Intervenciones farmacéuticas en usuarios de benzodiacepinas durante la pandemia COVID-19 / Pharmaceutical interventions in benzodiazepine users during the COVID-19 pandemic

Introducción: la Intervención Farmacéutica busca optimizar y racionalizar el uso, la efectividad y la seguridad de los medicamentos dispensados resolviendo problemas relacionados con el medicamento (PRM) y resultados negativos asociados a la medicación (RNM).Objetivo: evaluar las Intervenciones Farmacéuticas realizadas a usuarios de benzodiacepinas durante la pandemia COVID-19 desde una Farmacia Comunitaria.Método: estudio prospectivo observacional, descriptivo y transversal (código AEMPS: DAA-CLO-2020-01) de las Intervenciones Farmacéuticas llevadas a cabo por una farmacia comunitaria tinerfeña entre agosto 2020 y febrero 2021.Resultados: un total de 306 Intervenciones Farmacéuticas fueron realizadas sobre 127 pacientes. La educación sanitaria y la información personalizada sobre el medicamento fueron las Intervenciones Farmacéuticas mayoritarias tras detectar entre los pacientes un alto grado de desconocimiento sobre las benzodiacepinas usadas. Las Intervenciones Farmacéuticas que se acompañan de derivación al médico alcanzan el 37,8 % tras detectar PRM y/o RNM o identificar al paciente como candidato para deprescripción. Estas derivaciones incluyen a los pacientes con un estado de depresión muy alto según el test Euroqol 5D-3L. La Intervención Farmacéutica con derivación al Servicio de Seguimiento Farmacoterapéutico se realiza en el 3,1 % de los pacientes. El grado de aceptación de la Intervención Farmacéutica por parte de los pacientes alcanza el 98,4 %.Conclusiones: el alto porcentaje de aceptación de las Intervenciones Farmacéuticas refuerza el valor de la Farmacia Comunitaria en la optimización y racionalización del uso de benzodiacepinas y fortalece el vínculo farmacéutico-paciente. La pandemia COVID-19 dificultó la colaboración farmacéutico-médico, a pesar de la existencia de protocolos telemáticos de comunicación entre sanitarios.(AU)

Impact of ABCB1 genetic polymorphism on carbamazepine dose requirement among Southern Indian persons with epilepsy.

OBJECTIVES: Carbamazepine (CBZ) is one of the oldest, yet first line drugs for treating epilepsy. However, there is a large inter-individual difference in requirement of maintenance dose and one third of persons treated with antiepileptic drugs (AEDs) exhibit drug resistance to therapy. One of the proposed mechanisms for the drug resistance was increased expression of efflux transporter P-glycoprotein. The pharmacogenetic studies of drug transporters (ABCB1) done in combination therapies of AEDs were inconclusive. Hence, we have attempted to study the impact of ABCB1 3435C>T genetic polymorphism and CBZ monotherapy in persons with epilepsy (PWE) from South India, which is a genetically distinct population. With this background, this study was aimed to determine the dose of CBZ in ABCB1 3435C>T genotypes and to determine the distribution of ABCB1 3435C>T genotypes (which codes P-glycoprotein) between responders and non-responders to CBZ therapy. METHODS: A cross sectional study was conducted in 200 persons with epilepsy, who were categorised as responders and non-responders according to ILAE (international league against epilepsy) criteria. Eligible participants were enrolled from the epilepsy clinic of the neurology department and five ml of blood was collected. DNA extraction and genotyping were done by phenol-chloroform method and real time polymerase chain reaction (RT-PCR), respectively. RESULTS: The mean maintenance dose of carbamazepine was statistically significant among different genotypes (p<0.05) of ABCB1 3435C>T (526 vs. 637 mg/day in CC vs. TT genotype). There was no significant association between ABCB1 3435C>T polymorphism (p=0.827) and CBZ resistance in PWE. Duration of disease and age of onset were found to be significant in predicting the response to CBZ therapy. CONCLUSIONS: We report that ABCB1 3435C>T polymorphism is significantly associated with an increase in dose requirement of CBZ in persons with epilepsy from South India.

Benzodiazepine Dose Intensity among Patients Concurrently Prescribed Buprenorphine in Rhode Island.

