Venlafaxine Research Articles

Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network.

BackgroundMost cases of idiopathic autism spectrum disorder (ASD) likely result from unknown environmental triggers in genetically susceptible individuals. These triggers may include maternal exposure of a fetus to minute concentrations of pharmaceuticals, such as carbamazepine (CBZ), venlafaxine (VNX) and fluoxetine (FLX). Unmetabolized pharmaceuticals reach drinking water through a variety of routes, including ineffectively treated sewage. Previous studies in our laboratory examined the extent to which gene sets were enriched in minnow brains treated with pharmaceuticals. Here, we tested the hypothesis that genes in fish brains and human cell cultures, significantly enriched by pharmaceuticals, would have distinct characteristics in an ASD-associated protein interaction network. We accomplished this by comparing these groups using 10 network indices.ResultsA network of 7212 proteins and 33,461 interactions was generated. We found that network characteristics for enriched gene sets for particular pharmaceuticals were distinct from each other, and were different from non-enriched ASD gene sets. In particular, genes in fish brains, enriched by CBZ and VNX 1) had higher network importance than that in the overall network, and those enriched by FLX, and 2) were distinct from FLX and non-enriched ASD genes in multivariate network space. Similarly, genes in human cell cultures enriched by pharmaceutical mixtures (at environmental concentrations) and valproate (at clinical dosages) had similar network signatures, and had greater network importance than genes in the overall ASD network.ConclusionsThe results indicate that important gene sets in the ASD network are particularly susceptible to perturbation by pharmaceuticals at environmental concentrations.

Mini-tablets versus pellets as promising multiparticulate modified release delivery systems for highly soluble drugs

Whether mini-tablets (tablets, diameters ≤6mm) belong to single- or multiple-unit dosage forms is still questionable. Accordingly, Pharmacopoeial evaluation procedures for mini-tablets are lacking. In this study, the aforementioned points were discussed. Moreover, their potential for oral controlled delivery was assessed. The antidepressant venlafaxine hydrochloride (Vx), a highly soluble drug undergoing first pass effect, low bioavailability and short half-life was selected as a challenging payload. In an attempt to weigh up mini-tablets versus pellets as multiparticulate carriers, Vx-loaded mini-tablets were compared to formulated pellets of the same composition and the innovator Effexor®XR pellets.Formulations were prepared using various polymer hydrogels in the core and ethyl cellulose film coating with increasing thickness. Mini-tablets (diameter 2mm) showed extended Vx release (<60%, 8h). Indeed, release profiles comparable to Effexor®XR pellets were obtained. Remarkably higher coating thickness was required for pellets to provide equivalent retardation. Ethyl cellulose in the core ensured faster release due to polymer migration to the surface and pore formation in the coat. mini-tablets showed higher stability to pellets upon storage. Industrially speaking, mini-tablets proved to be superior to pellets in terms of manufacturing, product quality and economical aspects. Results point out the urgent need for standardized evaluation procedures for mini-tablets.

Can We “iSPOT” Predictors of Antidepressant Response?

Identification of pretreatment indicators of response to specific antidepressants is highly desirable, but clinically useful tools are not available. To explore possible predictors, two research groups analyzed data from the 17-site, industry-supported iSPOT-D trial, in which 1006 adults with major depression were randomized to 8-week, open treatment with escitalopram, sertraline, or extended-release venlafaxine and were assessed by blinded raters. Arnow and colleagues analyzed response by clinical subtype (atypical, 153; melancholic, 107; anxious, 130; …

Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.

Generic drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations. The aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches. We conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations. We extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding. After retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria-8 examining FDA-approved versions and 18 examining non-FDA-approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non-FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports. Pharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre-approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed.

Venlafaxine extended-release for depression following spinal cord injury: a randomized clinical trial.

