Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A.

Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for Cmax and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC0-∞ , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.

Effect Of Chinese Herb Danzhi Xiaoyao Pills On Pharmacokinetics Of Venlafaxine In Beagles.

OBJECTIVE: To investigate the effects of Chinese herb Danzhi Xiaoyao pills on the pharmacokinetics of venlafaxine and its metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) in beagles by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: Six beagles (half male, half female) were chosen to test, being fasted before the experiment but having free access to drinking water 1 day before being fed drugs. After oral administration of venlafaxine hydrochloride tablets (10.28 mg/kg), the blood samples were collected in succession at different points in time. After 1-week washout period, Danzhi Xiaoyao pills (0.6g/kg) were given through oral administration to the six beagles every morning until the 7th day, venlafaxine hydrochloride tablets (10.28 mg/kg) were given after feeding Danzhi Xiaoyao pills (0.6g/kg) half an hour and blood samples were collected continuously at different points. All samples were analyzed by UPLC-MS/MS, and the main pharmacokinetic parameters of venlafaxine, ODV and NDV were computed by DAS 2.0. RESULTS: The Cmax of the venlafaxine group (control group) and the combination group (experimental group) were (2267.26±252.89) ng/mL and (1542.64±190.73) ng/mL, respectively. The AUC(0-∞) of the two groups were (13,934.79±3609.23) ng·h/mL and (8001.91±2167.58) ng·h/mL, respectively. The ODV Cmax of the two groups were (2253.80±215.81) ng/mL and (2721.37±118.20) ng/mL, and AUC(0-∞) were (13,974.99±2784.04) ng·h/mL and (17,539.44±1894.29) ng·h/mL, respectively. The NDV Cmax of the two groups were (50.98±5.76) ng/mL and (58.74±12.33) ng/mL, and AUC(0-∞) were (179.26±34.94) ng·h/mL and (220.68±51.41) ng·h/mL, respectively. After administration of Danzhi Xiaoyao pills, the Cmax and AUC(0-∞) of venlafaxine decreased significantly, indicating that the plasma exposure of venlafaxine decreased. The increase of Cmax and AUC(0-∞) of ODV and NDV indicated a rise in plasma exposure. CONCLUSION: Danzhi Xiaoyao pills can accelerate the metabolism of venlafaxine in beagles. In clinical, when venlafaxine was co-administrated with Danzhi Xiaoyao pills, dose adjustment of venlafaxine should be taken into account.

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.

AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.

Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism.

BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording.

Isoflavin-ß modifies muscle oxidative stress and prevents a thyrotoxicosis-induced loss of muscle mass in rats.

INTRODUCTION: We sought to verify whether isoflavin-beta (Iso-ß), a mixture of isoflavones with antioxidant properties, could prevent thyrotoxicosis-induced loss of muscle mass and the participation of oxidative stress (OS) in the mechanisms of this prevention. METHODS: Two experimental periods of thyrotoxicosis induction were used in Wistar rats: 3 and 5 days to assess Iso-ß effects before and after thyrotoxicosis-induced muscle wasting. After euthanasia, peritoneal fat and gastrocnemius muscle were collected, weighed, and muscle OS was assessed. RESULTS: Iso-ß prevented the loss of gastrocnemius mass in thyrotoxic rats through the prevention of muscle OS generation during thyrotoxicosis, increasing muscle total antioxidant capacity and decreasing mitochondrial cytochrome c oxidase activity, lipid peroxidation, and protein carbonyl content. CONCLUSION: Iso-ß decreased oxidative modification of proteins, which is known to exert a major role during proteolysis induction and is present in thyrotoxic myopathy, highlighting the potential action of Iso-ß in this complication of the disease. Muscle Nerve 56: 975-981, 2017.

DETERMINATION OF VENLAFAXINE, VILAZODONE AND THEIR MAIN ACTIVE METABOLITES IN HUMAN SERUM BY HPLC-DAD AND HPLC-MS.

