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PubMed2006

QT interval prolongation associated with venlafaxine administration.

A significant number of non-antiarrhythmic drugs including psychotropic agents have been shown to prolong cardiac repolarization increasing the risk for torsade de pointes ventricular tachycardia. We briefly describe a 60-year-old woman who admitted to the hospital due to hypertension and mild dyspnea having a prolonged QT interval (QTc: 582 ms). The patient had a known history of depression treated with venlafaxine. The QT interval normalised a few days after cessation of the antidepressant agent. This is the first report of venlafaxine-induced QT interval prolongation.

Cyclohexanols↗
PubMed2004

Transdermal permeation of WIN 55,212-2 and CP 55,940 in human skin in vitro.

Synthetic cannabinoids have a promising future as treatments for nausea, appetite modulation, pain, and many neurological disorders. Transdermal delivery is a convenient and desirable dosage form for these drugs and health conditions. The aim of the present study was to investigate the in vitro transdermal permeation of two synthetic cannabinoids, WIN 55,212-2 and CP 55,940. Transdermal flux, drug content in the skin, and lag times were measured in split-thickness human abdominal skin in flow-through diffusion cells with receiver solutions of 4% bovine serum albumin (BSA) or 0.5% Brij 98. Differential thermal analysis (DSC) was performed in order to determine heats of fusion, melting points, and relative thermodynamic activities. The in vitro diffusion studies in 0.5% Brij 98 indicated that WIN 55,212-2 diffuses across human skin faster than CP 55,940. The WIN 55,212-2 skin disposition concentration levels were also significantly higher than that of CP 55,940. Correspondingly, CP 55,940 was significantly metabolized in the skin. WIN 55,212-2 flux and skin disposition were significantly lower into 4% BSA than into 0.5% Brij 98 receiver solutions. There was no significant difference in the flux, lag time, and drug content in the skin of CP 55,940 in 4% BSA versus 0.5% Brij 98 receiver solutions. The DSC studies showed that CP 55,940 had a significantly lower melting point, smaller heat of fusion, and corresponding higher calculated thermodynamic activity than the more crystalline WIN 55,212-2 mesylate salt. The permeation results indicated that WIN 55,212-2 mesylate, CP 55,940, and other potent synthetic cannabinoids with these physicochemical properties could be ideal candidates for the development of a transdermal therapeutic system.

Administration, Cutaneous↗
PubMed2006

Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the 'pull' effect.

The simultaneous skin permeation of drug and penetration enhancer have been studied in vitro. Simple formulations of mefenamic acid in PEG400 incorporating various proportions of ethanol or 1,8-cineole were prepared and applied to porcine ear skin in diffusion cells under infinite conditions. Receptor phases were assayed for mefenamic acid by HPLC and ethanol or 1,8-cineole by GC. Concentration-dependent permeation profiles were obtained for both ethanol or 1,8-cineole, in addition to concentration-dependent enhancement of mefenamic acid. When the steady state flux of mefenamic acid was plotted against ethanol or 1,8-cineole, linear relationships were observed with r2 values of 0.988 and 0.999, respectively. The close connection between rates of excipient and solute permeation is generally referred to as the 'pull' (or 'drag') effect, where in this case permeation of the enhancer facilitated permeation of the solute. This appears to be sufficient to account for the enhancing activity of ethanol and 1,8-cineole, notwithstanding initial modulations that may occur within the stratum corneum.

Animals↗
PubMed2006

Effect of DC/mDC iontophoresis and terpenes on transdermal permeation of methotrexate: in vitro study.

The systemic toxicity caused by methotrexate limits its use and transdermal delivery would be a possible alternative. Transdermal permeation of methotrexate loaded into polyacrylamide-based hydrogel patch, across mice skin was studied in vitro after pretreatment with terpenes and ethanol, alone or in combination with iontophoresis (DC/mDC). Polyacrylamide patches gave the maximum flux as compared to the copolymers of acrylamide and acrylic acid. Of the terpenes used, pure menthol showed maximum enhancement (38%), whereas pure limonene elicited a minimum of 9.9% enhancement. Binary combination of menthol and ethanol increased the permeation to 54.9%, which was further enhanced to 93.69% and 117% when used in combination with DC and square wave (mDC) iontophoresis, respectively. ATR-FTIR of the stratum corneum treated with terpenes showed a split in the asymmetric C-H stretching vibrations along with decrease in peak heights and areas of asymmetric, symmetric C-H stretching, C=O stretching and amide bands. A split in amide II band was observed with iontophoresis. ATR-FTIR studies suggest conformational changes in the lipid-protein domains thereby increasing permeation. Histopathological studies on treated skin samples, gave an insight about the anatomical changes brought by the application of various enhancers. Binary mixture of menthol and ethanol in combination with square wave gave best results.

