Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

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)

The 5-HT(4) receptor agonist, tegaserod, is a potent 5-HT(2B) receptor antagonist in vitro and in vivo

1. Tegaserod (Zelnorm®) is a potent 5-hydroxytryptamine(4) (5-HT(4)) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT(2) receptors, and compared its potency in this respect to its 5-HT(4) receptor agonist activity. 2. Tegaserod had significant binding affinity for human recombinant 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors (pK(i)=7.5, 8.4 and 7.0, respectively). The 5-HT(2B) receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT(4(c)) receptors (mean pK(i)=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT(4(c)) receptor. 3. Tegaserod (0.1–3 μM) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA(2)=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3′,5′ cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT(4(c)) receptor (mean pEC(50)=8.6), as well as 5-HT(4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC(50)=8.2) and contraction of the guinea-pig isolated colon (mean pEC(50)=8.3). 4. Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(−1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of α-methyl 5-HT (0.03 mg kg(−1)) and BW 723C86 (0.3 mg kg(−1)), selective 5-HT(2B) receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(−1) subcutaneously) evoked a 5-HT(4) receptor-mediated increase in colonic transit in conscious guinea-pigs. 5. The data from this study indicate that tegaserod antagonizes 5-HT(2B) receptors at concentrations similar to those that activate 5-HT(4) receptors. It remains to be determined whether this 5-HT(2B) receptor antagonist activity of tegaserod contributes to its clinical profile