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PubMed1997

Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.

AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.

1-Naphthylamine↗
PubMed1998

Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk.

AIMS: To characterise the transfer of venlafaxine (V) and its O-desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant. METHODS: Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83 h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk x a milk intake of 0.15 l kg(-1) day(-1), relative to the weight-adjusted maternal dose. RESULTS: Mean M/P for V was 4.1 (range 2.8-4.8) and 3.1 for ODV (range 2.8-3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7-9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100 microg I(-1)) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects. CONCLUSIONS: These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants' plasma. We recommend that exposed infants should be observed closely.

Adult↗
PubMed1999

Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein.

AIMS: To examine whether the antidepressant venlafaxine, a novel serotonin-noradrenaline re-uptake inhibitor (SNRI), can modify alpha-adrenoceptor-mediated venoconstriction in man. The effects of venlafaxine were compared with those of desipramine, a tricyclic antidepressant with noradrenaline uptake inhibiting properties, and paroxetine, a selective serotonin re-uptake inhibitor (SSRI), on noradrenaline-and methoxamine-evoked venoconstriction using the dorsal hand vein compliance technique. METHODS: Fifteen healthy male volunteers participated in five weekly experimental sessions. Each session was associated with a clinically effective dose of an antidepressant or placebo. The following oral dosages were used: venlafaxine 75 mg, venlafaxine 150 mg, desipramine 100 mg, paroxetine 20 mg, or placebo. A double-blind, cross-over, balanced design was used. In each session, dose-response curves to both locally infused noradrenaline acid tartrate (0.1-33.33 ng min-1 ) and methoxamine hydrochloride (0.5-121.5 microg min-1 ) were constructed. Systolic and diastolic blood pressure and pulse rate were measured in the supine and erect positions. Salivation was measured by the dental roll technique. RESULTS: Venlafaxine 150 mg and desipramine 100 mg potentiated the venoconstrictor response to noradrenaline (anova of log ED50s: P<0.01; individual comparisons: venlafaxine 150 mg vs placebo: P<0.005; mean difference, 95% CI: -0. 49 (-0.81, -0.17); desipramine 100 mg vs placebo: P<0.005; mean difference, 95% CI: -0.34 (-0.60, -0.09) without affecting the response to methoxamine. Neither paroxetine nor placebo had any effects on the venoconstrictor responses. Both doses of venlafaxine increased systolic blood pressure (supine and erect) and venlafaxine 150 mg increased diastolic blood pressure (supine) (anova, P<0.05). Desipramine increased heart rate (P<0.05). Desipramine and both doses of venlafaxine reduced salivation (P<0.025). CONCLUSIONS: These results show that, similarly to desipramine 100 mg, venlafaxine 150 mg can potentiate venoconstrictor responses to noradrenaline, consistent with venlafaxine's ability to block noradrenaline uptake in man. The importance of noradrenaline uptake blockade in these observations is confirmed by the lack of effect of the antidepressants on methoxamine-evoked venoconstriction and the failure of paroxetine to modify noradrenaline-evoked venoconstriction.

Adrenergic alpha-Agonists↗
PubMed1999

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

AIMS: Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. METHODS: Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. RESULTS: The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. CONCLUSIONS: These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.

Adult↗
PubMed2003

Removal of gutta-percha from root canals using an Nd:YAG laser.

