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Biomedicine & Pharmacotherapy =... Nov 2022Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and...
Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUCDW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25-50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50-70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007
Topics: Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Diazepam; Phenotype; Humans
PubMed: 36162369
DOI: 10.1016/j.biopha.2022.113747 -
ASN Neuro 2023Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory...
Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65 kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.
Topics: Rats; Animals; Glucose; Ventromedial Hypothalamic Nucleus; Hypoglycemic Agents; Rats, Sprague-Dawley; Diazepam Binding Inhibitor; Glucokinase; Glycogen; Hypoglycemia; RNA, Messenger; RNA, Small Interfering; Diazepam
PubMed: 38031405
DOI: 10.1177/17590914231214116 -
PloS One 2024Pulmonary fibrosis caused by lung injury is accompanied by varying degrees of inflammation, and diazepam can reduce the levels of inflammatory factors. Therefore, the...
BACKGROUND AND OBJECTIVE
Pulmonary fibrosis caused by lung injury is accompanied by varying degrees of inflammation, and diazepam can reduce the levels of inflammatory factors. Therefore, the purpose of this study was to determine whether diazepam can inhibit inflammation and ameliorate pulmonary fibrosis by regulating the let-7a-5p/myeloid differentiation factor 88 (MYD88) axis.
METHODS
Lipopolysaccharide (LPS) was used to induce cell pyroptosis in an animal model of pulmonary fibrosis. After treatment with diazepam, changes in cell proliferation and apoptosis were observed, and the occurrence of inflammation and pulmonary fibrosis in the mice was detected.
RESULTS
The results showed that LPS can successfully induce cell pyroptosis and inflammatory responses and cause lung fibrosis in mice. Diazepam inhibits the expression of pyroptosis-related factors and inflammatory factors; moreover, it attenuates the occurrence of pulmonary fibrosis in mice. Mechanistically, diazepam can upregulate the expression of let-7a-5p, inhibit the expression of MYD88, and reduce inflammation and inhibit pulmonary fibrosis by regulating the let-7a-5p/MYD88 axis.
CONCLUSION
Our findings indicated that diazepam can inhibit LPS-induced pyroptosis and inflammatory responses and alleviate pulmonary fibrosis in mice by regulating the let-7a-5p/MYD88 axis.
Topics: Animals; Pyroptosis; Lipopolysaccharides; Mice; Diazepam; Pulmonary Fibrosis; Myeloid Differentiation Factor 88; MicroRNAs; Inflammation; Male; Mice, Inbred C57BL; Disease Models, Animal; Signal Transduction
PubMed: 38875245
DOI: 10.1371/journal.pone.0305409 -
Drugs in R&D Mar 2022Urine is conventionally used as a specimen to document diazepam-related crimes; however, few reports have described the pharmacokinetics of diazepam and its metabolites...
BACKGROUND
Urine is conventionally used as a specimen to document diazepam-related crimes; however, few reports have described the pharmacokinetics of diazepam and its metabolites in urine.
OBJECTIVE
This study aimed to investigate the pharmacokinetics of diazepam and its metabolites, including glucuronide compounds, in the urine of Chinese participants.
METHODS
A total of 28 volunteers were recruited and each participant ingested 5 mg of diazepam orally. Ten milliliters of urine were collected from each participant at post-consumption timepoints of prior (zero), 1, 2, 4, 8, 12, and 24 h and 2, 3, 6, 12, and 15 days. All samples were extracted by solid-phase extraction and analyzed using high-performance liquid chromatography-tandem mass spectrometry. Diazepam and its main metabolites, except for temazepam, were detected in the urine of volunteers. Pharmacokinetic parameters were analyzed using the pharmacokinetic software DAS according to the non-compartment model.
RESULTS
Urinary diazepam peaked at 2.38 ng/mL (C) and 1.93 h (T). The urinary metabolite nordiazepam peaked at 1.17 ng/mL and 100.21 h; temazepam glucuronide (TG) peaked at 145.61 ng/mL and 41.14 h; and oxazepam glucuronide (OG) peaked at 101.57 ng/mL and 165.86 h. The elimination half-life (t) and clearance (CLz/F) for diazepam were 119.58 h and 65.77 L/h, respectively. The t of the metabolites nordiazepam, TG, and OG was 310.58 h, 200.17 h, and 536.44 h, respectively. Finally, this study found that both diazepam and its main metabolites in urine were detectable for at least 15 days, although there were individual differences.
