapbox says: it belongs to the American taxpayers; they funded it; it's theirs. Excellent start. What else? If doctors and scientists become businessmen (or businesswomen), who will take care of humanity and discover new things? Perfect for a campaign ad. Sold. Bring it to the patients solely from academia: no pharma, no biotech, no investors, no nothing. Soapbox meme for the day: Yes, we can. It's going to cost. So? I'll write a grant, that's what I do for a living anyway. And the fact that I know zero about drug discovery? Or drug development? Laboratory-Clinical Transition Award from the Department of Defense. Great title. Three years of funding. Perfect for me. Pass-through money, nothing for the laboratory, but it pays the bills of outsourcing. First things first. Synthesize Good Laboratory Practice (GLP) Gamitrinib. Already getting a pretty good hang on the acronyms. Hey, we made this drug lots of times before and has never taken this long. It's almost a year and counting. The Department of Defense (DoD) is on my case because I am already behind. What's going on? Yes, I understand that we don't make anything in this country anymore. New import permits that need to clear the Indian government? The what? This is just a chemical, not an international incident. Yes, I get it, nothing I can do about it. My new job is mailman. And telephone operator. Finally shipped the GLP drug for the toxicology. Two animal species, says the US Food and Drug Administration (FDA). Rats and dogs sound good to me. Should I feel sorry for the dogs? Rats not so much. But what if Gamitrinib poisons the mitochondria in the brains? Or hearts? Wait, you said it's just perfect? Animals are doing great, all of them. And no toxicity at all, like giving them…water. Wow, that's some news. Feeling quite pleased with myself. See? I said it all along: mitochondria are wired differently in cancer. That's why the drug is safe for normal tissues. Maybe I should write a review article about that. Serious boost of the citation index. I am sorry, what? Yes, of course I know that the drug is purple. Okay, you filtered it before giving it to the animals and instead of purple it turned white? And you did that to all animals. For the entire time. Oh, what do I think it means? I think it means that you filtered out the drug and we have been giving animals…water. Yes, I get it. I need a new formulation. And start over. Note to self: find a new Contract Research Organization (CRO) that doesn't give water to the animals. Formulation experts. Big pharma ex-pats who now have their own CRO. Everybody is an entrepreneur here. Is this drug oral? Nope. Is it soluble in water? Not at all. So, it's an intravenous (IV) infusion? Yes, that's what it is. Sorry, then it's not a drug. It's not? And what about things like, you know, paclitaxel or doxorubicin? Aren't they also insoluble and given IV? Last time I checked, we used them for half a century and saved millions. Oh, now we think differently? I see, Fail Fast: that's how we think now. And mine, whatever it is if it is not a drug, has already failed. Nobody likes to take risks. Soapbox meme for the day: If nobody takes risks, how do we make progress, exactly? So, maybe I am in good company: paclitaxel and doxorubicin would also Fail Fast today. It's doable. Nobody likes it but it's doable. Sterile-filter the emulsion components and then bring the particle size below 200 nm. Nice. How do I do that? With a microfluidizer. And why nobody likes it? Oh, because the microfluidizer is a dirty machine and where you make Good Manufacturing Practice is called a clean room. Impeccable logic. But a place in California may do it. For a fee, of course. Oh, and you have to buy the machine. Buy what? Or lease it, whatever. People may not like it, but the whole thing works like a charm. Except, of course, when the microfluidizer stops for no reason in the middle of the run. Media fill looks good. Drug is stable for months in the new formulation. Release testing coming together nicely. I am running out of money. Burned through not just one but two DoD grants and all my research kitty. Nothing saved for the swim back: talk about risk-taking. At least the repeat toxicology is paid for and looks good. The drug, the real thing this time, is safe. They even did ECGs on the dogs. Thank goodness I didn't have to read those, but they are normal: no QTc liability. Can't drop the ball now, but I really need money. Here is how you do it: silence the inner soapbox and enchant the big pharma suits that are coming over. Use the right words. It's not early stage anymore. Asset totally derisked. Sure it's ready for prime time. It works. I am a natural. Maybe I should have done this before. A lot of nodding around the table. The suits must be in awe with the great pharmacokinetics, long half-life, and fabulous safety. A hand goes up. I am sorry? Sales data? Sales of what? What is the unit price? No, no, no, we are not there yet. I haven't even filed an Investigational New Drug (IND) application. Something different now. Analysts who advise big-time investors. They don't wear suits. Sweaters for sure. Maybe black tees a la Steve Jobs. They like new things and totally live by risks. Sounds like my crowd. And don't forget, they can get tons of money from people who already have tons of money and want to make even more money. My crowd? Voices out of a polyphone. Yes, it is Hsp90. Yeah, the