Midazolam Research Articles

Abstract 393: Distribution and Elimination Kinetics of Midazolam and Metabolites in Patients With Post-Cardiac Arrest Care

Background: Administration of midazolam (MDZ) can make neuroprognostication more complex, especially in determining the safe timing for avoiding inappropriately pessimistic prognostications. This study aims to investigate the distribution and elimination kinetics of MDZ and metabolites in patients with post-resuscitation care. Methods: This was a prospectively observational study between May 2020 and April 2022. Samples for analyzing plasma concentration of MDZ and seven metabolites were obtained immediately, at 4, 8, 12, and 24 h from discontinuation of MDZ infusion. Briefly, absolute and relative concentrations of MDZ and metabolites were determined by LC-MS/MS and LC-QTOF. The area under the plasma concentration-time curve from time 0 to last measurable time point (AUC last ) and estimated half-life ( t 1/2 ) were calculated according to pharmacokinetic rules. Results: Of the 13 enrolled patients, 8 (61.5%) awakened after discontinuation of MDZ administration. MDZ, 1-hydroxylmidazolam (1-OH-MDZ), 1-hydroxylmidazolam-glucuronide (1-OH-MDZ-Glu), and midazolam-glucuronide (MDZ-Glu) were identified as the major compounds, comprising approximately 96% of the total proportion. All compounds had individual mean t 1/2 (MDZ, 1-OH-MDZ, 1-OH-MDZ-Glc, and MDZ-Glc: 6.4, 7.6, 14.3, and 10.5 h, respectively). In the subgroup analysis for the awakened patients, the significant correlation between AUC last and awakening time measured from discontinuation of MDZ infusion was demonstrated in MDZ (r 2 = 0.66) and 1-OH-MDZ (r 2 = 0.55). Conclusions: Even in the normothermia state of the patients, t 1/2 of MDZ and metabolites was prolonged compared with that reported in healthy individuals. Among all compounds, MDZ and 1-OH-MDZ concentrations may be mainly active compounds related to the sedation effect. Hence, to prevent inappropriate WLST for patients with potential for recovery, we recommend clinicians consider the prolonged t 1/2 of the main active compounds.

Pharmacokinetic-Pharmacodynamic Modeling of Midazolam in Pediatric Surgery.

Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic-pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2-17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5-120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects.

Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5.

CYP 3A4 and CYP 3A5 are two important members of the human cytochrome P450 family. Although their overall structures are similar, the local structures of the active site are different, which directly leads to obvious individual differences in drug metabolic efficacy and toxicity. In this work, midazolam (MDZ) was selected as the probe substrate, and its interaction with two proteins, CYP 3A4 and CYP 3A5, was studied by molecular dynamics simulation (MD) along with the calculation of the binding free energy. The results show that two protein-substrate complexes have some similarities in enzyme-substrate binding; that is, in both complexes, Ser119 forms a high occupancy hydrogen bond with MDZ, which plays a key role in the stability of the interaction between MDZ and the enzymes. However, the complex formed by CYP 3A4 and MDZ is more stable, which may be attributed to the sandwich structure formed by the fluorophenyl group of the substrate with Leu216 and Leu482. Our study interprets the binding differences between two isoform-substrate complexes and reveals a structure-function relationship from the atomic perspective, which is expected to provide a theoretical basis for accurately measuring the effectiveness and toxicity of drugs for individuals in the era of precision medicine.

