Drug-Drug Interaction Between Cannabidiol, Cyclosporine, and Mycophenolate Mofetil: A Case Report.

Kidney transplantation remains the optimal therapy for many patients with end-stage kidney disease (ESKD). Chronic pain is one of the most common and distressing symptoms among patients with ESKD, and its treatment is a complex and challenging task to accomplish. The benefits of cannabidiol (CBD) in chronic pain treatment have been reported recently. Cannabidiol is metabolized by cytochrome P450, mainly CYP3A4 and CYP2C19, and can also undergo direct conjugation via UDP-glucuronosyltransferase enzymes, with a growing body of evidence suggesting it is also a potent inhibitor or inducer of these pathways. Cannabidiol was also found to be a potent inhibitor of carboxylesterases in vitro. Because cytochrome P450 enzymes and carboxylesterases are also responsible for the clearance and activation of immunosuppressants, respectively, drug-drug interactions are likely to occur. Here, we report a pharmacokinetic drug interaction between CBD and cyclosporine and mycophenolate mofetil in a patient with ESKD with a kidney transplantation. It is thus crucial to take into account these interactions and monitor drug levels to avoid drug toxicity or a lack of efficacy. This study is in accordance with the guidelines of the Declaration of Helsinki and the Declaration of Istanbul.

Human Data on Pharmacokinetic Interactions of Cannabinoids: A Narrative Review.

Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications. A search on Pubmed/Medline, Google Scholar, and Cochrane Library was performed. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. All original research papers discussing interactions between cannabinoids, used for medical or recreational/adult-use purposes, and other medications in humans were included. Thirty-two studies with medicinal or recreational/adult-use cannabis were identified (seventeen case reports/series, thirteen clinical trials, and two retrospective analyses). In three of these studies, a bidirectional pharmacokinetic drug-drug interaction was reported. In the rest of the studies, cannabinoids were the perpetrators, as in most of them, concentrations of cannabinoids were not measured. In light of the widespread use of prescribed and non-prescribed cannabinoids with other medications, pharmacokinetic interactions are likely to occur. Physicians should be aware of these potential interactions and closely monitor drug levels and/or responses. The existing literature regarding pharmacokinetic interactions is limited, and for some drugs, studies have relatively small cohorts or are only case reports. Therefore, there is a need for high-quality pharmacological studies on cannabinoid-drug interactions.

Neuroprotective Effect of a Pharmaceutical Extract of Cannabis with High Content on CBD Against Rotenone in Primary Cerebellar Granule Cell Cultures and the Relevance of Formulations.

Introduction: Preclinical research supports the benefits of pharmaceutical cannabis-based extracts for treating different medical conditions (e.g., epilepsy); however, their neuroprotective potential has not been widely investigated. Materials and Methods: Using primary cultures of cerebellar granule cells, we evaluated the neuroprotective activity of Epifractan (EPI), a cannabis-based medicinal extract containing a high level of cannabidiol (CBD), components like terpenoids and flavonoids, trace levels of Δ9-tetrahydrocannabinol, and the acid form of CBD. We determined the ability of EPI to counteract the rotenone-induced neurotoxicity by analyzing cell viability and morphology of neurons and astrocytes by immunocytochemical assays. The effect of EPI was compared with XALEX, a plant-derived and highly purified CBD formulation (XAL), and pure CBD crystals (CBD). Results: The results revealed that EPI induced a significant reduction in the rotenone-induced neurotoxicity in a wide range of concentrations without causing neurotoxicity per se. EPI showed a similar effect to XAL suggesting that no additive or synergistic interactions between individual substances present in EPI occurred. In contrast, CBD did show a different profile to EPI and XAL because a neurotoxic effect per se was observed at higher concentrations assayed. Medium-chain triglyceride oil used in EPI formulation could explain this difference. Conclusion: Our data support a neuroprotective effect of EPI that may provide neuroprotection in different neurodegenerative processes. The results highlight the role of CBD as the active component of EPI but also support the need for an appropriate formulation to dilute pharmaceutical cannabis-based products that could be critical to avoid neurotoxicity at very high doses.