CONCLUSION
The results regarding diazepam pharmacokinetics in urine would be of great help in forensic science and drug screening.
Topics: China; Chromatography, High Pressure Liquid; Diazepam; Humans; Nordazepam; Solid Phase Extraction
PubMed: 35099786
DOI: 10.1007/s40268-021-00375-y -
Neurological Sciences : Official... Oct 2021Seizure emergencies-status epilepticus and seizure clusters-require rapid evaluation and treatment. Several consensus-based guidelines support a prompt use of... (Review)
Review
INTRODUCTION
Seizure emergencies-status epilepticus and seizure clusters-require rapid evaluation and treatment. Several consensus-based guidelines support a prompt use of intravenous benzodiazepines as the first-line therapy in seizure emergencies. However, most seizure emergencies start outside the hospital settings. Until recently, approved prehospital rescue therapies were limited to rectal diazepam and buccal midazolam (Europe only).
METHODS
The author provides a narrative review of rescue therapies for seizure emergencies based on a comprehensive literature review (PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence) to highlight the changing landscape of seizure recue therapies.
RESULTS
A commercial version of intranasal midazolam was approved by the FDA in 2019 for 12 ≥ years old with seizure clusters. In 2020, the FDA also approved a proprietary vitamin E solution-based diazepam nose spray to abort seizure clusters in ≥ 6 years old subjects. Other than these two new options, the author discussed two previously approved therapies: rectal diazepam and buccal midazolam. The review also includes the use of intramuscular diazepam and midazolam, clonazepam wafer, sublingual and intranasal lorazepam in seizure emergencies. Besides the availability of new therapies from successful trials in controlled settings, the real-world challenges of using rescue medicines in community settings are slowly emerging.
DISCUSSION
With multiple options, a more robust and updated cost-effective analysis of different rescue medicines needs to be performed using effectiveness data from the literature and cost data from publicly available market prices. Further research is also ongoing to develop alternative non-intravenous treatment options for outpatient settings. Lastly, several other non-benzodiazepine drugs, such as allopregnanolone, propofol, and brivaracetam, are also currently under development for seizure emergencies.
Topics: Anticonvulsants; Child; Diazepam; Emergencies; Humans; Seizures; Status Epilepticus
PubMed: 34269935
DOI: 10.1007/s10072-021-05468-9 -
Epilepsia Sep 2022The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status... (Review)
Review
The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status epilepticus. Rescue therapies are key components of treatment plans for patients with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. This review characterizes the pharmacological function of rescue therapies for seizure clusters, as well as describing γ-aminobutyric acid A (GABA ) receptor functions. GABA receptors are heteropentamers, consisting primarily of α1-6, β1-3, γ2, and δ subunits in the central nervous system. These subunits can traffic to and from the membrane to regulate membrane potential. Benzodiazepines, such as diazepam and midazolam, are positive allosteric modulators of GABA receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABA receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABA receptor modulators, individual formulations have unique profiles in practice. Diazepam rectal gel is an effective rescue therapy for seizure clusters; however, adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration and exhibit a rapid onset. Off-label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.
Topics: Administration, Intranasal; Adolescent; Adult; Anticonvulsants; Benzodiazepines; Diazepam; Epilepsy, Generalized; Humans; Midazolam; Nasal Sprays; Receptors, GABA-A; Seizures; Status Epilepticus; gamma-Aminobutyric Acid
PubMed: 35999174
DOI: 10.1111/epi.17341 -
The Cochrane Database of Systematic... May 2016Midazolam is used for sedation before diagnostic and therapeutic medical procedures. It is an imidazole benzodiazepine that has depressant effects on the central nervous... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Midazolam is used for sedation before diagnostic and therapeutic medical procedures. It is an imidazole benzodiazepine that has depressant effects on the central nervous system (CNS) with rapid onset of action and few adverse effects. The drug can be administered by several routes including oral, intravenous, intranasal and intramuscular.
OBJECTIVES
To determine the evidence on the effectiveness of midazolam for sedation when administered before a procedure (diagnostic or therapeutic).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL to January 2016), MEDLINE in Ovid (1966 to January 2016) and Ovid EMBASE (1980 to January 2016). We imposed no language restrictions.
SELECTION CRITERIA
Randomized controlled trials in which midazolam, administered to participants of any age, by any route, at any dose or any time before any procedure (apart from dental procedures), was compared with placebo or other medications including sedatives and analgesics.
DATA COLLECTION AND ANALYSIS
Two authors extracted data and assessed risk of bias for each included study. We performed a separate analysis for each different drug comparison.