Background: The concomitant use of buprenorphine and benzodiazepines has been linked to patient fatalities, with greater risk occurring with higher doses of benzodiazepines. We assessed benzodiazepine dose intensity among patients who were concurrently prescribed buprenorphine, as compared with patients prescribed benzodiazepines who were not receiving buprenorphine. Methods: We conducted a cross-sectional analysis of adult patients who received at least a 30-day supply of benzodiazepines during 2018, using data from the Rhode Island (RI) Prescription Drug Monitoring Program. Mean daily diazepam milligram equivalents (DME) were calculated overall and according to patient sex, age group, payment type, and RI county. Multivariable logistic regression analyses were conducted to assess the odds of higher-dose benzodiazepine utilization among patients with concurrent use of buprenorphine, as compared with patients not prescribed buprenorphine, adjusting for patient demographics. Results: Compared to patients prescribed benzodiazepines who were not receiving buprenorphine, those with concurrent buprenorphine utilization had a significantly higher mean DME/day (19.22, 95% CI: 18.70-19.74; vs 10.94, 95% CI: 10.93-10.95; p < 0.001). Patients who were prescribed benzodiazepines with concurrent utilization of buprenorphine also had a comparatively higher odds of a DME/day ≥15 (aOR: 2.86, 95% CI: 2.63-3.10), ≥20 DME/day (aOR: 2.98, 95% CI: 2.75-3.24), and ≥25 DME/day (aOR: 2.99, 95% CI: 2.65-3.18). Conclusion: Compared to patients prescribed benzodiazepines for at least 30 days who were not receiving buprenorphine, patients concurrently utilizing benzodiazepines and buprenorphine had more than twice the odds of higher dose benzodiazepine utilization. Future studies are needed to assess the relationship between benzodiazepine dose intensity, overdose outcomes, and treatment retention among patients receiving buprenorphine.

Racial Inequality in Receipt of Medications for Opioid Use Disorder.

BACKGROUND: Since 2010, Black persons in the United States have had a greater increase in opioid overdose-related mortality than other groups, but national-level evidence characterizing racial and ethnic disparities in the use of medications for opioid use disorder (OUD) is limited. METHODS: We used Medicare claims data from the 2016-2019 period for a random 40% sample of fee-for-service beneficiaries who were Black, Hispanic, or White; were eligible for Medicare owing to disability; and had an index event related to OUD (nonfatal overdose treated in an emergency department or inpatient setting, hospitalization with injection drug use-related infection, or inpatient or residential rehabilitation or detoxification care). We measured the receipt of medications to treat OUD (buprenorphine, naltrexone, and naloxone), the receipt of high-risk medications (opioid analgesics and benzodiazepines), and health care utilization, all in the 180 days after the index event. We estimated differences in outcomes according to race and ethnic group with adjustment for beneficiary age, sex, index event, count of chronic coexisting conditions, and state of residence. RESULTS: We identified 25,904 OUD-related index events among 23,370 beneficiaries, with 3937 events (15.2%) occurring among Black patients, 2105 (8.1%) among Hispanic patients, and 19,862 (76.7%) among White patients. In the 180 days after the index event, patients received buprenorphine after 12.7% of events among Black patients, after 18.7% of those among Hispanic patients, and after 23.3% of those among White patients; patients received naloxone after 14.4%, 20.7%, and 22.9%, respectively; and patients received benzodiazepines after 23.4%, 29.6%, and 37.1%, respectively. Racial differences in the receipt of medications to treat OUD did not change appreciably from 2016 to 2019 (buprenorphine receipt: after 9.1% of index events among Black patients vs. 21.6% of those among White patients in 2016, and after 14.1% vs. 25.5% in 2019). In all study groups, patients had multiple ambulatory visits in the 180 days after the index event (mean number of visits, 6.6 after events among Black patients, 6.7 after events among Hispanic patients, and 7.6 after events among White patients). CONCLUSIONS: Racial and ethnic differences in the receipt of medications to treat OUD after an index event related to this disorder among patients with disability were substantial and did not change over time. The high incidence of ambulatory visits in all groups showed that disparities persisted despite frequent health care contact. (Funded by the National Institute on Drug Abuse and the National Institute on Aging.).