Depression is prevalent and associated with negative outcomes in individuals with spinal cord injury (SCI). Antidepressants are used routinely to treat depression, yet no placebo-controlled trials have been published in this population to our knowledge. To determine the efficacy and tolerability of venlafaxine hydrochloride extended-release (XR) for major depressive disorder (MDD) or dysthymic disorder in persons with chronic SCI. Multisite, randomized (1:1), double-blind, placebo-controlled Project to Improve Symptoms and Mood After SCI (PRISMS) trial. All research staff conducting screening, intervention, and outcome procedures were blinded to randomization status. We screened 2536 patients from outpatient clinics at 6 SCI treatment centers in the United States and randomized 133 participants into the trial. Participants were 18 to 64 years old and at least 1 month after SCI, with MDD or dysthymic disorder. Seventy-four percent of participants were male, and participants were on average 40 years old and 11 years after SCI. Forty-seven percent had cervical injuries, 53.4% had American Spinal Injury Association injury severity A (complete injury) SCI, 24.1% had at least 2 prior MDD episodes, and 99.2% had current MDD. Common comorbidities included chronic pain (93.9%), significant anxiety (57.1%), and history of substance dependence (44.4%). Twelve-week trial of venlafaxine XR vs placebo using a flexible-dose algorithm. The Hamilton Depression Rating Scale (HAM-D 17-item version and Maier subscale, which focuses on core depression symptoms and excludes somatic symptoms) over 12 weeks. Mixed-effects models revealed a significant difference between the venlafaxine XR and placebo groups in improvement on the Maier subscale from baseline to 12 weeks (treatment effect, 1.6; 95% CI, 0.3-2.9; P = .02) but not on the HAM-D 17-item version (treatment effect, 1.0; 95% CI, -1.4 to 3.4; P = .42). Participants receiving venlafaxine XR reported significantly less SCI-related disability on the Sheehan Disability Scale at 12 weeks compared with placebo (treatment effect, 4.7; 95% CI, 1.5-7.8; P = .005). Blurred vision was the only significantly more common new or worsening adverse effect in the venlafaxine XR group compared with the placebo group over 12 weeks. Venlafaxine XR was well tolerated by most patients and an effective antidepressant for decreasing core symptoms of depression and improving SCI-related disability. Further research is needed to determine the optimal treatment and measurement approaches for depression in chronic SCI. clinicaltrials.gov Identifier: NCT00592384.

Fate of pharmaceuticals in a subsurface flow constructed wetland and two ponds

Removal and fate of 18 pharmaceuticals of different compound classes and 11 human metabolites were investigated in a subsurface flow constructed wetland (SSF), a pond and a pond with floating plants. Equal in surface area and flow rate, they functioned as the advanced treatment stage following conventional biological wastewater treatment in a municipal wastewater treatment plant equipped for nutrient removal. The influent and the effluents of the three treatment wetlands were measured in two studies during summer and one study during winter. The influence of the treatment design and the inherent environmental conditions (redox potential and irradiation) on the range of compounds removed as well as on the removal efficiency was investigated. This field-site study was accompanied by an in situ degradation experiment to assess the influence of photodegradation and biodegradation on the overall removal of pharmaceuticals.In total, 13 compounds (diclofenac, 3-hydroxycarbamazepine (3-OH-CBZ), venlafaxine (VLX), O-desmethylvenlafaxine (O-DM-VLX), tramadol (TMD), trimethoprim, erythromycin, clarithromycin, metoprolol, atenolol, bezafibrate, acyclovir and codeine) were consistently removed in quantities more than 70% in at least one of the treatment systems during summer. In the open water pond, photodegradation was found to be an important process for the removal of diclofenac, O-desmethyltramadol (O-DM-TMD), O-DM-VLX as well as 2-hydroxycarbamazepine (2-OH-CBZ) and 3-OH-CBZ. In contrast to the field-site study, no removal of target compounds by biodegradation was observed in the in situ degradation experiments without sediment additions except for metoprolol. This suggests that biodegradation of most substances is improved by the presence of microbially active surfaces such as those provided by the sediment in the pond and, to a higher extent, by the filter passage in the SSF.Low redox conditions (absence of nitrate) within the SSF and the pond with floating plants in summer were favourable for the anaerobic degradation of some compounds that are aerobically quite persistent, such as sulfamethoxazole (SMX) and diatrizoate. During winter, the increase of redox conditions (presence of oxygen) in the SSF consistently led to an enhanced removal of aerobically degradable compounds such as iopromide. In contrast, the removal of the target pharmaceuticals in the open water pond was generally lower during winter. This could be attributed to a decrease of photodegradation and biodegradation due to the lower global radiation and microbial activity, respectively.Based on the conclusion drawn from the influence of constructed wetland design and season on the compound specific removal, a hybrid constructed wetland is suggested. The combination of an inundated SSF followed by a shallow open water pond would steadily remove a wide range of aerobically degradable pharmaceuticals throughout the year. Additionally during summer, the open water pond would allow for photodegradation and the SSF for partial degradation of anaerobically degradable pharmaceuticals.