chaperone. Sure, I know, it has been around for a long time. But this is a completely new story: nobody ever tested a cancer drug that goes to a subcellular organelle: that's really where the action is. Yes, Hsp90. And mitochondria, they used to be bacteria two and a half billion years ago, but they turned out to be important in cancer. I know that too, Hsp90 drugs didn't fare well in the clinic. Lot of toxicity, basically no efficacy. Yes, very unfortunate. But this one has a completely different mechan…Sure, I would like to hear that perspective. I am sorry, did you say, Wall Street doesn't believe in this target? Triaged the first time but funded on the resubmission. Could have been worse. This one is a grant from the National Cancer Institute. And a nice award from the Gateway Foundation is coming too. Enough to pay for the clinical trial. Single site, standard phase I. Accelerated dose escalation. Up to 35 patients with advanced cancer. All comers. Drug vials ready to go. And a fantastic clinical investigator to run the trial. You really don't want me in the clinic. The only thing missing is IND approval. Right, there is that. No, not a commercial IND, investigator-initiated IND, thank you very much. The FDA people are the nicest in the world. Super-helpful, don't believe otherwise. Or maybe they just feel sorry for the clueless applicant. Thirty days to respond to the questions. Totally getting a promotion to a higher rank of telephone operator. And publisher of FDA modules. And certifier of United States Pharmacopeia (USP) . recommendations. And fixer of Chemistry, Manufacturing, and Controls deficiencies. Oh, and let's not forget the specs for polytetrafluoroethylene filters. Then the examiner mutters two words at the end of a phone call. Good luck. Then, nothing. No more questions, e-mails, or phone calls. Right on the thirty-day mark. Were you expecting this? It's a letter; it says study may proceed. What would the day look like? The first patient to be dosed. Maybe I should go to the clinic: it's in town, not far from where I am. I don't think I can pass muster as one of those confidence-inspiring docs in pharma ads. But I do well as chief executive officer. The cufflinks look good, and so do the shoes. I can impress the family. My Italian accent can pass as straight from South Philly, so I have that also going for me. And I can more than hold my own if I need to talk about Philadelphia Eagles football and worries with Jalen Hurts' arm for next season. I used to be good with my patients. Or at least I convinced myself of that. Yes, this is an experimental drug straight out of our backyard, right here in Philadelphia. No, I don't know if it will work, but I sure hope it will. And thank you, thank you so much for being part of the trial. What if I make these people even sicker than they are? I took an oath a long time ago. Anyway, I know the literature on phase I studies, chances are it just won't do anything, so nobody gets hurt and I am finally done with it. I never thought this moment would arrive. There is none of that. January 10, 2022. It's just a late-night e-mail on the anniversary of my mom passing from lung cancer. Hey, the first patient did great at the starting dose of Gamitrinib. No problem whatsoever. The next patient will now get twice the dose. I hope we get that started this month. Happy new year. And that was that. Twelve years, 10 months, and nine days from that Journal of Clinical Investigation paper.1 Affiliation: 1The Wistar Institute, Philadelphia, PA Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology. I'm Lidia Schapira, Associate Editor for Art of Oncology, and Professor of Medicine at Stanford University. And I'll be the host of this show. Cancer Stories is brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows including this one at podcast.asco.org. With me today is Dr. Dario Altieri, president, and CEO at the Wister Institute. We'll be discussing his Art of Oncology article: Wall Street Doesn't Believe in This Target. Our guest is a named inventor for patent number 2,699,794. Titled: Mitochondria Targeted Anti-Tumor Agents. Dario, welcome to our podcast. Dr. Dario Altieri: Thank you so much for having me, Lidia. It's a great privilege. Dr. Lidia Schapira: My first question to you and to our authors is this, people who enjoy writing are usually also readers, what are you reading now? Dr. Dario Altieri: Well, absolutely it has been a passion of mine since the floods. I am an absolute avid reader of novels, and history, in particular, contemporary history and modern history. Those are my favorite topics. Dr. Lidia Schapira: Do you read in English, Italian, or other languages? Dr. Dario Altieri: I typically read in English, even though some of the Italian literature is best read in the native tongue. And so, I am still attached to that. Dr. Lidia Schapira: You're clearly a very accomplished scientist. But tell me a little bit about your writing in this particular area in what I'll call creative nonfiction. How has this writing helped you perhaps process experiences or communicate with others? Dr. Dario Atieri: It has been, it's been a passion of mine for a very long time, I think. In finishing up college, of course, my major was contemporary literature and philosophy. The question was whether to continue on in a classic literature career or go to medical school, probably the wrong choice was made. But it