Hospitalizaciones por reacciones adversas a medicamentos y abandono del tratamiento farmacológico en el hospital universitario / Hospitalization due to adverse drug reaction and discontinuation of drug treatment at the Clinicas Hospital (Teaching Hospital)

Introducción: a nivel mundial las enfermedades causadas por medicamentos constituyen unproblema de salud pública. En Uruguay se desconoce la magnitud de este problema. Objetivo: estimar la frecuencia y describir las características de las hospitalizaciones por reacciones adversas a medicamentos (RAM) y abandono del tratamiento farmacológico (ATF) en el Hospital de Clínicas.Material y método: se incluyeron pacientes hospitalizados por sospecha de RAM y ATF en el Hospital de Clínicas entre el 1° de diciembre de 2006 y el 15 de mayo de 2007. Se realizómuestreo aleatorio simple en forma bisemanal durante 30 días. Se analizó edad, sexo, fármacos implicados, enfermedad ocasionada, duración de la estadía hospitalaria y evolución.Resultados: la frecuencia de hospitalizaciones por RAM y ATF fue 4,3 (IC 95, 2,8-5,3). La edad promedio fue 57 años. Las RAM fueron causadas por antibióticos (n=4), antineoplásicos e inmunomoduladores (n=3), fármacos cardiovasculares (n=2), anticoagulantes (n=1),antitiroideos (n=1), antiinflamatorios no esteroideos (AINE) (n=1) y antiandrógenos (n=1). Presentaron riesgo vital 5/13 pacientes con RAM. La causa de ATF fue: RAM (n=2), falta decomprensión de las indicaciones o desconocimiento de la importancia del tratamiento, o ambos (n=8), razones económicas (n=3), desconocidas (n=5). Presentaron riesgo vital 4/18 con ATF; uno falleció. Conclusión: estos constituyen los primeros datos nacionales de hospitalización por RAM yATF en el subsector público de salud. Para evaluar la magnitud real del problema es necesario prolongar la observación e incluir otros centros asistenciales. Se destaca su impacto en términos de gravedad y prolongación de la estadía hospitalaria.

Introduction: globally, drug-caused diseases are a public health issue. In Uruguay, the importance of this topic isunknown. Objective: to describe the characteristics of hospitalizationdue to adverse drug reaction (ADR) and discontinuation of drug treatment at the Clinicas Hospital, and to estimate its frequency. Methods: patients hospitalized at the Clinicas Hospitalbetween 1 December 2006 and 15 May, 2007, due to suspect of ADR and discontinuation of drug treatmentwere included in the study. We conducted a simple randomizedsampling twice a week, for 30 days. We analyzed age, sex, drugs implied, disease causes, duration of hospitalization and evolution.Results: frequency of hospitalization due to ADR and discontinuation of drug treatment was 4.3 (Confidenceinterval was 95, 2.8-5.3) Average age was 57 years old. The ADR were caused by antibiotics (n=4 ), antineoplastic agents andimmunemodulators n=3),cardiovascular drugs (n=2), anticoagulants(n=1), Antithyroid drugs (ATDs) (n=1), Nonsteroidal anti-inflammatory drugs NSAIDs (n=1) and antiandrogens (n=1).Five out of 13 patients with ADR were in life risk. The main cause for discontinuation of drug treatment was: ADR (n=2), failure to understand indications or not knowing the importance of treatment, or both (n=8), economic reasons (n=3), unknown (n=5). Four out of 18 patients whohad discontinued drug treatment were in like risk, and one of them died.Conclusions: information collected in this study constitutes the first data about hospitalization due to adversedrug reaction and discontinuation of drug treatment at national level, in the public health sub sector. In order tofully assess the importance of the problem we need to expand observation and include other self-care providingcenters. We stress the importance of the issue due to its seriousness and the fact that it prolongs hospital stay.