Increased brain uptake of venlafaxine loaded solid lipid nanoparticles by overcoming the efflux function and expression of P-gp.

Venlafaxine (VLX) could be pumped out of the brain by P-glycoprotein (P-gp). Moreover, the expression of P-gp distributed in blood-brain barrier could be significantly induced by VLX. Thus, P-gp could be considered as the nature barrier for delivering of VLX to the brain. The aim of this study was to investigate whether the efflux function and increased expression of P-gp could be reversed by utilizing solid lipid nanoparticles (SLN). VLX solid lipid nanoparticles (VLX - SLN) were prepared and evaluated. Pharmacokinetics and brain distribution of VLX in different formulations were conducted after oral or intravenous administration. P-gp efflux function to VLX was evaluated by the brain uptake amount of VLX, while P-gp expression was investigated by Western blotting. Results indicated that the entrapment, mean size and zata potential of VLX - SLN was 74.9 ± 3.0 %, 186.3 ± 69.26 nm and -22.8 ± 7.78 mv, respectively. After vein injection of VLX formulations, the brain uptake amount of VLX from VLX - SLN was significantly higher than that of VLX solution, VLX solution with empty SLN (VLX+ empty SLN) and VLX solution with Verapamil (VLX + Ver), respectively. Furthermore, the protein mass of P-gp in VLX - SLN treated group was the lowest among all the investigated groups. These results indicated that SLN could overcome P-gp and achieve brain target by intravenous administration.

Novel chewable tablet-in-tablet dosage form of Orlistat and Venlafaxine hydrochloride: development and evaluation

Obesity is a chronic pathological condition characterized by an increased body fat accumulation to the extent that it may have an adverse effect on the health. Depression is the most common co-morbidity of obesity, which may cause the Binge Eating Disorder (BED), leading to morbid obesity. In the present project a dispersible 60mg Orlistat (ORST) and β-cyclodextrin (β-CD), (1:2M) complexed core tablet is press coated with the taste masked 75mg Venlafaxine Hcl. (VLFXN) microparticles, prepared with Eudragit EPO(1:3), by emulsification solvent evaporation method, to obtain the chewable tablet-in-tablet dosage form. A Reverse phase (RP)-HPLC method was developed for the simultaneous estimation of ORST and VLFXN in the formulation. The optimized formulation was palatable and there was no drug excipients interaction which was confirmed by IR Spectrum. Press coated, tablet-in-tablets were evaluated for physicochemical properties. All the values obtained were within the standard limits. And in the in-vitro dissolution study the release of both drugs, ORST and VLFXN at the end of 15mins was found to be 86% and 92% respectively. Hence, the developed chewable tablet-in-tablet formulation of ORST and VLFXN can be a viable drug delivery system for treating patients with obesity and BED.

