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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 -
Expert Opinion on Pharmacotherapy Jan 2021Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and... (Review)
Review
INTRODUCTION
Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and duration; therefore, prompt and proper pharmacological intervention is paramount. In a pre-hospital setting, establishing venous access can be difficult, so other routes of drug administration should be considered.
AREAS COVERED
The paper summarizes the data from the literature and provides an evaluation of the efficacy and safety of intramuscular midazolam (IM MDZ) as it pertains to the management of acute seizures and SE.
EXPERT OPINION
The cascade of events involved in the genesis and sustenance of seizures, if not promptly stopped, lead to the perpetuation of the condition and may contribute to the refractoriness of pharmacological treatment. Hence, non-venous routes for drug administration were developed to allow untrained personnel to rapidly stop seizures. Among benzodiazepines (BDZs), IM MDZ is at least as effective and safe as other intravenously administered BDZs. Moreover, thanks to IM MDZ's favorable pharmacodynamic and pharmacokinetic profile, it is a promising alternative to other non-venous drugs such as intranasal-MDZ, buccal-MDZ, and rectal-diazepam in the pre-hospital management of SE cases with motor features.
Topics: Anticonvulsants; Diazepam; Humans; Injections, Intramuscular; Midazolam; Status Epilepticus
PubMed: 32840150
DOI: 10.1080/14656566.2020.1810236 -
Drugs & Aging Feb 2023Status epilepticus (SE) is one of the leading life-threatening neurological emergencies in the elderly population, with significant morbidity and mortality. SE presents...
Status epilepticus (SE) is one of the leading life-threatening neurological emergencies in the elderly population, with significant morbidity and mortality. SE presents unique diagnostic and therapeutic challenges in the older population given overlap with other causes of encephalopathy, complicating diagnosis, and the common occurrence of multiple comorbid diseases complicates treatment. First-line therapy involves the use of rescue benzodiazepine in the form of intravenous lorazepam or diazepam, intramuscular or intranasal midazolam and rectal diazepam. Second-line therapies include parenteral levetiracetam, fosphenytoin, valproate and lacosamide, and underlying comorbidities guide the choice of appropriate medication, while third-line therapies may be influenced by the patient's code status as well as the cause and type of SE. The standard of care for convulsive SE is treatment with an intravenous anesthetic, including midazolam, propofol, ketamine and pentobarbital. There is currently limited evidence guiding appropriate therapy in patients failing third-line therapies. Adjunctive strategies may include immunomodulatory treatments, non-pharmacological strategies such as ketogenic diet, neuromodulation therapies and surgery in select cases. Surrogate decision makers should be updated early and often in refractory episodes of SE and informed of the high morbidity and mortality associated with the disease as well as the high probability of subsequent epilepsy among survivors.
Topics: Humans; Aged; Anticonvulsants; Midazolam; Status Epilepticus; Diazepam; Benzodiazepines
PubMed: 36745320
DOI: 10.1007/s40266-022-00998-z -
Respiratory Investigation May 2022Disinhibition is sometimes experienced during bronchoscopy with sedation. However, data on disinhibition during bronchoscopy are scarce. We examined the prevalence and...
BACKGROUND
Disinhibition is sometimes experienced during bronchoscopy with sedation. However, data on disinhibition during bronchoscopy are scarce. We examined the prevalence and characteristics of disinhibition during bronchoscopy with midazolam.
METHODS
This retrospective study analyzed consecutive patients who underwent bronchoscopy between November 2019 and December 2020. The severity of disinhibition was defined as follows: mild, disinhibition sometimes requiring restraints by assistants; moderate, disinhibition always requiring restraints by assistants; and severe, disinhibition requiring antagonization of sedation by flumazenil to continue bronchoscopy.