Sedative use and incidence of falls and hip fractures among older adults in an outpatient geriatric clinic / Perfil de uso de sedativos e ocorrência de quedas e fratura de fêmur entre idosos em um ambulatório de geriatria

OBJECTIVE: To investigate the use of sedatives by older adults attending a private outpatient geriatric clinic in Belo Horizonte (MG), Brazil, and its association with falls and hip fractures. METHODS: Using a longitudinal design, the prevalence of benzodiazepine and nonbenzodiazepine ("z-drugs") intake by older adults was described and their association with the incidence of falls and fractures (30 days after the initial visit) was evaluated through logistic regression. RESULTS: A total of 7821 older adults were included in the study, most of them women (72.50%), with a mean age of 77.5 years and a mean Clinical-Functional Vulnerability Index (IVCF-20) score of 16.5. The overall prevalence of sedative use (any sedative) was 6.19%, with 4.48% benzodiazepines and 1.98% z-drugs. The most widely used sedatives were clonazepam (29.04%), zolpidem (28.65%), and alprazolam (23.44%). Falls were reported for 182 patients (2.33%), with a higher incidence among users of any sedatives (4.34; p = 0.002; OR = 1.94, adjusted for sex, age, and IVCF-20) and benzodiazepines (5.14%; p < 0.001; OR = 2.28) than among non-users (2.19%). Hip fractures occurred in 33 patients (0.42%), and again were more frequent among users of sedatives (1.03%; p = 0.032; OR = 2.57) and benzodiazepines (1.43%; p = 0.003; OR = 3.45) than among non-users (0.38%). CONCLUSIONS: The use of sedatives, especially benzodiazepines, is associated with an increased incidence of falls and hip fractures in older adults

OBJETIVO: Investigar a utilização de sedativos entre idosos atendidos em ambulatório privado de geriatria em Belo Horizonte (MG), bem como sua associação com quedas e fraturas de fêmur. METODOLOGIA: Trata-se de estudo longitudinal, no qual foi descrita a prevalência de uso de benzodiazepínicos e drogas Z entre idosos (60 anos ou mais) e avaliada sua associação com a incidência de queda e fratura (30 dias após consulta inicial) por meio de regressão logística. RESULTADOS: Foram incluídos no estudo 7821 idosos, com maioria feminina (72,50%), idade média de 77,5 anos e Índice de Vulnerabilidade Clínico Funcional (IVCF-20) médio de 16,5 pontos. A prevalência de uso de sedativos em geral foi de 6,19%, sendo 4,48% de benzodiazepínicos e 1,98% de drogas Z. Os medicamentos sedativos mais utilizados foram clonazepam (29,04%), zolpidem (28,65%) e alprazolam (23,44%). Relatou-se queda para 182 idosos (2,33%), com incidência maior entre usuários de sedativos (4,34; p = 0,002; OR = 1,94 ajustada por sexo, idade e IVCF-20) e de benzodiazepínicos (5,14%; p < 0,001; OR = 2,28) do que entre não usuários (2,19%). Identificou-se fratura de fêmur em 33 idosos (0,42%), sendo mais frequente entre usuários de sedativos (1,03%; p = 0,032; OR = 2,57) e de benzodiazepínicos (1,43%; p = 0,003; OR = 3,45) do que entre não usuários (0,38%). CONCLUSÃO: Concluiu-se que a incidência de quedas e fraturas de fêmur em idosos possui associação com o uso de medicamentos sedativos, em especial os benzodiazepínicos

A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept.

INTRODUCTION: Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABAA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABAA receptor antagonist, may be a useful agent to allow for rapid detoxification. AIM: To collect pilot data on the safety and efficacy of low-dose subcutaneous flumazenil to reduce BZD use, withdrawal symptoms, and craving in participants taking above and below the therapeutic maximum diazepam equivalent of 30 mg to inform on sample size for future trials. METHOD: In a randomised double-blinded crossover study design, participants received low-dose flumazenil first (4 mg/24 h for approximately eight days) or placebo first. Groups were divided into those taking < 30 mg diazepam equivalent and ≥ 30 mg diazepam equivalent at baseline. Main outcome measures were percentage reduction in daily diazepam use, withdrawal symptoms, and craving scores from baseline, difference in diazepam use across the placebo first group, and flumazenil related adverse events. RESULTS: Twenty-eight participants were recruited and randomised to flumazenil first (n = 14) and placebo first (n = 14). In participants taking ≥ 30 mg diazepam equivalent at baseline (n = 15), flumazenil significantly reduced diazepam use by 30.5% (p = 0.024) compared to placebo. CONCLUSION: Low-dose flumazenil may aid in BZD detoxification in participants taking daily diazepam equivalent doses greater than or equal to the therapeutic maximum (≥30 mg) by reducing the need for diazepam.