Eco-friendly electrochemical sensor for determination of conscious sedating drug “midazolam’’ based on Au-NPs@Silica modified carbon paste electrode

Benzodiazepines (BZDs) are a group of drugs prescribed for their sedating effect. Their misuse and addictive properties stipulate different authorities for developing simple, fast and accurate analytical methods for instantaneous detection. Differential pulse voltammetric technique (DPV) was utilized for the selective assay of midazolam hydrochloride (MDZ) in the pure, parenteral dosage forms and plasma samples. A chemically modified carbon paste electrode (CPE) was implemented during the study. The method depended on the electroreduction of MDZ on the surface of the electrode over a potential range of 0.0 V to −1.6 V. The electrode was fabricated using silica nanoparticles (Si-NPs) which were incorporated into the composition of the CPE and used to enhance the electrode performance. Then, to enhance the sensitivity of the method, a chronoamperometric modification step was applied for depositing gold nanoparticles (Au-NPs) on the carbon paste electrode surface. Modification with Au-NPs showed a higher reduction current peak for MDZ with well-defined peaks. Various parameters such as pH of the media and measurements scan rate were investigated and optimized to enhance the sensor sensitivity. The sensor showed a dynamic linear response over a concentration range of 4.0 × 10−7 M to 2.9 × 10−4 M of MDZ with a LOD of 2.24 × 10−8 M using 0.1 M acetate buffer (pH 5.6). The sensor was validated in accordance with the ICH guidelines regarding accuracy, precision and specificity for the selective assay of MDZ in the presence of excipients. A greenness evaluation was performed using three different assessment tools, namely, the “Green Analytical Procedure Index” (GAPI), the “Analytical Greenness metric” (AGREE) and the “Whiteness Analytical Chemistry tool” (WAC) using the RGB12 model.

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM) in 12- and 7-day-old rats. The anticonvulsants were administered 1 hour after soman exposure; neuropathology data were collected up to 6 months postexposure. In both ages, the total duration of SE within 24 hours after soman exposure was significantly shorter in the LY293558 plus CRM groups compared with the MDZ groups. Neuronal degeneration was substantial in the MDZ-treated groups but absent or minimal in the groups treated with LY293558 plus CRM. Loss of neurons and interneurons in the basolateral amygdala and CA1 hippocampal area was significant in the MDZ-treated groups but virtually absent in the LY293558 plus CRM groups. Atrophy of the amygdala and hippocampus occurred only in MDZ-treated groups. Neuronal/interneuronal loss and atrophy of the amygdala and hippocampus deteriorated over time. Reduction of inhibitory activity in the basolateral amygdala and increased anxiety were found only in MDZ groups. Spontaneous recurrent seizures developed in the MDZ groups, deteriorating over time; a small percentage of rats from the LY293558 plus CRM groups also developed seizures. These results suggest that brain damage can be long lasting or permanent if nerve agent-induced SE in infant victims is treated with midazolam at a delayed timepoint after SE onset, whereas antiglutamatergic treatment with tezampanel and caramiphen provides significant neuroprotection. SIGNIFICANCE STATEMENT: To protect the brain and the lives of infants in a mass exposure to nerve agents, an anticonvulsant treatment must be administered that will effectively stop seizures and prevent neuropathology, even if offered with a relative delay after seizure onset. The present study shows that midazolam, which was recently approved by the Food and Drug Administration for the treatment of nerve agent-induced status epilepticus, is not an effective neuroprotectant, whereas brain damage can be prevented by targeting glutamate receptors.

Parental Presence during Induction of Anesthesia and Emergence Delirium Influence the Incidence of Postoperative Maladaptive Behavioral Changes.

Surgical intervention in pediatric patients can cause variable degrees of psychological stress with potential consequences in the perioperative period and even in the long term, after hospital discharge in the form of behavioral changes days and months later. The aim of our study was to determine which preoperative preparation strategy reduces postoperative maladaptive behavioral changes in children undergoing ambulatory pediatric surgery. This prospective observational study included 638 pediatric American Society of Anesthesiologists physical status I or II patients who underwent ambulatory pediatric surgery. They were grouped into four preoperative preparation groups: not premedicated (NADA), premedicated with midazolam (MDZ), parental presence during induction of anesthesia (PPIA), and parental presence during induction of anesthesia and premedicated with midazolam (PPIA + MDZ). All patients included in the study were contacted by telephone during 1 year posthospital discharge to assess the postoperative maladaptive behavioral changes using the Posthospitalization Behavior Questionnaire (PHBQ). We performed a multivariate analysis to evaluate the influence of type of preparation and behavioral changes. Patients in the PPIA and PPIA + MDZ preparation groups presented less postoperative maladaptive behavioral changes compared to patients in the NADA and MDZ groups (odds ratio [OR]: 1.8 [1.1-2.8] and OR 2.2 [1.03-4.49]) during the first week and first month. The intensity of emergence delirium measured by the Pediatric Anesthesia Emergence Delirium (PAED) scale increases the probability of postoperative maladaptive behavioral changes (OR: 1.05 [1.006-1.103]). The presence of parents during induction of anesthesia (PPIA and PPIA + MDZ) is a very effective strategy in reducing postoperative behavioral changes. These benefits are more significant in children under 5 years of age.

