Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication.

Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC(0-∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.

Comparison of two sedation protocols, with and without analgesia, in pigs: Assessment of sedation end points and propofol requirements.

OBJECTIVE: To compare the effects of intramuscular premedication with a novel nonanalgesic [alfaxalone-midazolam-acepromazine (AMA)] and an analgesic [ketamine-midazolam-detomidine (KMD)] protocol on sedation end points and propofol requirements for induction of anesthesia in swine. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 27 Yorkshire cross gilts weighing approximately 30 kg. METHODS: Two sedation protocols, AMA and KMD, were compared. Time from intramuscular injection to ataxia, recumbency and nonresponsiveness to tactile stimulation was recorded. The propofol dose requirement for induction of general anesthesia and tracheal intubation, and any adverse events (paddling, twitching), were recorded. Data were tested for normality using a Shapiro-Wilk test. Propofol requirements were compared using a Student's t test. Times from injection to sedation end points were compared using a Mood's test, and significance was confirmed using a Kaplan-Meier curve with Wilcoxon test survival analysis. RESULTS: Sedation end points were reached significantly faster with KMD than with AMA. Nonresponsiveness occurred in 5 (0-16) and 9.5 (5-36) minutes for KMD and AMA, respectively (p = 0.011). No significant difference (p = 0.437) was found between propofol doses used in either group (KMD; 64.38 ± 5.98 mg, AMA; 72.00 ± 7.57 mg). More adverse events were noted with AMA (11/16 pigs) than with KMD (1/11 pigs). CONCLUSIONS AND CLINICAL RELEVANCE: In pigs, AMA can be used as a reliable sedation protocol. Frequency of adverse events and time to reach sedation end points between AMA and KMD differed, but the dose of propofol needed to induce general anesthesia was not significantly different.

Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.

Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp. Two clinical studies were conducted to investigate the effect of multiple dose tepotinib (500 mg once daily orally) on the single dose pharmacokinetics of a sensitive CYP3A4 substrate (midazolam 7.5 mg orally) and a P-gp substrate (dabigatran etexilate 75 mg orally) in healthy participants. Tepotinib and MSC2571109A showed little evidence of direct or time-dependent CYP3A4/5 inhibition (IC50 > 15 µM) in vitro, although MSC2571109A did show mechanism-based CYP3A4/5 inhibition. Tepotinib did not induce CYP3A4/5 activity in vitro, although both tepotinib and MSC2571109A increased CYP3A4 mRNA. In clinical studies, tepotinib had no effect on the pharmacokinetics of midazolam or its metabolite 1'-hydroxymidazolam. Tepotinib increased dabigatran maximum concentration and area under the curve extrapolated to infinity by 38% and 51%, respectively. These changes were not considered to be clinically relevant. Tepotinib was considered safe and well tolerated in both studies. The potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the clinical dose is considered low. Study 1 (midazolam): NCT03628339 (registered 14 August 2018). Study 2 (dabigatran): NCT03492437 (registered 10 April 2018).

Assessment of First-line Therapy With Midazolam for Prehospital Seizures in Children.

This cohort study assesses the effectiveness of midazolam treatment in terminating pediatric seizures in the prehospital setting.

Economic benefits of remimazolam compared to midazolam and propofol for procedural sedation in colonoscopies and bronchoscopies.