Segundo estudio de consumo de benzodiazepinas en una población uruguaya (2014-2018): el problema avanza / Second study on the use of benzodiazepines in a Uruguayan population (2014-2018): the problem advances / Segundo estudo de consumo de benzodiazepínicos em uma população uruguaia (2014-2018): o problema avança

Resumen: Introducción: las benzodiazepinas (BZD) constituyen uno de los grupos farmacológicos más prescritos. La forma de uso y el riesgo de aumento de efectos adversos evitables a partir del amplio uso, pueden representar en sí mismos problemas de salud pública. Objetivos: conocer el consumo de BZD en una población uruguaya en el período 2014-2018. Métodos: se realizó un estudio de utilización de medicamentos para evaluar el consumo de BZD por vía oral, a través del dato de dispensación de farmacias de instituciones de salud, mediante la variable DHD (dosis diaria definida/1.000 habitantes/día). Resultados: participaron siete instituciones, representando el 65% de la población uruguaya. Las DHD globales fueron 116,05, 114,36, 117,32, 131,17 y 124,4 DHD para los años 2014, 2015, 2016, 2017 y 2018 respectivamente, con un aumento de 7% en el período. Conclusiones: el consumo de BZD a nivel nacional entre 2014 y 2018 persiste elevado y superior al estudio previo realizado entre 2010 y 2012. Comparado con otros países, los valores para Uruguay se encuentran entre los más altos. Es necesario que todos los actores relevantes de la cadena del medicamento desarrollen estrategias para controlar la situación.

Summary: Introduction: benzodiazepines (BZD) constitute one of the most widely prescribed pharmacological groups. The use modality and the risk of increase of avoidable adverse effects resulting from wide consumption may represent a public health problem in itself. Objectives: to learn about the use of benzodiazepine in a Uruguayan population between 2014 and 2018. Method: a study was conducted on the use of medications to evaluate BZD consumption administered orally, by consulting dispensing of pharmacies in the health institutions, through the DHD variable (daily human doses/1.000 inhabitants/day). Results: 7 institutions participated in the study, representing 65% of the Uruguayan population. Global DHD were 116.05, 114.36, 117.32, 131.17 and 124.4 for 2014, 2015, 2016, 2017 and 2018 respectively, with a 7% increase in the period of study. Conclusions: the use of benzodiazepines was still high at the national level between 2014 and 2018 and greater than the figure found in the previous study, conducted between 2010 and 2012. Compared to other countries, Uruguayan figures are among the highest. All relevant actors in the drug chain need to develop strategies to control the situation.

Resumo: Introdução: os benzodiazepínicos (BZD) constituem um dos grupos farmacológicos mais prescritos. A forma de uso e o risco de aumento dos efeitos adversos evitáveis pelo uso extensivo podem representar, por si só, problemas de saúde pública. Objetivos: conhecer o consumo de BZD em uma população uruguaia no período 2014-2018. Métodos: foi realizado um estudo de uso de medicamentos para avaliar o consumo de BZD por via oral, utilizando dados da dispensação em farmácias de instituições de saúde, utilizando a variável DHD (dose diária definida/1000 habitantes/dia). Resultados: dados de sete instituições foram estudados, representando 65% da população uruguaia. Os DHDs globais foram 116,05, 114,36, 117,32, 131,17 e 124,4 DHDs para os anos de 2014, 2015, 2016, 2017 e 2018 respectivamente, com aumento de 7% no período. Conclusões: o consumo de BZD em nível nacional entre 2014 e 2018 continua alto e é superior aos resultados de um estudo anterior realizado entre 2010 e 2012. Quando comparados com outros países, os valores para o Uruguai estão entre os mais altos. É necessário que todos os atores relevantes da cadeia de medicamentos desenvolvam estratégias para controlar a situação.

Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial.

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

Outcomes After Implementation of a Benzodiazepine-Sparing Alcohol Withdrawal Order Set in an Integrated Health Care System.

