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At least 19 recordsLinked to original sources
PubMed1981

Antileptazol activity and kinetics of clobazam and N-desmethyl-clobazam in the guinea-pig.

The kinetic profiles and antileptazol activity of clobazam and its main metabolite were compared to assess the metabolite's contribution to the anticonvulsant activity of clobazam in the guinea-pig. The metabolite was less effective than the parent compound in terms of doses and active brain levels. However, the metabolite formed after clobazam administration accounted for the persistence of antileptazol activity in this animal species.

Animals↗
PubMedDate not supplied

Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group.

During the past 7 years in Canada, more than 1,300 refractory epileptic patients have been treated with clobazam (CLB) by 104 adult and pediatric neurologists. Using a standard case report, 32 neurologists, who had each treated greater than or equal to 10 patients, provided retrospective data for 877 patients. The population had the following characteristics; the percentages of children and adults were 51 and 49%, respectively; 38% of the patients were mentally retarded; the percentages for single and multiple seizure type diseases were 46 and 54%, respectively; and adults had more complex partial seizures, whereas children had more atypical absence and myoclonic types. Before clobazam, patients received an average of 2 other antiepileptic drugs (AEDs) (range 0-5 AEDs). Average dose of CLB in children was 0.87 mg/kg per day (range 0.05-3.8 mg/kg per day) and in adults 30 mg/day (range 2.5-150 mg/day). Duration of CLB therapy ranged from a few days to greater than 4 years, with 40% being treated greater than 1 year. Using Kaplan-Meier curves, we found that 4 years after starting, 40-50% of patients continued CLB. More than 40% of patients with single seizure type had at least a 50% reduction in seizure frequency (improved). At least 60% of patients with multiple seizure type had improvement in one or more seizure types, and nearly 40% of the patients had all their seizure types improved. The seizure frequency for each seizure type, except tonic, was reduced greater than 50% in 40-50% of patients and by 100% in 10-30% of patients. Twenty percent stopped CLB for poor efficacy, 4% stopped for safety-related reasons including drug interactions, and 8% stopped for both reasons. Possible side effects (predominantly somnolence) were reported by 32%; however, in only 11% were the side effects sufficiently severe to cause discontinuation of medication. "Tolerance," leading to discontinuation of CLB, was reported for 9%. Patients treated with CLB for at least 1 year were generally maintained with CLB greater than 1 year. Thus, CLB is useful in refractory epilepsy of all types, suggesting that a monotherapy trial in less severe epilepsy is now desirable.

Adolescent↗
PubMed1987

Simultaneous determination of clobazam, N-desmethyl clobazam and clonazepam in plasma by high performance liquid chromatography.

A method is described for the simultaneous determination of clobazam, its active metabolite N-desmethylclobazam, and clonazepam in plasma by high performance liquid chromatography. The drugs are extracted with diethyl ether from 1.0 ml plasma adjusted to pH 9.0 and separated on a C18 reverse phase column using a mobile phase of 40% acetonitrile in phosphate buffer pH 3.0. The ultraviolet absorbance is monitored at a wavelength of 313 nm. The method has a coefficient of variation of less than 5% and an overall recovery of greater than 85% and is sufficiently sensitive for the therapeutic monitoring of these drugs.

Anti-Anxiety Agents↗
PubMed1997

Interactions of clobazam with conventional antiepileptics in children.

