Remimazolam.

Remimazolam is a new reversible γ-aminobutyric acid type A agonist benzodiazepine that displays a fast onset of action, short recovery time with a safe cardiopulmonary profile and favorable pharmacokinetics in comparison with other intravenous sedatives.

Development and characterization of novel fast-dissolving pentobarbital suppositories for pediatric procedural sedation and comparison with lipophilic formulations.

For pediatric radiological procedures (RP), pentobarbital sodium (PNa) can be used orally or rectally to replace intravenous anesthesia. Since no commercial PNa suppositories exist, they must be prepared by compounding pharmacies. This study aims to develop fast-dissolving PNa suppositories for fast pharmacological activity during RP. We prepared gelatin (G), gelatin/polyethylene glycol 4000 (GP), and polyethylene glycol 4000 (P) suppositories, with and without pH adjustment, and assessed their dosage uniformity (DU), softening time, rupture resistance, and in-vitro dissolution. An optimal formulation was selected, and PNa release was compared to that of fat-based suppositories using dissolution tests. Additionally, the quality control process (analytical performance, safety/eco-friendliness and productivity/practical effectiveness) of these formulas were compared using a RGB method. All hydrophilic formulas (HF) met the DU requirement (AV < 8 %) except for P (AV 15.62 ± 4 %). pH adjustment enhanced G and GP suppositories resistance to 2.2 ± 0.2 kg and 2.0 ± 0.3 kg, respectively, and allowed 100 % release of PNa in under 10 min. In contrast, lipophilic formulas released less than 80 % of PNa at best after 120 min. These results show the biopharmaceutical suitability of HF for RP compared to lipophilic ones, but a pharmacokinetic study is needed to confirm data.

Extraction of ketamine and dexmedetomidine by extracorporeal life support circuits☠.

BACKGROUND: Patients supported with extracorporeal life support (ECLS) circuits such as ECMO and CRRT often require high doses of sedatives and analgesics, including ketamine and dexmedetomidine. Concentrations of many medications are affected by ECLS circuits through adsorption to the circuit components, dialysis, as well as the large volume of blood used to prime the circuits. However, the impact of ECLS circuits on ketamine and dexmedetomidine pharmacokinetics has not been well described. This study determined ketamine and dexmedetomidine extraction by extracorporeal circuits in an ex-vivo system. METHODS: Medication was administered at therapeutic concentration to blood-primed, closed-loop ex-vivo ECMO and CRRT circuits. Drug concentrations were measured in plasma, hemofiltrate, and control samples at multiple time points throughout the experiments. At each sample time point, the percentage of drug recovery was calculated. RESULTS: Ketamine plasma concentration in the ECMO and CRRT circuits decreased rapidly, with 43.8% recovery (SD = 0.6%) from ECMO circuits after 8 h and 3.3% (SD = 1.8%) recovery from CRRT circuits after 6 h. Dexmedetomidine was also cleared from CRRT circuits, with 20.3% recovery (SD = 1.8%) after 6 h. Concentrations of both medications were very stable in the control experiments, with approximately 100% drug recovery of both ketamine and dexmedetomidine after 6 h. CONCLUSION: Ketamine and dexmedetomidine concentrations are significantly affected by ECLS circuits, indicating that dosing adjustments are needed for patients supported with ECMO and CRRT.

Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure-activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA 42. In vitro and in vivo parameters of DORA 42, and its PK-PD simulation for human use are detailed.

Biopharmaceutical studies of a novel sedative sublingual lozenge based on glycine and tryptophan: A rationale for mucoadhesive agent selection.