A high performance liquid chromatography (HPLC) method for simultaneous analysis of venlafaxine and its major metabolite 0-desmethylvenlafaxine and vilazodone and its methabolite M10 have been devel- oped and validated. Chromatography was performed on the Phenyl-Hexyl column with mobile phase containing methanol, acetate buffer at pH 3.5 and diethylamine. The application of stationary phase with 7r-7c moieties and mobile phase containing diethylamine as silanol blocker lets to obtain double protection against silanols and thus very high theoretical plate numbers were obtained. The good separation selectivity, good peaks' symmetry and very high systems efficiency for all investigated compounds were obtained in applied chromatographic system. The method is very efficient and suitable for the analysis of investigated drugs and their metabolites in human serum for patients' pharmacotherapy control.

Selective solid-phase extraction using molecularly imprinted polymers for analysis of venlafaxine, O-desmethylvenlafaxine, and N-desmethylvenlafaxine in plasma samples by liquid chromatography-tandem mass spectrometry.

This paper focuses on the development of a novel miniaturized molecularly imprinted solid-phase extraction (MISPE) and ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine venlafaxine (VEN), O-desmethylvenlafaxine (ODV), and N-desmethylvenlafaxine (NDV) in plasma samples. The molecularly imprinted polymer (MIP) was prepared by the precipitation polymerization approach; VEN, metacrylic acid, ethylene glycol dimethacrylate, 2,2-azobisisobutyronitrile, and toluene were used as template, monomer, crosslinker, initiator, and porogen solvent, respectively. MIP and of the non-imprinted control polymer (NIP) sorbents were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. MIP phase presented higher extraction efficiency (MISPE, using plasma samples spiked with VEN) than the NIP phase (84 and 49% recovery rates, respectively). Analysis of other antidepressants with different chemical structures by MISPE-UHPLC-MS/MS attested to the selectivity of the developed MIP. The developed method presented precision assays with coefficients of variation (CV) smaller than 15%; accuracy assays with relative standard error (RSE%) values ranging from -12 to 16%, and linear ranges from 3 to 700ngmL(-1) for VEN, from 5 to 700ngmL(-1) for ODV, and from 3 to 500ngmL(-1) for NDV. The coefficients of determination (r(2)) were higher than 0.995. The lack-of-fit test also attested to the linearity of this method. This method was successfully applied to determine VEN, NDV, and ODV in plasma samples from depressed patients undergoing therapy with VEN.

[The enantioselective pharmacokinetic study of desvenlafaxine sustained release tablet in Chinese healthy male volunteers after oral administration].

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 µm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

Venlafaxine and O-desmethylvenlafaxine concentrations in plasma and cerebrospinal fluid.

OBJECTIVE: To investigate whether drug concentrations of venlafaxine and its metabolite O-desmethylvenlafaxine in plasma can be considered as a surrogate marker of concentrations in brain/cerebrospinal fluid (CSF). METHOD: For therapeutic drug monitoring purposes, plasma and CSF concentrations of venlafaxine and O-desmethylvenlafaxine were measured between November 2011 and August 2013 in 16 depressive inpatients (ICD-10 diagnoses) who were treated with daily doses of venlafaxine extended release (dose range, 75-225 mg). Daily doses were correlated with plasma and CSF levels. The correlation between venlafaxine, O-desmethylvenlafaxine, and the active moiety (AM) in plasma and CSF was calculated. RESULTS: Venlafaxine in plasma (P = .005) and CSF (P = .023) correlated significantly with the daily dose, while O-desmethylvenlafaxine and the active moiety (AM = venlafaxine + O-desmethylvenlafaxine) did not. The correlation between venlafaxine, O-desmethylvenlafaxine, and the AM in plasma and CSF was highly significant (P < .001). The calculated CSF/plasma ratio was 0.74 for venlafaxine, 0.88 for O-desmethylvenlafaxine, and 0.84 for the AM. CONCLUSIONS: Venlafaxine and O-desmethylvenlafaxine were found to penetrate well into CSF in patients, which indicated good availability of the drug in the brain, although the findings on CSF concentrations do not allow calculation of concentrations at the target structure within the brain. CSF/plasma ratios for venlafaxine and its metabolite were high probably due to low plasma protein binding. The poor correlation of dose to concentrations in body fluids and the highly significant correlation of plasma to CSF concentrations indicate that plasma concentration is a much better marker of drug concentration in brain than the dose.

