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Epilepsy Research Aug 2021In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for... (Clinical Trial)
Clinical Trial
A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects.
BACKGROUND
In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE.
METHODS
A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed.
RESULTS
The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation.
CONCLUSIONS
The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.
Topics: Anticonvulsants; Child; Child, Preschool; Diazepam; Humans; Japan; Midazolam; Status Epilepticus
PubMed: 34020149
DOI: 10.1016/j.eplepsyres.2021.106651 -
American Journal of Veterinary Research Feb 2013To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas.
ANIMALS
6 healthy alpacas.
PROCEDURES
Midazolam (0.5 mg/kg) was administered IV or IM in a randomized crossover design. Twelve hours prior to administration, catheters were placed in 1 (IM trial) or both (IV trial) jugular veins for drug administration and blood sample collection for determination of serum midazolam concentrations. Blood samples were obtained at intervals up to 24 hours after IM and IV administration. Midazolam concentrations were determined by use of tandem liquid chromatography-mass spectrometry.
RESULTS
Maximum concentrations after IV administration (median, 1,394 ng/mL [range, 1,150 to 1,503 ng/mL]) and IM administration (411 ng/mL [217 to 675 ng/mL]) were measured at 3 minutes and at 5 to 30 minutes, respectively. Distribution half-life was 18.7 minutes (13 to 47 minutes) after IV administration and 41 minutes (30 to 80 minutes) after IM administration. Elimination half-life was 98 minutes (67 to 373 minutes) and 234 minutes (103 to 320 minutes) after IV and IM administration, respectively. Total clearance after IV administration was 11.3 mL/min/kg (6.7 to 13.9 mL/min/kg), and steady-state volume of distribution was 525 mL/kg (446 to 798 mL/kg). Bioavailability of midazolam after IM administration was 92%. Peak onset of sedation occurred at 0.4 minutes (IV) and 15 minutes (IM). Sedation was significantly greater after IV administration.
CONCLUSIONS AND CLINICAL RELEVANCE
Midazolam was well absorbed after IM administration, had a short duration of action, and induced moderate levels of sedation in alpacas.
Topics: Administration, Intravenous; Animals; Area Under Curve; Biological Availability; Camelids, New World; Chromatography, Liquid; Cross-Over Studies; Female; Half-Life; Heart Rate; Hypnotics and Sedatives; Injections, Intramuscular; Male; Mass Spectrometry; Midazolam; Respiratory Rate
PubMed: 23363357
DOI: 10.2460/ajvr.74.2.294 -
British Journal of Anaesthesia Apr 2022Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the...
BACKGROUND
Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-Kras;Trp53;Pdx-1 transgenic mice with pancreatic ductal adenocarcinoma.
METHODS
Six-week-old transgenic mice were administered midazolam 30 mg kg day p.o. (n=13); midazolam 30 mg kg day with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg day i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines.
RESULTS
Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase tumour-associated neutrophils, arginase-1 M2-like tumour-associated macrophages, and CD11bLy-6G polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro.
CONCLUSIONS
These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.
Topics: Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Midazolam; Pancreatic Neoplasms
PubMed: 35120712
DOI: 10.1016/j.bja.2021.12.042 -
Anaesthesia Nov 1997
Topics: Administration, Oral; Child; Humans; Hypnotics and Sedatives; Midazolam; Premedication
PubMed: 9404195
DOI: No ID Found -
Epilepsia Open Dec 2021Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate...
OBJECTIVE
Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist.
METHODS
We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset.
RESULTS
The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity.
SIGNIFICANCE
Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.
Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Ketamine; Midazolam; Phenobarbital; Rats; Soman
PubMed: 34657398
DOI: 10.1002/epi4.12552 -
The pharmacokinetics and pharmacodynamics of midazolam after intravenous administration to donkeys .Canadian Journal of Veterinary Research... Apr 2022The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory...