Cost analysis of oral antidepressant drugs available in India

Background: Depression is a disorder that disrupts the public health through factors such as its occurrence, distress, ill health, and economic burden. There is a wide variation in the prices of antidepressant drugs marketed in India. Aims and Objective: To find out the price variations in the oral antidepressant drugs available in India either as a single drug or in combination and to evaluate the differences in the cost of various brands of the same oral antidepressant drug by calculating the percentage variation in cost in Indian rupees. Materials and Methods: The cost of a particular drug being manufactured by different companies, in the same strength and dosage forms, was obtained from “Current Index of Medical Specialties” July–October, 2014, and “Indian Drug Review, 2014;21(4)”. The difference between the maximum and minimum prices of the same drug and the percentage variation in the prices was calculated. Result: The prices of a total of 25 drugs (21 single and 4 combination preparations) available in 66 different formulations were analyzed. In single drug therapy, among tricyclic antidepressants, reboxetine (2 mg) showed the maximum price variation of 900%. In atypical antidepressants, bupropion hydrochloride (150 mg) showed the maximum price variation of 447.94%. In selective serotonin reuptake inhibitors (SSRIs), paroxetine (37.5 mg) showed the maximum price variation of 1116.66%. In serotonin norepinephrine reuptake inhibitors (SNRIs), Venlafaxine hydrochloride (37.5 mg) showed the maximum price variation of 246.15%. In monoamine oxidase (MAO)-A inhibitors, moclobemide (150 mg) showed the maximum price variation of 246.15%. In combination therapies, chlordiazepoxide with amitriptyline showed the maximum price variation of 227.23%. Conclusion: The average percentage variations of different brands of the same drug manufactured in India is very wide. The management of the marketing drugs should be directed toward maximizing the therapeutic benefits to the community and minimizing the economic burden.

Spectrofluorometric determination of venlafaxine in biological samples after selective extraction on the superparamagnetic surface molecularly imprinted nanoparticles

This paper reports on a procedure for selective extraction of the venlafaxine (VEN) drug from biological samples before its sensitive spectrofluorometric determination.

Estimation of Venlafaxine in Commercial Dosage Forms Using Simple and Convenient Spectrophotometric Method

Venlafaxine belongs to a group of Antidepressant with a novel chemical structure. In these studies describes a simple, accurate, precise and cost effective UV-visible spectrophotometric method for the estimation of Venlafaxine hydrochloride in bulk and pharmaceutical formulations. The method is based on the measurement of absorbance of Venlafaxine hydrochloride solution in 0.1N NaOH at 225 nm. The method obeys Beer's Lambert's law in the selected concentration range 5–25 μg/ml in selected solvent. The slope, intercept and correlation coefficient were also calculated. Results of percentage recovery study shows that the method was not affected by the presence of common excipients in tablets. The parameters like linearity, precision, accuracy were studied according to International Conference on Harmonization (ICH) guidelines. The developed method was validated in terms of accuracy, precision, linearity, limit of detection and limit of quantitation which proves suitability of proposed method for routine estimation of venlafaxine hydrochloride in bulk and pharmaceutical formulations.

Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes.

ObjectivesVenlafaxine (VLX), a serotonine-noradrenaline reuptake inhibitor, is one of the most commonly used antidepressant drugs in clinical practice for the treatment of major depressive disorder (MDD). Despite being more potent than its predecessors, similarly to them, the therapeutical effect of VLX is visible only 3–4 weeks after the beginning of treatment. Furthermore, recent papers show that antidepressants, including also VLX, enhance the motor recovery after stroke even in non depressed persons. In the present, transcriptomic-based study we looked for changes in gene expressions after a long-term VLX administration.MethodsOsmotic minipumps were implanted subcutaneously into Dark Agouti rats providing a continuous (40 mg/kg/day) VLX delivery for three weeks. Frontal regions of the cerebral cortex were isolated and analyzed using Illumina bead arrays to detect genes showing significant chances in expression. Gene set enrichment analysis was performed to identify specific regulatory networks significantly affected by long term VLX treatment.ResultsChronic VLX administration may have an effect on neurotransmitter release via the regulation of genes involved in vesicular exocytosis and receptor endocytosis (such as Kif proteins, Myo5a, Sv2b, Syn2 or Synj2). Simultaneously, VLX activated the expression of genes involved in neurotrophic signaling (Ntrk2, Ntrk3), glutamatergic transmission (Gria3, Grin2b and Grin2a), neuroplasticity (Camk2g/b, Cd47), synaptogenesis (Epha5a, Gad2) and cognitive processes (Clstn2). Interestingly, VLX increased the expression of genes involved in mitochondrial antioxidant activity (Bcl2 and Prdx1). Additionally, VLX administration also modulated genes related to insulin signaling pathway (Negr1, Ppp3r1, Slc2a4 and Enpp1), a mechanism that has recently been linked to neuroprotection, learning and memory.ConclusionsOur results strongly suggest that chronic VLX treatment improves functional reorganization and brain plasticity by influencing gene expression in regulatory networks of motor cortical areas. These results are consonant with the synaptic (network) hypothesis of depression and antidepressant-induced motor recovery after stroke.

