Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites.

OBJECTIVE: To assess the effect of liver impairment on the pharmacokinetics of tolcapone and to derive appropriate dose recommendations for patients with this disease who are undergoing treatment for Parkinson's disease. STUDY DESIGN: In an open, two-way crossover study, 16 patients with moderate liver disease (eight with cirrhotic and eight with noncirrhotic liver disease) and eight healthy subjects received an oral dose of 200 mg tolcapone and an intravenous dose of 50 mg tolcapone on separate occasions. The concentrations of total and unbound tolcapone and its three major metabolites (tolcapone glucuronide, carboxylic acid, and 3-O-methyl metabolite) were assessed in plasma and urine. RESULTS: On the basis of total drug concentration, the differences in tolcapone pharmacokinetics between the groups were small. However, lower clearance and volume of distribution of unbound drug were found among patients with cirrhosis than among control subjects. Plasma concentration of the pharmacologically inactive glucuronide metabolite was increased among patients with cirrhosis. CONCLUSIONS: Half of the recommended dosage of tolcapone should be administered to patients with cirrhosis of the liver to maintain the target steady-state concentration of unbound drug and to avoid accumulation of tolcapone glucuronide. Our data did not indicate a requirement for dosage adjustment in the presence of moderate chronic hepatitis.

[Endothelins: possibly a new pharmacological approach in cardiovascular diseases, kidney diseases and oncological disorders]. / Endothelinen: mogelijk een nieuw farmacologisch aangrijpingspunt bij hart-en vaatziekten, nierziekten en oncologische aandoeningen.

Only 10 years ago, the vasoconstricting peptide endothelin was discovered; it is produced by endothelial cells. Different isoforms and receptors of endothelin have been identified. The effects of endothelin-I, the most important isoform, are mainly vasoconstriction and proliferation of cells. In the last few years endothelin receptor antagonists have become available, which can delineate the clinical importance of the endothelin system. Possible indications for endothelin receptor blockers are renal disease (acute and chronic renal failure) and cardiovascular disease (heart failure; restenosis after percutaneous transluminal coronary angioplasty (PTCA); pulmonary hypertension; systemic hypertension). There is also a possible role for endothelin receptor blockers in oncology (prostatic carcinoma). Currently clinical trials are being carried out to determine the efficacy of these compounds for the above-mentioned indications.

Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension.

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohypophyseal hormones and excessive grooming behaviour.

The pattern of excessive grooming displayed by rats treated with vasopressin and oxytocin was investigated by calculating the frequencies and contribution of the behavioural elements head washing, body grooming, anogenital grooming, paw licking and scratching. In addition, the suppressive effect on peptide-induced grooming of the dopamine D1 receptor antagonist SCH 23390, of neurotensin and of the opiate receptor antagonists naloxone and naloxone-methobromide was studied. The pattern of excessive grooming induced by vasopressin and by oxytocin was characterized by the contribution of most behavioural elements to the total grooming scores. Oxytocin-induced excessive grooming was characterized by a marked increase in the frequency of anogenital grooming. SCH 23390, neurotensin and naloxone, but not naloxone-methobromide, suppressed excessive grooming induced by vasopressin and oxytocin. It is suggested that dopamine D1 receptors as well as opiate receptors located within the blood-brain barrier are involved in the excessive grooming induced by neurhypophyseal hormones.