Clobazam is a 1,5-benzodiazepine effective in antiepileptic therapy of children and adults. Presently it is mainly used as adjuvant therapy for intractable seizures. Our objective was to evaluate the effect of clobazam on the apparent clearance of other antiepileptic drugs at steady state, and to determine the factors that determine the plasma levels of clobazam and its active metabolite N-desmethylclobazam. Patients were 74 children with intractable seizures who received treatment with clobazam at our institution as part of the Canadian Cooperative Clobazam Study Group during the years 1987 to 1991. Serum concentrations of clobazam, N-desmethylclobazam, and of concomitant antiepileptic drugs were monitored and prospectively collected. The effect of clobazam treatment on the apparent clearance steady state of the other antiepileptic drugs was determined by statistical comparison of the clearances of each drug before and after initiation of clobazam treatment using Wilcoxon's signed rank test. The effects of dosage, age, and concomitant antiepileptic therapy on the levels of clobazam and N-desmethylclobazam was assessed by multivariate analysis. Response to treatment and incidence of adverse effects were evaluated for each conventional antiepileptic drug to possibly identify favorable or unfavorable combinations with clobazam. Whereas the clearances of most conventional antiepileptics are not affected by cotherapy with clobazam, the apparent clearances of valproic acid and primidone are significantly reduced in the presence of clobazam. Serum concentrations of clobazam increased with dosage and age, and decreased with phenobarbital cotherapy. Serum concentrations of N-desmethylclobazam significantly correlated with clobazam serum levels, age, or clobazam dosage and were significantly increased by cotherapy with phenytoin or carbamazepine. None of the concomitantly used drugs were associated with increased or decreased rate of seizure control. Twelve patients experienced mild adverse drug effects that were not associated with particular cotherapy, clobazam dose, or plasma concentrations. When clobazam is added to a therapy regimen that includes valproic acid, the patient should be closely followed for possible adverse drug reactions caused by elevated valproic acid serum concentrations, and monitoring of valproate serum levels should be considered. When clobazam doses are gradually increased to achieve an optimal clinical effect, the interactions with phenobarbital, carbamazepine, and phenytoin do not necessitate therapeutic drug monitoring of clobazam or N-desmethylclobazam, because there is a large therapeutic window and a poor correlation between plasma concentrations and therapeutic efficacy.

Adolescent↗
PubMed1982

Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats.

The 1.5-benzodiazepine (clobazam), the 1,4-benzodiazepine (diazepam), and two nonbenzodiazepine antiepileptic drugs (phenobarbital and valproate) were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that clobazam and valproate exhibit a wider range of experimental anticonvulsant activity than either diazepam or phenobarbital. Except for clobazam by the maximal electroshock seizure (MES) test in rats, clobazam and valproate are effective in nontoxic doses against MES and all four chemically induced seizures (Metrazol, bicuculline, picrotoxin, and strychnine). Clobazam is effective by the MES test in rats only in doses that exceed the median minimal toxic dose. Phenobarbital is effective against all of the above tests, but minimal toxic doses must be employed to prevent strychnine seizures. Diazepam, on the other hand, is effective in nontoxic doses against seizures induced by Metrazol, bicuculline, and picrotoxin, but protects animals from maximal electroshock and strychnine seizures only when given in toxic doses. When compared on the basis of protective indices (PI = TD50/ED50) calculated from intraperitoneal data, the PIs for clobazam were 1.6 to 13 times higher than those for diazepam. Overall, except for the MES test in rats, the PIs for clobazam were from 1.5 to 44 times higher than those for any of the other three substances. With respect to the MES test in rats, the PI for clobazam was 10.8 times higher than that for diazepam; however, the PIs for phenobarbital and valproate were 3.5 and 4.4 times higher, respectively, than that for clobazam. These data suggest that the spectrum of anticonvulsant activity for the 1,5-benzodiazepine (clobazam) is superior to that for the 1,4-benzodiazepine (diazepam). Also, the broad experimental profile of anticonvulsant activity of clobazam agrees well with its reported broad clinical efficacy.

Animals↗
PubMed1996

Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture.

PURPOSE: The antiepileptic effects of clobazam, a 1,5-benzodiazepine, have been well documented in animal experiments and clinical trials. However, the drug's mechanisms of antiepileptic actions are still undetermined. The purpose of this study was to learn how clobazam and its active metabolite modulate gamma-aminobutyric acid (GABA)-activated currents in rat cerebral neurons in culture. METHODS: Whole-cell voltage-clamp recordings were performed on cultured cerebral neurons of the rat. Clobazam or its metabolite N-desmethylclobazam was dissolved in the extracellular solution and applied for 2 s by pressure ejection from a micropipette. To maintain GABA-activated currents, 2 mM Mg adenosine triphosphate (ATP) was added to the intracellular solution. RESULTS: GABA elicited outward currents that were mediated by GABAA receptor-coupled Cl- channels. Applying clobazam with 10 microM GABA elicited enhanced outward currents. Flumazenil, an antagonist of the benzodiazepine receptor, inhibited the enhancing effect of clobazam. The enhancement ratio increased as much as 2.28-fold in a dose-dependent manner at a concentration of 3 microM clobazam. However, it started to decrease at a concentration of 10 microM clobazam. The metabolite N-desmethylclobazam was tested in the same manner, and exhibited an identical dose-dependent enhancement of GABA-activated currents. CONCLUSIONS: The antiepileptic effects of the 1,5-benzodiazepines are attributed to the enhancement of GABAergic inhibitory neurotransmission. The antiepileptic effects of clobazam are thought to depend mainly on its active metabolite N-desmethylclobazam, which is present in high concentrations in patients who receive long-term clobazam. Clobazam's enhancement of GABA-activated currents was most marked on weaker GABA currents. We therefore infer that clobazam acts more efficiently on tissues in which the release of GABA is diminished.

