Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635.

Serotonin(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT(1A) receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10-20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development.

The comparative pharmacokinetics of acemetacin in young subjects and elderly patients.

Single and multiple dose pharmacokinetics of acemetacin in 10 young healthy subjects and 10 elderly patients with osteoarthritis were studied. Peak plasma concentrations of acemetacin and its metabolite, indomethacin, were found between 2.4 and 4 h after an oral dose of the drug. After dosing to steady state (7 days), the mean plasma elimination half-life for acemetacin was 1.1 h and 1.0 h, and for indomethacin 7.1 h and 7.2 h in the young and elderly groups respectively. Statistical analysis of tmax, AUC, plasma t1/2 and residual drug concentrations for acemetacin or indomethacin revealed no significant differences (P greater than 0.05) between young subjects and elderly patients after acute or chronic dosing. The results suggest that drug accumulation did not occur in the elderly subjects over the time period studied and that, on pharmacokinetic grounds, dose adjustment in the elderly is unlikely to be required.

A double-blind comparison of the pharmacodynamic effects of single doses of lofepramine, amitriptyline and placebo in elderly subjects.

In a double-blind five-way cross-over study, six drug free healthy elderly subjects received single oral doses of lofepramine (70 mg, 105 mg and 140 mg), amitriptyline (50 mg) and matched placebo tablets. A dose related increase in plasma drug levels and pharmacological effects of lofepramine was observed. Lofepramine (140 mg) improved psychomotor performance (choice reaction time and letter cancellation), but no such change was seen with lower dose regimes or placebo. No significant differences between lofepramine and placebo were observed in other parameters measured. Amitriptyline, as expected, reduced salivary volume, produced drowsiness and impaired psychomotor performance. These changes correlated with plasma amitriptyline levels. The incidence of subjective side-effects with amitriptyline was also higher than that of lofepramine or placebo. In the dosage used, lofepramine exhibited no deleterious effect on the peripheral cholinergic system or psychomotor performance. This drug therefore is likely to be a relatively safe antidepressant for the elderly, but further investigations during long-term medication are required to verify these observations.