Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L -dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L -dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L -dopa given as standard release L -dopa/carbidopa. Methods Six different doses of L -dopa/carbidopa were investigated in this placebocontrolled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups ( n = 14-16). Two different L -dopa/carbidopa doses were administered to each subject (50/ 12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/ 25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L -dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of L -dopa to a similar extent at all doses of L -dopa/carbidopa, that is by about 30-40% compared with placebo ( P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for L -dopa at all L -dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L -dopa were maintained for a longer period at all doses of L -dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-Omethyldopa (3-OMD) to about 55-60% of the placebo treatment level ( P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) 2-2.6-fold compared with placebo ( P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo ( P < 0.001-0.05, 95% CI -0.76, -0.01) at each L -dopa/carbidopa dose except the 50/12.5 mg dose ( P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L -dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD ( P < 0.001, 95% CI -0.85, -0.68) and HVA ( P < 0.001, 95% CI -1.01, -0.18) in plasma at each L -dopa/carbidopa dose, whereas the AUC DOPAC/AUC L -dopa ratio was increased again at all doses ( P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L -dopa/carbidopa affect the pharmacokinetics of entacapone.H. Heikkinen et al. 364

We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Stalevo was well tolerated, with a low incidence of adverse events. The study shows that Stalevo is an effective, preferred and well-tolerated means of delivering levodopa/carbidopa/entacapone in one easy-to-use tablet.

The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.

In 104 patients undergoing anaesthesia of short duration, two different solvents, propylene glycol and cremophor, were compared in a double-blind trial. Diazepam 10 mg in a coded solution was injected into a superficial vein of the hand using a small-gauge needle. The vein was examined after 14 days. The frequency of thrombophlebitis with propylene glycol was 62.2% and with cremophor 3.4% (P less than 0.001). The frequency of pain on injection was also in favour of the new solvent (P less than 0.001). The possibility of anaphylactic reactions accredited to cremophor, however, restricts the use of the new injection.