The pharmacokinetics and pharmacodynamics of midazolam were studied in eight 1-to-3-year-old healthy gelded donkeys. Blood samples were obtained. Heart rate, respiratory rate, rectal temperature, sedation/excitement, ataxia, and response to tactile and auditory stimuli were recorded at baseline until 48 hours after intravenous (IV) midazolam (0.1 mg/kg) administration. Plasma midazolam and 1-hydroxymidazolam were measured using reversed-phase high-performance liquid chromatography. Pharmacokinetic variables were calculated using non-compartmental analysis. Physiologic data were analyzed using a mixed-effects model followed by Dunnett's test and behavioral data were analyzed using a Friedman test then a Dunn's test; < 0.05 was considered significant. Midazolam was detectable for up to 60 minutes post-treatment in 7 donkeys. The median total body clearance, volume of distribution at steady state, elimination half-life, and area under concentration-time profile were 1210 mL/kg/h, 359 mL/kg, 0.27 hours, and 82.7 h × ng/mL, respectively. 1-hydroxymidazolam was detected (29 to 105 ng/mL) between 5 to 15 minutes post-treatment in 4 donkeys. Compared to baseline, rectal temperature and ataxia increased from 90 to 720 minutes ( ≤ 0.038) and 3 to 15 minutes ( ≤ 0.024) post-treatment, respectively. No other parameters showed statistically significant differences. Healthy donkeys cleared midazolam rapidly from plasma after IV administration. Transient ataxia and recumbency without sedation were observed.
Topics: Administration, Intravenous; Animals; Ataxia; Equidae; Half-Life; Midazolam
PubMed: 35388227
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2017Proper sedation for neonates undergoing uncomfortable procedures may reduce stress and avoid complications. Midazolam is a short-acting benzodiazepine that is used... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Proper sedation for neonates undergoing uncomfortable procedures may reduce stress and avoid complications. Midazolam is a short-acting benzodiazepine that is used increasingly in neonatal intensive care units (NICUs). However, its effectiveness as a sedative in neonates has not been systematically evaluated.
OBJECTIVES
Primary objeciveTo assess the effectiveness of intravenous midazolam infusion for sedation, as evaluated by behavioural and/or physiological measurements of sedation levels, in critically ill neonates in the NICU. Secondary objectivesTo assess effects of intravenous midazolam infusion for sedation on complications including the following.1. Incidence of intraventricular haemorrhage (IVH)/periventricular leukomalacia (PVL).2. Mortality.3. Occurrence of adverse effects associated with the use of midazolam (hypotension, neurological abnormalities).4. Days of ventilation.5. Days of supplemental oxygen.6. Incidence of pneumothorax.7. Length of NICU stay (days).8. Long-term neurodevelopmental outcomes.
SELECTION CRITERIA
We selected for review randomised and quasi-randomised controlled trials of intravenous midazolam infusion for sedation in infants aged 28 days or younger.
DATA COLLECTION AND ANALYSIS
We abstracted data regarding the primary outcome of level of sedation. We assessed secondary outcomes such as intraventricular haemorrhage, periventricular leukomalacia, death, length of NICU stay and adverse effects associated with midazolam. When appropriate, we performed meta-analyses using risk ratios (RRs) and risk differences (RDs), and if the RD was statistically significant, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH), along with their 95% confidence intervals (95% CIs) for categorical variables, and weighted mean differences (WMDs) for continuous variables. We assessed heterogeneity by performing the I-squared (I2) test.
MAIN RESULTS
We included in the review three trials enrolling 148 neonates. We identified no new trials for this update. Using different sedation scales, each study showed a statistically significantly higher sedation level in the midazolam group compared with the placebo group. However, none of the sedation scales used have been validated in preterm infants; therefore, we could not ascertain the effectiveness of midazolam in this population. Duration of NICU stay was significantly longer in the midazolam group than in the placebo group (WMD 5.4 days, 95% CI 0.40 to 10.5; I2 = 0%; two studies, 89 infants). One study (43 infants) reported significantly lower Premature Infant Pain Profile (PIPP) scores during midazolam infusion than during dextrose (placebo) infusion (MD -3.80, 95% CI -5.93 to -1.67). Another study (46 infants) observed a higher incidence of adverse neurological events at 28 days' postnatal age (death, grade III or IV IVH or PVL) in the midazolam group compared with the morphine group (RR 7.64, 95% CI 1.02 to 57.21; RD 0.28, 95% CI 0.07 to 0.49; NNTH 4, 95% CI 2 to 14) (tests for heterogeneity not applicable). We considered these trials to be of moderate quality according to GRADE assessment based on the following outcomes: mortality during hospital stay, length of NICU stay, adequacy of analgesia according to PIPP scores and poor neurological outcomes by 28 days' postnatal age.