Animals↗
PubMed1990

Study of the interaction of clobazam with cyclodextrins in solution and in the solid state.

Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.

Anti-Anxiety Agents↗
PubMed1983

Pharmacokinetic aspects of the interaction between clobazam and cimetidine.

The pharmacokinetic interaction between clobazam and cimetidine was studied in 9 healthy male volunteers in an open-labelled study. After a single oral dose of clobazam 30 mg, a wash-out period of 14 days was followed by daily doses of cimetidine 1 g for one week. Thereafter a single oral dose of clobazam 30 mg was again given. The plasma concentrations of clobazam and its main metabolite N-desmethyl-clobazam were measured by gas-chromatography. The area under the curve (AUC0-infinity) of plasma clobazam level was significantly larger after pretreatment with cimetidine and the elimination half life of clobazam was significantly longer. There were no statistically significant differences in Cmax and tmax for plasma clobazam. The plasma levels of N-desmethyl-clobazam did not show any significant change after the intake of cimetidine.

Adult↗
PubMed2005

Intermittent clobazam therapy in febrile seizures.

OBJECTIVE: To evaluate the efficacy of intermittent clobazam therapy in preventing the recurrence of febrile seizures and to assess its safety. METHODS: The study was a prospective, randomized, double-blind placebo-controlled trial conducted in the Department of Child Health, Christian Medical College Hospital, Vellore between July 2001 and September 2002. Neurologically normal children between 6 months and 3 years of age with a history of febrile seizures and no evidence of acute CNS infection or EEG abnormality were included into the study. 19 children in a clobazam group and 20 in the placebo group were randomly allocated. Temperature reduction measures with paracetamol and tepid sponging were advised to all children. In addition the dispensed medication was to be administered at the onset of fever and continued for 48 hours irrespective of the duration of fever. The children were then monitored for seizures and adverse effects of clobazam. The children were followed up for a mean period of 9.9 months. The analysis was done on the number of febrile episodes in both the groups. RESULTS: There were a total of 110 episodes of fever during the study period. Mean number of febrile episodes in the clobazam group was 3.1 and in placebo group 2.56. Six (12.5%) of the 48 episodes in placebo group and one (1.7%) of 60 episodes in clobazam group had seizure recurrence. This was statistically significant (p = 0.01). Drowsiness and weakness were present equally in both clobazam and placebo groups whereas ataxia was present only in the clobazam group, the difference being statistically significant (p=0.04). CONCLUSION: Intermittent clobazam therapy is an effective measure in the prevention of recurrence of febrile seizures. The ataxia due to clobazam was much lower than that reported with diazepam.

Anticonvulsants↗
PubMed1987

The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N-desmethylclobazam.

The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N-desmethylclobazam (NDMC) was studied in volunteers. Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. The increases in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant.

Adult↗
PubMedDate not supplied

Clobazam in therapy-resistant patients with partial epilepsy: a double-blind placebo-controlled crossover study.

Clobazam was compared with placebo as antiepileptic adjunct medication in 129 therapy-resistant epileptic patients who were mainly suffering from complex partial seizures. The study was performed in five European countries according to a double-blind crossover design lasting 7 months. Two treatment periods of 3 months (1 month adjustment and 2 months maintenance medication) were separated by one medication switch-over month. The difference in seizure reduction between clobazam and placebo was significant (p less than 0.05). Nineteen percent of patients receiving clobazam became seizure-free during the maintenance dose period. In contrast, freedom from seizures was not observed in any placebo patient. Electroencephalogram (EEG) signs, mood ratings, and global impressions also indicated therapeutic effects of clobazam in epilepsy. The most frequent adverse reactions to clobazam were drowsiness and dizziness. However, the sedative effects of clobazam seemed to be less pronounced in comparison with other benzodiazepines. The study gives evidence of the therapeutic value of clobazam as adjunct medication in therapy-resistant partial seizures. The use of clobazam as monotherapy and long-term treatment, as well as the particular seizure response pattern to clobazam, has to be further investigated.