Change in Negative Affective Bias following a Single Ketamine Treatment for Treatment-Resistant Depression

Ketamine has recently emerged as a highly effective new treatment for people with treatment-resistant depression with rapid antidepressant effects. However, these effects are often short lasting, and the potential cognitive mechanisms underlying the therapeutic effects, such as effects on emotional processing bias, remain poorly understood. In the present study, we explored potential changes in emotional and cognitive processing following a single treatment of subcutaneous ketamine in a randomised double-blind controlled study with an active control. Participants with treatment-resistant major depressive disorder (MDD) were recruited from a single site from the Ketamine for Adult Depression Study (KADS Trial) and were randomly assigned to receive racemic ketamine hydrochloride ( n = 10 ) or midazolam hydrochloride ( n = 11 ) in a 1 : 1 ratio. A healthy control sample ( n = 23 ) was recruited to attend a single experimental session without any treatment. All MDD participants completed mood ratings and cognitive assessments prior to and one day after a single randomised treatment. The results showed no significant differences in performance changes after treatment across the majority of emotion-related (i.e., Emotional Stroop Task, Affective Go/No-Go Task) and cognitive (Ruff 2 and 7 Selective Attention Test, Controlled Word Association Test) outcome measures. Participants who received ketamine showed a significant improvement in a negative processing bias test (i.e., The Scrambled Sentence Task; Cohen’s d = .67 , p = .016 ), which was not significantly associated with improvement in psychological symptoms ( r = − .662 , p = .074 ). The results from this exploratory study suggest that a single ketamine treatment may modulate negative affective bias. Limitations to this study included the small sample size and lack of follow-up. Future larger trials are required to confirm this finding.

Impact of Heterotropic Allosteric Modulation on the Time-Dependent Inhibition of Cytochrome P450 3A4.

The current study was designed to investigate the influence of allosteric effectors on the metabolism of the prototypical cytochrome P450 (CYP) 3A4 substrate midazolam (MDZ), and on the determination in vitro time-dependent inhibition (TDI) of CYP3A4 using human liver microsomes (HLM). As the concentration of midazolam increased to 250 µM in HLMs, homotropic cooperativity resulted in a decrease in the 1'-hydroxymidazolam to 4-hydroxymidazolam ratio to a maximum of 1.1. The presence of varying concentrations of testosterone, progesterone (PGS), or carbamazepine (CBZ) in HLMs with MDZ could recapitulate the effect of homotropic cooperativity such that the formation rates of the 1'hydroxymidazolam and 4-hydroxymidazolam were equal even at low concentrations of MDZ. The presence of PGS (10 or 100 µM) and CBZ (100 or 1000 µM) in in vitro TDI determination of four known CYP3A4 time-dependent inactivators (clarithromycin, troleandomycin, mibefradil, raloxifene) simultaneously decreased potency and inactivation rate constant, resulting in fold changes in inactivation efficiency on average of 1.6-fold and 13-fold for the low and high concentrations of allosteric modulator tested, respectively. The formation of a metabolic-intermediate complex (MIC) for clarithromycin and troleandomycin decreased in the presence of the allosteric modulators in a concentration-dependent manner, reaching a new steady state formation that could not be overcome with increased incubation time. Maximum reduction of the MIC formed by clarithromycin was up to ∼91%, while troleandomycin MIC decreased up to ∼31%. These findings suggest that the absence of endogenous allosteric modulators may contribute to the poor translation of HLM-based drug-drug interaction predictions. SIGNIFICANCE STATEMENT: The reported overprediction of in vitro human liver microsome time-dependent inhibition of CYP3A4 and observed drug interactions in vivo remains an issue in drug development. We provide characterization of allosteric modulators on the CYP3A4 metabolism of the prototypical substrate midazolam, demonstrating the ability of the modulators to recapitulate the homotropic cooperativity of midazolam. Furthermore, we demonstrate that allosteric heterotropic cooperativity of CYP3A4 can impact the time-dependent inhibition kinetics of known mechanisms-based inhibitors, providing a potential mechanism to explain the overprediction.