Acrylic Resins↗
PubMed2004

Downregulation of class II transactivator (CIITA) expression by synthetic cannabinoid CP55,940.

Cannabinoid receptors are known to be expressed in microglia; however, their involvement in specific aspects of microglial immune function has not been demonstrated. Many effects of cannabinoids are mediated by two G-protein coupled receptors, designated CB1 and CB2. We have shown that the CB1 receptor is expressed in microglia that also express MHC class II antigen (J. Neuroimmunol. 82 (1998) 13-21). In our present study, we have analyzed the effect of cannabinoid agonist CP55,940 on MHC class II expression on the surface of IFN-gamma induced microglial cells by flow cytometry. CP55,940 blocked the class II MHC expression induced by IFN-gamma. It has been shown that the regulation of class II MHC genes occurs primarily at the transcriptional level, and a non-DNA binding protein, class II transactivator (CIITA), has been shown to be the master activator for class II transcription. We find that mRNA levels of CIITA are increased in IFN-gamma induced EOC 20 microglial cells and that this increase is almost entirely eliminated by the cannabinoid agonist CP55,940. These data suggests that cannabinoids affect MHC class II expression through actions on CIITA at the transcriptional level.

Animals↗
PubMed2004

Stimulatory effect of antidepressants on the production of IL-6.

A body of evidence indicates that the therapeutic activity of antidepressants is connected with their modulatory effect on the inflammatory response system and cell-mediated immunity. The present study was carried out to examine the effects of antidepressant agents, such as imipramne, venlafaxine, l-5-hydroxytryptophan, fluoxetine and a combination of l-5-hydroxytryptophan and fluoxetine, on the production of the pleotrophic cytokines TNF-alpha and IL-6. Diluted whole blood from fluoxetine-treated patients with treatment-resistant depression (TRD) (mean age: 50.6+/-3.9 years), age-matched healthy controls (mean age: 51.6+/-1.7 years) and younger healthy volunteers (mean age: 35.4+/-1.7 years) was stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) for 48 h with or without incubation with the antidepressants at 10(-6) and 10(-5) M. The major findings of this study are: (1). imipramine and venlafaxine (at the higher concentration), 5-HTP (at lower and higher concentrations) and a combination of 5-HTP and fluoxetine (both at the lower concentration) increased the production of IL-6; (2). all drugs used did not affect TNF-alpha production. IL-6 production was significantly higher in depressed patients than in age-matched volunteers, whereas TNF-alpha production was significantly higher in older volunteers than in younger ones. We speculate that the therapeutic activity of these antidepressants is at least partly connected with their effect on the cytokine network and IL-6 production.

5-Hydroxytryptophan↗
PubMed2006

The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder.

It has been postulated that major depression may be accompanied by significant changes in cell-mediated and humoral immunity related to the pathophysiology or pathogenesis of that illness. We explored the role of 2 cytokines, IL-12 and TGF-beta1, which represent the cytokines of the Th1 and Th3 types, in the pathophysiology of major depressive disorder (MDD). Cytokine levels were measured in 30 major depressed patients at the time of admission and 6 weeks after effective antidepressant treatment; levels were measured once in 30 normal controls. At the time of admission, TGF-beta1 levels of MDD patients showed no differences from normal controls, but IL-12 was significantly higher than in normal controls. However, the IL-12/TGF-beta1 (Th1/Th3) ratios of depressed patients were not different from those of controls. In MDD patients, IL-12 values were significantly decreased after treatment, while TGF-beta1 levels were significantly increased. IL-12/TGF-beta1 ratios of patients were significantly decreased after treatment compared with before treatment. There were no significant correlations between changes in the cytokine levels and changes in scores representing the severity of depression. These findings suggest that major depression is accompanied by immune activation during the acute depressed state, and antidepressant treatments have anti-inflammatory effects.

