venlafaxine (Effexor)
Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.

Ciraulo DA, Sarid-Segal O, Knapp CM, Ciraulo AM, Locastro J, Bloch DA, Montgomery MA, Leiderman DB, Elkashef A.

Division of Psychiatry, Boston University School of Medicine and VA Boston Healthcare System Medication Development Research Unit (MDRU), Boston, MA, USA.

ABSTRACT Aims The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. Design A multi-arm, modified blinded, placebo-controlled design was used. Setting The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants Participants met criteria for cocaine dependence during a 2-week screening period. Intervention Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. Findings None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. Conclusions This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

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Effexor, Effexor XR

venlafaxine (Effexor)
Effect of venlafaxine on the pharmacokinetics of risperidone.

Amchin J, Zarycranski W, Taylor KP, Albano D, Klockowski PM.

Wyeth-Ayerst Laboratories, Philadelphia, PA 19101-8299, USA.

An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risperidone before and after venlafaxine dosing to steady state. No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety. However, venlafaxine weakly altered the pharmacokinetics of risperidone. Oral clearance decreased 38%, and the volume of distribution decreased 17%, resulting in a 32% increase in the AUC for risperidone. Renal clearance of 9-hydroxyrisperidone also decreased by 20% in the presence of venlafaxine. Safety profiles of both drugs were not altered. This study demonstrated that venlafaxine did not affect the pharmacokinetic profile of 9-hydroxyrisperidone or the total active moiety, although it weakly inhibited the metabolism of risperidone. These results show that venlafaxine is unlikely to be involved in a pharmacokinetic interaction with concomitant risperidone.

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Effexor, Effexor XR

venlafaxine (Effexor)
O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants.

Fogelman SM, Schmider J, Venkatakrishnan K, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, K(m) = 41 microM, and Ks 22901 microM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 microM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 microM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, -2C19, and -2D6. CYP2D6 was dominant with the lowest K(m), 23.2 microM, and highest intrinsic clearance (Vmax/K(m) ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and K(m) = 2504 microM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, -2C19, and -3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 microM, decreased NDV production by 46% consistent with the capacity of FX to inhibit CYP3A, 2C9, and 2C19. These results are consistent with previous studies that show CYP2D6 and -3A4 play important roles in the formation of ODV and NDV, respectively. In addition we have shown that several other CYPs have important roles in the biotransformation of VF.

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Effexor, Effexor XR

venlafaxine (Effexor)
Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers.

Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K, Azuma J.

Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.

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.

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Effexor, Effexor XR

venlafaxine (Effexor)
Venlafaxine: discrepancy between in vivo 5-HT and NE reuptake blockade and affinity for reuptake sites.

Beique JC, de Montigny C, Blier P, Debonnel G.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Using an in vivo electrophysiological paradigm, venlafaxine and paroxetine displayed similar potency for suppressing the firing activity of dorsal raphe 5-HT neurons (ED50: 233 and 211 microg/kg i.v., respectively), while venlafaxine was three times less potent than desipramine (ED50: 727 and 241 microg/kg i.v., respectively) to suppress the firing activity of locus coeruleus NE neurons. The selective 5-HT1A receptor antagonist WAY 100635 (100 microg/kg, i.v.) reversed the suppressant effect of venlafaxine and paroxetine on the firing activity of 5-HT neurons and the alpha2-adrenoceptor antagonist piperoxane (1 mg/kg, i.v.) reversed those of venlafaxine and desipramine on the firing activity of NE neurons. The ED50 of venlafaxine on the firing activity of 5-HT neurons was not altered (ED50: 264 microg/kg) in noradrenergic-lesioned rats, while the suppressant effect of venlafaxine on the firing activity of NE neurons was greater in serotonergic-lesioned rats (ED50: 285 microg/kg). Taken together, these results suggest that, in vivo, venlafaxine blocks both reuptake processes, its potency to block the 5-HT reuptake process being greater than that for NE. Since the affinities of venlafaxine for the 5-HT and NE reuptake carriers are not in keeping with its potencies for suppressing the firing activity of 5-HT and NE neurons, the suppressant effect of venlafaxine on the firing activity of 5-HT and NE neurons observed in vivo may not be mediated solely by its action on the [3H]cyanoimipramine and [3H]nisoxetine binding sites. In an attempt to unravel the mechanism responsible for this peculiarity, in vitro superfusion experiments were carried out in rat brain slices to assess a putative monoamine releasing property for venlafaxine. (+/-)Fenfluramine and tyramine substantially increased the spontaneous outflow of [3H]5-HT and [3H]NE, respectively, while venlafaxine was devoid of such releasing properties.

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Effexor, Effexor XR