Suicide with oral midazolam: post-mortem toxicological investigations using Ostro® plate and UPLC-MS/MS.

A middle-aged woman was found dead with multiple empty blisters of midazolam (DORMICUM®), equivalent to 450mg, near her body. The autopsy revealed that the cause of death was secondary to an asphyxia syndrome. Standard toxicological procedures identified midazolam only in blood, urine and gastric content. A quantitative analytical method for midazolam (MDZ) and 1-hydroxy-midazolam (1-OH-MDZ) was validated using protein precipitation, a phospholipid removal Ostro® plates and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). MDZ and 1-OH-MDZ were quantified in peripheral blood at 910 ng/mL and 534 ng/mL, respectively, and superior to 2000 ng/mL in urine. Reported to the body weight, the dose, which was lethal, was estimated to 6.7 mg/kg. The usual dose used in intensive care unit is 0.03-0.3 mg/kg. MDZ intoxication outside of hospital are rare given the restricted availably of this drug in France. Nevertheless, MDZ under oral form remains available in several countries. Toxic MDZ blood concentrations are described after intravenous administration for anesthesia and are not suited for oral intoxication. Based on the autopsy findings, police investigation and toxicology results, the cause of death was determined to be a self-inflicted oral MDZ acute intoxication, which is the first to be documented to the best of our knowledge. This fatal intoxication provides analytical data that could support subsequent toxicological result interpretation in similar forensic cases.

Effects of dexmedetomidine at different dosages on perioperative haemodynamics and postoperative recovery quality in elderly patients undergoing hip replacement surgery under general anaesthesia: a randomized controlled trial

