venlafaxine (Effexor)
Relationship between clinical effects, serum drug concentration, and concurrent drug interactions in depressed patients treated with citalopram, fluoxetine, clomipramine, paroxetine or venlafaxine.

Charlier C, Pinto E, Ansseau M, Plomteux G.

University of Liege, Toxicology Laboratory, CHU Sart Tilman, B-4000 Liege, Belgium.

The relationship between clinical effects and plasma concentrations of citalopram, fluoxetine, clomipramine, paroxetine and venlafaxine was studied in 119 cases of major depression. Clinical effects were evaluated using the Clinical Global Impression (CGI) improvement scale. Antidepressants were quantified by a separative chromatographic methodology. Plasma concentrations in responder patients were compared with the plasma concentrations proposed in literature as effective values. We found that the usual therapeutic window is convenient for citalopram and clomipramine, but could be reduced for fluoxetine and increased for venlafaxine and paroxetine. Concurrent drug interactions were also evaluated and clomipramine or citalopram plasma levels were found to be influenced by the presence of associated drugs. A larger study is needed, taking into account not only plasma concentrations and clinical effects, but also some pharmacokinetic data, especially the metabolic activity characterising the patient, and the presence or not of associated drugs. Copyright 2000 John Wiley & Sons, Ltd.

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Effexor, Effexor XR

venlafaxine (Effexor)
Nonaqueous capillary electrophoresis-mass spectrometry for separation of venlafaxine and its phase I metabolites.

Cherkaoui S, Rudaz S, Veuthey JL.

Laboratory of Pharmaceutical Analytical Chemistry, University of Geneva, Switzerland.

Aqueous and nonaqueous capillary electrophoresis (NACE) were investigated for separation of venlafaxine, a new second-generation antidepressant, and its three phase I metabolites. Working at basic pH, around the venlafaxine pKa value, was effective in resolving the investigated drugs, but created considerable peak tailing. To overcome electrostatic interactions between analytes and silanol groups, investigations were also carried out at acidic pH. However, despite the addition of up to 50% v/v of organic solvents (e.g., methanol or acetonitrile), complete separation of the studied compounds was not possible. NACE was found to be an appropriate alternative to resolve venlafaxine and its metabolites simultaneously. Using a conventional capillary (fused-silica, 64.5 cm length, 50 microm inner diameter), and a methanol-acetonitrile mixture (20/80 v/v) containing 25 mM ammonium formate and 1 M formic acid, complete resolution of these closely related compounds was performed in less than 3.5 min. Selectivity, efficiency and separation time were greatly affected by the organic solvent composition. As the electric current generated in nonaqueous medium was very low, the electric field was further increased by reducing the capillary length. This allowed a baseline resolution of venlafaxine and its three metabolities in 0.7 min. Selectivity was compared in aqueous and nonaqueous media in relation to the acid-base properties of the analytes as well as to the solvation degree. Finally, the method successfully coupled on-line to mass spectrometry with electrospray ionization interface allowed significant sensitivity enhancement.

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Effexor, Effexor XR

venlafaxine (Effexor)
A comparative study of venlafaxine with a focused education and psychotherapy program versus venlafaxine alone in the treatment of depression in general practice.

Judd FK, Piterman L, Cockram AM, McCall L, Weissman MM.

Department of Psychological Medicine, Monash University, Melbourne, Australia.

The efficacy of a focused education and psychotherapy program (FEPP) plus antidepressant was compared with that of usual psychosocial treatment and antidepressant in a general practice setting. The FEPP comprised interpersonal counselling (IPC) delivered in a modified way to suit the general practice setting, together with patient education and selected cognitive behavioural techniques. All patients were treated with venlafaxine-XR. Thirty-one patients entered the study, three withdrawing before completion of the 12 week trial. Both treatments produced a statistically significant reduction in BDI and POMS scores from baseline, with greater improvement evident in the FEPP plus antidepressant group. Copyright 2001 John Wiley & Sons, Ltd.

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Effexor, Effexor XR

venlafaxine (Effexor)
Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans.

Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O'Hara G, LeBlanc J, Turgeon J.

Quebec Heart Institute, Laval Hospital, Canada.

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.

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Effexor, Effexor XR

venlafaxine (Effexor)
Venlafaxine occupation at the noradrenaline reuptake site: in-vivo determination in healthy volunteers.

Melichar JK, Haida A, Rhodes C, Reynolds AH, Nutt DJ, Malizia AL.

Psychopharmacology Unit, University of Bristol, UK. jan.melichar bristol.ac.uk

Venlafaxine, a serotonin and noradrenaline reuptake inhibitor, is an effective antidepressant at doses of 75 mg p.o. daily and above. Preclinical and healthy volunteer studies have demonstrated that venlafaxine is more potent at the serotonin than at the noradrenaline reuptake site, with noradrenergic blocking effects being observed at doses >75 mg p.o. in man. We used the Multiple Organs Coincidences Counter and [11C] meta hydroxy ephedrine (MHED) to test whether significant occupation of cardiac sympathetic neurones was achieved in man in vivo after the acute administration of venlafaxine 75 mg p.o. in nine healthy volunteers. MHED is a tracer which binds at the noradrenaline reuptake site. This study demonstrates that the [11C]MHED signal is significantly reduced after the administration of venlafaxine 75 mg p.o. thus showing that noradrenaline reuptake blockade is observable at this dose. This effect is predominantly seen in volunteers who received > 1 mg/kg venlafaxine.

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Effexor, Effexor XR