RESULTS
Among 251 eligible patients who were sedated using midazolam, 36 (14.3%; 95% confidence interval [CI], 10.5%-19.2%), 42 (16.7%; 95% CI, 12.6%-21.8%), and 7 (2.8%; 95% CI, 1.4%-5.6%) experienced mild, moderate, and severe disinhibition, respectively. Depression (odds ratio [OR] 2.77; 95% CI, 1.20-6.41), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (OR 10.23; 95% CI, 1.02-103.01, referred to brushing/bronchial washing/observation), and increased administration of midazolam (OR 1.20; 95% CI, 1.02-1.42, per 1-mg increase) were independently associated with moderate-to-severe disinhibition. Patients experiencing moderate disinhibition reported significantly better scores for discomfort during bronchoscopy. Besides the maximum systolic and diastolic blood pressures during bronchoscopy, the changes in hemodynamic and respiratory statuses during bronchoscopy or complications did not significantly differ between patients experiencing moderate-to-severe disinhibition and those experiencing none-to-mild disinhibition.
CONCLUSIONS
Moderate-to-severe disinhibition occurred in 19.5% of patients during bronchoscopy with midazolam. We should focus on disinhibition when patients have depression or are planning to undergo EBUS-TBNA, and sparing the administration of midazolam might reduce the occurrence of disinhibition.
CLINICAL TRIAL REGISTRATION
UMIN000038571.
Topics: Bronchoscopy; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Midazolam; Prevalence; Retrospective Studies
PubMed: 34969650
DOI: 10.1016/j.resinv.2021.11.010 -
Anesthesiology Jun 2022
Topics: Amnesia; Conscious Sedation; Humans; Hypnosis; Hypnotics and Sedatives; Midazolam; Receptors, GABA; gamma-Aminobutyric Acid
PubMed: 35482970
DOI: 10.1097/ALN.0000000000004234 -
Addiction Biology Sep 2022The high-drinking-in-the-dark (HDID) lines of mice were selectively bred for achieving high blood alcohol levels in the drinking-in-the-dark (DID) task and have served...
The high-drinking-in-the-dark (HDID) lines of mice were selectively bred for achieving high blood alcohol levels in the drinking-in-the-dark (DID) task and have served as a unique genetic risk model for binge-like alcohol intake. However, little is known about their willingness to consume other addictive drugs. Here, we examined (a) whether the HDID-1 and HDID-2 lines of mice would voluntarily consume midazolam, methamphetamine, morphine and nicotine in a DID test and (b) whether the HDID lines differ from their founders, heterogeneous stock/Northport (HS/NPT), in consumption levels of these drugs at the concentrations tested. Separate groups of HDID-1, HDID-2 and HS/NPT mice were given 4 days of access to each drug, using the single-bottle, limited-access DID paradigm. Male and female mice of both HDID lines consumed all four offered drugs. We observed no genotype differences in 40 μg/ml methamphetamine intake, but significant differences in nicotine, midazolam and morphine intake. Both HDID lines drank significantly more (150 μg/ml) midazolam than their founders, providing strong support for a shared genetic contribution to binge ethanol and midazolam intake. HDID-2 mice, but not HDID-1 mice, consumed more morphine (700 μg/ml) and more nicotine across a range of concentrations than HS/NPT mice. These results demonstrate that the HDID mice can be utilized for tests of voluntary drug consumption other than ethanol and highlight potentially important differences between HDID lines in risk for elevated drug intake.
Topics: Alcohol Drinking; Animals; Ethanol; Female; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Midazolam; Morphine; Nicotine
PubMed: 36001437
DOI: 10.1111/adb.13212 -
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 -
Clinical Pharmacokinetics May 2020Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity,... (Clinical Trial)
Clinical Trial
BACKGROUND
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
OBJECTIVE
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11-18 years.
METHODS
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration-time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
RESULTS
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
CONCLUSIONS
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
TRIAL REGISTRATION
EudraCT: 2014-004554-34.
Topics: Adolescent; Body Mass Index; Body Weight; Child; Humans; Midazolam; Models, Biological; Pediatric Obesity
PubMed: 31745864
DOI: 10.1007/s40262-019-00838-1 -
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 -
Progress in Neuro-psychopharmacology &... Jun 2021Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of...
Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.
Topics: Animals; Conditioning, Classical; Fear; Generalization, Psychological; Male; Mental Recall; Midazolam; Rats; Rats, Wistar; Retention, Psychology
PubMed: 33186637
DOI: 10.1016/j.pnpbp.2020.110161