Importance: Alcohol withdrawal syndrome (AWS) is a common inpatient diagnosis managed primarily with benzodiazepines. Concerns about the adverse effects associated with benzodiazepines have spurred interest in using benzodiazepine-sparing treatments. Objective: To evaluate changes in outcomes after implementation of a benzodiazepine-sparing AWS inpatient order set that included adjunctive therapies (eg, gabapentin, valproic acid, clonidine, and dexmedetomidine). Design, Setting, and Participants: This difference-in-differences quality improvement study was conducted among 22 899 AWS adult hospitalizations from October 1, 2014, to September 30, 2019, in the Kaiser Permanente Northern California integrated health care delivery system. Data were analyzed from September 2020 through November 2021. Exposures: Implementation of the benzodiazepine-sparing AWS order set on October 1, 2018. Main Outcomes and Measures: Adjusted rate ratios for medication use, inpatient mortality, length of stay, intensive care unit admission, and nonelective readmission within 30 days were calculated comparing postimplementation and preimplementation periods among hospitals with and without order set use. Results: Among 904 540 hospitalizations in the integrated health care delivery system during the study period, AWS was present in 22 899 hospitalizations (2.5%), occurring among 16 323 unique patients (mean [SD] age, 57.1 [14.8] years; 15 764 [68.8%] men). Of these hospitalizations, 12 889 (56.3%) used an order set for alcohol withdrawal. Among hospitalizations with order set use, any benzodiazepine use decreased after implementation from 6431 hospitalizations (78.1%) to 2823 hospitalizations (60.7%) (P < .001), with concomitant decreases in the mean (SD) total dosage of lorazepam before vs after implementation (19.7 [38.3] mg vs 6.0 [9.1] mg; P < .001). There were also significant changes from before to after implementation in the use of adjunctive medications, including gabapentin (2413 hospitalizations [29.3%] vs 2814 hospitalizations [60.5%]; P < .001), clonidine (1476 hospitalizations [17.9%] vs 2208 hospitalizations [47.5%]; P < .001), thiamine (6298 hospitalizations [76.5%] vs 4047 hospitalizations [87.0%]; P < .001), valproic acid (109 hospitalizations [1.3%] vs 256 hospitalizations [5.5%]; P < .001), and phenobarbital (412 hospitalizations [5.0%] vs 292 hospitalizations [6.3%]; P = .003). Compared with AWS hospitalizations without order set use, use of the benzodiazepine-sparing order set was associated with decreases in intensive care unit use (adjusted rate ratio [ARR], 0.71; 95% CI, 0.56-0.89; P = .003) and hospital length of stay (ARR, 0.71; 95% CI, 0.58-0.86; P < .001). Conclusions and Relevance: This study found that implementation of a benzodiazepine-sparing AWS order set was associated with decreased use of benzodiazepines and favorable trends in outcomes. These findings suggest that further prospective research is needed to identify the most effective treatments regimens for patients hospitalized with alcohol withdrawal.

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 µM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.

Application of a diazepam milligram equivalency algorithm to assess benzodiazepine dose intensity in Rhode Island in 2018.