BackgroundDexmedetomidine could provide some advantages to prevent postoperative complications in elderly patients undergoing under general anaesthesia. However, dexmedetomidine inhibits haemodynamics to some extent due to its sympathetic inhibition.ObjectiveTo evaluate the effects of different doses of dexmedetomidine on haemodynamics during surgery and recovery after general anaesthesia in elderly patients undergoing hip replacement.MethodsThis was a prospective randomized double-blind controlled clinical trial. Eligible patients were randomly allocated into comparative groups (normal saline (NS) and midazolam (MD), n = 30) and dexmedetomidine groups at different doses (D0.25/D0.5/D0.75, n = 30). In the D0.25/D0.5/D0.75 groups, dexmedetomidine was administered at different initial loading doses (0.25/0.5/0.75 μg/kg for 15 min) following 0.5 μg/kg/h continuous infusion until the end of the operation. In the MD group, patients were administered 0.03 mg/kg midazolam at the beginning of anaesthesia induction.ResultsCompared to the MD and NS groups, there were significant decreases in MAP in the D0.5 and D0.75 groups at many time points, such as skin incision, end of operation, and from extubation until 30 min after extubation (P < 0.05); there were also significant decreases in HR in the D0.5 and D0.75 groups at time points including anaesthesia induction, end of operation, and from extubation to 2 h after operation (P < 0.05). In the D0.25 group, there were few differences in the changes in MAP and HR compared to the MD and NS groups during the entire perioperative period (P > 0.05). Moreover, the percentage of patients whose MAP and HR decreased > 20% of baseline was higher in the D0.75 and D0.5 groups than that in all other groups. Compared to the NS group, from the beginning to the end of the operation, the 95% confidence interval (CI) of RR for MAP below > 20% of baseline in the D0.5 and D0.75 groups was greater than 1. In particular, the CI of the RR in the D0.75 group was greater than 1 until the patient awoke from general anaesthesia (P < 0.05). In addition, the CI of the RR for HR below > 20% of baseline in the D0.5 group was greater than 1 compared to the NS group at the time of induction and extubation (P < 0.05). There was no significant difference in the possibility of developing hypotension or bradycardia in the MD or D0.25 groups compared to the NS group (P > 0.05). The recovery quality of patients during the post-anaesthesia period was also observed. No differences were observed among all the groups in the time to awakening or extubation after general anaesthesia (P > 0.05). According to the Riker Sedation-agitated Scale, dexmedetomidine significantly alleviated emergency agitation or delirium compared to NS (P < 0.05). In addition, the scores in the D0.5 and D0.75 groups were lower than those in the D0.25 group (P < 0.05).ConclusionDexmedetomidine could alleviate the agitation of elderly patients undergoing hip replacement after intravenous general anaesthesia combined with inhaled sevoflurane without delayed recovery. However, it is necessary to be vigilant about the haemodynamic inhibition of the drug at high dosages throughout the perioperative period. Dexmedetomidine 0.25–0.5 μg/kg as the initial loading dose followed by 0.5 μg/kg/h continuous infusion might provide comfortable recovery after general anaesthesia with slight haemodynamic inhibition.Trail registrationClinicalTrial.gov, No. NCT05567523. Registered 05 October 2022, https://clinicaltrials.gov/ct2/show/NCT05567523?term=NCT05567523&draw=2&rank=1.

Danazol increases the oral bioavailability of midazolam by inactivation of hepatic and intestinal CYP3A in rats

Danazol (DNZ) is a synthetic androgen derivative used for the treatment of intractable hematological disorders. In this study, we investigated the effects of DNZ on CYP3A activity in hepatic and small intestinal microsomes and the pharmacokinetics of midazolam (MDZ), a typical substrate for CYP3A, in rats. MDZ 4-hydroxylation activities in hepatic and small intestinal microsomes significantly decreased 24 h after DNZ (100 mg/kg, i.p.) treatment. Time-dependent inactivation of MDZ 4-hydroxylation activities was noted when microsomes were pre-incubated with DNZ in the presence of a NADPH-generating system. The Western blot analysis indicated that the decrease observed in enzyme activity was not due to changes in the protein expression of CYP3A. In contrast to the intravenous administration, serum MDZ concentrations in DNZ-treated rats were markedly higher than those in control rats when administered orally. DNZ treatment increased MDZ oral bioavailability by approximately 2.5-folds. We herein demonstrated that DNZ increased the bioavailability of orally administered MDZ through irreversible inactivation of hepatic and intestinal CYP3A in rats.

Tolerability and pharmacokinetics of intravenous allopregnanolone with and without midazolam pretreatment in two healthy dogs.

The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, the dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 min later by ALLO. Behavioral state, vital signs, arterial blood gasses, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 h after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/mL. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.

Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development.