has remained with me for a very long time, and it's a form of expression that I truly enjoy. In writing, this particular contribution was a bit transformative for me. It doesn't happen every time that you write a scientific article to express a little bit about yourself and your passions and dreams. Dr. Lidia Schapira: Let's talk a little bit about your passions and dreams in this article. You described an intensely personal journey of 12 years that led to the discovery or the availability of this drug now in the clinic. When did you think that you wanted to share this story with your colleagues? And tell me a little bit about the process of writing this article? Dr. Dario Altieri: It has certainly been a roller coaster experience. I would like to describe it as life-defining and life-changing. I've learned so much and so many things, not just about the process, but also a little bit about myself. I recognize reaching the clinic, especially in a phase one trial, is really just the beginning. But for me, as a basic scientist, somebody who has seen his last patient in the 13th century. As a basic scientist, that was a little bit of a milestone, and I wanted to share what it took, the experiences that I lived through, especially with our youngest colleagues, scientists, and doctors, starting their own careers in oncology, whether it's basic research, clinical research, translational research, I really don't think it matters. And so, issues of resilience, staying the course, passion, and not really giving up are the parameters that I had hoped to convey with this contribution. Dr. Lidia Schapira: In your article, I was so impressed by how you used humor, often self-deprecating humor, and the particular narrative style and writing style that you chose and defended as you were revising it. You know, this choppy phrasing, a staccato, and you said, this is what it feels like, how can I pack it into a small number of words and describe it all? Tell us a little bit about how you allowed your imagination to take over and how you found the proper voice and style for this particular narrative. Dr. Dario Altieri: Again, it's been a thrilling experience and it's been a thrilling experience to answer to the editors and the reviewers of the JCO, who provided incredible insightful comments. The challenge was, how do I tell a story without sounding obvious, fright, or expected, and more importantly, without sounding boring? And I think to paraphrase one of our reviewers about this journey. What the reviewer said, the author, that would be me, has encountered many of the absurdities of the path in drug development, something that we don't talk about too much because it's been the realm of a drug company for the longest time. And so, I wanted to try to capture that absurdity in a positive way. Things that the reviewer indicated, may be second nature to the pharmaceutical industry, but for academic investigators, that's been publicly funded for 30 years, is not second nature and is unusual, and is a world all in itself. And so, that was the impetus of trying to use literature advice on short sentences that are really intended to convey the impression of the moment that was what I tried to accomplish. Dr. Lidia Schapira: Well, you certainly picked a catchy title, and we have not published this sort of article in Art of Oncology before. For our listeners, tell us a little bit about why Wall Street doesn't care about your discovery? Dr. Dario Altieri: Unfortunately, I think, I mean, I don't know for sure. But I think that dealing with this particular molecule, heat shock protein 90 in the clinic has been difficult. Hsp90 has long been recognized as an important cancer target. There have been several generations of small molecule inhibitors that have been tested in the clinic. And unfortunately, I hope I'm not offending anybody, but unfortunately, the clinical results of those studies, and some of them moved all the way to really large phase two trials have been disappointing. And so, that is the idea that perhaps this was a dead target. And therefore, trying to leverage industry or biotechnology interest around it was quite a remarkable challenge. Dr. Lidia Schapira: What message do you want the young investigators to take away from your story in terms of the collaboration between academia where thoughts start, as you say, in your article, and all of the rest of the partners that you actually need it to bring this discovery and this idea to fruition? Dr. Dario Altieri: Lydia, this may sound trite, I really hope to convey one simple notion. It's not even a message, it's a very personal account. And that is don't give up. If you have run the controls. If you have done your experiments enough time. If you're convinced of the results, if you explore alternative explanations, and you keep coming back to the same conclusions, go for it. That has been a little bit of my own personal experience and if there are things that you don't know about, that's perfectly fine. Actually, that is the fun of the process, and the things that I didn't know about drug development, I can fill in the encyclopedia. I've learned some of them through people who have been doing this for a living, for a very long time. And that has been truly inspiring for me, a life lesson and professional lesson about how we can think of a drug target that has been discounted and remain true to the core value of strong