MAIN RESULTS
We included 30 trials (2319 participants) of midazolam for gastrointestinal endoscopy (16 trials), bronchoscopy (3), diagnostic imaging (5), cardioversion (1), minor plastic surgery (1), lumbar puncture (1), suturing (2) and Kirschner wire removal (1). Comparisons were: intravenous diazepam (14), placebo (5) etomidate (1) fentanyl (1), flunitrazepam (1) and propofol (1); oral chloral hydrate (4), diazepam (2), diazepam and clonidine (1); ketamine (1) and placebo (3); and intranasal placebo (2). There was a high risk of bias due to inadequate reporting about randomization (75% of trials). Effect estimates were imprecise due to small sample sizes. None of the trials reported on allergic or anaphylactoid reactions. Intravenous midazolam versus diazepam (14 trials; 1069 participants)There was no difference in anxiety (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.39 to 1.62; 175 participants; 2 trials) or discomfort/pain (RR 0.60, 95% CI 0.24 to 1.49; 415 participants; 5 trials; I² = 67%). Midazolam produced greater anterograde amnesia (RR 0.45; 95% CI 0.30 to 0.66; 587 participants; 9 trials; low-quality evidence). Intravenous midazolam versus placebo (5 trials; 493 participants)One trial reported that fewer participants who received midazolam were anxious (3/47 versus 15/35; low-quality evidence). There was no difference in discomfort/pain identified in a further trial (3/85 in midazolam group; 4/82 in placebo group; P = 0.876; very low-quality evidence). Oral midazolam versus chloral hydrate (4 trials; 268 participants)Midazolam increased the risk of incomplete procedures (RR 4.01; 95% CI 1.92 to 8.40; moderate-quality evidence). Oral midazolam versus placebo (3 trials; 176 participants)Midazolam reduced pain (midazolam mean 2.56 (standard deviation (SD) 0.49); placebo mean 4.62 (SD 1.49); P < 0.005) and anxiety (midazolam mean 1.52 (SD 0.3); placebo mean 3.97 (SD 0.44); P < 0.0001) in one trial with 99 participants. Two other trials did not find a difference in numerical rating of anxiety (mean 1.7 (SD 2.4) for 20 participants randomized to midazolam; mean 2.6 (SD 2.9) for 22 participants randomized to placebo; P = 0.216; mean Spielberger's Trait Anxiety Inventory score 47.56 (SD 11.68) in the midazolam group; mean 52.78 (SD 9.61) in placebo group; P > 0.05). Intranasal midazolam versus placebo (2 trials; 149 participants)Midazolam induced sedation (midazolam mean 3.15 (SD 0.36); placebo mean 2.56 (SD 0.64); P < 0.001) and reduced the numerical rating of anxiety in one trial with 54 participants (midazolam mean 17.3 (SD 18.58); placebo mean 49.3 (SD 29.46); P < 0.001). There was no difference in meta-analysis of results from both trials for risk of incomplete procedures (RR 0.14, 95% CI 0.02 to 1.12; downgraded to low-quality evidence).
AUTHORS' CONCLUSIONS
We found no high-quality evidence to determine if midazolam, when administered as the sole sedative agent prior to a procedure, produces more or less effective sedation than placebo or other medications. There is low-quality evidence that intravenous midazolam reduced anxiety when compared with placebo. There is inconsistent evidence that oral midazolam decreased anxiety during procedures compared with placebo. Intranasal midazolam did not reduce the risk of incomplete procedures, although anxiolysis and sedation were observed. There is moderate-quality evidence suggesting that oral midazolam produces less effective sedation than chloral hydrate for completion of procedures for children undergoing non-invasive diagnostic procedures.
Topics: Administration, Intranasal; Administration, Oral; Adult; Anxiety; Child; Chloral Hydrate; Diagnostic Techniques and Procedures; Diazepam; Humans; Hypnotics and Sedatives; Injections, Intravenous; Midazolam; Randomized Controlled Trials as Topic; Therapeutics
PubMed: 27198122
DOI: 10.1002/14651858.CD009491.pub2 -
Arquivos de Neuro-psiquiatria Dec 2022The fact that inflammation triggers epileptic seizures brings to mind the antiepileptic properties of anti-inflammatory drugs.
BACKGROUND
The fact that inflammation triggers epileptic seizures brings to mind the antiepileptic properties of anti-inflammatory drugs.