AUTHORS' CONCLUSIONS
Data are insufficient to promote the use of intravenous midazolam infusion as a sedative for neonates undergoing intensive care. This review raises concerns about the safety of midazolam in neonates. Further research on the effectiveness and safety of midazolam in neonates is needed.
Topics: Humans; Hypnotics and Sedatives; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Intensive Care Units, Neonatal; Intensive Care, Neonatal; Length of Stay; Midazolam; Randomized Controlled Trials as Topic
PubMed: 28141899
DOI: 10.1002/14651858.CD002052.pub3 -
Systematic Reviews Dec 2022The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between...
A comprehensive evaluation between dexmedetomidine and midazolam for intraoperative sedation in the elderly: protocol for a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
The sedative effect of intraoperative sedation in elderly surgery exerts critical influence on the prognosis. Comparison on the safety and efficacy between dexmedetomidine and midazolam in many clinical randomized controlled trials (RCTs) was inconsistent and suspicious. We aim to comprehensively evaluate the safety and efficacy between dexmedetomidine and midazolam for intraoperative sedation in the elderly via meta-analysis and systematic reviews.
METHODS
RCTs regarding to the comparison of sedative effects and safety between dexmedetomidine and midazolam in elderly patients (aged ≥ 60 years) will be comprehensively searched from 2000 October to 2022 May through 4 English databases and 4 Chinese databases. After extraction in duplicate, the systematic review and meta-analysis will be performed on the primary outcomes (hemodynamic changes, sedative effect, cognitive function) and secondary outcomes (analgesic effect, surgical characteristics, complications, or adverse reactions) for assessing the two therapy methods using Review Manager software (Version 5.3). Sensitivity analysis will be conducted to evaluate the heterogeneity of the results; funnel plot and Egger's trial will be performed to analyze publication bias of the included studies, and trial sequential analysis will be applied to assess the robustness and reliability of preliminary meta-analysis results. Finally, rating quality of evidence and strength of recommendations on the meta results will be summarized by Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.
DISCUSSION
This systematic review and meta-analysis will evaluate the safety and efficacy between dexmedetomidine and midazolam for intraoperative sedation in the elderly; it will give an insight on the application of dexmedetomidine and midazolam and will provide evidence-based reference for clinical decision-making.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42021221897.
Topics: Humans; Aged; Midazolam; Dexmedetomidine; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Meta-Analysis as Topic; Hypnotics and Sedatives
PubMed: 36564829
DOI: 10.1186/s13643-022-02144-7 -
Anaesthesia Aug 1993
Topics: Abreaction; Aged; Anesthesia, Spinal; Humans; Male; Midazolam
PubMed: 8214481
DOI: 10.1111/j.1365-2044.1993.tb07215.x -
Revista Medica de Chile Feb 2021Benzodiazepines are used for perioperative conscious sedation. However, its use may be associated with paradoxical reactions. The known risk factors for these reactions...
BACKGROUND
Benzodiazepines are used for perioperative conscious sedation. However, its use may be associated with paradoxical reactions. The known risk factors for these reactions are age, alcohol and drug abuse and psychiatric disorders.
AIM
To assess the incidence and impact of risk factors of paradoxical reactions to midazolam.
MATERIAL AND METHODS
Cross sectional study of 218 patients aged 50 ± 16 years (51% women) scheduled for elective surgical procedures under regional anesthesia and midazolam sedation. The paradoxical reactions were classified according to their severity in three categories.
RESULTS
The incidence of paradoxical reactions to midazolam was 8.3% (95% confidence interval (CI) 5.0-12.7). All were mild and only 28% of the affected patients required pharmacological treatment, none of them flumazenil. A multivariable logistic regression model showed that the variables independently associated with a paradoxical reaction to midazolam were the use of psychoactive medications (Odds Ratio (OR) = 3.4 [1.1-11], p = 0.04, and the dose of midazolam (OR 1.35 [1.03-1.78], p = 0.03.
CONCLUSIONS
The incidence of paradoxical reactions to midazolam was 8,3% and all were mild. Their risk factors are the use of psychoactive medications and the use of higher doses of midazolam.
Topics: Conscious Sedation; Cross-Sectional Studies; Female; Flumazenil; Humans; Hypnotics and Sedatives; Male; Midazolam
PubMed: 34479268
DOI: 10.4067/s0034-98872021000200237