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Objective: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations.Design: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study.Patients and Participants: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations.Methods: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days.Results: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8.Conclusions: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa. [ABSTRACT FROM AUTHOR]

Sevoflurane is a comparatively recent addition to the range of inhalational anaesthetics which has been recently released for clinical use. In comparison to older inhalational agents such as isoflurane or halothane, the most important property of sevoflurane is its low solubility in the blood. This results in a more rapid uptake and induction than the 'older' inhalational agents, improved control of depth of anaesthesia and faster elimination and recovery. The more rapid pharmacokinetics are a result of the low blood/gas partition coefficient of 0.69. With an oil/gas partition coefficient of 47.2, the minimum alveolar concentration (MAC) of sevoflurane is 2.05%. Two to 5% of the drug taken up is metabolised by the liver. The pharmacokinetics of sevoflurane do not change in children, obese patients or patients with renal insufficiency. The pharmacokinetics and pleasant odour of sevoflurane make mask induction feasible, which is an obvious advantage in paediatric anaesthesia. The hepatic metabolism of sevoflurane results in the formation of inorganic fluoride. Upon contact with alkaline CO2 absorbent, a small amount of sevoflurane is degraded and a metabolite (compound A) is formed and inhaled in trace amounts. Whether inorganic fluoride or compound A are nephrotoxic is presently a matter of controversy. [ABSTRACT FROM AUTHOR]