Effective sedative drugs are in great demand due to increasing incidence of nervous disorders. The present work was aimed to develop a novel sublingual sedative drug based on glycine and L-tryptophan amino acids. Carbopol and different hydroxypropyl methylcellulose species were alternatively tested as mucoadhesive agents intended to prolong tryptophan sublingual release time. A model lipid medium of fully hydrated L-α-dimyristoylphosphatidylcholine was used for optimal mucoadhesive agents selection. Simultaneous processes of drug release and diffusion in lipid medium were first investigated involving both experimental and theoretical approaches. Individual substances, their selected combinations as well as different drug formulations were consecutively examined. Application of kinetic differential scanning calorimetry method allowed us to reveal a number of specific drug-excipient effects. Lactose was found to essentially facilitate tryptophan release and provide its ability to get into the bloodstream simultaneously with glycine, which is necessary to achieve glycine-tryptophan synergism. Introduction of a mucoadhesive agent into the formulation was shown to change kinetics of drug-membrane interactions variously depending on viscosity grade. Among the mucoadhesive agents, hydroxypropyl methylcellulose species K4M and E4M were shown to further accelerate drug release, therefore they were selected as optimal. Thus, effectiveness of the novel sedative drug was provided by including some excipients, such as lactose and the selected mucoadhesive agent species. A dynamic mathematical model was developed properly describing release and diffusion in lipid medium of various drug substances. Our study clearly showed applicability of a lipid medium to meet challenges such as drug-excipient interactions and optimization of drug formulations.

Remimazolam in General Anesthesia: A Comprehensive Review of Its Applications and Clinical Efficacy.

Remimazolam is a novel ultra-short-acting benzodiazepine with a unique pharmacokinetic profile that makes it an attractive option for use in general anesthesia. This review paper provides an in-depth analysis of remimazolam's applications in the field of general anesthesia, focusing on its pharmacological properties, clinical efficacy, safety profile, and potential advantages compared to other anesthetic agents. Remimazolam acts on GABAa receptors, offering rapid onset and recovery times due to its unique metabolic pathway involving tissue esterases. Clinical trials have demonstrated its efficacy in procedural sedation and general anesthesia, showing a favorable safety profile with minimal cardiovascular and respiratory depression. Compared to traditional anesthetics such as propofol, remimazolam presents distinct advantages, including predictable pharmacokinetics, reduced risk of prolonged sedation, and a reliable safety margin. These attributes position remimazolam as a promising agent in various clinical settings. The purpose of this review is to synthesize current evidence on remimazolam and discuss its potential to improve clinical outcomes in anesthesia practice.

Sedation with inhaled sevoflurane in the intensive care unit.

INTRODUCTION: Critically ill patients often develop the Post-Intensive Care Syndrome (PICS). Current sedation guidelines mainly rely on intravenous agents. Inhaled sedatives are a promising alternative with favorable pharmacokinetics and potential benefits in critical care settings. However, their application in Latin America remains unexplored. METHODS: Case-series study that included adult ICU patients who underwent deep sedation with sevoflurane using the SEDANA anesthetic conserving device. Data on demographics, sedation protocols, adverse events, and outcomes were collected. Statistical analysis assessed changes over time in laboratory parameters. RESULTS: Eleven patients were included, with sevoflurane administered via artificial airways. Inhaled sedation led to the successful cease of intravenous sedatives in 10 of 11 patients, and reduction of at least 30% in opioid dose. No significant adverse effects were observed. Barriers to adherence included device-related issues and challenges in healthcare staff training. CONCLUSION: Sevoflurane effectively achieved sedation goals in ICU patients, reducing the need for additional sedatives and opioids. Our findings support the safety and efficacy of inhaled sedatives in ICU settings and highlight the importance of further research in this area. Longer-term studies are needed to fully determine the impact of inhaled sedatives in ICU patients.

Introducción: Los pacientes críticamente enfermos a menudo desarrollan el Síndrome Post-Cuidados Intensivos (PICS). Las pautas actuales de sedación se basan principalmente en agentes intravenosos. Los sedantes inhalados son una alternativa prometedora con farmacocinética favorable y beneficios potenciales en entornos de cuidados críticos. Sin embargo, su aplicación en América Latina sigue sin explorarse. Métodos: Estudio de serie de casos que incluyó a pacientes adultos de UCI que recibieron sedación profunda con sevoflurano utilizando el dispositivo conservador anestésico SEDANA. Se recopilaron datos demográficos, protocolos de sedación, eventos adversos y resultados. El análisis estadístico evaluó los cambios en el tiempo en los parámetros de laboratorio. Resultados: Se incluyeron once pacientes, a quienes se les administró sevoflurano a través de vías respiratorias artificiales. Se incluyeron once pacientes, a quienes se les administró sevoflurano a través de vías respiratorias artificiales. La sedación inhalada llevó a la cesación exitosa de sedantes intravenosos en 10 de los 11 pacientes, con una reducción de al menos 30% la dosis de opioides. No se observaron efectos adversos significativos. Las barreras para la adherencia incluyeron problemas relacionados con el dispositivo y desafíos en la capacitación del personal de salud. Conclusión: El sevoflurano logró de manera efectiva los objetivos de sedación en pacientes de UCI, reduciendo la necesidad de sedantes y opioides adicionales. Nuestros hallazgos respaldan la seguridad y eficacia de los sedantes inhalados en entornos de UCI y resaltan la importancia de una mayor investigación en esta área. Se necesitan estudios a más largo plazo para determinar completamente el impacto de los sedantes inhalados en pacientes de UCI.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Drug-Drug Interaction Potential of Remimazolam: CYP 450, Transporters, and Protein Binding.