Ellagic acid enhances the antinociceptive action of venlafaxine in mouse acetic acid-induced pain: An isobolographic analysis

BackgroundSeveral antidepressants have been used to treat severe pain in clinics. Recently, it has been shown that ellagic acid (EA), a major constituent of pomegranate juice, produced antinociceptive and anti-inflammatory effect through the central and peripheral sites of action. Materials and methodsIn this study, we examined the interaction between EA and venlafaxine (VLF) on pain induced by intraperitoneal acetic acid in mice using isobolographic analysis. ResultsEA (0.3–10mg/kg, ip) and VLF (3–60mg/kg, ip) produced a dose-dependent inhibition of the writhing response evoked by acetic acid. Fifty percent effective dose (ED50) values against writhing behaviors were 1.02 (0.86–1.19)mg/kg and 12.37 (9.74–15.37)mg/kg for EA and VLF, respectively, and also with higher potency than that of VLF. Co-administration of increasing fractional increments of ED50 doses of EA and VLF produced synergistic interaction against writhing behaviors, as revealed by isobolographic analysis. ConclusionThe synergistic action of EA and VLF provides valuable tool referring to the management of visceral pain.

Assessment of in-utero venlafaxine induced, ROS-mediated, apoptotic neurodegeneration in fetal neocortex and neurobehavioral sequelae in rat offspring

Venlafaxine (VEN), a serotonin and noradrenaline reuptake inhibitor is being used as a drug of choice for treating clinical depression even during pregnancy. It is an important therapeutic option in the treatment of perinatal depression, but the effects of VEN on fetus and the newborn are uncertain. Therefore, present study was undertaken to investigate the safety of in-utero exposure to VEN in terms of developmental neurotoxicity and neurodegenerative potential by using prenatal rat model. The selected doses of VEN (25, 40 and 50mg/kg) were administered to pregnant rats from GD 5 to 19 through oral gavage. The fetal brains were dissected and processed for histopathological measurements of neocortical thickness that showed significant reduction. Considering vulnerability of immature brain to free radical injury, VEN exposed neocortices were tested for reactive oxygen species (ROS) levels which were significantly increased. As ROS play important role in the initiation of apoptotic mechanisms, we explored for in situ detection of apoptosis by confocal microscopy that showed enhanced apoptosis including chromatin condensation which was further reconfirmed by electron microscopy. Substantially increased levels of pro-apoptotic protein Bax and decreased levels of anti-apoptotic protein Bcl2 as shown by western blotting also supported the increased neuro-apoptotic degeneration. For further correlation of these findings, prenatally VEN exposed young-adult rat offspring were assessed for open field exploratory behavior that showed increased anxiety-like and stereotypic responses indicating disturbed neurobehavioral pattern. The study concludes that prenatal VEN exposure may primarily enhance ROS generation that plays a key role in regulating release of proapoptotic factors from mitochondria and thereby enhancing apoptotic neurodegeneration that affect proliferation, migration and differentiation of cells, resulting in neuronal deficits manifested as long term neurobehavioral impairments.

First MEPS/HPLC assay for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in human plasma.

