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British Dental Journal Jan 2023
Topics: Benzodiazepines; Midazolam; Hypnotics and Sedatives
PubMed: 36707554
DOI: 10.1038/s41415-023-5475-8 -
Journal of Clinical Oncology : Official... Oct 2021
Topics: Cancer Pain; Deep Sedation; Humans; Hypnotics and Sedatives; Male; Midazolam; Palliative Care; Terminal Care
PubMed: 34357800
DOI: 10.1200/JCO.21.01621 -
Veterinary Anaesthesia and Analgesia Mar 2020To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.
OBJECTIVE
To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.
STUDY DESIGN
Prospective pharmacokinetic study.
ANIMALS
A group of six healthy adult, female domestic cats.
METHODS
Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (f), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling.
RESULTS
The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute kg, respectively. No significant changes in HR, MAP, f or Pe'CO were observed following midazolam administration.
CONCLUSION AND CLINICAL RELEVANCE
In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.
Topics: Adjuvants, Anesthesia; Anesthetics, Inhalation; Animals; Cats; Drug Interactions; Female; Half-Life; Injections, Intravenous; Midazolam; Sevoflurane
PubMed: 31983556
DOI: 10.1016/j.vaa.2019.11.005 -
Clinical Drug Investigation Jun 2023Midazolam 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... (Randomized Controlled Trial)
Randomized Controlled Trial
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 (T) of 1.00 h, and mean values of the peak concentration (C) and area under the concentration-time curve (AUC) 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).
Topics: Child; Female; Humans; Male; Administration, Oral; Administration, Rectal; Area Under Curve; Cross-Over Studies; East Asian People; Healthy Volunteers; Hypnotics and Sedatives; Midazolam; Administration, Intravenous; Gels; Biological Availability
PubMed: 37270744
DOI: 10.1007/s40261-023-01276-5 -
Digestive Endoscopy : Official Journal... Jan 2015Patients who undergo gastrointestinal endoscopy often require sedatives such as midazolam and the more recently developed alpha-2 agonist, dexmedetomidine. To assess the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIM
Patients who undergo gastrointestinal endoscopy often require sedatives such as midazolam and the more recently developed alpha-2 agonist, dexmedetomidine. To assess the efficacy and safety of dexmedetomidine sedation for gastrointestinal endoscopy, we conducted a systematic review and meta-analysis of randomized controlled trials comparing dexmedetomidine with midazolam.
METHODS
We searched PubMed, the Cochrane library, and the Igaku-chuo-zasshi database in order to identify randomized trials eligible for inclusion in our meta-analysis. Data from the eligible studies were combined to calculate pooled odds ratios (OR) or weighted mean differences (WMD).
RESULTS
We identified nine randomized trials from the database search. Compared to that of midazolam, the pooled OR for restlessness of dexmedetomidine was 0.078 (95% confidence interval [CI]: 0.013-0.453, P < 0.0001), and there was no significant heterogeneity among the trial results. Dexmedetomidine significantly increased Ramsay sedation score compared with midazolam (WMD: 0.401, 95% CI: 0.110-0.692, P = 0.0069), without significant heterogeneity. Compared with midazolam, the pooled OR for hypoxia, hypotension, and bradycardia with dexmedetomidine sedation were 0.454 (95% CI: 0.098-2.11), 1.370 (95% CI: 0.516-3.637), and 2.575 (95% CI: 0.978-6.785), respectively, with no significant differences detected between the groups.
CONCLUSION
This meta-analysis shows that dexmedetomidine is a safe and effective sedative agent for gastrointestinal endoscopy, especially endoscopic retrograde cholangiopancreatography and endoscopic submucosal dissection.
Topics: Adrenergic alpha-2 Receptor Agonists; Conscious Sedation; Dexmedetomidine; Endoscopy, Gastrointestinal; Humans; Hypnotics and Sedatives; Midazolam
PubMed: 25369736
DOI: 10.1111/den.12399 -
Minerva Anestesiologica Apr 2023Midazolam hydrochloride is a widely accepted benzodiazepine for premedication in pediatric patients. However, there is no consistent conclusion regarding which route of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
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.
EVIDENCE ACQUISITION
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.
EVIDENCE SYNTHESIS
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; I=0%), satisfactory sedation at separation from parents (RR, 0.99; 95% CI, 0.89-1.10; P=0.90; I=57%), and postoperative recovery time (WMD, -8.01; 95% CI, -20.16-4.14; P=0.20; I=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.
CONCLUSIONS
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.
Topics: Child; Humans; Midazolam; Hypnotics and Sedatives; Dexmedetomidine; Postoperative Nausea and Vomiting; Premedication; Administration, Intranasal
PubMed: 36852568
DOI: 10.23736/S0375-9393.22.16937-3 -
Drug Research Oct 2018Midazolam has been successfully used for sedation, which the tablets, injections and oral solutions were available in market. However, the oral bioavailability of...