AIM: To examine the use of an Nd:YAG laser in removing gutta-percha fillings from root canals when used in conjunction with eucalyptol, dimethylformamide (DMF) or no solvent. METHODOLOGY: Root-canal fillings (sealer and gutta-percha) were removed with laser irradiation of 20 Hz/1.5 W from 30 roots randomly divided in three groups. In group 1, the solvent was eucalyptol; in group 2, the solvent was DMF; and in group 3, no solvent was used. Laser irradiation was performed until the temperature measured on the root surface increased by 4 degrees C over room temperature. The treatment was deemed complete when the apical foramen was reached with the optical fibre and a reamer. The samples were split longitudinally, and the area of remaining gutta-percha on the root-canal walls was determined with the aid of a computer program. The total number of laser pulses to achieve length and the highest temperature recorded was determined for each tooth. The results were statistically analysed using Student's t-test (P < 0.05) for independent samples. RESULTS: The average temperature increase in group 1 was 9.17 +/- 0.56 degrees C; in group 2, 9.56 +/- 0.28 degrees C; and in group 3, 8.29 +/- 0.41 degrees C. The shortest time to achieve length was in group 3 (6.4 +/- 0.49 min), then in group 1 (6.7 +/- 0.85 min) and group 2 (7.05 +/- 0.79 min). The area of remaining gutta-percha was the largest in group 2 (6.13 +/- 5.76%), whilst the smallest was for group 3 (4.69 +/- 4.03%), but the difference was not statistically significant. The number of pulses was not statistically significant between the groups. CONCLUSIONS: Use of an Nd:YAG laser alone is capable of softening gutta-percha. The addition of solvents did not improve the retreatment, either in terms of the time required for the procedure or in terms of the area of remaining gutta-percha on root-canal walls.

Aluminum Silicates↗
PubMed2003

Antifungal activity of the components of Melaleuca alternifolia (tea tree) oil.

AIMS: To investigate the in vitro antifungal activity of the components of Melaleuca alternifolia (tea tree) oil. METHODS AND RESULTS: Activity was investigated by broth microdilution and macrodilution, and time kill methods. Components showing the most activity, with minimum inhibitory concentrations and minimum fungicidal concentrations of < or =0.25%, were terpinen-4-ol, alpha-terpineol, linalool, alpha-pinene and beta-pinene, followed by 1,8-cineole. The remaining components showed slightly less activity and had values ranging from 0.5 to 2%, with the exception of beta-myrcene which showed no detectable activity. Susceptibility data generated for several of the least water-soluble components were two or more dilutions lower by macrodilution, compared with microdilution. CONCLUSIONS: All tea tree oil components, except beta-myrcene, had antifungal activity. The lack of activity reported for some components by microdilution may be due to these components becoming absorbed into the polystyrene of the microtitre tray. This indicates that plastics are unsuitable as assay vessels for tests with these or similar components. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has identified that most components of tea tree oil have activity against a range of fungi. However, the measurement of antifungal activity may be significantly influenced by the test method.

Acyclic Monoterpenes↗
PubMed1999

Effect of venlafaxine hydrochloride in different preparations of isolated guinea-pig and rat organ tissues.

A study was undertaken to know better the effects of venlafaxine hydrochloride on the responses of isolated rat vas deferens to noradrenaline and dopamine, those of isolated rat uterus to serotonin and histamine, and those of isolated guinea-pig ileum to acetylcholine and histamine. Venlafaxine hydrochloride increased the response of rat vas deferens to noradrenaline but not to dopamine. Venlafaxine did not alter the response of rat isolated uterus to serotonin. In rat uterus, venlafaxine did not modify the response to histamine but was able to increase it in guinea-pig ileum. An anticholinergic effect was observed with the lowest concentration tested. Although venlafaxine is a selective serotonine reuptake inhibitor in the central nervous system, serotonin uptake was not seen in the rat uterus. The anticholinergic effects observed in the present study might be consistent with some of the side-effects associated with venlafaxine.

Acetylcholine↗
PubMed2002

Alternative venlafaxine kinetics in overdose.

UNLABELLED: The pharmacokinetics of venlafaxine in therapeutic doses is well established. It is metabolized by the cytochrome P450 enzymes including CYP2D6. The toxicokinetics in overdose is less well known. CASE REPORT: A 33-year-old Caucasian female who ingested 3.0 g venlafaxine, and 210 mg zolpidem. The patient remained symptomatic for the following 24 h. Plasma pharmacokinetic analysis demonstrated a prolonged elimination half-life of venlafaxine, estimated to be 15.3 h. We postulate that the patient was a slow metabolizer of substrates for CYP2D6, an enzyme known to exhibit polymorphism.