OBJECTIVE
To investigate the electrophysiological and anti-inflammatory effects of fingolimod on an experimental penicillin-induced acute epileptic seizure model in rats.
METHODS
Thirty-two male Wistar rats were divided into four groups: control (penicillin), positive control (penicillin + diazepam [5 mg/kg]), drug (penicillin + fingolimod [0.3 mg/kg]) and synergy group (penicillin + diazepam + fingolimod). The animals were anesthetized with urethane, and epileptiform activity was induced by intracortical injection of penicillin (500,000 IU). After electrophysiological recording for 125 minutes, IL-1β, TNF-α, and IL-6 were evaluated by ELISA in the serum of sacrificed animals.
RESULTS
During the experiment, animal deaths occurred in the synergy group due to the synergistic negative chronotropic effect of diazepam and fingolimod. Although not statistically significant, fingolimod caused a slight decrease in spike-wave activity and spike amplitudes in the acute seizure model induced by penicillin ( > 0.05). Fingolimod decreased serum IL-1β ( < 0.05); fingolimod and diazepam together reduced IL-6 ( < 0.05), but no change was observed in serum TNF-α values.
CONCLUSION
Even in acute use, the spike-wave and amplitude values of fingolimod decrease with diazepam, anticonvulsant and anti-inflammatory effects of fingolimod will be more prominent in chronic applications and central tissue evaluations. In addition, concomitant use of fingolimod and diazepam is considered to be contraindicated due to the synergistic negative inotropic effect.
Topics: Animals; Male; Rats; Anti-Inflammatory Agents; Anticonvulsants; Diazepam; Disease Models, Animal; Electroencephalography; Fingolimod Hydrochloride; Interleukin-6; Penicillins; Rats, Wistar; Seizures; Tumor Necrosis Factor-alpha; Contraindications, Drug
PubMed: 36580959
DOI: 10.1055/s-0042-1758754 -
Scientific Reports Jun 2023We aimed to evaluate the potential anxiolytic effects of premedication with pregabalin, compared with diazepam and placebo. We conducted this non-inferiority,... (Randomized Controlled Trial)
Randomized Controlled Trial
We aimed to evaluate the potential anxiolytic effects of premedication with pregabalin, compared with diazepam and placebo. We conducted this non-inferiority, double-blind, randomized controlled trial in ASA classification I-II patients aged 18-70 years, scheduled for elective surgery under general anesthesia. They were allocated to receive pregabalin (75 mg the night before surgery and 150 mg 2 h before surgery), diazepam (5 and 10 mg in the same manner) or placebo. Preoperative anxiety was evaluated using verbal numerical rating scale (VNRS) and Amsterdam Preoperative Anxiety and Information Scale (APAIS) before and after premedication. Sleep quality, sedation level, and adverse effects were assessed as secondary outcomes. A total of 231 patients were screened and 224 completed the trial. The mean change (95%CI) in anxiety scores from before to after medication in pregabalin, diazepam, and placebo groups for VNRS were - 0.87 (- 1.43, - 0.30), - 1.17 (- 1.74, - 0.60), and - 0.99 (- 1.56, - 0.41), and for APAIS were - 0.38 (- 1.04, 0.28), - 0.83 (- 1.49, - 0.16), and - 0.27 (- 0.95, 0.40). The difference in change for pregabalin versus diazepam was 0.30 (- 0.50, 1.11) for VNRS and 0.45 (- 0.49, 1.38) for APAIS, exceeding the limit of inferiority for APAIS of 1.3. Sleep quality was statistically different between pregabalin and placebo groups (p = 0.048). Sedation in pregabalin and diazepam groups were significantly higher than placebo group (p = 0.008). No significant differences of other side effects, except dry mouth was higher in placebo group compared with diazepam (p = 0.006). The study filed to provide evidence at non-inferiority of pregabalin compared to diazepam. Furthermore, premedication with either pregabalin or diazepam did not significantly reduce the preoperative anxiety in comparison to placebo, despite the fact that both resulted in higher levels of sedation. Clinicians should weigh the benefits and risks of premedication with these 2 drugs.Thai Clinical Trials Registry: TCTR20190424001 (24/04/2019) Registry URL: https://www.thaiclinicaltrials.org/ .
Topics: Humans; Anti-Anxiety Agents; Pregabalin; Diazepam; Anxiety; Drug-Related Side Effects and Adverse Reactions; Anesthesia, General; Double-Blind Method
PubMed: 37322140
DOI: 10.1038/s41598-023-36616-0