Recently, the long-term use of sedative agents in the neonatal intensive care unit (NICU) has raised concerns about neurodevelopmental outcomes in exposed neonates. Midazolam (MDZ), a common neonatal sedative in the NICU, has been suggested to increase learning disturbances and cognitive impairment in children. However, molecular mechanisms contributing to such outcomes with long-term MDZ use during the early stages of life remain unclear. In this study, we for the first time elucidate the role of brain-derived extracellular vesicles (BDEVs), including mining the BDEV proteome post long-term MDZ exposure during early development. Employing our previously established rodent model system that mimics the exposure of MDZ in the NICU using an increasing dosage regimen, we isolated BDEVs from postnatal 21-days-old control and MDZ groups using a differential sucrose density gradient. BDEVs from the control and MDZ groups were then characterized using a ZetaView nanoparticle tracking analyzer and transmission electron microscopy analysis. Next, using RT-qPCR, we examined the expression of key ESCRT-related genes involved in EV biogenesis. Lastly, using quantitative mass spectrometry-based proteomics, we mined the BDEV protein cargo that revealed key differentially expressed proteins and associated molecular pathways to be altered post long-term MDZ exposure. Our study characterized the proteome in BDEV cargo from long-term MDZ exposure at early development. Importantly, we identified and validated the expression of YWHAH as a potential target for further characterization of its downstream mechanism and a potential biomarker for the early onset of neurodevelopment and neurodegenerative diseases. Overall, the present study demonstrated long-term exposure to MDZ at early development stages could influence BDEV protein cargo, which potentially impact neural functions and behavior at later stages of development.

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) causes seizure activity in larval zebrafish via antagonism of γ-aminobutyric acid type A receptor α1β2γ2

Hexahydro-1,3,5-trinitro-1,3,5-triazine, or Royal Demolition Explosive (RDX), is a major component of plastic explosives such as C-4. Acute exposures from intentional or accidental ingestion are a documented clinical concern, especially among young male U.S. service members in the armed forces. When ingested in large enough quantity, RDX causes tonic–clonic seizures. Previous in silico and in vitro experiments predict that RDX causes seizures by inhibiting α1β2γ2 γ-aminobutyric acid type A (GABAA) receptor-mediated chloride currents. To determine whether this mechanism translates in vivo, we established a larval zebrafish model of RDX-induced seizures. After a 3 h of exposure to 300 µM RDX, larval zebrafish exhibited a significant increase in motility in comparison to vehicle controls. Researchers blinded to experimental group manually scored a 20-min segment of video starting at 3.5 h post-exposure and found significant seizure behavior that correlated with automated seizure scores. Midazolam (MDZ), an nonselective GABAAR positive allosteric modulator (PAM), and a combination of Zolpidem (α1 selective PAM) and compound 2-261 (β2/3-selective PAM) were effective in mitigating RDX-triggered behavioral and electrographic seizures. These findings confirm that RDX induces seizure activity via inhibition of the α1β2γ2 GABAAR and support the use of GABAAR-targeted anti-seizure drugs for the treatment of RDX-induced seizures.

Efficacy and safety of oral versus intranasal midazolam as premedication in children: a systematic review and meta-analysis.

Midazolam hydrochloride is a widely accepted benzodiazepine for premedication in pediatric patients. However, there is no consistent conclusion regarding which route of administration is best. We performed a meta-analysis to assess the efficacy and safety of oral versus intranasal midazolam premedication in children. The PubMed, Embase, Cochrane Library, and Google Scholar databases were searched from inception to June 2022, for randomized controlled trials comparing oral versus intranasal midazolam. Primary outcomes included satisfactory mask acceptance for induction and satisfactory sedation at separation from parents. Secondary outcomes included the incidence of postoperative nausea and vomiting, incidence of nasal irritation, postoperative recovery time, and hemodynamic changes. Data from 14 studies involving a total of 901 children were obtained. The results indicated that intranasal and oral midazolam premedication in children provided similar satisfactory mask acceptance for induction (RR, 1.02; 95% CI, 0.93-1.13; P=0.64; I2=0%), satisfactory sedation at separation from parents (RR, 0.99; 95% CI, 0.89-1.10; P=0.90; I2=57%), and postoperative recovery time (WMD, -8.01; 95% CI, -20.16-4.14; P=0.20; I2=85%). Additionally, intranasal midazolam premedication was associated with lower incidence of postoperative nausea and vomiting (RR, 0.70; 95% CI, 0.51-0.96; P=0.03; I2=0%) and shorter onset time. Differences between intranasal and oral midazolam in satisfactory mask acceptance for induction, satisfactory sedation at separation from parents, and postoperative recovery time were not significant. Intranasal midazolam premedication was associated with shorter onset time and higher incidence of nasal irritation.