basic research and try to advance that to the clinic, whether this will ever become something useful for our patients? I don't have the faintest idea. I certainly hope so. But that would be the experiment that is being done right now in the clinic. Dr. Lidia Schapira: In your article towards the end, you just give us two little glimpses into something that is personal and meaningful to you by telling us that there's an anniversary of a loss, the passing of your mother from cancer. Can you tell us a little bit more about that, and why you chose to put that sentence just where you did? Dr. Dario Altieri: I didn't know if anybody would have noticed, frankly, so I appreciate you bringing it up, Lidia. It's been a very personal journey for me as well. Both my parents died of lung cancer. They were a different generation. Both were heavy smokers. I remember those dates very well and I remember the void that they're passing is created. And so, I thought it was an interesting circumstance, that in fact, the first patient was enrolled in a clinical trial, the notion about that and of course, I am technically conflicted. So, I am not supposed to know anything about what is happening in the clinic. But it was interesting that the first notion about the first dosing came on that day, on January 10. Dr. Lidia Schapira: Well, I'm sure other readers will notice that too, the timing of that in the article and the fact that there was some emotion implied, I think, in how you chose to end your story by saying that this had happened in the clinic, but somehow, you were not there, that you had to be removed. Tell us a little bit more about that, about why you needed to be removed from the clinical site and why do you talk about yourself as a former doctor? In my mind, once you are you always are, but somehow you feel that you need to make the distinction. What does it all mean to you? Dr. Dario Altieri: Well, Lidia, let me just say you don't want me in the clinic right now. At 64years of age, like I said that the last patient was a very long time ago. I have to say, sometimes I miss those days, just as a personal account. I need to be removed because I'm technically conflicted on the trial, I was the IND holder, and then the FDA asked me to transfer the IND to the clinical investigator as proper because I'm not involved in patient care or research, in this particular case. And technically, because I am the inventor on a patent, I could potentially stand to benefit financially from the results of the trial, something that is certainly not on my mind, but that I have been reminded of. And so, I try to stay away as much as I can. Obviously, I think about this every day. But whatever information I can gain, that I can gather from my colleagues across town will be wonderful, but I'm not the one initiating those calls. Dr. Lidia Schapira: So back to the humorous side of your essay, you say that you've learned to be a telephone operator and a mailman, and a whole bunch of other things. Have those lessons been useful to the other aspects of your life? Or do you see that as a total waste of your time? Dr. Dario Altieri: Not at all. Not at all. I have been an incredible component and I think I was trying to be humorous and to take myself seriously, but not too seriously. But in fact, maintaining that level of interaction, particularly with aspects of the work that I've never encountered, for instance, regulatory aspects of an early-stage clinical trial with the Food and Drug Administration, that has been part of the life journey and I only have very good things to say about my experience. You know, it's been interesting, Lidia, being part of the experience of being a telephone operator and a mailman. I had this sense, and I could be completely wrong, but I had this sense that people out there want to see us taking small risks. They want to see testing new drugs, they want to see new targets being somehow examined, developed, if at all possible. I had the sense that there was support, you know, for the idea, and this was an entirely publicly funded program. I funded both the preclinical and now the clinical trial of Gamitrinib out of the American taxpayer's commitment and in many different study sections, in dealing with the FDA, in dealing with other regulatory consultants, I always get the sense people who wanted to help, then had perhaps the mindset, okay, we don't know whether this is going to work or not but let's give it a try. Let's give it a shot. It was wonderful, that was an absolutely awe-inspiring experience. Dr. Lidia Schapira: I'm glad they did and I'm glad you shared your experience with all of us. Is there something else that you'd like our listeners or your readers to know about you or this story? Dr. Dario Altieri: I just would like to say that I would do it again, 12 years, I would do every step of the way but I think I'm done. If I were to start over, I'll do it again, but I don't think I'm ready to do it again with another target. Dr. Lidia Schapira: And with that, I want to thank you and I want to thank our listeners. Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode of JCO's Cancer Stories: The Art of Oncology podcast. This is just one of many of ASCO's podcasts. You can find all of the shows at the podcast.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 or service organization activity or therapy should not be construed as an ASCO endorsement.