BACKGROUND: The ultra-short-acting benzodiazepine, remimazolam, is a new treatment modality for procedural sedation and general anesthesia. Its activity is terminated by carboxylesterase 1 (CES1). OBJECTIVE: The objective of this study was to determine the drug-drug interaction (DDI) potential of remimazolam through mechanisms unrelated to its metabolizing enzyme, CES1. METHODS: Conventional in vitro co-exposure experiments were conducted to study possible interactions of remimazolam and its primary metabolite, CNS7054, mediated by competitive binding to plasma protein or reactions with cytochrome P450 isoforms or drug transporters. RESULTS: No relevant interactions of remimazolam or its metabolite with cytochrome P450 (CYP) isoforms at clinically relevant concentrations were identified. Likewise, standard experiments revealed no clinically relevant interactions with drug transporters and plasma proteins. CONCLUSION: The present data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CYP isoforms, drug transporters, and protein binding.

Remimazolam for sedation and anesthesia in children: A scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, shows considerable promise in clinical practice. Its pharmacodynamic profile closely resembles that of midazolam, while its pharmacokinetic properties are similar to those of remifentanil. While research in adult populations continues to accumulate, the pace of pediatric studies is not as significant. This scoping review aims to systematically examine published studies, clinical trials, observational research, case reports, and relevant literature to provide a comprehensive understanding of remimazolam in pediatric sedation and anesthesia. By synthesizing the gathered evidence, we aim to identify gaps in the literature, guide future research endeavors, and inform clinical practices. METHODS: The review follows the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Review. A thorough search strategy was implemented across prominent peer-reviewed databases, with focused efforts to identify relevant grey literature. All primary studies involving the use of remimazolam in pediatric populations were included in this review. RESULTS: Eighteen studies were included in this analysis, comprising 2 randomized controlled trials, 4 prospective cohort trials, 12 case reports, and 692 children in total. CONCLUSION: This scoping review highlights the increasing interest in using remimazolam as a sedative or anesthetic for children. Although initial evidence indicates its effectiveness and safety, more research is necessary to fill knowledge gaps, establish standard protocols, and optimize its use in pediatric anesthesia and sedation. Addressing these challenges will enable clinicians to improve the quality of care and outcomes for pediatric patients undergoing sedation and anesthesia.

Remimazolam for sedation and anesthesia in children: Protocol for a scoping review.

BACKGROUND: Remimazolam, a novel intravenous benzodiazepine recently approved by both the European Medicines Agency and the Food and Drug Agency, holds significant promise in clinical practice. Its pharmacodynamic profile closely mirrors that of midazolam, while its pharmacokinetics properties bear resemblance to remifentanil. Research in adult populations continues to accumulate, but the pediatric studies' pace is not significant. This scoping review aims to methodically scrutinize published studies, clinical trials, observational research, case reports, and pertinent literature to offer a comprehensive insight into the existing understanding of remimazolam in pediatric sedation and anesthesia. The synthesis of gathered evidence will discern lacunae in the literature, direct forthcoming investigations, and enlighten clinical practices. METHODS: The review will adhere to the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) for Scoping Review. A meticulous search strategy will be executed across prominent peer-reviewed databases, with concerted efforts to identify relevant gray literature. All primary investigations involving the administration of remimazolam in pediatric populations will be encompassed within the scope of this review. RESULTS: The encompassed studies will be elucidated through a narrative synopsis, complemented by descriptive statistical analyses of quantitative data where deemed applicable. CONCLUSION: The planned scoping review aims to delineate the existing evidence regarding the utilization of remimazolam in pediatric anesthesia and sedation. It will discern areas of knowledge deficiency, provide guidance for future inquiries, and enhance clinical practices within the field.

