Synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines and their actions at adrenoceptors in vivo and in vitro.

An improved synthesis of 1-(aminomethyl)-1,2,3,4-tetrahydroisoquinolines has been developed by using aluminum hydride reduction of 1-cyano-1,2,3,4-tetrahydroisoquinolines. Three 1-(aminomethyl)-6,7-dihydroxytetrahydroisoquinolines were tested for actions at beta adrenoceptors in order to examine a proposed similarity between this series and the related phenylethanolamines. The aminomethyl, (isopropylamino)methyl, and (tert-butylamino)methyl derivatives all showed weak partial agonist activity at beta adrenoceptors and the first also showed weak alpha adrenoceptor agonist activity in vivo. Their low potency implies that the catechol group of THIQ sympathomimetics, such as trimetoquinol, binds differently from that of the natural catecholamines. The protonation behavior of representative aminomethyl-THIQ's was investigated by pKa measurement and 1H and 13C NMR, and the compounds were shown to be substantially monoprotonated, on the exocyclic nitrogen, at physiological pH.

Effects of increasing the frequency of twitches and of isoprenaline on maximal twitches and cyclic AMP levels in slow- and fast-contracting cat skeletal muscles.

Increasing the frequency of twitches and treatment with isoprenaline have been compared for effects on twitch tension, tension-time integral and cyclic adenosine 3', 5'-monophosphate (cyclic AMP) levels in the slow-contracting soleus muscle of cats, anaesthetized with chloralose and pentobarbitone. The effect of change in frequency of contractions on cyclic AMP in the fast-contracting extensor digitorum longus muscle was also examined. Although both isoprenaline and increasing the frequency of contractions depressed twitch tension in the soleus, only isoprenaline enhanced cyclic AMP levels. The effects of isoprenaline were independent of the existing frequency of contractions of the muscle. Increasing the frequency of contractions enhanced twitches in the extensor digitorum longus muscle but did not change cyclic AMP levels. It is concluded that cyclic AMP may mediate effects of beta-adrenoceptor agonists but not those caused by increasing the frequency of contractions on slow- or fast-contracting skeletal muscles.

Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers.

Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.

Neuromuscular blocking activity of methanolic extract of Piper sarmentosum leaves in the rat phrenic nerve-hemidiaphragm preparation.

Methanolic extract of Piper sarmentosum Roxb. (Piperaceae) leaves was studied for the neuromuscular blocking activity in rat phrenic nerve-hemidiaphragm preparations. The plant extract, at concentrations of 3.2, 4.0, 4.8 and 6.4 mg/ml, exhibited an initially transient increase in twitch tension which was followed by a marked dose-related neurally-evoked twitch depression. The neuromuscular blocking effect produced by the plant extract was compared with d-tubocurarine (dTC) and succinylcholine (SCh). The EC50 for neurally-evoked twitch depression of the extract, dTC and SCh was 4.07 mg/ml, 1.1 microM and 15 microM, respectively. The neurally-evoked twitch depression produced by the extract was partially antagonized by tetraethylammonium (TEA) but not by neostigmine (NS). These findings suggested that the plant extract possessed a marked neuromuscular blocking activity at the neuromuscular junction and a possible mechanism which was likely to inhibit neurotransmitter (acetylcholine) release at the presynaptic terminal.

Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers.

BACKGROUND: Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible for the metabolism of risperidone, many reports suggest that CYP3A may be involved too. Rifampin, a potent CYP3A inducer, has been known to markedly decrease plasma concentrations of various drugs, which are concomitantly administered during treatment. OBJECTIVE: To examine the effect of rifampin on plasma concentrations of a single oral dose of risperidone in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study, separated by a 2-week period, 10 healthy Thai male volunteers received a single oral dose of 4-mg risperidone alone or with 600 mg rifampin, orally once daily for 5 days. Serial blood samples were collected at specific time points for a 48-h period. Risperidone was measured in plasma using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined by using non-compartmental analysis. RESULTS: Co-administration with 600-mg rifampin once daily for 5 days was associated with a significant decrease in risperidone area under the curve (AUC(0-48)) and maximal concentration (C(max)) by 72% (157 x 49 +/- 48 x 80 vs. 42 x 66 +/- 7 x 81 ng/L/h; P<0 x 01) and 50% (32 x 44 +/- 6 x 05 vs. 16 x 16 +/- 2 x 73 ng/mL; P<0 x 05), respectively when compared with risperidone alone. CONCLUSIONS: Rifampin when used concurrently with risperidone significantly decreases the plasma concentration of risperidone. Our results provide in vivo evidence of the involvement of CYP3A in the metabolism of risperidone, in addition to CYP2D6. Thus, co-administration of risperidone with CYP3A inducer(s), including rifampin should be recognized or avoided in clinical practice.

Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers.

BACKGROUND: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. OBJECTIVE: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. METHODS: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. RESULTS: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone. CONCLUSIONS: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.

Effects of cimetidine and ranitidine on the pharmacokinetics of quinine.

The pharmacokinetics of orally administered quinine were determined in six normal volunteers before and after a 7-day course of cimetidine (1 g day-1) or ranitidine (300 mg day-1). Peak plasma quinine concentration and the time of peak concentration were not altered after cimetidine or ranitidine pretreatment. After cimetidine pretreatment there was a significant reduction in the apparent oral clearance of quinine, from 0.182 +/- 0.063 (mean +/- s.d.) to 0.133 +/- 0.055 1 h-1 kg-1 (P less than 0.05). This was reflected in a 49% (range 17 to 90%) increase in the mean elimination half-life from 7.6 +/- 1.3 to 11.3 +/- 3.7 h (P less than 0.05). In contrast to cimetidine, ranitidine had no significant effect on the clearance or half-life of quinine. The apparent interaction between quinine and cimetidine may have therapeutic implications. Special care should be taken in patients taking these two common drugs concomitantly. Additionally, to avoid unnecessary risks due to drug interaction, the use of ranitidine may be preferable in the patients in whom it is desirable to administer an H2-receptor antagonist together with quinine.