BACKGROUND: Sedation is common practice in endoscopic procedures to suppress a patient's level of consciousness while maintaining the cardio-respiratory function. Midazolam and propofol are the sedatives most frequently used for procedural sedation at hospitals in Scandinavia. Remimazolam is a new ultra-short-acting benzodiazepine sedative and the present analysis aimed at estimating the economic benefits of introducing remimazolam for procedural sedation in colonoscopies and bronchoscopies in hospitals in Scandinavia. METHOD: We developed a cost model applying a micro-costing approach that comprised the cost components that are affected by differences in the efficacy of remimazolam, midazolam, and propofol, and the model estimated the cost per successful colonoscopy and bronchoscopy when using remimazolam, midazolam or propofol as sedation. A micro-costing approach was applied, and the model consisted of six stages representing the journey for patients undergoing endoscopies and was informed primarily by data from clinical studies on remimazolam. RESULTS: We found a total cost of DKK 1200 per successful colonoscopy procedure when using remimazolam, a total cost of DKK 1320 when using midazolam, and a total cost of DKK 1255 when using propofol. Hence, the incremental saving per successful colonoscopy procedure of using remimazolam was estimated to be DKK 120 compared to midazolam and DKK 55 compared to propofol. The total cost per successful bronchoscopy procedure when using remimazolam was DKK 1353 and DKK 1724 for midazolam, resulting in an incremental saving per bronchoscopy of DKK 372 when using remimazolam. Performed sensitivity analyses identified the time in recovery as the largest contributor to uncertainty in the analyses of remimazolam compared to midazolam in colonoscopies and bronchoscopies. In the comparison of remimazolam and propofol in colonoscopies, procedure time was the largest contributor to uncertainty. CONCLUSION: We found that procedural sedation with remimazolam was associated with economically meaningful savings compared to procedural sedation with midazolam and propofol in colonoscopies and to midazolam in bronchoscopies.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug-drug interactions via CYP3A metabolism and transporters.

Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug-drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P-glycoprotein (P-gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co-administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P-gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two-drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration-time curve (AUC). A weak DDI (AUC increase 48%-50%) was observed for gepotidacin co-administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1-methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P-gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (<2-fold AUC increase). There were no new safety-risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co-administered with other drugs.

Evaluation of maximum dose intravenous midazolam used in dental intravenous sedation: a West of Scotland regional audit.

Background Intravenous (IV) midazolam sedation is commonly used in the delivery of dentistry for phobic patients. There is currently no guidance on a maximum dose for use specifically in dentistry. Dentists practise with the British National Formulary recommended maximum dose of 7.5 mg; however, anecdotally, this is often exceeded. We aim to evaluate prescribing and propose recommendations for a maximum dose for dentists.Method Data was collected from ten dentists across four Scottish health boards regarding their last 20 IV sedation patients, giving a total of 200. Data obtained from standard Dental Sedation Teachers Group IV logbooks included: dose of midazolam administered; justification for doses over 7.5 mg; flumazenil or supplemental oxygen usage; significant medical/social factors; and the Ramsay Sedation Score.Results Mean midazolam dose was 6.1 mg with a range of 14 mg. The recommended maximum dose of 7.5 mg was exceeded in 28% of cases. The mean sedation score was 2.7 and there were no reported adverse events or use of flumazenil.Conclusion IV midazolam is an effective way to achieve conscious sedation in dentistry. Acknowledgement of current off-label prescribing is important; however, 7.5 mg as a recommended maximum dose is too conservative as it is regularly exceeded without adverse events. Further investigation and expert opinion is required to set a maximum dose specifically for dentistry.

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

Cost-Effectiveness of Midazolam Versus Haloperidol Versus Olanzapine for the Management of Acute Agitation in the Accident and Emergency Department.

OBJECTIVES: A multicenter randomized clinical trial in Hong Kong Accident and Emergency (A&E) departments concluded that intramuscular (IM) olanzapine is noninferior to haloperidol and midazolam, in terms of efficacy and safety, for the management of acutely agitated patients in A&E setting. Determining their comparative cost-effectiveness will further provide an economic perspective to inform the choice of sedative in this setting. METHODS: This analysis used data from a randomized clinical trial conducted in Hong Kong A&E departments between December 2014 and September 2019. A within-trial cost-effectiveness analysis comparing the 3 sedatives was conducted, from the A&E perspective and a within-trial time horizon, using a decision-analytic model. Sensitivity analyses were also undertaken. RESULTS: In the base-case analysis, median total management costs associated with IM midazolam, haloperidol, and olanzapine were Hong Kong dollar (HKD) 1958.9 (US dollar [USD] 251.1), HKD 2504.5 (USD 321.1), and HKD 2467.6 (USD 316.4), respectively. Agitation management labor cost was the main cost driver, whereas drug costs contributed the least. Midazolam dominated over haloperidol and olanzapine. Probabilistic sensitivity analyses supported that midazolam remains dominant > 95% of the time and revealed no clear difference in the cost-effectiveness of IM olanzapine versus haloperidol (incremental cost-effectiveness ratio 667.16; 95% confidence interval -770.89, 685.90). CONCLUSIONS: IM midazolam is the dominant cost-effective treatment for the management of acute agitation in the A&E setting. IM olanzapine could be considered as an alternative to IM haloperidol given that there is no clear difference in cost-effectiveness, and their adverse effect profile should be considered when choosing between them.