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

Pharmacokinetics and exposure-safety relationship of ciprofol for sedation in mechanically ventilated patients in the intensive care unit.

Ciprofol (HSK3486) is a newly developed, highly selective γ-aminobutyric acid-A (GABAA) receptor potentiator that is recently approved for a new indication of sedation for patients in the intensive care unit (ICU) in China. This analysis aimed to characterize the population pharmacokinetics (PopPKs) of ciprofol and evaluate the relationship of exposure with hypotension in mechanically ventilated patients in the ICU. A total of 462 subjects with 3918 concentration measurements from two clinical trials of mechanically ventilated patients in the ICU, four clinical trials of elective surgical patients, and six clinical trials of healthy subjects were used in the PopPK analysis. Exposure-safety relationship for hypotension was evaluated based on the data gathered from 112 subjects in two clinical trials of mechanically ventilated patients in the ICU. Ciprofol pharmacokinetics (PKs) was adequately described by a three-compartment linear disposition model with first-order elimination. Body weight, age, sex, blood sampling site (vein vs. arterial), study design (long-term infusion vs. short-term infusion), and patient population (ICU vs. non-ICU) were identified as statistically significant covariates on the PKs of ciprofol. Within the exposure range of the mechanically ventilated ICU patient population, no meaningful association was observed between ciprofol exposure and the incidence of hypotension. These results support the dosing regimen currently used in mechanically ventilated patients in the ICU.

The Metabolism of the New Benzodiazepine Remimazolam.

BACKGROUND: Remimazolam (RMZ) is a novel ultrashort-acting benzodiazepine used for sedation by intravenous administration. The pharmacophore of RMZ includes a carboxyl ester group sensitive to esterase- mediated hydrolysis, which is the primary path of metabolic elimination. However, for the sake of drug safety, a deeper and broader knowledge of the involved metabolic pathways and the evolving metabolites is required. Information is needed on both humans and experimental animals to evaluate the possibility that humans form harmful metabolites not encountered in animal toxicity studies. OBJECTIVE: The current study aimed at identifying the mechanisms of remimazolam's metabolism and any potential clinically significant metabolites. METHODS: Using tissue homogenates from various animals and humans, the liver was identified as the tissue primarily responsible for the elimination of RMZ. CNS7054, the hydrolysis product of remimazolam, was identified as the only clinically relevant metabolite. Using bacterial or eukaryotic over-expression systems, carboxylesterase 1 (CES1) was identified as the iso-enzyme predominantly involved in RMZ metabolism, with no role for carboxylesterase 2. Using a variety of inhibitors of other esterases, the contribution to elimination mediated by esterases other than CES1 was excluded. RESULTS: Besides tissue carboxylesterases, rodents expressed an RMZ esterase in plasma, which was not present in this compartment in other laboratory animals and humans, hampering direct comparisons. Other pathways of metabolic elimination, such as oxidation and glucuronidation, also occurred, but their contribution to overall elimination was minimal. CONCLUSION: Besides the pharmacologically non-active metabolite CNS7054, no other clinically significant metabolite of remimazolam could be identified.

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants.

Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from -1% to 120% for PRED, and -24% to 60% for IPRED. The model by James et al, which was developed using similar "real-world" data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects. METHODS: An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study. RESULTS: All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (Tmax) of 1.00 h, and mean values of the peak concentration (Cmax) and area under the concentration-time curve (AUC0-t) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam. CONCLUSION: Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study. CLINICAL TRIAL REGISTRATION: The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).

Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane.

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. A total of 151 individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G > C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG, and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G > C and rs2031920 C > T, GABRG1 rs279858 T > C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G > A, and rs1801394 A > G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that 9 single nucleotide polymorphisms in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane.