Acute administration of levodopa-benserazide and tolcapone, a COMT inhibitor, Parkinson's disease.

Tolcapone, a catechol-O-methyltransferase inhibitor, can interfere with the metabolism of levodopa and dopamine and could prolong the motor effect induced by levodopa in parkinsonian patients. To test this hypothesis, we studied the motor effect induced by three acute administrations of a dose of levodopa-benserazide (Madopar) with either 200 mg or 400 mg of tolcapone or placebo, in a double-blind latin-square design. The duration of the on-phase could be compared in 10 parkinsonian patients suffering from square-shaped motor effect. In comparison to placebo, 200 mg and 400 mg of tolcapone significantly increased the mean duration of the on-phase by 61.7 min ( +/- 19.4 SEM) and by 72.2 min ( +/- 18.5), respectively. This clinical effect is suggested to be related mainly to the increase in levodopa area under the curve and half-life induced by tolcapone. The intensity in dyskinesias was increased by 400 mg of tolcapone. Tolcapone appears to be well tolerated and could be helpful as an adjuvant treatment to levodopa in parkinsonian patients with motor fluctuations.

[Relation between the clinical effect and plasma concentration of midazolam in volunteers]. / Relation entre l'effet clinique et la concentration plasmatique du midazolam chez des sujets volontaires.

In 12 healthy volunteers, the pharmacological effects of midazolam were investigated following intravenous (0.15 mg X kg-1 and 12.5 mg in 6 subjects each), intramuscular (12.5 mg in 6 subjects) and oral administration (20 mg in 6 subjects and 10 mg in 4 subjects). The findings were correlated with the plasma concentrations of midazolam and its alpha-hydroxy metabolite. The effects were assessed using objective and subjective methods (reaction time, memory test and subjects' self-assessment with an analog scale covering the degree of sedation). Plasma samples were assayed for midazolam and its alpha-hydroxy metabolite by gas chromatography. The results of the memory test showed that mnemonic retention and recall of a number remained intact for the period preceding intravenous or intramuscular administration. The maximum impairment occurred at 30 min after injection for recall of a number presented at the 15th min. The impairment was no longer detectable 4 h after injection. The plasma concentration time course was similar to that of the reaction time after administration of an identical intravenous or intramuscular dose. The maximum effect was attained within 15 min and 30 min after intravenous and intramuscular administration respectively. Within 2 to 4 h after parenteral administration, the reaction time had returned to normal. At identical plasma concentrations of midazolam, the reaction time was slightly longer in the period immediately following oral administration than after parenteral administration. This result suggested that the alpha-hydroxy metabolite contributed actively to the effect of midazolam. After its intravenous injection, this metabolite's sedative effects attained their maximum with 15 min, having disappeared 4 h later.

[Relationship between clinical effects and pharmacokinetics of midazolam on i.m. and i.v. application to volunteers/1st comm.: Clinical aspects (author's transl)]. / Relations entre l'effet clinique et la pharmacocinétique du midazolam après administration i.m. et i.v. chez des volontaires. 1ère communication: Aspects cliniques.

The onset of action of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine (midazolam, Ro 21-3981, Dormicum), after i.v. injection of 12.5 mg, occurs towards the end of the injection and reaches its maximum level in about 3 min. After i.m. injection, the first effects are generally seen about 5 min later. The maximum effect is reached in about 20 min. Psychometric tests tend to return to normal within 2 h after the injection and are completely normalized within 4 h. Although no objective effect was measurable, the subjects sometimes reported subjective effects lasting up to 6 h. These were mainly signs of mild residual fatigue. The objective and subjective symptoms disappeared after 6 h. General and local tolerance was excellent. A transient sensation (lasting a few minutes) of slight burning was mentioned by some subjects after i.m. injection. Midazolam is therefore a sleep-inducing agent distinguished by rapid and regular onset of action, relatively short duration of action and a low incidence of side effects.