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Epilepsia 2004To confirm the efficacy and to clarify the problems of clobazam (CLB) as a new antiepileptic drug (AED) and clorazepate (CLP) as an alternative AED in Japan.
PURPOSE
To confirm the efficacy and to clarify the problems of clobazam (CLB) as a new antiepileptic drug (AED) and clorazepate (CLP) as an alternative AED in Japan.
METHODS
CLB and CLP were added on or replaced with conventional AEDs in 55 and 170 patients with refractory epilepsies, respectively. Short-term efficacy was studied after at least 2 months of CLB administration and at least 4 weeks of CLP administration. Long-term efficacy was examined in 31 cases with CLB for > or =6 months and in 86 cases with CLP for > or =6 months. CLB was initiated at 0.15-0.40 mg/kg and increased by 0.1-0.2 mg/kg every 1-2 weeks up to 0.28-1.25 mg/kg. CLP was started at 0.3-0.7 mg/kg and increased by 0.2-0.3 mg/kg every 1-2 weeks up to 2.5 mg/kg. Tolerance was examined in 42 cases with CLB for > or =3 months and 112 cases with CLP for > or =4 weeks.
RESULTS
CLB was effective, defined as > or =50% reduction in seizure frequency, in 71% of the short-term subjects and 81% of the long-term subjects. Short-term efficacy was better in symptomatic localization-related epilepsies, but long-term efficacy did not differ according to seizure classification. Short-term efficacy was not different by seizure types or EEG findings. CLP was effective in 70% of the short-term subjects and 80% of the long-term subjects. CLP was more effective in patients with localization-related epilepsies or in patients with partial seizures or focal epileptiform discharges on EEG. Adverse effects developed in 47% of CLB cases and 31% of CLP cases, but the incidence was reduced by lower initial doses and slow dose titration. Tolerance occurred in 24% of CLB cases and 48% of CLP cases, half within 3-4 months after the initiation of CLB and half by 2 months after the start of CLP. Upon rechallenge, 70% of CLB-tolerant cases and 50% of CLP-tolerant cases responded to each drug again by increasing or maintaining the dosage.
CONCLUSIONS
Excellent efficacy of CLB and excellent and prolonged efficacy of CLP for refractory epilepsies were confirmed. Frequent tolerance and adverse effects were major problems, but were manageable.
Topics: Anticonvulsants; Benzodiazepines; Clobazam; Clorazepate Dipotassium; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Epilepsy; Follow-Up Studies; Humans; Japan; Longitudinal Studies; Treatment Outcome
PubMed: 15610190
DOI: 10.1111/j.0013-9580.2004.458005.x -
British Journal of Clinical Pharmacology Jan 1980In the first study, eight healthy volunteers were given single oral doses of 5, 7.5 and 15 mg clorazepate dipotassium (Tranxene), a precursor of n-desmethyldiazepam,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In the first study, eight healthy volunteers were given single oral doses of 5, 7.5 and 15 mg clorazepate dipotassium (Tranxene), a precursor of n-desmethyldiazepam, and placebo. Drug effects up to 5 h after administration were assessed on a battery of physiological, psychomotor and subjective tests. Psychotropic effects were not marked but decreases in EEG auditory responses and increases in EEG fast-wave activity were detected. Some psychomotor impairment was apparent after the 15 mg dose. Subjective effects comprised some lowering of alertness and changes in sociability. Plasma concentrations of n-desmethyldiazepam 3 h after ingestion were related to dose and correlations were found with the other variables. In the second study, nine subjects received clorazepate 7.5 and 15 mg, and placebo, in a single daily dose for 14 days, with at least 5 weeks between courses. Psychotropic effects were evaluated on the first and last days of drug administration, for up to 5 h following the daily dose. After 15 days, EEG auditory responses were diminished and fast-wave activity increased. Anxiety was diminished but psychomotor effects were minimal. Psychotropic effects following the dose of clorazepate dipotassium on day 15 were compared with those on day 1. Objective measures, the EEG auditory response, fast-wave activity and critical flicker fusion, were significantly less affected on day 15 than on day 1 whereas subjective ratings and the digit-symbol substitution test were more affected. Plasma concentrations of n-desmethyldiazepam increased in a dose-related way over the 2 weeks. Increases following the drug on day 15 were at least as large as those on day 1 suggesting that pharmacokinetic factors could not account for the physiological tolerance noted above. It was concluded that clorazepate dipotassium in doses of 7.5 mg/day provided useful anxiolytic actions without undue sedation.