A new high-performance liquid chromatography-fluorescence detection assay based on microextraction by packed sorbent as sample preparation approach is described to quantify venlafaxine (VEN) and its main metabolite [O-desmethylvenlafaxine (ODV)]in human plasma. Chromatographic separation of the target analytes (VEN and ODV) and internal standard (licarbazepine) was achieved in less than 6 min on a reverse-phase C18 column using isocratic elution. Calibration curves were linear in the ranges of 10-1000 ng ml(-1) for VEN and 20-1000 ng ml(-1) for ODV. The method was successfully applied to real plasma samples. This microextraction by packed sorbent/high-performance liquid chromatography-fluorescence detection assay offers a cost-effective tool that can be applied for therapeutic drug monitoring and also support other pharmacokinetic-based studies in humans.

Antidepressant efficacy of theta-burst transcranial magnetic stimulation in treatment of first-episode depression: a randomized, double blind controlled trial

Objective To evaluate the antidepressant efficacy, cognitive effect and safety of theta-burst transcranial magnetic stimulation (TBS) in treatment of first-episode depression. Methods 43 hospitalized patients with first-episode depression meeting with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) were randomly divided into theta-burst stimulation group(TBS group, n=21)and sham-stimulation group(sham group, n=22). All patients were treated at left dorsolateral prefrontal cortex (DLPFC) for 4 weeks, and were concomitantly taking venlafaxine (150-300)mg/d. Hamilton Depression Scale-24 was used to assess the severity of depression before treatment, at week 2 and week 4 in both groups. Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) were used to estimate cognitive function of depression before and after treatment. Results There was no difference on HAMD score before treatment between two groups((38.2±7.1)vs.(37.5±6.8), t=0.314, P=0.754). The reduction of HAMD score in TBS group showed significantly faster than that in sham group at week 2 ((20.5±4.8)vs.(16.1±5.9), t=2.547, P=0.015) and week 4((30.3±5.2)vs.(26.0±6.3), t=2.318, P=0.026). After 2-week stimulation, the response rate was higher in TBS group than that in sham group (57.9%vs. 25%, χ2 =4.358, P=0.037). The response and remission rates were significantly higher in TBS group than those in sham group after 4-week stimulation period (94.7%vs.65%, χ2 =5.284, P=0.021; 78.9%vs.45%, χ2=4.744, P=0.029). The improvements on WCST and CPT after treatment in TBS group, such as categories completed, correct responses, error responses, perseverative responses errors, nonperseverative responses errors, CPT1, CPT2 and CPT3, were significant than those in sham group (P<0.05). Conclusions Theta-burst stimulation of the left dorsolateral prefrontal cortex is safe and well-tolerated, while offering the potential to enhance early effects and modulate cognition in first-episode depressive patients. Key words: Theta-burst stimulation; Transcranial magnetic stimulation; Depression

Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.

We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

Case report: Interaction of valproic acid and the antidepressant drug doxepin

Doxepin (DOX) is a widely used antidepressant which is often combined with the mood stabilizer and anticonvulsant valproic acid (VPA) in patients with affective disorders. We report the case of a 56-year-old woman with a schizoaffective disorder and a renal failure. She was treated with DOX in a daily dose of 225 mg, with VPA 1800 mg and risperidone 2 mg. Additionally she received other drugs like phenprocoumon 3 mg, acarbose 150 mg and metamizol 1000 mg. At admission the patient suffered from drop-attacks, ataxia, apraxia and tremor as well as from acoustic hallucinations and depressive symptoms. After immediate reduction of the DOX dose to 125 mg the patient's serum concentration of DOX and N-DOX remained elevated with 804 and 535 ng/ml. Consequently DOX was discontinued, but on the next day the serum concentration was still considerably elevated with DOX/N-DOX 483/399 ng/ml. Even 21 days after DOX discontinuation a blood level of DOX/N-DOX (31/61 ng/ml) was measured. In addition we started an antidepressant treatment with venlafaxine (VEN) and dosed up to 150 mg. Under this dose therapeutic drug monitoring (TDM) also revealed elevated serum concentrations of VEN and O-Desmethyl-VEN.