The Evaluation of the Efficacy and Safety of Midazolam Nasal Spray in Patients With Seizure Clusters: A Systematic Review and Meta-Analysis.

Midazolam nasal spray (MDZ-NS) is a new emerging rescue medication that suppresses epileptic seizures. Until now, few studies, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and clinical trials have shown that midazolam nasal spray could become an effective and promising alternative to conventional routes (intravenous {IV}/rectal). Therefore, we thought of conducting a systematic review and meta-analysis of midazolam (MDZ) to assess its potential outcomes. The analysis was also evaluated based on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of midazolam nasal spray. A systematic literature search was carried out through various databases to identify studies of accounted outcomes of midazolam nasal spray (MDZ-NS). Randomized and other studies of patients (12 years or older) with seizure clusters (SCs) were included. A total of three full-text articles were considered for systematic review and meta-analysis as per the inclusion and exclusion criteria. The 5 mg MDZ-NS was observed to be equally safe as a placebo, and the risk ratio (RR) was 1.01 (95% confidence interval (CI): 0.67-1.53). After the administration of MDZ-NS, either the patientsremained seizure-free for six hours or moreor the seizure was terminated within 10 minutes and had no recurrence between 10 minutes and six hours. The risk ratio (RR) obtained was 1.54 (95% CI: 1.25-1.91). The result was statistically significant as a higher success rate was observed with the use of 5 mg midazolam nasal spray compared to placebo (p < 0.0001). Heterogeneity was not observed in the results of the included studies (inconsistency index {I2}:0%). The present systematic review and meta-analysisdemonstrated that 5 mg midazolam nasal spray was efficacious in treating patients with seizure clustersand is well-tolerated. Also, its use is relatively safe.

Comparison of intravenous ketamine hydrochloride plus dexmedetomidine hydrochloride and ketamine hydrochloride plus midazolam hydrochloride in procedural sedation for short surgical procedures: A prospective randomized double-blind study

Background: The growing popularity of ambulatory anesthesia has led to the development of newer drug regimens and combinations. We decided to compare the effects of ketamine plus dexmedetomidine versus ketamine plus midazolam in procedural sedation. Aims and Objectives: The present study aimed to compare the effects of ketamine plus dexmedetomidine versus ketamine plus midazolam on the adequacy of anesthesia, level of sedation and analgesia, hemodynamic and respiratory parameters, recovery time, and post-operative side effects in short surgical procedures. Materials and Methods: Hundred adult patients were randomized into two groups: Group KD: A bolus dose of Dexmedetomidine 1 mcg/kg in 100 ml NS over 10 min and Group KM: A bolus dose of Midazolam 0.05 mg/kg in 100 ml NS over 10 min. Both groups received bolus dose of Ketamine 1 mg/kg at the start of the procedure. Level of sedation, adequacy of anesthetic technique, hemodynamic parameters, time for rescue analgesia, post-operative recovery time, and complications was measured. Results: In Group KD 7 (14%) patients and in Group KM 13 (26%) patients had inadequate anesthesia. A significant reduction in pulse rate (P&lt;0.001) was observed in Group KD as compared to Group KM. MAP between the two study groups showed a statistically significant reduction in Group KD as compared to Group KM (P&lt;0.05). Time for first rescue analgesia was delayed in Group KD (70.20±14.35) compared to that of Group KM (49±4.73) (P=0.000). Four (8%) patients in Group KD and 11 (22%) patients in Group KM had post-operative nausea and vomiting. Conclusion: Dexmedetomidine-ketamine combination is a good and safe alternative agent for procedural sedation in patients undergoing short surgical procedures.