Coupling of solid phase microextraction with electrospray ionization ion mobility spectrometry and direct analysis of venlafaxine in human urine and plasma.

The capability of electrospray ionization-conventional ion mobility spectrometry (ESI-IMS) for direct analysis of the samples extracted by solid phase microextraction (SPME) was investigated and evaluated for the first time. To that end, an appropriate new desorption chamber was designed and constructed, resulting in the possibility of direct exposure of the SPME fiber to the electrospray solvent flow. Two different elution methods in dynamic and static modes were exhaustively investigated. The results indicated that the interface could help us to have an accurate and sensitive analysis without disturbing the electrospray process, in static elution method. Venlafaxine as a test compound was extracted from human urine and plasma by a convenient headspace SPME method. The positive ion mobility spectrum of the extracted drug was obtained and the analyte responses were calculated. The coupled method of SPME-ESI-IMS was comprehensively validated in terms of sensitivity, dynamic range, and recovery percentage. Finally, various real samples of human urine and plasma were analyzed, all verifying the feasibility and success of the proposed method for the easy routine analysis.

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

BACKGROUND: 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. METHODS & RESULTS: 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. CONCLUSION: 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.

SLC6A2 and SLC6A4 variants interact with venlafaxine serum concentrations to influence therapy outcome.

OBJECTIVE: The effects of genetic variants in genes encoding the target structures of antidepressants on the therapeutic efficacy of antidepressant drugs have been investigated with unconclusive results. One possible confounding factor in most studies was the fact that drug serum concentrations had not been determined. METHODS: Within a clinical setting, 56 inpatients suffering from depressive episodes in the context of either major depressive disorder or bipolar affective disorder were studied. Response to venlafaxine was assessed after 4 weeks of treatment and correlated to serum concentration and functional variants in genes encoding the norepinephrine (SLC6A2; rs28386840) and the serotonin transporter (SLC6A4; [5-HTTLPR], rs25531). Symptom change was evaluated using the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: No association between therapeutic response, venlafaxine serum concentration (active moiety) and rs28386840 was found. In carriers of the high expressing SLC6A4 genotype (lAlA-), a poor response to venlafaxine was found significantly more often. In subsamples stratified for serum concentration this held true for patients with serum concentrations between 201 and 400 ng/mL (n=21), while in patients with sub- (≤ 200 ng/mL; n=12) and supra-recommended (> 400 ng/mL; n=23) concentrations, no significant differences were observed. DISCUSSION: The observed association is consistent with findings of some previous studies, whereas others showed differing results highlighting the need for further investigations.

Concentrations of venlafaxine and its main metabolite O-desmethylvenlafaxine during pregnancy.