Uso de sedación endovenosa en pacientes con COVID-19 crítico en ventilación mecánica invasiva / Use of intravenous sedation in patients with critical COVID-19 in invasive mechanical ventilation

ANTECEDENTES: El objetivo del presente informe es: Describir el proceso para la elaboración de recomendaciones por el grupo de trabajo designado por el Ministerio de Salud, en adelante denominado grupo de trabajo. Trasladar las Recomendaciones efectuadas por dicho grupo de trabajo en atención al uso de sedación endovenosa en pacientes con COVID-19 crítico en ventilación mecánica invasiva, según la pregunta PICO (P: Población, I: Intervención, C: Comparador, O: Outcome o desenlaces) priorizada por el grupo de trabajo. La metodología considerada para arribar a la recomendación fue el Marco de Evidencia a la Decisión/Recomendación (EtD) desarrollado por el Grupo de Trabajo GRADE (1,2). ANALISIS: Formulación de la pregunta: En personas con COVID-19 crítico en ventilación mecánica invasiva, ¿cuál es el medicamento que debe administrarse para la sedación endovenosa? Y ¿Cuál pauta de dosificación? Identificación de la evidencia para la pregunta PICO: Se siguieron las orientaciones establecidas en el documento interno de UNAGESP: Orientaciones para el soporte metodológico otorgado al grupo de trabajo designado por el MINSA. Se describe a continuación los resultados del proceso: Se efectuó la búsqueda de guías de práctica clínica (GPC) que incluyeran recomendaciones respecto al uso de sedación endovenosa en la población de interés, con fecha de búsqueda 22 de octubre de 2021 en las siguientes plataformas: eCOVID-19 living map of recommendations (eCovid-19 RecMap), Base internacional de Guías GRADE (BIGG) , Guidelines International Network (GIN), COVID-19 Guidelines Dashboard, National Institute for Health and Care Excellence - UK (NICE) y Trip database, identificándose 7 guías de práctica clínica (Ver Anexo 1). En base a criterios como fecha de búsqueda de la evidencia, uso de metodología GRADE para evaluar la certeza de la evidencia, disponibilidad de la tabla Perfil de evidencia o Resumen de hallazgos, disponibilidad de los criterios o Tabla EtD y tipo de recomendación. Se identificaron tres guías de la Organización Panamericana de la Salud y una de la Society of Critical Care Medicine (SCCM)(3­6), sin embargo, las guías de OPS no brindan recomendaciones especificas para responder directamente a todas las alternativas de intervenciones planteadas por SOPEMI. Por otro lado, las guías de SCCM contienen recomendaciones respecto al uso de todas las alternativas de intervenciones planteadas en pacientes no COVID. La búsqueda se realizó en MEDLINE/ vía PubMed, plataforma L·OVE de Epistemonikos (7) y en MedRxiv, con fecha 22 de octubre de 2021. Los criterios de selección de los estudios fueron: ensayos clínicos aleatorizados, cohortes o casos y control que evalúen la PICO planteada y reportaran al menos uno de los desenlaces de interés. La certeza de la evidencia fue realizada según el enfoque GRADE que toma en cuenta los siguientes criterios: diseño del estudio, riesgo de sesgo, inconsistencia en los resultados, ausencia de evidencia directa, imprecisión, sesgo de publicación, tamaño de efecto, gradiente dosis-respuesta, y efecto de los potenciales factores de confusión residual (los tres últimos aplicables en estudios observacionales) (8,9). Los resultados fueron presentados utilizando la Tablas de Resumen de Hallazgos (SOF, por sus siglas en inglés) construidas a partir del software en línea GRADEpro (https://gradepro.org/)(10) a partir de la adaptación de tablas SoF de la guía de SCCM (6) para pacientes no críticos. Metodología considerada para la elaboración de las recomendaciones: Marco de Evidencia a la Decisión/Recomendación (EtD: Evidence to decisión framework): Los marcos EtD (1,2) son una herramienta del Enfoque GRADE, que tiene como finalidad fomentar el uso de la evidencia de una manera estructurada y transparente para informar decisiones relacionadas al manejo clínico de una enfermedad, salud pública, políticas del sistema de salud o en situaciones como el contexto actual de pandemia acerca de acciones con repercusión socio-económica entre otras. Se aplicaron los principios del enfoque "GRADE-ADOLOPMENT" para identificar guías de práctica clínica orientadas a las preguntas PICO propuestas por el grupo de