Comparison of vital sign stability and cost effectiveness between midazolam and dexmedetomidine during third molar extraction under intravenous sedation

To compare the vital sign stability and cost of two commonly used sedatives, midazolam (MDZ) and dexmedetomidine (DEX). Patients and. This retrospective study targeted patients who underwent mandibular third molar extractions under intravenous sedation using MDZ or DEX. The predictor variable was the type of sedative used. The primary outcome variables were vital signs (heart rate and blood pressure), vital sign outliers, and cost of the sedatives. A vital sign outlier was defined as a 30% or more change in vital signs during sedation; the fewer changes, the higher the vital sign stability. The secondary outcome variables included the observer's assessment of alertness/sedation scale, level of amnesia, patient satisfaction, and bispectral index score. Covariates were sex, age, body mass index, sleeping time, dental anxiety score, and Pederson scale. Descriptive statistics were computed including propensity score matching (PSM). The P-value was set at 0.05. The study enrolled 185 patients, 103 in the MDZ group and 82 in the DEX group. Based on the data after PSM, the two samples had similar baseline covariates. The sedative effect of both agents was satisfactory. Heart rate outliers were more common with MDZ than with DEX (49.3% vs 22.7%, P=0.001). Heart rate was higher with MDZ (P=0.000). The cost was higher for DEX than for MDZ (29.27±0.00 USD vs 0.37±0.04 USD, P=0.000). DEX showed more vital sign stability, while MDZ was more economical. These results could be used as a reference to guide clinicians during sedative selection.

Laser-scribing fabrication of a disposable electrochemical device for forensic detection of crime facilitating drugs in beverage samples

A portable and disposable laser-scribed graphene (LSG) device was fabricated on polyetherimide (PEI) substrate for electrochemical detection of benzodiazepines (BZ) drugs such as diazepam (DZ) and midazolam (MZ) in commercial beverage samples. Morphological characterizations of the LSG material recorded by scanning electron microscopy (SEM) revealed the porous nature of the proposed electrochemical device, which contributed to the enhancement of the electroactive area. Besides, the structural and electrochemical characterizations performed by Raman spectroscopy, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) measurements revealed that the PEI-LSG material presents highly disordered graphene-like structures and high electron transfer features, respectively. The electrochemical detection of DZ and MZ was carried out by Square Wave Voltammetry (SWV), whose analytical curves exhibited two linear intervals in concentrations ranging from 2.5 μmol L−1 to 25.0 μmol L−1 and from 25.0 μmol L−1 to 100.0 μmol L−1 for both BZ. We obtained limits of detection (LOD) and quantification (LOQ) of 0.66 and 2.18 μmol L−1 for DZ and 0.61 μmol L−1 and 2.01 μmol L−1 for MZ, respectively. The developed sensor was applied to detect DZ and MZ in commercial beverages such as juice, whisky, and sugarcane spirit samples to mimic potential forensic evidence of drug-facilitated crimes. The recoveries ranged from 97.1% to 117.2% for DZ and from 92.2% to 114.3% for MZ. In addition, the proposed method presented high manufacturing reproducibility (relative standard deviation (RSD) = 2.18% for DZ and RSD = 3.82% for MZ, n = 8 sensors) and adequate selectivity, highlighting the potential of PEI-LSG sensor as an excellent alternative method for forensic detection of crime facilitating drugs in commercial beverage samples.

1131. Evaluation of drug-drug interaction potential of ensitrelvir for CYP3A by clinical studies and physiologically-based pharmacokinetic model

Abstract Background Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days. Disclosures Ryosuke Shimizu, Shionogi &amp; Co., Ltd.: employee Kana Horiuchi, Shionogi &amp; Co., Ltd.: employee Hiroki Koshimichi, n/a, Shionogi &amp; Co., Ltd.: employee Takanobu Matsuzaki, Ph.D., Shionogi &amp; Co., Ltd.: Employee Shinpei Yoshida, Ph.D., Shionogi &amp; Co., Ltd.: employee Shingo Sakamoto, n/a, Shionogi &amp; Co., Ltd.: employee Ryuji Kubota, Ph.D., Shionogi &amp; Co., Ltd.: employee|Shionogi &amp; Co., Ltd.: employee.