Introdução: as patologias causadas por medicamentos são um problema de saúde pública em todo o mundo. Nãose conhece a magnitude deste problema no Uruguai. Objetivo: estimar a freqüência e descrever as característicasdas hospitalizações por reações adversas a medicamentos (RAM) e abandono de tratamento farmacológico(ATF) no Hospital das Clínicas.Material e método: foram incluídos todos os pacientes hospitalizados por suspeita de RAM e ATF no Hospital das Clínicas no período 1° de dezembro de 2006-15 de março de 2007. Fez-se uma amostragem aleatória simples bi semanal durante 30 dias. Foram analisados sexo, idade, fármacos implicados, patologias causadas, duração do período de hospitalização e evolução. Resultados: a freqüência de hospitalização por RAM e ATF foi de 4,3 (IC 95, 2,8-5,3). A idade média foi de 56 anos. As RAM foram causadas por antibióticos (n=4), anti-neoplásicos e imunomoduladores (n=3), fármacoscardiovasculares (n=2), anticoagulantes (n=1), antitiróideos (n=1), antiinflamatórios não esteróides (AINE) (n=1) e antiandrogenios (n=1). Apresentaram risco de vida 5/13pacientes com RAM. As causas de ATF foram: RAM (n=2); falta de compreensão das indicações ou desconhecimento da importância do tratamento, ou ambos (n=8), razõeseconômicas (n=3), desconhecidas (n=5). Por ATF 4/18 pacientes apresentaram risco de vida; um faleceu.Conclusões: estes são os primeiros dados nacionais de hospitalização por RAM e ATF no subsetor público desaúde. Para conhecer a magnitude real do problema é necessário realizar uma observação mais prolongada e incluiroutros centros de assistência. É importante destacar o impacto sobre a gravidade e sobre o aumento do períodode hospitalização.

Dislipemia y lipodistrofia en niños uruguayos VIH positivos en tratamiento antirretroviral / Dyslipidemia and lipodistrophy in HIV Uruguayan children under anti-retroviral therapy (HAART)

La sobrevida de los pacientes infectados por el virus de la inmunodeficiencia humana (VIH) ha mejorado con el tratamiento antirretroviral de alta eficacia. Nuevos problemas han surgido, como la aparición de efectos adversos.El objetivo del siguiente trabajo fue describir la prevalencia de lipodistrofia y dislipemia en niños infectados tratados y determinar si el estadio de la enfermedad y la duración del tratamiento se asocian con estas alteraciones.Material y método: estudio descriptivo de corte transversal. Se definió lipoatrofia al niño con índice de masa corporal (IMC) normal y pliegue tricipital <5percentil (p) o mejillas hundidas, o ambos; lipohipertrofia al IMC normal y pliegue subescapular >90p o grasa de disposición central, o ambos; lipodistrofia combinada, la que incluye ambos tipos. Se definieron hipertrigliceridemia e hipercolesterolemia a los valores >90p según tablas de referencia. Se clasificó la duración del tratamiento en menor e igual a cinco años y el estadio de la enfermedad. Los resultados se expresaron como porcentajes con sus intervalos de confianza de 95 p/ ciento. Se utilizó el test de c2.Resultados: se incluyeron 60 niños con una edad media de 6,8 años ± 3,3. Trece presentaron lipodistrofia (21,7p/ciento, IC95p/ciento,12,5-34,5) y 33 dislipemia (55 p/ciento, IC95 p/ciento, 41,7-67,7). Ni la dislipemia ni la lipodistrofia se asociaron al estadio de la enfermedad. La dislipemia mixta predominó en los niños con cinco años o más de tratamiento a diferencia de la hipertrigliceridemia. La lipodistrofia no se asoció a la duración del tratamiento.Conclusiones: la lipodistrofia y la dislipemia son alteraciones frecuentes. El monitoreo de los lípidos y de la composición corporal son imprescindibles para lograr niños más saludables.