trabajo de MINSA, además que tener disponibles los perfiles de evidencia GRADE o Tablas de resumen de hallazgos y los marcos EtD. Dependiendo de la evaluación, estas pueden ser consideradas para la adaptación con contextualización o para la adopción (11). Los siguientes criterios del marco EtD fueron seleccionados para la discusión y juicio por el grupo de trabajo: Efectos deseables, Efectos indeseables, Certeza de la evidencia, Valores y preferencias de los pacientes, Balance de efectos, Recursos necesarios, Equidad, Aceptabilidad y Factibilidad. En caso de no haber consenso en la valoración del juicio, se efectuó una votación, determinándose la valoración por mayoría simple. La perspectiva fue del sistema de salud. Elaboración de las Recomendaciones: La metodología EtD considera determinar la fuerza y dirección de una recomendación (12). Ambas, como resultado del juicio acerca del balance beneficio-riesgo, calidad global de la evidencia, confianza en los valores y preferencias de los pacientes, uso de recursos, equidad en salud, aceptabilidad, y factibilidad. En este sentido, existirán recomendaciones "a favor de la intervención" o "en contra de la intervención" (a favor de la alternativa u opción). Asimismo, las recomendaciones fueron determinadas como fuertes o condicionales. Una recomendación será fuerte si existe una clara diferencia entre los efectos deseables e indeseables de la intervención, la certeza global de la evidencia alta o moderada, todos o casi todos los pacientes informados toman la misma decisión, el costo de la intervención está plenamente justificado, existe un impacto favorable en la equidad en salud, la intervención es aceptable para los usuarios interesados (pacientes y personal de salud) y la implementación de dicha intervención es viable. Una recomendación será condicional si alguna de las consideraciones siguientes está presente: Exista poca diferencia entre los efectos deseables e indeseables de la intervención, la calidad de la evidencia es baja o muy baja, existe variabilidad o incertidumbre respecto de lo que decidirán los pacientes informados o el costo de la intervención pudiera no estar justificado en algunas circunstancias. Diálogo Deliberativo para la valoración de los criterios del Marco EtD y elaboración de las recomendaciones: El Diálogo deliberativo se llevó a cabo el día 27 de octubre de 2021, reunión virtual a través de la herramienta Zoom, con la participación de: 1. Profesionales del Grupo de trabajo designado por el Ministerio de Salud: integrantes de la Sociedad Peruana de Medicina Intensiva y Representantes del Ministerio de Salud, en su calidad de panel de expertos, habilitados para emitir los juicios para cada criterio, votar en caso de ser necesario y elaborar la recomendación. 2. Representantes de la Unidad de Análisis y Generación de Evidencias en Salud Pública (UNAGESP) del INS, quienes efectuaron la identificación de la evidencia presentada ante los expertos, en calidad de facilitadores y conductores de los aspectos metodológicos de la reunión. RECOMENDACIÓN: Se sugiere el uso de Propofol sobre benzodiazepinas para la sedación en pacientes con COVID 19 críticos en ventilación mecánica invasiva. Recomendación condicional, basada en evidencia de muy baja calidad: Consideraciones adicionales: La sedación en pacientes COVID 19 críticos en ventilación mecánica invasiva debe ser precedida por una adecuada analgesia. En los pacientes COVID 19 críticos en ventilación mecánica invasiva que no se alcance el objetivo de sedación con las dosis adecuadas de Propofol, o se tenga efectos colaterales, se podría considerar el uso de otro sedante. No se ha establecido la seguridad de Propofol en el embarazo, porque atraviesa la barrera placentaria y puede causar depresión neonatal. Se sugiere usar dexmedetomidina sobre benzodiazepinas para la sedación en pacientes COVID 19 críticos en ventilación mecánica durante la fase de destete. Recomendación condicional, calidad de la evidencia muy baja: Consideraciones adicionales: Tener precaución sobre los efectos adversos como bradicardia e hipotensión. Evitar su uso en pacientes inestables hemodinámicamente. No se recomienda dar dosis de carga de dexmedetomidina. Se sugiere el uso de dexmedetomidina sobre Propofol para la sedación en pacientes COVID 19 críticos en ventilación mecánica durante la fase de destete.