Adult↗
PubMed1990

Development of tolerance to clobazam in fully kindled rats: effects of intermittent flumazenil administration.

The effects of acute and chronic treatment with the 1,5-benzodiazepine, clobazam, were studied on fully kindled amygdaloid seizures in rats. After acute dosing, clobazam significantly reduced all parameters of kindled seizures (seizure severity, seizure duration, duration of amygdalar afterdischarges) at doses of 7.5 or 10 mg/kg i.p. 'Active' plasma concentrations of clobazam ranged between 300-800 ng/ml. The elimination half-life of clobazam in plasma was about 1 h. Only very low (10-75 ng/ml) levels of the major metabolite, N-desmethylclobazam, were detected in rats. Administration of N-desmethylclobazam indicated that plasma concentrations of at least 300 ng/ml were necessary for anticonvulsant effects. During chronic administration of clobazam, 10 mg/kg 3 times daily, marked tolerance developed to the anticonvulsant and adverse (ataxiogenic and sedative) effects of the benzodiazepine. The experiment was repeated using a different protocol with minimized environmental stimuli and no amygdala stimulation during chronic clobazam administration. The loss of effects on seizure severity and motor function was similar to the first chronic experiment, whereas the loss of effects on seizure and afterdischarge duration was less marked. This indicates that conditioning of 'learned tolerance' is partly involved in clobazam tolerance in kindled rats. Intermittent injection of the benzodiazepine receptor antagonist, flumazenil, 5 mg/kg i.p. every third day, did not alter the loss of pharmacodynamic effects during chronic treatment with clobazam, but seemed to prevent hyperexcitation and other abstinence symptoms in the withdrawal period. The data indicate that periodic injection of a benzodiazepine receptor antagonist does not represent a possible therapeutic approach for preventing the development of tolerance during long-term benzodiazepine exposure.

Animals↗
PubMed1999

The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy.

PURPOSE: To compare the cognitive and behavioural effects of clobazam versus standard monotherapy in the treatment of childhood epilepsy. METHODS: A randomized, double-blind, prospective design was carried out at three Canadian pediatric epilepsy centres. This study was part of a larger multi-centre study on the efficacy of clobazam. Children with newly diagnosed epilepsy were assigned randomly to receive clobazam or carbamazepine. Children who had failed previous treatment with carbamazepine were assigned randomly to clobazam or phenytoin. Children who had failed on any other antiepileptic drug were assigned randomly to receive clobazam or carbamazepine. In a subset of patients neuropsychological assessments were carried out at 6 weeks and 12 months after initiation of medication. Intelligence, memory, attention, psychomotor speed, and impulsivity were assessed. RESULTS: There were no differences between the clobazam and standard monotherapy groups on any of the neuropsychological measures obtained at 6 weeks or 12 months. There was no evidence for a deterioration in performance for those children who remained on clobazam for the entire 12-month study period. CONCLUSION: The cognitive and behavioural effects of clobazam appear to be similar to those of standard monotherapy.

Adolescent↗
PubMed2005

Clobazam as add-on therapy for temporal lobe epilepsy and hippocampal sclerosis.

BACKGROUND: Clobazam is a benzodiazepine with known antiepileptic action; however, it is not considered first line therapy in the treatment of epilepsy. The objective of this study was to evaluate the efficacy of clobazam as add-on therapy in adults with temporal lobe epilepsy associated with MRI evidence of hippocampal sclerosis (HS). METHOD: This is a retrospective study, conducted at our epilepsy clinic which evaluated clobazam as add-on therapy in patients with temporal lobe epilepsy and MRI signs of HS. Clobazam was prescribed based on the minimum effective dose up to the maximum tolerated dose. RESULTS: Seventy-eight patients met the inclusion criteria (51 women), ages ranging from 16 to 76 years old (mean=42.2). Dosage of clobazam ranged from 5 to 60 mg/day (mean=22.6 mg/day). Clobazam was used from one month to eight years (mean=29 months). Sixteen (20.5%) patients were seizure-free, 20 (25.5%) had more than 75% improvement in seizure control, eight (10%) had more than 50% and 20 (26%) were non responders to clobazam. In 14 (18%) we could not determine seizure frequency during follow-up. The improvement in seizure control lasted for more than one year in 30 (68%) patients. CONCLUSION: Our data suggest that clobazam should be considered as add-on therapy in the treatment of patients with temporal lobe epilepsy associated with MRI signs of HS.

Adolescent↗