Adult↗
PubMed2004

Reboxetine adjunct for partial or nonresponders to antidepressant treatment.

BACKGROUND: To investigate the usefulness of the combination therapy with two antidepressants from different pharmacological families in treatment-resistant depressive patients. METHODS: In this prospective 6 weeks open-label study, we assessed the effectiveness of the addition of reboxetine to 61 depressive patients that had previously not responded, or had done so only in a partial way, to conventional treatment, in monotherapy, with selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine. Data were analyzed on an intent-to-treat basis, using the last-observation-carried-forward (LOCF) method. RESULTS: Mean decrease on the 21-item Hamilton Depression Rating Scale (HDRS) score was 48.9% and on the Clinical Global Impressions Scale (CGI), 38.9%. At the end of the treatment, 62.3% of the patients were evaluated as improvement (CGI < 4), 54.1% as responders (HDRS < or = 50%) and 45.9% in remission (HDRS < or = 10). No serious side effects were observed during combination therapy, being more frequent increased sweating (8.2%) and dry mouth (6.6%). CONCLUSIONS: These findings suggest that the strategy of combination with reboxetine may be an effective and well-tolerated tool in treatment-resistant patients who have failed to adequately respond to monotherapy with SSRIs, venlafaxine or mirtazapine.

Adult↗
PubMed2005

Do venlafaxine XR and paroxetine equally influence negative and positive affect?

BACKGROUND: We assessed the therapeutic effects of venlafaxine XR and paroxetine on mood and anxiety symptoms derived from the tripartite model of mood. We hypothesized that the two antidepressants would have largely similar effects on symptoms of negative affect because both agents influence serotonergic systems. However, based on evidence indicating linkages between catecholaminergic activity and the emotional dimension of positive affect, we hypothesized that the catecholaminergic effects of venlafaxine XR would yield particularly pronounced effects on symptoms of positive affect. METHODS: Twenty depressed outpatients were randomly assigned to treatment with either venlafaxine XR (225 mg/day) or paroxetine (30 mg/day) during a 12-week treatment trial. Weekly mood ratings were collected using the Mood and Anxiety Symptom Questionnaire [Watson, D., Clark, L.A., Weber, K., Assenheimer, J.S., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J. Abnorm. Psychol. 104 (1), 15-25] [Watson, D., Weber, K., Assenheimer, J.S., Clark, L.A., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychol. 104 (1), 3-14]. RESULTS: Consistent with predictions, analyses revealed that there were no significant differences between venlafaxine XR and paroxetine on measures of negative affect. However, contrary to predictions, the two medications produced similar changes on measures of positive affect. LIMITATIONS: Replication and extension using a larger sample size are mandated. CONCLUSIONS: These preliminary results suggest that two antidepressants that appear to have dissimilar mechanisms of action may nevertheless have similar effects on the positive and negative affective components of depression. Alternatively, paroxetine may have a clinically relevant noradrenergic effect at the dose tested.

Adult↗
PubMed2005

Relationship of white matter hyperintensities to cerebrospinal fluid glucose polyol pathway metabolites-a pilot study in treatment-resistant affective disorder patients.

BACKGROUND: Magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are found at higher rates in patients with affective disorders, particularly late-life or treatment-resistant disorders. Studies support a vascular pathogenesis for WMHs in late-life onset disorders; however, pathogenesis in typical early-life onset disorders is less clear. Based on associations between diabetes mellitus and both WMHs and affective disorders, this study investigated the relationship between WMHs and brain glucose metabolism by the polyol pathway-a pathway linked to nervous tissue disease in diabetes. METHODS: Burdens of fluid-attenuated inversion recovery (FLAIR) WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 10 nondiabetic inpatients with treatment-resistant bipolar, unipolar, and schizoaffective disorders and 10 nondiabetic control patients who had been investigated clinically for transient neurological symptoms. RESULTS: Deep but not periventricular WMH burden correlated positively and significantly with elevated CSF concentrations of sorbitol, the specific polyol pathway metabolite of glucose (rho=0.86, p=0.002), in the affective disorders but not the control group. LIMITATIONS: This was a pilot study with a relatively small number of subjects; therefore, conclusions are tentative. Controls were not healthy subjects; they were patients with transient neurological symptoms. CONCLUSIONS: This is the first reported evidence of a relationship between WMHs and increased brain glucose metabolism by the polyol pathway in patients with affective disorders. More extensive studies are necessary to determine whether this preliminary finding represents a pathogenetic relationship.

