Assessment of adverse drug events during the clinical investigation of a new drug.

Identification and documentation of adverse drug events (ADEs) is an essential prerequisite for the evaluation of the therapeutic value of drug treatment. The present article focuses on the methods used to elicit ADEs during the early drug development phase. These methods vary in the sources of information (patient or physician) used to identify and document ADEs and in the areas (e.g., general scales or special motor performance scales) studied for ADEs.

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.

Serum and cerebrospinal fluid concentration of clobazam and N-desmethylclobazam.

Twelve adult neurological patients undergoing lumbar puncture for diagnostic purposes received acute or repeated doses of the 1,5-benzodiazepine clobazam 20-40 mg/day. In one patient, additional ventricle cerebrospinal fluid samples were collected in the course of the diagnostic procedure and the respective concentrations of clobazam and N-desmethylclobazam were determined. The serum and lumbar cerebrospinal fluid concentrations of clobazam and its main metabolite N-desmethylclobazam were compared. The concentrations of both clobazam and N-desmethylclobazam were higher in serum than in cerebrospinal fluid (CSF). Clobazam and N-desmethylclobazam showed similar increase and decline in the ventricle CSF of one patient. This result differed from the pharmacokinetics of clobazam and its main metabolite in the blood which is characterized by a slower increase and a more prolonged elimination of N-desmethylclobazam, as opposed to the parent compound.

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.

[Long-term treatment of depressive syndromes with Psyton (author's transl)]. / Langzeitbehandlung depressiver Syndrome mit Psyton.

23 patients (in-patients and out-patients) with anxious-depressive symptoms were treated orally with the combination drug Psyton (nomifensine/clobazam) up to 6 months. Significant improvement of both anxiety and depression were observed by both the patients' and physician's assessment, particularly during the first month of treatment. Physical examination and laboratory investigations (weight, pulse rate, blood pressure, EKG, ophthalmology, blood and urine analysis, liver function tests) were not influenced by Psyton. Drug tolerance was good, and side effects observed in 39% of the patients were minimal and mainly occurred within 4 weeks after onset of treatment. There was no tendency to physical drug dependence during treatment and during a one-week placebo phase after discontinuation of Psyton. Hence, a long-term treatment of anxious depressive syndromes with this combination drug appears justified without development of drug dependence.

A three-month double-blind study of clobazam versus diazepam in out-patients suffering from neurotic disturbances.

Efficacy and safety of the 1,5 benzodiazepine, clobazam, in comparison to the 1,4 benzodiazepine, diazepam, were controlled in sixty psychiatric out-patients over a period of three months. In the course of this long treatment period data were obtained confirming findings of shorter-lasting studies. Global assessment of the therapeutic efficacy and the total scores of the Hamilton Anxiety Scale revealed no significant the compounds. Both groups showed a significant (p less than 0.01) improvement in the total scores of the Hamilton Anxiety Scale after two weeks of treatment. Scores of the individual items indicated distinct spectra of action: Clobazam was more effective in diminishing anxious mood, whereas diazepam was better able to influence muscular symptoms of anxiety. The relevance of the findings for a more individualized therapy is pointed out.

Review of clinical studies on clobazam.

1 Clobazam was compared with placebo and diazepam in 45 double-blind studies. 2 Clobazam dosage ranged from 5 mg daily (paediatric patients) to 120 mg daily (psychiatric in-patients). Usual daily dosage in out-patient therapy ranged from 20-30 mg clobazam. 3 Treatment duration varied from a few days up to 3.5 years. The usual duration of treatment was 2-4 weeks. 4 Clobazam was shown to be an efficacious and well tolerated anxiolytic agent in various neurotic and psychosomatic disorders. 5 Dosages showing distinct anxiolytic effects in out-patient therapy did not impair psychomotor performance.

[Clobazam (Frisium) in everyday practice. An open six-months' study of its efficacy and tolerance (author's transl)]. / Clobazam (Frisium) in der täglichen Praxis Offene Halbjahresstudie zur Wirksamkeit und Verträglichkeit.

Fifty patients suffering principally from neurotic and psychosomatic disturbances were treated for 6 months with an average of 30 mg clobazam (Frisium) per day. For documentation of the efficacy and tolerance a set of assessment scales and procedures from the ECDEU system (Early Clinical Drug Evaluation Unit) was compiled. The results showed unanimously the anxiolytic efficacy and good tolerance of clobaza. After the second week of treatment there was a significant reduction in the anxiety symptoms in the judgement of the doctor and patient (p less than 0.01). Parallel to the reduction of anxiety symptoms the general condition also improved. The good tolerance of clobazam was shown in the overall clinical assessment and in the recording of specific side effects, which could never be called severe in any case. Moreover, there were no suggestions of changes in tolerance of of dependency.

[Thyroidal autoregulation in nontoxic goiter patients: normalization of the T3/T4 ratio in serum by treatment with potassium iodide (author's transl)]. / Normalisierung des T3/T4-Quotienten im Serum bei Strumma-Patienten unter Kaliumjodid: Ein Beispiel der Autoregulation der Schilddrüse

In iodine deficiency areas, an increased T3/T4 ratio in serum was reported earlier. In this study the influence of potassium iodide on the T3/T4 ratio was investigated. Treatment with 200 mug KI per day for only 4 weeks normalized the initially elevated T3/T4 ratio in 16 nontoxic goiter patients (24.6 plus or minus 9.9 times 10-3, mean plus or minus S.D., before, respectively 18.9 plus or minus 5.5 times 10-3 after KI treatment, p smaller than 0.0025). The mean basal TSH levels (1.42 plus or minus 0.68 before, respectively 1.29 plus or minus 0.52 mugU/ml after KI), and the TSH increase 30 min after 200 mug TRH i.v. (5.54 plus or minus 4.22 and 6.50 plus or minus 5.09 mugU/ml, respectively) did not change significantly. Since the normalization of the T3/T4 ratio in nontoxic goiter patients was independent from changes in the TSH levels, this effect of KI obviously represents an example of thyroidal autoregulation.