Uma análise de custo-efetividade de propofol versus midazolam para sedação de pacientes adultos admitidos à unidade de terapia intensiva / A cost-effectiveness analysis of propofol versus midazolam for the sedation of adult patients admitted to the intensive care unit

RESUMO Objetivo: Construir um modelo de custo-efetividade para comparar o uso de propofol com o de midazolam em pacientes críticos adultos sob uso de ventilação mecânica. Métodos: Foi construído um modelo de árvore decisória para pacientes críticos submetidos à ventilação mecânica, o qual foi analisado sob a perspectiva do sistema privado de saúde no Brasil. O horizonte temporal foi o da internação na unidade de terapia intensiva. Os desfechos foram custo-efetividade por hora de permanência na unidade de terapia intensiva evitada e custo-efetividade por hora de ventilação mecânica evitada. Foram obtidos os dados do modelo a partir de metanálise prévia. Assumiu-se que o custo da medicação estava incluído nos custos da unidade de terapia intensiva. Conduziram-se análises univariada e de sensibilidade probabilística. Resultados: Pacientes mecanicamente ventilados em uso de propofol tiveram diminuição de sua permanência na unidade de terapia intensiva e na duração da ventilação mecânica, respectivamente, em 47,97 horas e 21,65 horas. Com o uso de propofol, ocorreu redução média do custo de U$2.998,971 em comparação ao uso do midazolam. A custo-efetividade por hora de permanência na unidade de terapia intensiva evitada e por hora de ventilação mecânica evitada foi dominante, respectivamente, em 94,40% e 80,8% do tempo. Conclusão: Ocorreu diminuição significante do custo associado ao uso de propofol, no que se refere à permanência na unidade de terapia intensiva e à duração da ventilação mecânica para pacientes críticos adultos.

ABSTRACT Objective: To build a cost-effectiveness model to compare the use of propofol versus midazolam in critically ill adult patients under mechanical ventilation. Methods: We built a decision tree model for critically ill patients submitted to mechanical ventilation and analyzed it from the Brazilian private health care system perspective. The time horizon was that of intensive care unit hospitalization. The outcomes were cost-effectiveness per hour of intensive care unit stay avoided and cost-effectiveness per hour of mechanical ventilation avoided. We retrieved data for the model from a previous meta-analysis. We assumed that the cost of medication was embedded in the intensive care unit cost. We conducted univariate and probabilistic sensitivity analyses. Results: Mechanically ventilated patients using propofol had their intensive care unit stay and the duration of mechanical ventilation decreased by 47.97 hours and 21.65 hours, respectively. There was an average cost reduction of US$ 2,998.971 for propofol when compared to midazolam. The cost-effectiveness per hour of intensive care unit stay and mechanical ventilation avoided were dominant 94.40% and 80.8% of the time, respectively. Conclusion: There was a significant reduction in costs associated with propofol use related to intensive care unit stay and duration of mechanical ventilation for critically ill adult patients.

Echocardiographic Assessment of Healthy Midazolam/Butorphanol or Midazolam/Morphine-Sedated Dogs.

The purpose of this study was to assess the effects of midazolam combined with morphine or butorphanol on echocardiographic variables of healthy dogs. Twenty-four dogs of various breeds aged 34.33 ± 23.41 months and weighing 8.1 ± 4.7 kg were enrolled in the study. Subjects were randomly allocated in one of two experimental groups of sedation with intramuscular midazolam (0.3 mg/kg) combined with butorphanol (0.2 mg/kg) (GB, n = 12) or morphine (0.3 mg/kg) (GM, n = 12). Transthoracic echocardiographic examinations comprised B-Mode, M-Mode, spectral Doppler and pulsed tissue Doppler assessment. Data were recorded before sedation (TB) and 20 minutes following intramuscular administration of either sedation protocol (TS). Data were analyzed using repeated measures ANOVA followed by Tukey's posthoc test. Shortening fraction, ejection fraction, left ventricular diameter and volume did not differ among groups and time points. The A and E' waves were decreased in GM at TS compared to TB. Isovolumic relaxation time, Ae/Ao ratio, aortic and pulmonary flows and S' wave did not differ among time points and groups. These sedation protocols did not cause clinically relevant changes in echocardiographic variables, therefore can be used for sedation of uncooperative dogs during echocardiographic evaluation.

