The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

The human histamine H 1 receptor (H 1 R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H 1 R by evaluating Ͼ130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H 1 R agonist (Mol Pharmacol 65: 538 -549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H 1 R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.

1 The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20-44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post-dose. 2 The overall mean ± s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 ± 0.3 (1.7-9.4) ng ml-l; time of peak, 1.3 ± 0.1 (0.5-4.0) h after dose; elimination half-life, 2.6 ± 0.1 (1.1-4.4) h; total AUC: 19.1 ± 1.1 (4.4-47.7) ng ml-h; oral clearance, 526 ± 38 (175-1892) ml min-'. 3 All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov-Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. 4 Peak plasma level was highly correlated with clearance (r = -0.85, P < 0.0001), and AUC (r = 0.85, P < 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = -0.01). 5 Triazolam clearance may vary widely even within a homogeneous group of healthy young men.

No abstract

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15‐30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml‐1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half‐life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min‐1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.