Adult↗
PubMed2006

Antidepressant withdrawal symptoms-telephone calls to a national medication helpline.

AIMS AND METHOD: Withdrawal symptoms are associated with cessation of all antidepressants but particularly paroxetine and venlafaxine. We aimed to examine rates of withdrawal symptoms reported to a national medication helpline over seven and a half year period. All calls reporting symptoms of antidepressant withdrawal were noted from a retrospective examination of contemporaneous handwritten records. RESULTS: Between October 1997 and March 2005, the national medication helpline received 22,422 calls of which 1753 (7.8%) concerned antidepressant discontinuation symptoms. Of these, 690 calls (39.36%) related to paroxetine and 252 (14.38%) to venlafaxine. Calls regarding paroxetine increased ten-fold in the month following a BBC 'Panorama' programme centring on problems associated with its use. Comparing number of calls with the number of prescriptions written over the same period revealed that MAOIs have the highest rate of reported reactions. CLINICAL IMPLICATIONS: Withdrawal symptoms were reported with nearly all antidepressants but most commonly with paroxetine and venlafaxine. Television programmes reporting adverse consequences of drug therapy can greatly increase reporting of discontinuation reactions. The highest rate of reporting adverse discontinuation symptoms was for MAOIs.

Antidepressive Agents↗
PubMed2006

Is it possible to predict the long-term response to venlafaxine with the use of biological markers and psychophysiological methods?

INTRODUCTION: The present study investigated whether it is possible to predict the medium term response to venlafaxine using biological markers and psychophysiological methods. MATERIAL: Fourteen (14) patients aged 21-60 years suffering from Major Depression according to DSM-IV were included in the study. METHODS: The SCAN v 2.0 and the IPDE were used to assist clinical diagnosis. Patients were investigated with electrooculogram (EOG), Pattern-Reversal Visual Evoked Potentials (PR-VEPs), Dexamethasone Suppression Test (DST), D-fenfluramine Challenge Test, and brain Single Photon Emission Tomography (SPECT). Venlafaxine 150-225 mg per os daily was administered. The follow-up period was 2 years. STATISTICAL ANALYSIS: Chi-square test and ANOVA were used for the analysis of data. RESULTS: There was a lower left globus pallidus regional cerebral blood flow in patients with better response. On the contrary, chronic patients were closer to normality. DISCUSSION: The results of the current study provide preliminary evidence concerning our ability to predict response to venlafaxine and to understand its way of action.

Adult↗
PubMed2006

Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression.

BACKGROUND: Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression. METHODS: Subjects with (N=18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants. RESULTS: Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory. LIMITATIONS: Limitations include a small sample size and variety of antidepressants used. CONCLUSIONS: These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.

Adult↗
PubMed2005

Simultaneous determination of fluoxetine, citalopram, paroxetine, venlafaxine in plasma by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI).

UNLABELLED: Fluoxetine, citalopram, paroxetine and venlafaxine have been widely used in the treatment of depression. However, no study has been conducted to determine the four drugs simultaneously by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI). OBJECTIVE: To establish a new, rapid and sensitive HPLC-MS/ESI method for simultaneous determination and screening in human plasma of the four most commonly prescribed nontricyclic antidepressants: fluoxetine, citalopram, paroxetine and venlafaxine. METHODS: The analytes in plasma were extracted by solid-phase-extraction column after samples had been alkalinized. The HPLC separation of the analytes was performed on a MACHEREY-NAGEL C(18) (250 mmx4.6 mm, 5 microm, Germany) column, using water (formic acid 0.6 per thousand, ammonium acetate: 30 mmol/l)-acetonitrile (35:65, v/v) as mobile phase, with a flow-rate of 0.85 ml/min. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer and were detected in the selected ion recording (SIR) mode. RESULTS: The calibration curves were linear in the 5.0-1000.0 ng/ml range for all compounds, all of them with coefficients of determination above 0.9900. The average extraction recoveries for all the four analytes were above 73.2%. The methodology recoveries were higher than 95.0%. The limits of detection (LODs) were 0.5, 0.3, 0.3 and 0.1 ng/ml for fluoxetine, citalopram, paroxetine and venlafaxine, respectively. The intra- and inter-day variation coefficients were less than 15.0%. CONCLUSION: The method is accurate, sensitive and simple for routine therapeutic drug monitoring (TDM) as well as toxicologic screening, and for the study of the pharmacokinetics and metabolism of the four drugs.