BACKGROUND: Benzodiazepines are indicated for the treatment of many conditions, such as anxiety disorders, muscle spasms, alcohol withdrawal, agitation, movement disorders, and epilepsy, and are one of the most frequently prescribed medication classes. This class of medication has important safety considerations, including an increased risk of dependence and addiction, falls, and death from opioid overdose. Although benzodiazepine safety and prescribing encompasses a rich and important research area, there is a lack of pharmacoepidemiologic literature addressing benzodiazepine dosing intensity in real-world settings. OBJECTIVE: To develop and apply a standardized benzodiazepine milligram equivalency conversion algorithm and assess the dose intensity of benzodiazepine use in Rhode Island (RI) in 2018. METHODS: A systematic literature review was conducted to identify the most commonly used benzodiazepine equivalency values. We then conducted a cross-sectional analysis of 2018 data from the RI Prescription Drug Monitoring Program (PDMP) to calculate the mean daily diazepam milligram equivalency (DME) based on a patient's most recent dispensing. A multivariable logistic regression analysis was conducted to determine the association between higher benzodiazepine doses (≥ 15 DME/day) and recipient characteristics, including concurrent use of opioids or stimulants. RESULTS: We identified 143,026 patients who received at least 1 prescription for a benzodiazepine in RI in 2018. The mean (SD) daily DME was 10.60 (9.05), and 26.2% of individuals had a mean DME per day of at least 15. Approximately 14% (n = 20,168) of patients prescribed a benzodiazepine had concurrent use with a prescription opioid, and 6.7% (n = 9,547) had concurrent use with a prescription stimulant. Females had a 28% lower adjusted odds of receiving a benzodiazepine dose of at least 15 DME per day compared with males (adjusted odds ratio [aOR] = 0.72, 95% CI = 0.70-0.73). The adjusted odds of receiving a benzodiazepine prescription of at least 15 DME per day was lower among the younger (aged 18-34 years) and older age groups (aged 65 years and older) compared with patients aged 35-64 years. Compared with commercial insurance, all other forms of payment had significantly higher adjusted odds of a daily benzodiazepine dose of at least 15 DME per day. The adjusted odds receiving a daily DME of at least 15 was 67% higher among those who also received a concurrent pharmacy dispensing for an opioid and 84% higher among those who also received a concurrent dispensing for a stimulant drug (aOR = 1.67, 95% CI = 1.61-1.72; aOR = 1.84, 95% CI = 1.76-1.93, respectively). CONCLUSIONS: Individuals aged 35-64 years with Medicaid insurance and those aged under 65 years with Medicare were more likely to be prescribed a benzodiazepine of at least 15 DME per day. Higher benzodiazepine DMEs were also dispensed to patients who concurrently used prescription opioids or stimulants who may be at increased risk of medication-related harm. We advocate for routine measurement of benzodiazepine dose intensity as a risk reduction strategy. DISCLOSURES: No funding supported this study. The authors have no conflicts of interest to disclose. The content and results of this study are solely the responsibility of the authors and do not necessarily represent the official views of the Rhode Island Department of Health. Kogut is partially supported by Institutional Development Award Numbers U54GM115677 and P20GM125507 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds Advance Clinical and Translational Research (Advance-CTR) and the RI Lifespan Center of Biomedical Research Excellence (COBRE) on Opioids and Overdose, respectively. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Contents of this study were presented as a poster presentation at AMCP 2019 Nexus; October 29-November 1, 2019; National Harbor, MD.

Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study.

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

Trends and variation in benzodiazepine use in nursing homes in the USA.

PURPOSE: Because of toxicities, benzodiazepines are not usually recommended in older adults. We therefore sought to describe the trends in benzodiazepine use in long-term care and examine the variation in benzodiazepine use among nursing homes. METHODS: In this retrospective repeated cross-sectional analysis of Medicare Parts A, B, and D claims data linked to the Minimum Data Set from 2013 to 2018, we included long-term residents who stayed in a nursing home for at least one entire quarter of a calendar year in 2013-2018. The outcome was whether residents were prescribed a benzodiazepine drug for at least 30 days during each quarter stay. We use mixed effects logistic regression models to assess the variation in benzodiazepine use among nursing homes, adjusting for patient and nursing home characteristics. RESULTS: The cohort for the time trend analysis included 270,566 unique residents and 1,843,580 quarter stays for 2013-2018. Prescribing rates for short-acting benzodiazepines were stable over 2013-2016, then declined from 12.1% in 2016 to 10.6% in 2018. The rate of long-acting benzodiazepine use remained relatively steady at around 4% over 2013-2018. During 2017-2018, the variation among nursing homes in benzodiazepine use was 7.2% for short-acting vs. 9.3% for long-acting benzodiazepines, after controlling for resident characteristics. CONCLUSION: Prescribing for short-acting benzodiazepines in long-term care declined after 2016, while long-acting benzodiazepine use did not change. The variation in benzodiazepine use among nursing homes is substantial. Identifying factors that explain this variation may help in developing strategies for deprescribing benzodiazepines in nursing home residents.

Optimized Benzodiazepine Treatment of Pediatric Status Epilepticus Through a Standardized Emergency Medical Services Resuscitation Tool.

