Comparison of central and peripheral pharmacologic effects of biperiden and trihexyphenidyl in human volunteers.

In this double-blind, randomized study, indices of central (memory, sedation) and peripheral (salivation, ratio of R-R interval on electrocardiogram) muscarinic function were evaluated in 14 healthy volunteers who received trihexyphenidyl, biperiden, and placebo. Additionally, serum drug levels were obtained 2 hours after oral administration. All subjects participated in three study sessions. During each session, subjects received two doses of biperiden (4 mg), trihexyphenidyl (5 mg), or placebo, and four series of tests were administered. The tests included the determination of cardiac response to standing (R-R ratio), mouth salivation, finger-tapping speed, digit span (forward and backward), a selective reminding task, and visual analog scales (VAS). On the VAS, subjects rated biperiden as significantly more sedating than either trihexyphenidyl or placebo, and both biperiden and trihexyphenidyl were associated with more dizziness than was placebo. Saliva production was significantly reduced by both trihexyphenidyl and biperiden compared with placebo. Digit span performance was significantly decreased in only the backward direction. The selective reminding task revealed highly significant decrements in the number of words recalled and consistent long-term retrieval after both biperiden and trihexyphenidyl. Delayed recall was significantly decreased by both active drugs. Both trihexyphenidyl and biperiden caused a significant increase in the R-R ratio comparison with placebo. With the exception of the VAS measurement of sedation, the effects caused by biperiden and trihexyphenidyl did not differ. The results of this study do not support the hypothesis that the side effect profile of biperiden is significantly different from that of trihexyphenidyl.

Mechanism of action of the redox affinity reagent [(trimethylammonio)methyl]catechol.

The synthesis of 4- and 5-hydroxy-3-[(trimethylammonio)methyl]catechol (4- and 5-HTMC) was carried out to examine their proposed involvement as intermediates in the spontaneous redox-dependent half-of-sites inactivation of neurotoxin binding sites in the nicotinic acetylcholine receptor (nAcChR) mediated by the parent compound 3-[(trimethylammonio)methyl]catechol (TMC) [Nickoloff et al. (1985) Biochemistry 24, 999-1007]. Oxidation of 4- and 5-HTMC occurred with sodium periodate with facile conversion to the corresponding p-quinones which were intercepted with thiols and cyclopentadiene. Both 4- and 5-HTMC inactivated neurotoxin binding in the nAcChR in a time course and over a concentration range consistent with their involvement as intermediates in the TMC redox-dependent inactivation of neurotoxin ([125I]-alpha-bungarotoxin) binding sites. Rapid concentration-dependent inactivation of neurotoxin sites occurred over a 10-1000 microM range and was resistant to further inactivation after 50% loss of available toxin binding sites on the nAcChR. Both 4- and 5-HTMC inactivated nAcChR neurotoxin sites much more rapidly and efficiently than was observed previously with TMC. The apparent binding constants for 4- and 5-HTMC with the nAcChR, calculated from their concentration-dependent inactivation behavior toward toxin binding sites, were Kd = 224 +/- 98 and 39 +/- 17 microM, respectively. The observed results and the redox potentials (vs Ag/AgCl reference electrode) measured by cyclic voltammetry at pH 1.8 for TMC (719 mV) and the 4- and 5-HTMC derivatives (519 and 443 mV, respectively) supported the previously proposed mechanism for inactivation of the nAcChR by TMC.(ABSTRACT TRUNCATED AT 250 WORDS)