Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers.
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AIMS: Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. METHODS: Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. RESULTS: The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. CONCLUSIONS: These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population. (+info)
Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.
(10/579)
Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor. (+info)
Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1).
(11/579)
Two subtypes of the cannabinoid receptor (CB1 and CB2) are expressed in mammalian tissues. Although selective antagonists are available for each of the subtypes, most of the available cannabinoid agonists bind to both CB1 and CB2 with similar affinities. We have synthesized two analogs of N-arachidonylethanolamine (AEA), arachidonylcyclopropylamide (ACPA) and arachidonyl-2-chloroethylamide (ACEA), that bind to the CB1 receptor with very high affinity (KI values of 2.2 +/- 0.4 nM and 1.4 +/- 0.3 nM, respectively) and to the CB2 receptor with low affinity (KI values of 0.7 +/- 0.01 microM and 3.1 +/- 1.0 microM, respectively). Both ACPA and ACEA have the characteristics of agonists at the CB1 receptor; both inhibit forskolin-induced accumulation of cAMP in Chinese hamster ovary cells expressing the human CB1 receptor, and both analogs increase the binding of [35S]GTPgammaS to cerebellar membranes and inhibit electrically evoked contractions of the mouse vas deferens. ACPA and ACEA produce hypothermia in mice, and this effect is inhibited by coadministration of the CB1 receptor antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the CB1 receptor but do not bind the CB2 receptor, suggesting that structural analogs of AEA can be designed with considerable selectivity for the CB1 receptor over the CB2 receptor. (+info)
Cannabinoid inhibition of the processing of intact lysozyme by macrophages: evidence for CB2 receptor participation.
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Delta9-tetrahydrocannabinol (THC) impairs multiple immunological functions. The ability of a macrophage hybridoma to function as an antigen-presenting cell was examined by the stimulation of a soluble protein antigen-specific helper T cell hybridoma to secrete interleukin-2. THC exposure significantly reduced the T cell response to the native form of the antigen after a 24-h pretreatment of the macrophages with nanomolar drug concentrations. However, THC did not affect interleukin-2 production when the macrophages presented a synthetic peptide of the antigen to the T cells, suggesting that the drug may interfere with antigen processing, not peptide presentation. Cannabinoid inhibition of the T cell response to the native antigen was stereoselective consistent with the involvement of a cannabinoid (CB) receptor. Bioactive CP-55,940 diminished T cell activation, whereas the inactive stereoisomer CP-56,667 did not. The macrophage hybridoma expressed mRNA for the CB2 but not the CB1 receptor whereas the T cells expressed an extremely low level of mRNA for the CB2 receptor. The CB1-selective antagonist SR141716A did not reverse the suppression caused by THC, demonstrating that the CB1 receptor was not responsible for the drug's inhibitory effect. In contrast, the CB2-selective antagonist SR144528 completely blocked THC's suppression of the T cell response, implicating the participation of the CB2 receptor. These findings suggest that the CB2 receptor may be involved in CB inhibition of antigen processing by macrophages in this system. (+info)
Effect of ethanol on the urinary excretion of cyclohexanol and cyclohexanediols, biomarkers of the exposure to cyclohexanone, cyclohexane and cyclohexanol in humans.
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OBJECTIVES: This study explored the acute effect of ethanol (EtOH) on the urinary excretion of cyclohexanol (CH-ol), 1,2- and 1,4-cyclohexanediol (CH-diol), biomarkers of exposure to important solvents, and chemical intermediates cyclohexanone (CH-one), cyclohexane (CH) and cyclohexanol. METHODS: Volunteers (5-8 in each group) were exposed for 8 hours either to CH-one, CH or CH-ol vapor at concentrations of about 200, 1000, and 200 mg/m3, respectively, with concomitant ingestion of EtOH (4 14-g doses taken during the exposure). Urine was collected for 72 hours and analyzed for CH-ol and CH-diols using a procedure involving acidic hydrolysis and gas chromatographic determination. RESULTS: The metabolic yields of CH-ol, 1,2-, and 1,4-CH-diol, respectively, in the exposures with EtOH were as follows: 11.3%, 36%, 23% after the exposure to CH-one, 3.1%, 15%, 8% after the exposure to CH, and 6.6%, 24%, 18% after the exposure to CH-ol. [The corresponding values obtained previously in matching experiments without EtOH were as follows: 1.0%, 39%, 18% (CH-one); 0.5%, 23%, 11% (CH); and 1.1%, 19%, 8% (CH-ol).] The excretion curves of the metabolites in the exposures with EtOH were not delayed when compared with the corresponding curves of a comparison group. CONCLUSIONS: The urinary excretion of CH-diols is much less sensitive to EtOH than that of CH-ol. It is recommended to employ CH-diols as useful and more reliable biomarkers of exposure to CH-one, CH and CH-ol in field examinations. (+info)
Mechanism of sodium channel block by venlafaxine in guinea pig ventricular myocytes.