Descriptive assessment of adverse events associated with midazolam-etomidate versus saline-etomidate in healthy hydromorphone premedicated dogs.

OBJECTIVES: To determine the frequency, severity and duration of adverse events including myoclonus, pain on injection, hypersalivation, regurgitation and apnoea after administration of midazolam or saline followed by etomidate in hydromorphone premedicated dogs. MATERIALS AND METHODS: Dogs undergoing elective dental prophylaxis or soft tissue surgeries were enrolled in this randomised trial. Dogs were premedicated with hydromorphone 0.1 mg/kg IV. Sixty seconds later, midazolam 0.3 mg/kg or saline at an equivalent volume was administered IV. Sixty seconds after that, etomidate 1.5 mg/kg IV was administered over 60 seconds. Additional doses of 0.5 mg/kg etomidate were administered until endotracheal intubation was successful. Observers were blinded to the treatment. Frequency, duration and a severity score of 0 to 3 were recorded for myoclonus, pain on injection, hypersalivation and regurgitation. Duration of apnoea and frequency of any additional complications was recorded. RESULTS: Forty variable breed healthy dogs were enrolled in the study. Myoclonus, pain on injection, regurgitation, hypersalivation, gagging, tachypnoea and pigmenturia occurred, respectively, in 10%, 40%, 0%, 15%, 35%, 25% and 5% of dogs in the saline group and 0%, 65%, 0%, 10%, 45%, 15% and 5% of dogs in the midazolam group. Apnoea occurred for 115 seconds (range 0 to 660 seconds) and 160 seconds (range 0 to 600 seconds) in the saline and midazolam groups, respectively. Two dogs developed pigmenturia. The trial was stopped early due to the occurrence of pigmenturia. CLINICAL SIGNIFICANCE: Due to early stopping of the trial, the predefined sample size was not reached. Further investigation is needed to determine if midazolam reduced the incidence of adverse events or improved the induction quality when combined with hydromorphone and etomidate.

Verification of a cocktail approach for quantitative drug-drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug.

A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82-1.09, and 2 combinations ranged between 0.74-1.32.The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.

Clinical and Economic Evaluation of the Impact of Midazolam on Morphine Therapy for Pain Relief in Critically Ill Ventilated Infants with Respiratory Distress Syndrome.

BACKGROUND: The impact of midazolam on the overall performance of morphine therapy for pain in ventilated neonates with respiratory distress syndrome (RDS) has never been investigated. OBJECTIVE: This study is a clinical and economic analysis of morphine monotherapy versus morphine plus midazolam in ventilated infants with RDS. METHODS: A decision-analytic model from the hospital perspective was developed to follow the consequences of the use of the study drugs. Clinical and resource utilization data were extracted based on a retrospective cohort study of 104 neonates with RDS receiving morphine alone versus in combination with midazolam at the main neonatal intensive care unit (NICU) in Qatar, from 2014 to 2019. Primary outcome measures were the analgesia success rate, via the Premature Infant Pain Profile scale, and overall costs of therapies. Multivariate statistical analyses confirmed no significant variations in baseline characteristics between study groups. RESULTS: With 0.05 significance and 80% power, morphine had a higher rate of successful analgesia (65.4 vs. 34.6%; risk ratio 1.91; 95% confidence interval 1.11-3.28; p = 0.019). Overall costs were also in favor of morphine compared with its combination with midazolam, with cost savings of 40,959 Qatari Riyal ($US11,222), year 2019/20 values. The Monte Carlo analyses confirmed the economic advantage of morphine alone in 100% of cases and demonstrated that it is not sensitive to uncertainties in study model inputs. CONCLUSIONS: Morphine monotherapy enabled enhanced pain relief over its combination with midazolam in the NICU, at a reduced overall cost. Morphine alone, therefore, seems to be a dominant analgesia strategy.

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.