BACKGROUND: Optimized benzodiazepine (BZD) dosing decreases morbidity and mortality in children with status epilepticus (SE), but previous studies have documented widespread underdosing. Prior interventions have focused on in-hospital SE treatment, although more than 75% of pediatric patients with SE are initially treated by emergency medical services (EMS). Our goal was to assess whether an EMS-focused, collaboratively developed dosing resuscitation aid (Medic One Pediatric [MOPed] cards) and training could improve BZD dosing and pediatric SE outcomes. METHODS: We conducted a retrospective review of patients aged 12 years and younger treated by EMS for SE and transferred to Seattle Children's Hospital during the 1 year before and immediately after MOPed card training. The primary outcome was the percentage of patients receiving underdosed BZD treatment. Secondary outcomes included time to second-line antiseizure medication (ASM), intubation, and intensive care unit (ICU) admission. RESULTS: The 44 children before and 33 after MOPed implementation were similar with respect to age, gender, and pre-existing epilepsy diagnosis. The percentage of children receiving underdosed BZDs fell from 52% to 6% after MOPed implementation (P < 0.001). There was no significant decrease in requirement for intubation and ICU admission. The interval to treatment with a second-line ASM remained prolonged. CONCLUSIONS: EMS-focused training significantly increased the percentage of outpatient pediatric patients with SE who received recommended initial BZD treatment. This improvement in management of SE did not significantly alter the rate of intubation or ICU admission, suggesting the need for further optimization of out-of-hospital SE care, particularly access to and timely use of second-line ASMs.

Automated multi-dose dispensing in persons with and without Alzheimer's disease-impacts on pharmacotherapy.

PURPOSE: We investigated the drug use before and after transition to automated multi-dose dispensing (MDD) service among persons with Alzheimer's disease (AD) and compared whether the changes were similar in persons without AD. METHODS: The register-based Finnish nationwide MEDALZ cohort includes 70,718 community-dwelling persons diagnosed with AD during 2005-2011. Each person who initiated MDD was matched in both groups with a comparison person without MDD by age, gender and for persons with AD, also time since AD diagnosis at the start of MDD. The study cohort included 15,604 persons with AD in MDD and 15,604 no-MDD, and 5224 persons without AD in MDD and 5224 no-MDD. Point prevalence of drug use was assessed every 3 months, from 1 year before to 2 years after the start of MDD and compared between persons in MDD to those who did not have MDD. RESULTS: MDD was started on average 2.9 (SD 2.1) years after AD diagnosis. At the start of MDD, the prevalence of drug use increased especially for antipsychotics, antidepressants, opioids, paracetamol and use of ≥ 10 drugs among persons with and without AD. Prevalence of benzodiazepine use (from 12% 12 months before to 17% at start of MDD), memantine (from 29 to 46%) and ≥ 3 psychotropics (from 3.2 to 6.0%) increased among persons with AD. Decreasing trend was observed for benzodiazepine-related drugs, urinary antispasmodics and non-steroidal anti-inflammatory drugs. CONCLUSION: MDD seems to be initiated when use of psychotropics is initiated and the number of drugs increases.

Evidence on sociodemographic and clinical correlates of antidepressant combination or augmentation with second-generation antipsychotics in major depressive disorder.

About two thirds of the patients with major depressive disorder (MDD) do not sufficiently respond to monotherapy with antidepressants (ADs) which makes them reliant on further treatment approaches. Hereby, combination of different ADs and augmentation with second-generation antipsychotics (SGAs) are widely used and recommended psychopharmacotherapeutic strategies. The present secondary analyses are based on an international, naturalistic, cross-sectional multicenter study conducted by the European Group for the Study of Resistant Depression. Comparing socio-demographic and clinical characteristics of 436 adult MDD patients receiving either SGAs (N = 191, 43.8%) or ADs (N = 245, 56.2%), that were additionally administered to their first-line AD psychopharmacotherapy, we aimed to identify possible trajectories of decision-making for clinicians regarding which treatment option to prefer in individual patients. Our most robust findings represent an association of SGA augmentation with the presence of psychotic symptoms, longer mean duration of lifetime psychiatric hospitalizations, employment of further augmentation strategies with mood-stabilizers and benzodiazepines, and a trend towards higher mean daily dosages of their first-line ADs and current suicidal risk. Treatment outcome was not significantly different between patients receiving either SGA augmentation or AD combination. Being aware of limitations inherent to the cross-sectional study design and the lack of randomization, more severe and rather chronic conditions in MDD seemed to encourage clinicians to choose SGA augmentation over AD combination. The fact that mood-stabilizers and/or benzodiazepines were more frequently co-administered with SGAs may represent a requirement of an overall refined psychopharmacotherapy including additional fast-acting agents with potent AD, tranquilizing and anti-suicidal effects in MDD patients experiencing challenging clinical manifestations. New glutamatergic substances seem to be promising in this regard.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.