Welcome to PICU Doc On Call, a podcast dedicated to current and aspiring intensivists. My name is Pradip Kamat. My name is Rahul Damania, a current 2nd-year pediatric critical care fellow. We come to you from Children's Healthcare of Atlanta-Emory University School of Medicine. Today's episode is dedicated to pediatric post-cardiac arrest care. We are going to split this topic into two episodes, part one of pediatric post-cardiac arrest syndrome will address the epidemiology, causes, and pathophysiology. I will turn it over to Rahul to start with our patient case... 11 yo previously healthy M who is admitted to the PICU after cardiac arrest. The patient was noted to be found unresponsive and submerged in a neighborhood pool. He was pulled out by bystanders and CPR was started for 5 minutes with two rounds of epinephrine prior to achieving ROSC. During transport to the OSH, the patient developed hypotension requiring a continuous epinephrine infusion. His initial blood gas was notable for a mixed respiratory and metabolic acidosis: 7.0/60/-20 His initial serum lactate was 6.8 mmol/L. He presents to the PICU with a temperature of 36.6, HR 130s, MAPs 50s on Epinephrine infusion at 0.03mcg/kg/min He is mechanically ventilated with notable settings PEEP of 10, FiO2 65%. The patient is taken to head CT which shows diffuse cerebral edema and diffusely diminished grey-white differentiation most pronounced in the basal ganglia. Great Rahul, can you please comment on his physical exam & PMH? Important physical exam findings include an unresponsive intubated patient with a cervical collar and bilateral non-reactive pupils at 4mm. The patient received mechanical ventilation with coarse breath sounds. A heart exam revealed tachycardia with no murmur or gallop. The patient does not respond to stimuli, intermittent jerking movements of arms and legs were observed. There was no evidence of rash or trauma. No past medical history of seizures or any heart disease. No home medications or toxic ingestions are suspected. So now he is transferred to the ICU, what did we do? An arterial line, central venous line, urinary catheter, esophageal temperature probe was placed. The patient was ventilated using a TV of 6cc/kg and a PEEP of 10 (FIO2 ~65%) to keep SPO2 >94%. The patient initially had runs of ventricular tachycardia for which lidocaine was used. Although the initial EKG showed mild QTc prolongation, it subsequently normalized and was considered to be due to his cardiac arrest and resuscitation. An echocardiogram revealed normal biventricular systolic function (on epinephrine) and also showed normal origins of the coronary arteries. Comprehensive Arrhythmia Panel did not identify a specific genetic cause for the patient's sudden cardiac arrest. The patient was placed on continuous EEG, which demonstrated severe diffuse encephalopathy with myoclonic status likely from anoxic brain injury Patient was also started on Levetiracetam and valproic acid. Initial portable CT scan done on day # of admission showed diffuse cerebral edema and diffusely diminished gray-white differentiation (most pronounced in the basal ganglia). MRI was deferred due to patient instability. The case we talked about highlights a patient who had a trigger that then resulted in cardiac arrest is common is one of the common reasons for admission to the PICU at Children's hospitals whether from submersion injury, trauma, ingestion, cardiac arrhythmia, sepsis, etc. Can we start by defining post-cardiac arrest syndrome? Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after the return of spontaneous circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Prior to 2008, the AHA pediatric advanced life support (PALS) guidelines...

Dr Phillip Mehler, MD, CEDS HOPE becomes a reality with dedication and expert evidence-based care.   How to build hope into your medical practice.  Medical malnutrition looks different for eating disorders than for other illnesses.  ACUTE breaks all the rules of nutrition in the best ways possible – go RD's!  Myth's dispelled about how to treat severe hypoglycemia, about having a baby post-recovery, QTc elongation.  The heart, the liver, the bones – all things medical.  Cross-reference Dr. Voss's episode on differentials. Join us for more of Dr. Mehler next week as he discusses DEXA scans and reveals his new model to treat low-weight anorexia.  Bio:   Dr. Philip Mehler founded the ACUTE Center for Eating Disorders & Severe Malnutrition at Denver Health and continues to serve as its Chief Executive Officer. He began his career at Denver Health more than 30 years ago and was formerly its Chief of Internal Medicine. He was Denver Health's Chief Medical Officer (CMO) for 10 years until he was promoted to its Medical Director, a position he held until his retirement in 2014. He is also the Glassman Professor of Medicine at the University of Colorado School of Medicine and has conducted research into the optimal medical treatment of the most severe cases of Anorexia Nervosa and Bulimia. Dr. Mehler has authored more than 500 scientific publications, including three textbooks published by Johns Hopkins University Press and with a fourth edition slated for release later this year. Dr. Mehler was the recipient of the Academy of Eating Disorders 2012 Outstanding Clinician Award, has been recognized among the “Best Doctors in America” for the past 22 years in a row, and was voted the “Top Internal Medicine physician in Denver” multiple times by 5280 Magazine. Dr. Mehler is a member and fellow of the Eating Disorders Research Society and the Academy of Eating Disorders, as well as a member of the editorial board of the International Journal of Eating Disorders and serves as the Senior Editor of The Journal of Eating Disorders. He has lectured extensively on a national and international level as the leading medical expert on the topic of the medical complications of eating disorders.    Tour of ACUTE    With your host Beth Harrell Follow Beth on Instagram