Topics: Adult; Anti-Anxiety Agents; Clorazepate Dipotassium; Diazepam; Electroencephalography; Evoked Potentials; Flicker Fusion; Galvanic Skin Response; Humans; Male; Motor Skills; Reaction Time; Time Factors; Tremor
PubMed: 6101956
DOI: 10.1111/j.1365-2125.1980.tb04801.x -
British Journal of Clinical Pharmacology 1981The pharmacokinetic characteristics of the six benzodiazepine anxiolytic drugs available in the United States are reviewed. Concern over the abuse potential of the... (Review)
Review
The pharmacokinetic characteristics of the six benzodiazepine anxiolytic drugs available in the United States are reviewed. Concern over the abuse potential of the benzodiazepine class of drugs is discussed.
Topics: Anti-Anxiety Agents; Chlordiazepoxide; Clorazepate Dipotassium; Diazepam; Humans; Kinetics; Lorazepam; Metabolic Clearance Rate; Oxazepam; Prazepam; Substance Withdrawal Syndrome
PubMed: 6133535
DOI: 10.1111/j.1365-2125.1981.tb01832.x -
Effect of N-desmethyldiazepam (nordiazepam) and a precursor, potassium clorazepate, on sleep in man.British Journal of Clinical Pharmacology Jun 19761 The effect of N-desmethyldiazepam (nordiazepam, 5 and 10 mg) and potassium clorazepate (15 mg, a precursor of nordiazepam) on sleep was studied in six healthy adult... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1 The effect of N-desmethyldiazepam (nordiazepam, 5 and 10 mg) and potassium clorazepate (15 mg, a precursor of nordiazepam) on sleep was studied in six healthy adult males. Electroencephalography (EEG) was used for sleep measures, and analogue scales were used for subjective assessments of well-being and sleep quality. 2 Effects on total sleep time were limited to the night of ingestion. There were increases with nordiazepam (5 and 10 mg) (P = 0.05) and 0.001 respectively), and with clorazepate (15 mg) (P = 0.01). Sleep onset latencies were shortened, particularly with nordiazepam, and awakening to stage 0 activity was reduced, by both drugs. The latency to stage 3 was reduced by nordiazepam (5 and 10 mg) (P = 0.05). 3 There were no effects of nordiazepam (5 mg) on the duration (min) of sleep stages. Nordiazepam (10 mg) and clorazepate (15 mg) reduced the duration of stage 0 and stage 1, and there were increases in stage 2. Reduced stage 1 and increased stage 2 sleep were observed during the recovery night. No effects were observed with stage 3, but there was evidence that stage 4 activity was depressed on the recovery night only. No effects were observed on REM sleep, except that the appearnace of the first REM period was delayed with clorazepate (15 mg) P = 0.01). The effect of nordiazepam (10 mg) and clorazepate (15 mg) were comparable, and each modified sleep for about 28-30 h after ingestion. 4 With nordiazepam (10 mg) and clorazepate (15 mg) the subjects, as a group, reported improved sleep, but subjective assessments of well-being were not altered. Correlations were calculated for sleep measures and subjective assessments.