Mechanisms of morphine–venlafaxine interactions in diabetic neuropathic pain model

Backgroundwe investigated the possible mechanisms involved in the interactions of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, and morphine (MRF), an opioid receptor agonist, after acute and chronic VFX treatment in diabetic neuropathic pain model (DNPM). MethodsThe studies were performed on male rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall–Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of streptozotocin. In order to investigate the mechanism of interaction, animals were also pretreated with naloxone (NLX), a nonselective opioid antagonist, yohimbine (YOH), a nonselective α2-adrenergic antagonist, and p-chloroamphetamine (PCA), a neurotoxin that destroys serotonergic neurons. The μ-opioid receptors’ density was determined with the use of radioligand binding assay. ResultsVFX potentiated antinociceptive action of MRF after acute administration of VFX and this effect was decreased by pretreatment of NLX, YOH and PCA. On the contrary, VFX administered for 21 days prior to MRF significantly decreased the analgesic action of MRF; this effect was augmented only after YOH pretreatment. Also, 21-days administration of VFX caused decreasing tendency in the number of μ-opioid receptors in the brain stem. ConclusionsThe results of our study show that single administration of VFX potentiates antinociceptive action of morphine in DNPM. This effect is probably mediated by both, noradrenergic and serotonergic systems. On the other hand, 21-days administration of VFX significantly decreases analgesic action of MRF. Moreover, there is a possibility that VFX acts as an antagonist of N-methyl-d-aspartate receptors.

Association of CYP2D6 gene polymorphism and therapeutic efficacy of venlafaxine on depression in southern region of Fujian

Objective To explore the effect of CYP2D6 gene polymorphism on blood concentration, therapeutic efficacy and adverse effects of anti-depression drug venlafaxine. Methods 69 cases of patients with depression were selected randomly from southern region of FuJian, China. The blood concentration of venlafaxine was detected by HPLC, and the CYP2D6 genotype was determined by sequencing with the amplified PCR products from peripheral blood DNA. The therapeutic efficacy and adverse effects of venlafaxine were evaluated by Hamilton depression scale(HAMD) and treatment emergent symptom scale(TESS) respectively. Results Subjects was divided into CC, CT, TT three groups based on rs16947 locus genotyping. The blood concentrations of venlafaxine were (157.35±15.63)ng/ml, (70.17±5.11)ng/ml, (115.72±10.2)ng/ml respectively and there was no significant difference (F=1.257, P=0.301). The dose-corrected concentrations and normalized concentrations were not significantly different (F=1.683, 1.547, P>0.05). Similarly, the reduction rate of HAMD (CC: (40.6±7.23)%, CT: (51.7±7.09)%, TT: (42.8±14.1)%) and TESS scores (CC: 1.3±0.21, CT: 1.3±0.36, TT: 1.2±0.28) were not significantly different either (P>0.05). In 69 samples in this study, genotyping of rs3892097 locus only found GG type, and no further examination was performed. Genotyping divided rs1065852 locus into CC, CT, TT three groups. The blood concentrations of venlafaxine were (42.87±9.9)ng/ml, (64.25±13.59)ng/ml, (181.56±14.15)ng/ml respectively, and there was significant difference among the three groups (F=4.893, P=0.016). The dose-corrected concentrations and normalized concentrations were also significantly different (F=3.985, 3.648, P<0.05). The reduction rate of HAMD (CC: (42.6±8.23)%, CT: (48.8±10.8)%, TT: (63.4±9.15)%) was not significantly different (F=2.961, P=0.07). The difference of TESS scores was similar to that of HAMD reduction rate. Conclusion Among the 3 loci studied, only rs1065852 locus within CYP2D6 gene can affect its enzyme activity and then influence the therapeutic efficacy and adverse effects of venlafaxine. Key words: Venlafaxine; CYP2D6; Gene polymorphism; Blood concentration