RÉSUMÉ
A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).
Sujet(s)
Maladie d'Alzheimer/traitement médicamenteux , Anticholinestérasiques/administration et posologie , Anticholinestérasiques/pharmacocinétique , Phényl-carbamates/administration et posologie , Phényl-carbamates/pharmacocinétique , Administration par voie cutanée , Administration par voie orale , Sujet âgé , Maladie d'Alzheimer/enzymologie , Benzylamines/pharmacocinétique , Butyrylcholine esterase/sang , Capsules , Anticholinestérasiques/effets indésirables , Relation dose-effet des médicaments , Calendrier d'administration des médicaments , Femelle , Humains , Mâle , Adulte d'âge moyen , Modèles biologiques , Phénéthylamines , Phénols/pharmacocinétique , Phényl-carbamates/effets indésirables , Rivastigmine , Résultat thérapeutiqueRÉSUMÉ
The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.
Sujet(s)
Antiparkinsoniens/pharmacocinétique , Lévodopa/pharmacocinétique , Maladie de Parkinson/traitement médicamenteux , Thiazoles/pharmacocinétique , Sujet âgé , Aire sous la courbe , Benzothiazoles , Biodisponibilité , Carbidopa/pharmacologie , Relation dose-effet des médicaments , Interactions médicamenteuses , Antienzymes/pharmacologie , Femelle , Humains , Mâle , Post-ménopause , Pramipexole , Facteurs sexuelsRÉSUMÉ
Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.
Sujet(s)
Antagonistes bêta-adrénergiques/usage thérapeutique , Anorexigènes/effets indésirables , Anorexigènes/usage thérapeutique , Pression sanguine/effets des médicaments et des substances chimiques , Pression sanguine/physiologie , Cyclobutanes/effets indésirables , Cyclobutanes/usage thérapeutique , Rythme cardiaque/effets des médicaments et des substances chimiques , Rythme cardiaque/physiologie , Hypertension artérielle/traitement médicamenteux , Hypertension artérielle/physiopathologie , Obésité/traitement médicamenteux , Obésité/physiopathologie , Perte de poids/effets des médicaments et des substances chimiques , Perte de poids/physiologie , Adulte , Sujet âgé , Benzothiadiazines , Diurétiques , Méthode en double aveugle , Association de médicaments , Femelle , Humains , Hypertension artérielle/complications , Mâle , Adulte d'âge moyen , Obésité/complications , Inhibiteurs du symport chlorure sodium/usage thérapeutiqueRÉSUMÉ
In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.