Dopaminergic agonist Ro 8-4650 in Parkinson's disease. I. Patients treated with dopa.

An isoquinoline derivative Ro 8-4650 (rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride) with dopaminergic properties was studied in a randomized crossover trial. The group studied comprised 37 patients with idiopathic parkinsonism and persistent symptoms, despite levodopa treatment. Median Webster rating before allocation was 11.5. The trial drug did not differ significantly from placebo as regards effect and involuntary movements. It led to more frequent minor side effects.

Clonazepam in the treatment of epilepsy. A clinical long-term follow-up study.

Sixty-eight patients with various types of epileptic seizures have been treated with clonazepam (Rivotril). Fifty-four patients could be evaluated. In 44 patients, clonazepam was used as a supplement to insufficient previous medication. Ten patients received clonazepam alone. The mean duration of treatment was 2 years and 7 months. Thirty-three patients are still on clonazepam, with a mean duration of treatment of 3 years and 4 months. In 34 patients (63%) a reduction of more than 50% was seen in the seizure frequency of the only type suffered by a patient, or of one of several types. No significant decrease in antiepileptic potency with time was observed. Medication was withdrawn in a total of 21 of the 54 patients because of freedom from seizures (2 patients), lack of effect (7 patients), increased frequency of seizures (3 patients), or lack of cooperation and/or side-effects (3 patients). In 5 patients, the drug may have provoked new types of epileptic seizure. This long-term follow-up study seems to substantiate the favorable antiepileptic properties of clonazepam.

Clonazepam in the treatment of epilepsy. A controlled clinical trial in simple absences, bilateral massive epileptic myoclonus, and atonic seizures.

In a controlled clinical investigation based on ten patients with simple absences and ten patients with myoclonic atonic seizures, all patients who had insufficient response to conventional antiepileptic treatment received clonazepam (Rivotril [Denmark]; Clonopin, comparable US product) combined with previous antiepileptic drugs. The effects of the combined use of clonazepam and the previous antiepileptid drugs were compared with the effects of placebo combined with the same drugs. The trial was single-blind crossover with sequential analysis. In a daily dose of usually 3 to 6 mg, depending on patient age, the antiepileptic effect of clonazepam was significantly superior to placebo and was estimated as remarkably good. Side-effects of somnolence, fatigue, drowsiness, and coordination disturbances occurred in most of the patients, but subsided spontaneously or could be controlled by slow increase or slight reduction of dosage. Mental sideeffects such as agitation, confusion, and aggressiveness were more troublesome and caused discontinuation of clonazepam in two patients.

Parkinson's disease treated with Sinemet or Madopar. A controlled multicenter trial.

92 patients with Parkinson's disease not previously treated with levodopa were considered as eligible for this triple-blind trial. Patients were allocated at random to treatment with either levodopa + benserazide ratio 4:1 (Madopar) or levodopa + carbidopa ratio 10:1 (Sinemet) using dosage schedules recommended by the manufacturers which they had to adhere to for 6 months. Unless prohibitive side-effects occurred daily maximum dosage of 800 mg levodopa + 200 mg benserazide respectively 1,500 mg levodopa + 150 mg carbidopa were obtained after 6 weeks and 3 weeks, respectively. The effect of the two schedules on the Parkinsonian symptoms were equal and appeared equally fast. The frequency of gastrointestinal side-effects and involuntary movements were significantly higher and more severe for Sinemet than for Madopar. These side effects are usually symptoms of levodopa overdosing, but whether or not a different dosage schedule with Sinemet would have given fewer side-effects without concurrent lower efficacy remains open to speculation. The treatment schedules did not differ with regard to other side-effects and influence on blood pressure. Neither treatment seemed to influence liver function, renal function and hematological parameters in a statistically way.

Levodopa alone and in combination with a peripheral decarboxylase inhibitor benserazide (Madopar) in the treatment of Parkinson's disease: A controlled clinical trial.

A combination of levodopa and the extracerebrally acting decarboxylase inhibitor benserazide (ratio 4:1) (Madopar), was compared with levodopa alone in a controlled double-blind clinical multicenter trial on 94 patients with Parkinson's disease. During 4 months of therapy levodopa + benserazide proved superior to levodopa on several accounts. Nausea and vomiting occurred with statistically significant less severity and frequency. Clinical improvement expressed through improvement in Webster rating occurred sooner and was all together greater. The treatment schedules did not differ with regard to other side effects, in particular involuntary movements and reduction in supine blood pressure. Neither treatment seemed to influence liver function, renal function and hematological parameters.

Abnormal involuntary movements in relation to anticholinergics and levodopa therapy.

During a study comparing levodopa with and without benserazide in Parkinsonism, 19 of 41 patients (42 per cent) receiving concomitant anticholinergic therapy developed abnormal involuntary movements (AIM), in contrast to 11 of 58 patients (19 per cent) receiving only levodopa. This difference is statistically significant. Discontinuation or dose-reduction of anticholinergics in 10 patients without altering the levodopa-dosage resulted in disappearance or amelioration of the AIM in nine cases. The Parkinsonism, however, aggravated subsequently, necessitating resumption of anticholinergics in five cases. These results establich further the facilitating effect of anticholinergics on the emergence of AIM.

A controlled trial on clonazepam INN (Ro 5-4023, Rivotril (R)) in the treatment of focal epilepsy and secondary generalized grand mal epilepsy.

In a controlled clinical investigation based on 14 patients with focal seizures and 3 patients with secondary generalized grand mal epilepsy, all with insufficient response to conventional anti-epileptic treatment, clonazepam (Rivotril(R)) combined with previous anti-epileotic drugs was compared with placebo combined with the same drugs. The trial was singleblind cross-over with sequential analyses. With a daily dose, depending upon age, of usually 3-6 mg, the antiepileptic effect of Clonazepam was significantly superior to placebo and was estimated as remarkably good. Side-effects in the form of somnolence, fatique, drowsiness and co-ordination disturbances occurred in most of the patients but subsided spontaneously or could be managed by slow increase or slight reduction in dosage.