WHAT IS KNOWN AND OBJECTIVE: Depression during pregnancy is common and includes risks for mother and child. Pharmacokinetics of venlafaxine may be changed during pregnancy. This study aimed to describe changes in metabolic ratios and concentrations of venlafaxine and its main metabolite O-desmethylvenlafaxine during and after pregnancy. METHODS: To study this, we used data from our study of compliance to Antidepressants During Pregnancy (the ADAP study) to investigate the course of venlafaxine and O-desmethylvenlafaxine concentrations during pregnancy and in the period post-partum. RESULTS AND DISCUSSION: We found that the venlafaxine concentration significantly changed during pregnancy when compared to the post-partum period (P = 0·028). The median concentration of venlafaxine in the first trimester was 98·9% (54·2-292·0%), the second 100·0% (46·5-264·0%) and the third trimester 87·0% (61·5-217·2%). We did not found differences in O-desmethylvenlafaxine concentrations in the different trimesters of pregnancy compared with the post-partum period, P = 0·565. Also the ratio of O-desmethylvenlafaxine/venlafaxine concentrations increased significantly from 76·9% (range 32·8-142·0%) in the first trimester to 196·7% (range 83·3-427·6%) in the third trimester compared with the post-partum period, P = 0·004. Further, three of seven patients had concentrations below the therapeutic reference range (100-400 µg/L) in any period of pregnancy, whereas no one had subtherapeutic concentrations in the post-partum period. WHAT IS NEW AND CONCLUSION: Venlafaxine concentrations decreases during pregnancy, and the ratio of the concentrations of O-desmethylvenlafaxine/venlafaxine increases during pregnancy. Pregnant women using venlafaxine are at risk for subtherapeutic concentrations, therefore routine monitoring of concentrations venlafaxine and O-desmethylvenlafaxine is recommendable during pregnancy.

Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups.

PURPOSE: The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups. METHODS: Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40-65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses. RESULTS: In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups). CONCLUSION: This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

Determination of venlafaxine and O-desmethylvenlafaxine in dried blood spots for TDM purposes, using LC-MS/MS.

Dried blood spot (DBS) sampling and quantitative analyses of many current therapeutic drug monitoring (TDM)-guided drugs are advantageous because of the minimal invasive sampling strategy. Here, a fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV) in DBS. Six-millimeter circles were punched out from DBS collected on Whatman DMPK-C paper, and the DBS was extracted with acetonitrile/methanol at 1:3. The total run time was 4.8 min. The assay was linear in the range of 20-1,000 µg/L for both VEN and ODV. Assay accuracy and precision was well within limits of acceptance (LLOQ = 20 µg/L). Normal hematocrit concentrations (0.30-0.50) did not influence the results neither did a normal spot volume (40-80 µL). Punch position at the perimeter instead of the center of the blood spot gave a bias ranging from 2.4 to 10.4%. Correlation between plasma and spiked DBS samples was high. The concentrations found in spiked DBS samples were higher than those in plasma, indicating that a conversion factor for translation of DBS to plasma values is needed. This analytically validated method is suitable for determination of VEN and ODV in DBS and applicable for TDM. The method will be used for TDM of VEN in the Dutch CYSCE multicenter trial (NCT01778907).

The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis.

OBJECTIVE: Venlafaxine (VEN) is a widely used antidepressant drug, which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking. METHODS: In 2010, inpatients of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, were treated with either slow-release brand-name VEN (Trevilor) or slow-release generic VEN (Venlafaxin Hexal) depending on the respective inpatient ward. Routine therapeutic drug monitoring analyses of both groups were compared after matching samples regarding dose of VEN, gender, age, smoking habits, and evaluation of co-medication. RESULTS: Both groups did not differ in mean values of VEN, O-desmethyl-VEN (ODV), VEN + ODV serum concentrations, and ODV/VEN ratio. No difference in dose-corrected serum concentrations between generic and brand-name VEN was revealed for males, females, smokers, or nonsmokers. In both groups, Spearman Rho correlation between VEN dose and VEN + ODV serum concentration was moderate but significant (P < 0.001; generic: r = 0.554; brand name: r = 0.668). Within the generic subgroup, females had a significantly higher dose-corrected serum concentration of VEN (U test, P < 0.05), whereas within brand name, no gender influence was detected. Spearman Rho correlation of age and dose-corrected ODV (P < 0.05) and VEN + ODV (P < 0.05) was significant only in the generic group. In the brand-name sample, smokers had significantly lower dose-corrected serum concentrations of ODV (U test, P < 0.01) and VEN + ODV (P < 0.01). In the generic group, smoking habit was without any influence. DISCUSSION: No differences in serum concentrations in dependence of either VEN formulations suggest a safe and efficient treatment of patients using the evaluated generic VEN. However, differences within one formulation regarding gender, age, and smoking status suggest variability of serum concentrations and thus could endanger safety and efficacy of drug use.

Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression.

The purpose of the present study was to investigate the potential of Venlafaxine loaded alginate nanoparticles (VLF AG-NPs) for treatment of depression via intranasal (i.n.) nose to brain delivery route. The VLF AG-NPs were prepared and optimized on the basis of various physio-chemical characteristics. Pharmacodynamic studies of the VLF AG-NPs for antidepressant activity were carried in-vivo by forced swimming test and locomotor activity test on albino Wistar rats. VLF AG-NPsi.n. treatment significantly improved the behavioural analysis parameters i.e. swimming, climbing, and immobility in comparison to the VLF solutioni.n. and VLF tabletoral. The intranasal VLF AG-NPs also improved locomotor activity when compared with VLF solutioni.n. and VLF tabletoral. Confocal laser scanning fluorescence microscopy studies were performed on isolated organs of rats after intravenous and intranasal administrations of Rodamine-123 loaded alginate nanoparticles to determine its efficacy for nose to brain delivery and also for its qualitative distribution to other organs. Brain uptake and pharmacokinetic studies were performed by determination of VLF concentration in blood and brain respectively for VLF AG-NPsi.n., VLF solutioni.n. and VLF solutioni.v. The greater brain/blood ratios for VLF AG-NPsi.n. in comparison to VLF solutioni.n. and VLF solutioni.v. respectively at 30 min are indicative of superiority of alginate nanoparticles for direct nose to brain transport of VLF. Thus, VLF AG-NPsi.n. delivered greater VLF to the brain in comparison to VLF solution which indicates that VLF AG-NPs could be a promising approach for the treatment of depression.

A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients.

OBJECTIVE: To compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients in a randomized double-blind study. METHODS: The study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression (HAM-D) score ≥ 17. Patients were randomized to imipramine or venlafaxine. The dose of imipramine was adjusted for each patient to a predefined blood level of 200-300 ng/ml. The dose of venlafaxine was increased gradually to 300-375 mg/day. Efficacy was evaluated after 7 weeks of treatment. RESULTS: The mean age of the study group was 54.5 (range 29-82) years. There was no significant difference according to the primary outcome criterion of a ≥50% reduction on the HAM-D score: 17 of 43 (39.5%) patients on imipramine were responders compared to 21 of 42 (50%) patients on venlafaxine. When considering remission as outcome criterion (HAM-D score ≤ 7), 10 of 43 (23.3%) patients on imipramine were remitters compared to 15 of 42 (35.7%) patients on venlafaxine; again, no significant difference. When analysing a subpopulation of patients without psychotic features, with remission as outcome criterion, a significant difference was found: 5 of 34 (14.7%) patients on imipramine were remitters compared to 12 of 31 (38.7%) patients on venlafaxine. CONCLUSIONS: The present study used optimal doses in depressed inpatients and showed that venlafaxine is at least equal in efficacy to imipramine. The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine.

Hollow-fiber liquid-phase microextraction and chiral LC-MS/MS analysis of venlafaxine and its metabolites in plasma.

BACKGROUND: An enantioselective analytical method was developed and validated for determination of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in plasma samples. The method employed LC-MS/MS analysis and hollow-fiber liquid-phase microextraction (HF LPME) for sample preparation. RESULTS: After HF LPME optimization the following condition was established: sample volume of 4 ml, sample agitation at 1750 rpm, 20 min of extraction, 0.1 mol/l acetic acid as acceptor phase, 1-octanol as organic phase and donor phase pH adjustment to 10. Under these conditions, the method was linear over the concentration range of 5-500 ng/ml with quantification limits of 5 ng/ml. CONCLUSION: The use of HF LPME for sample preparation provided suitable recoveries, efficient clean-up and low consumption of organic solvent.