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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 -
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 -
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 -
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 -
Journal of Clinical Pharmacology Feb 2021Age-related changes in disposition of diazepam and its principal active metabolite, desmethyldiazepam (DMDZ), during and after extended dosage with diazepam were studied... (Clinical Trial)
Clinical Trial
Age-related changes in disposition of diazepam and its principal active metabolite, desmethyldiazepam (DMDZ), during and after extended dosage with diazepam were studied in healthy volunteers. Eight elderly subjects (ages 61-78 years) and 7 young subjects (21-33 years) received 2.5 mg of diazepam twice daily for 15 days. Predose (trough) concentrations of diazepam and DMDZ were measured during the 15 days of dosing, and in the postdosage washout period. Kinetic properties were determined by nonlinear regression using a sequential drug-to-metabolite pharmacokinetic model. Steady-state plasma concentrations of diazepam and DMDZ were 30% to 35% higher in elderly subjects compared to young volunteers, and steady-state clearances correspondingly lower, though differences did not reach significance. Large and significant differences were found between young and elderly groups in mean half-life of diazepam (31 vs 86 hours; P < .005) and DMDZ (40 vs 80 hours; P < .02). Half-life values from the multiple-dose study were closely correlated with values from previous single-dose studies of diazepam (R = 0.85) and DMDZ (R = 0.94) in the same subjects. With extended dosing of diazepam in the elderly, slow accumulation and delayed washout of diazepam and DMDZ is probable. After discontinuation, withdrawal or rebound effects are reduced in likelihood, but delayed recovery from sedative effects is possible due to slow elimination of active compounds. Safe treatment of elderly patients with diazepam is supported by understanding of age-related changes in pharmacologic and pharmacokinetic properties.
Topics: Adult; Aged; Aging; Anti-Anxiety Agents; Diazepam; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Young Adult
PubMed: 32856316
DOI: 10.1002/jcph.1726 -
Stress (Amsterdam, Netherlands) Jan 2021Distresses may induce behavioral phenotypes constituting heuristic models for psychopharmacology studies. In several species, including , antidepressants counteract...
Distresses may induce behavioral phenotypes constituting heuristic models for psychopharmacology studies. In several species, including , antidepressants counteract stress-induced phenotypes allowing the use of these models to test new psychoactive drugs. Here, we developed a novel and time-efficient protocol to provoke stress-induced phenotypes in for the study of psychopharmacological agents. In the first experiment, flies ( = 12/groups) were exposed to a random-sequence of different types of stresses during nearly 24 h (including social isolation, fasting, heat, and electric shock), a protocol named short-term variable stress (SVS). Second, flies were exposed to a single stressful stimulus (social isolation, fasting, heat shock or electric shock, = 12/groups). Next, flies submitted to SVS protocol were treated with vehicle, diazepam or fluoxetine ( = 12/groups). At the end of the stress protocols, behavioral phenotypes were evaluated in the open field (OF) and sucrose preference tests. In comparison to the unstressed group, flies exposed to SVS exhibited hyperactivity, as well as shorter times exploring the boundaries of the OF. In contrast to fasting stress, SVS reduced sucrose preference in flies. By analyzing the effects of individual stimuli on fly behavior, fasting and electric shock appear to be the predominant influences on the SVS-induced behaviors. Although fluoxetine or diazepam reduced the initial locomotor activity of flies, no treatment prevented the sequelae of SVS. Altogether, this study provides a time-efficient model system for the study of stress-mediated hyperactivity and anhedonia-like state resistant to fluoxetine and diazepam. The applications of SVS in to preclinical psychopharmacology require further studies. LAY SUMMARY Exposition to unpredictable stress plays a significant role in psychiatric disorder's onset. Behavioral traits of these disorders can be partially modeled in rodents aimed at developing psychopharmacological therapies. However, studies in rodents were questioned by ethical issues. Focused on 3Rs principles, we developed a preclinical model for stress and psychopharmacology research in . Variable stress induced behavioral alterations, including hyperlocomotion and reduced preference for sucrose in flies. However, behavioral alterations were resistant to fluoxetine and diazepam.
Topics: Anhedonia; Animals; Diazepam; Disease Models, Animal; Drosophila; Fluoxetine; Stress, Psychological
PubMed: 32319840
DOI: 10.1080/10253890.2020.1759547 -
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 -
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 -
Nordic Journal of Psychiatry Jan 2023Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and...
BACKGROUND
Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and some patients experience dose-dependent adverse drug reactions (ADR). Previous studies have shown that diazepam metabolism involves the CYP3A4 and CYP3A5 isoenzymes, whose activity is highly variable between individuals, which may contribute to differences in clinical response.
PURPOSE
The study aimed to investigate the effects of the genetic polymorphisms and on the efficacy and safety of diazepam in patients with AWS.
MATERIALS AND METHODS
One hundred male AWS patients received 30 mg/day diazepam by intramuscular injections for 5 days. Genotyping for (rs35599367) and (rs776746) was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessments were performed using psychometric scales.
RESULTS
Patients who carry and genotypes by polymorphic marker (rs35599367) of the gene had a higher risk for ADR and demonstrated lower safety of diazepam therapy ( < 0.001; two-way ANOVA).
CONCLUSION
These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment.
Topics: Humans; Male; Diazepam; Cytochrome P-450 CYP3A; Alcoholism; Substance Withdrawal Syndrome; Polymorphism, Genetic; Genotype
PubMed: 35471917
DOI: 10.1080/08039488.2022.2065531 -
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