Antidepressive Agents, Tricyclic↗
PubMed2005

Liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for simultaneous determination of venlafaxine and its active metabolite O-desmethyl venlafaxine in human plasma.

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for simultaneous quantification of venlafaxine (VEN) and O-desmethyl venlafaxine (ODV) in human plasma. The analytes were extracted from human plasma by using solid-phase extraction (SPE) technique. Escitalopram (ESC) was used as the internal standard. A Betasil C18 column provided chromatographic separation of analytes followed by detection with mass spectrometry. The mass transition ion-pair has been followed as m/z 278.27-->121.11 for VEN, m/z 264.28-->107.10 for ODV and m/z 325.00-->262.00 for ESC. The method involves a solid phase extraction from plasma, simple isocratic chromatography conditions and mass spectrometric detection that enables detection at nanogram levels. The proposed method has been validated with linear range of 3-300 ng/ml for VEN and 6-600 ng/ml for ODV. The intrarun and interrun precision and accuracy values are within 10%. The overall recoveries for VEN and ODV were 95.9 and 81.7%, respectively. Total elution time as low as 3 min only.

Antidepressive Agents, Second-Generation↗
PubMed2006

Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in human plasma by HPLC-ESI/MS using a vancomycin chiral column.

A high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI/MS) method for simultaneous stereoselective analysis of venlafaxine (VEN) and its major metabolite O-desmethylvenlafaxine (ODV) enantiomers in human plasma has been developed and validated. Chiral chromatography is performed on the CHRIOBIOTIC V (5 microm, 250 mm x 4.6 mm) column with mobile phase constituted of 30 mmol/l ammonium acetate-methanol (15:85, pH 6.0) at a flow rate of 1.0 ml/min and a postcolumn splitting ratio of 3:1. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer and detected using the selected ion recording (SIR) mode. Calibration curves obtained from spiked plasma were linear in the range of 5.0-400 ng/ml for S-(+)-VEN and R-(-)-VEN, 4.0-280 ng/ml for S-(+)-ODV and R-(-)-ODV, respectively, with linear correlation coefficient all above 0.999. The average extraction recoveries for all the four analytes were above 76%. The methodology recoveries were higher than 92%. The limit of detection were 1.0 ng/ml for S-(+)-VEN and R-(-)-VEN, 1.5 ng/ml for S-(+)-ODV and R-(-)-ODV, respectively. The intra- and inter-day variation coefficients were less than 9%.

Chromatography, High Pressure Liquid↗
PubMed2006

High performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI) method for simultaneous determination of venlafaxine and its three metabolites in human plasma.

A high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI) method for simultaneous determination of venlafaxine (VEN) and its three metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in human plasma has been developed and validated. Estazolam was used as the internal standard. The compounds and internal standard were extracted from plasma by a liquid-liquid extraction. The HPLC separation of the analytes was performed on a Thermo BDS HYPERSIL C18 (250 mm x 4.6 mm, 5 microm, USA) column, using a gradient elution program with solvents constituted of water (ammonium acetate: 30 mmol/l, formic acid 2.6 mmol/l and trifluoroacetic acid 0.13 mmol/l) and acetonitrile (60:40, V/V) at a flow-rate of 1.0 ml/min. All of the analytes were eluted within 6 min. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer and were detected in the selected ion recording (SIR) mode. Calibration curves in spiked whole blood were linear from 4.0-700 ng/ml, 2.0-900 ng/ml, 3.0-800 ng/ml and 2.0-700 ng/ml for VEN, ODV, NDV and DDV, respectively, all of them with coefficients of determination above 0.9991. The average extraction recoveries for all the four analytes were above 77%. The methodology recoveries were higher than 91%. The limits of detection were 0.4, 0.2, 0.3, and 0.2 ng/ml for VEN, ODV, NDV and DDV, respectively. The intra- and inter-day variation coefficients were less than 11%. The method is accurate, sensitive and reliable for the pharmacokinetic study of venlafaxine as well as therapeutic drug monitoring (TDM).

Antidepressive Agents, Second-Generation↗