Midazolam has been successfully used for sedation, which the tablets, injections and oral solutions were available in market. However, the oral bioavailability of midazolam is less due to the first effect, while injection formulation has a low patient compliance. The purpose of this study was to obtain midazolam rectal gel to meet the production and market requirements. We evaluated the in vitro release behavior of midazolam powder, a physical mixture of midazolam and HPMC, and midazolam gel. The results showed that the midazolam gel has superior release degree compared to the other. Correspondingly, midazolam gel produced relevant plasma concentrations result in the rats. At the same dose (1 mg/kg), the C and AUC (0-t) of midazolam after administration of the midazolam rectal gel were 8-10 times higher than that of the oral solution. The midazolam rectal gel was evaluated for physico-chemical tests including pH, viscosity, drug content at 40°C /75%RH (relative humidity) for 180 days (6 months). It provides information about the shelf lives of medicine, as well as the conditions for their storage. Rectum irritation test demonstrated that frequent application of midazolam rectal gel did not induce rectal mucosal damage. In conclusion, midazolam rectal gel was a potential new dosage form, which could alleviate the feeling of alien, discomfort and refusal during application of the patients. It was likely to be a more convenient and effective sedative medicine form specifically for infants and children.
Topics: Administration, Rectal; Animals; Biological Availability; Drug Compounding; Drug Liberation; Female; Gels; Hypnotics and Sedatives; Intestinal Mucosa; Male; Midazolam; Models, Animal; Powders; Rabbits; Rats; Rats, Sprague-Dawley; Rectum; Solubility; Solvents
PubMed: 29631297
DOI: 10.1055/a-0589-9886 -
JAMA Network Open Aug 2023Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive disorder (MDD); therefore, there is a need to develop novel effective treatment strategies.
OBJECTIVE
To assess the efficacy and safety of a single subanesthetic dose of esketamine in boosting the efficacy of oral antidepressants for treating fluctuating antidepressant response in MDD.
DESIGN, SETTING, AND PARTICIPANTS
This single-center, double-blind, midazolam-controlled pilot randomized clinical trial was conducted at Beijing Anding Hospital, Capital Medical University in China. The study enrolled participants aged 18 years and older with fluctuating antidepressant response, defined as patients with MDD experiencing fluctuating symptoms after symptom relief and stabilization. Patient recruitment was conducted from August 2021 to January 2022, and participants were followed-up for 6 weeks. Data were analyzed as intention-to-treat from July to September 2022.
INTERVENTIONS
All participants in the esketamine-treated group received intravenous esketamine at 0.2 mg/kg in 40 minutes. Participants in the midazolam control group received intravenous midazolam at 0.045 mg/kg in 40 minutes.
MAIN OUTCOMES AND MEASURES
The primary outcome was the response rate at 2 weeks, defined as a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included response rate at 6 weeks, remission rates at 2 and 6 weeks, and change in MADRS and Clinical Global Impression-Severity score from baseline to 6 weeks; remission was defined by a MADRS score of 10 or lower.
RESULTS
A total of 30 patients (median [IQR] age, 28.0 [24.0-40.0] years; 17 [56.7%] female) were randomized, including 15 patients randomized to midazolam and 15 patients randomized to esketamine; 29 patients completed the study. Response rates at 2 weeks were significantly higher in the esketamine-treated group than in the midazolam control group (10 patients [66.7%] vs 1 patient [6.7%]; P < .001). Participants treated with esketamine experienced significantly greater reduction in MADRS score from baseline to 2 weeks compared with those treated with midazolam (mean [SD] reduction, 15.7 [1.5] vs 3.1 [1.3]; P < .001). No serious adverse events were observed in this trial, and no psychotogenic effects and clinically significant manic symptoms were reported.
CONCLUSIONS AND RELEVANCE
This pilot randomized clinical trial found that a single subanesthetic dose of esketamine could boost the efficacy of oral antidepressants in treating fluctuating antidepressant response, with a good safety profile.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2100050335.
Topics: Humans; Female; Adult; Male; Depressive Disorder, Major; Midazolam; Pilot Projects; Antidepressive Agents
PubMed: 37578792
DOI: 10.1001/jamanetworkopen.2023.28817 -
Epilepsia Jun 2015This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. (Review)
Review
OBJECTIVE
This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication.
METHODS
Benzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action.
RESULTS
Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic γ-aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings.
SIGNIFICANCE
In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.
Topics: Animals; Anticonvulsants; Epilepsy; Humans; Midazolam; Organophosphate Poisoning
PubMed: 26032507
DOI: 10.1111/epi.12989 -
Journal of Pharmacokinetics and... Dec 2020CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient...
CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.
Topics: Adult; Area Under Curve; Biological Variation, Population; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Midazolam; Middle Aged; Models, Biological; Sensitivity and Specificity; Young Adult
PubMed: 32772302
DOI: 10.1007/s10928-020-09704-1