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Venlafaxine is a newly introduced antidepressant agent. The drug causes selective inhibition of neuronal reuptake of serotonine and norepinephrine with little effect on other neurotransmitter systems. Cases of seizures, tachycardia, and QRS prolongation have been observed following drug overdose in humans. The clinical manifestations of cardiac toxicity suggest that venlafaxine may exhibit cardiac electrophysiological effects on fast conducting cells. Consequently, studies were undertaken to characterize effects of venlafaxine on the fast inward sodium current (I(Na)) of isolated guinea pig ventricular myocytes. Currents were recorded with the whole-cell configuration of the patch-clamp technique in the presence of Ca(2+) and K(+) channel blockers. Results obtained demonstrated that venlafaxine inhibits peak I(Na) in a concentration-dependent manner with an estimated IC(50) of 8. 10(-6) M. Inhibition was exclusively of a tonic nature and rate-independent. Neither kinetics of inactivation (tau(inac)= 0.652 +/- 0.020 ms, under control conditions; tau(inac)= 0.636 +/- 0.050, in the presence of 10(-5) M venlafaxine; n = 5 cells isolated from five animals) nor kinetics of recovery from inactivation of the sodium channels (tau(re)= 58.7 +/- 1.6 ms, under control conditions; tau(re)= 54.4 +/- 1.8, in the presence of 10(-5) M venlafaxine; n = 10 cells isolated from six animals) were significantly altered by 10(-5) M venlafaxine. These observations led us to conclude that venlafaxine blocks I(Na) following its binding to the resting state of the channel. Thus, the characteristics of block of I(Na) by venlafaxine are different from those usually observed with most tricyclic antidepressants or conventional class I antiarrhythmic drugs. (+info)
Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein.
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AIMS: To examine whether the antidepressant venlafaxine, a novel serotonin-noradrenaline re-uptake inhibitor (SNRI), can modify alpha-adrenoceptor-mediated venoconstriction in man. The effects of venlafaxine were compared with those of desipramine, a tricyclic antidepressant with noradrenaline uptake inhibiting properties, and paroxetine, a selective serotonin re-uptake inhibitor (SSRI), on noradrenaline-and methoxamine-evoked venoconstriction using the dorsal hand vein compliance technique. METHODS: Fifteen healthy male volunteers participated in five weekly experimental sessions. Each session was associated with a clinically effective dose of an antidepressant or placebo. The following oral dosages were used: venlafaxine 75 mg, venlafaxine 150 mg, desipramine 100 mg, paroxetine 20 mg, or placebo. A double-blind, cross-over, balanced design was used. In each session, dose-response curves to both locally infused noradrenaline acid tartrate (0.1-33.33 ng min-1 ) and methoxamine hydrochloride (0.5-121.5 microg min-1 ) were constructed. Systolic and diastolic blood pressure and pulse rate were measured in the supine and erect positions. Salivation was measured by the dental roll technique. RESULTS: Venlafaxine 150 mg and desipramine 100 mg potentiated the venoconstrictor response to noradrenaline (anova of log ED50s: P<0.01; individual comparisons: venlafaxine 150 mg vs placebo: P<0.005; mean difference, 95% CI: -0. 49 (-0.81, -0.17); desipramine 100 mg vs placebo: P<0.005; mean difference, 95% CI: -0.34 (-0.60, -0.09) without affecting the response to methoxamine. Neither paroxetine nor placebo had any effects on the venoconstrictor responses. Both doses of venlafaxine increased systolic blood pressure (supine and erect) and venlafaxine 150 mg increased diastolic blood pressure (supine) (anova, P<0.05). Desipramine increased heart rate (P<0.05). Desipramine and both doses of venlafaxine reduced salivation (P<0.025). CONCLUSIONS: These results show that, similarly to desipramine 100 mg, venlafaxine 150 mg can potentiate venoconstrictor responses to noradrenaline, consistent with venlafaxine's ability to block noradrenaline uptake in man. The importance of noradrenaline uptake blockade in these observations is confirmed by the lack of effect of the antidepressants on methoxamine-evoked venoconstriction and the failure of paroxetine to modify noradrenaline-evoked venoconstriction. (+info)
Structural determinants of the partial agonist-inverse agonist properties of 6'-azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors.
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1. We have extended previous investigations of four analogues of Delta8-tetrahydrocannabinol (Delta8-THC): 6'-azidohex-2'-yne-Delta8-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta8-THC (O-1238) and octyl-2'-yne-Delta8-THC (O-584) and its 1-deoxy-analogue (O-1315). 2. O-1184, O-1238 and O-584 displaced [3H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pKi values of 8.28 to 8.45 (CB1) and 8.03 to 8.13 (CB2). The pKi values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2). 3. All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells (pEC50=9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line. 4. In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC50=10.18 and Emax=70.5%). Corresponding values for O-1184 were 9.08 and 21.1% respectively. At 1 nM, O-1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O-1184 did not attenuate CP55940-induced inhibition of cyclic AMP production by CB1-transfected CHO cells. 5. In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC50=8.59), enhanced by O-1184 and O-584 (pEC50=8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315. 6. At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC50 of CP55940 from 8.61 to 7.42 (O-1184) or from 8. 54 to 7.44 (O-1238). 7. These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta8-THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors. (+info)