Topics: Adult; Anti-Anxiety Agents; Clinical Trials as Topic; Clorazepate Dipotassium; Diazepam; Humans; Male; Nordazepam; Sleep; Sleep Stages; Time Factors
PubMed: 9963
DOI: No ID Found -
British Journal of Anaesthesia Mar 1979
Topics: Anti-Anxiety Agents; Anxiety; Clorazepate Dipotassium; Humans; Preanesthetic Medication
PubMed: 35186
DOI: 10.1093/bja/51.3.263-a -
The Journal of International Medical... 1999The efficacy of trazodone (mean once-daily dose 111.5 +/- 36.3 mg) versus clorazepate (mean once-daily dose 17.5 +/- 7.5 mg) to relieve anxious and depressive symptoms... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The efficacy of trazodone (mean once-daily dose 111.5 +/- 36.3 mg) versus clorazepate (mean once-daily dose 17.5 +/- 7.5 mg) to relieve anxious and depressive symptoms in 18 patients undergoing treatment for breast cancer was investigated in a 28-day randomized, double-blind study. Efficacy was evaluated using the Hospital Anxiety and Depression Scale, the Revised Symptom Checklist and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. A successful response to treatment was achieved in 91% (10/11) of patients who received trazodone and 57% (four of seven) of patients who were administered clorazepate (P = 0.1373). Bayesian analysis revealed that the prior probability of making a wrong decision in prescribing trazodone rather than clorazepate reduced from 26% to 8%. Assessment of the clinical scales suggested a benefit of trazodone compared with clorazepate, although the differences were not significant. Safety of both treatments was similar. Trazodone is devoid of an abuse risk and dependence and, therefore, could be a valuable alternative to clorazepate in the treatment of adjustment disorders in cancer patients.
Topics: Adjustment Disorders; Adult; Aged; Anti-Anxiety Agents; Anxiety; Breast Neoplasms; Clorazepate Dipotassium; Depression; Double-Blind Method; Female; Humans; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Safety; Trazodone
PubMed: 10726235
DOI: 10.1177/030006059902700602 -
British Journal of Pharmacology Nov 19771. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam...
1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection. 2. Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect. 3. The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concenqrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate. 4. It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.
Topics: Animals; Behavior, Animal; Clorazepate Dipotassium; Diazepam; Discrimination, Psychological; Half-Life; Haplorhini; Kinetics; Macaca mulatta; Male; Time Factors
PubMed: 412540
DOI: 10.1111/j.1476-5381.1977.tb08423.x -
Journal of the American Veterinary... Jan 2015
Topics: Animals; Anxiety, Separation; Behavior, Animal; Clomipramine; Clorazepate Dipotassium; Dogs; Male
PubMed: 25517322
DOI: 10.2460/javma.246.1.49 -
The Journal of International Medical... 1999The efficacy of trazodone and clorazepate to relieve anxiety and depressive symptoms in 21 HIV-positive subjects with adjustment disorders was determined in a 28-day... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The efficacy of trazodone and clorazepate to relieve anxiety and depressive symptoms in 21 HIV-positive subjects with adjustment disorders was determined in a 28-day single-centre, randomized, double-blind study. Subjects were evaluated using the Hospital Anxiety and Depression Scale, the Revised Symptom Checklist, the European Organization for Research and the Treatment of Cancer Quality of Life Questionnaire, and a binary criterion based on the Clinical Global Impression. The incidence of successful treatment was 80% for trazodone compared with 64% for clorazepate; the sample number was too small to establish a significant difference. Bayesian analysis revealed the probability of making a wrong decision in prescribing trazodone rather than clorazepate reduced from 35% to 18% in this small sample. Clinical evaluations using the different scales suggest some benefit from trazodone, although this was not significant. Safety of both treatments was similar. Trazodone is devoid of the risk of abuse and dependence, and may be a valuable alternative to benzodiazepines for the treatment of HIV-related adjustment disorders.
Topics: Adjustment Disorders; Adult; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Clorazepate Dipotassium; Double-Blind Method; HIV Infections; Humans; Pilot Projects; Trazodone
PubMed: 10689628
DOI: 10.1177/030006059902700502