Adult↗
PubMed2001

Effect of gutta-percha solvents at different temperatures on the calcium, phosphorus and magnesium levels of human root dentin.

The aim of this study in vitro investigation was to evaluate the alterations caused by warmed gutta-percha solvents on the calcium, phosphorus and magnesium levels of root dentin. Extracted human anterior teeth, whose crowns and apical root thirds had been removed were used as root dentin specimens. The roots were sectioned longitudinally into two segments, cleaned and dried. Segments were divided into 12 groups (n=12). In 6 groups, the specimens received treatment with the following solvents at room temperature (22 degrees C): Chloroform, xylene, eucalyptol, orange oil, halothane and saline (control). Within each group, the specimens were further subgrouped into two to be incubated (100% humidity at 37 degrees C) for 5 and 10 min, respectively, following treatment with the solvents. The remaining six groups were treated with the same solvents which had been previously warmed to body temperature (37 degrees C) and received the same experimental procedures. The levels of calcium, phosphorus and magnesium in each specimen were analysed using energy dispersive spectrometric microanalysis. Statistical analysis of the readings showed that neither warming of the solvents nor prolonged incubation (treatment) time was capable of altering the histochemical composition of cut root dentin surfaces.

Body Temperature↗
PubMed2003

Antidepressant monotherapy for bipolar type II major depression.

OBJECTIVES: Bipolar type II (BP II) disorder is thought to be distinct from BP I disorder on genetic and biological grounds, and it is not merely a milder form of the illness. It affects 1.5-2.5% of the US adult population, and is characterized by highly recurrent depressive episodes with a substantial morbidity from alcoholism and non-affective psychopathology, and a higher suicide rate than either BP I or unipolar depression. Treatment recommendations for BP II depression are based upon concerns over drug-induced manic-switch episodes, and suggest using either a mood stabilizer alone or a combination of an SSRI plus a mood stabilizer. Recent evidence, however, indicates that the rate of manic switch episodes may be modest in BP II patients. Recent studies have provided evidence that antidepressant monotherapy may be an effective initial and long-term treatment for BP II major depression with a low manic-switch rate. METHODS: In this article, we review the recent literature on BP II disorder, with a focus on the treatment of BP II major depression. RESULTS: We present a summary of data from recent studies by our group and others indicating that antidepressant monotherapy for BP II depression may be safe and effective with a low manic-switch rate. CONCLUSION: Antidepressant monotherapy may be beneficial for some patients with BP II major depression.

Adult↗
PubMed2003

Dual action antidepressants and some important considerations.

OBJECTIVE: To review controlled studies of long-term treatment and their side-effects with newer dual action antidepressants following an acute episode of major depression. METHOD: A literature review (MedLine) was undertaken and references were selected for their relevance and methodology in describing their contribution to the examination of our objective. RESULT AND CONCLUSION: Three dual action antidepressants are identified: venlafaxine, mirtazapine and milnacipran. These are more effective and better tolerated than the older tricyclic antidepressants in the treatment of an acute episode of depression and in the prevention of relapse. They also offer advantages in that they lack autonomic side-effects of the tricyclics. However, sedation, nausea and sexual side-effects may occur with venlafaxine, and weight gain with mirtazapine.

Adrenergic alpha-Antagonists↗
PubMed2003

Randomized controlled trials in psychiatry. Part 1: methodology and critical evaluation.

OBJECTIVE: To introduce clinicians to the methodology and critical appraisal of randomized controlled trials (RCTs) in psychiatry. METHOD: The methodology of RCTs in psychiatry is discussed. Using a systematic approach to critical appraisal, a published RCT of treatments for severe depression is examined and evaluated. RESULTS AND CONCLUSIONS: The RCT appraised illustrates certain problematic areas in the methodology of trials in psychiatry. A detailed knowledge of methodology and critique of RCTs is essential in determining whether reported results will influence clinicians' practice.

Cyclohexanols↗
PubMed2003

Effective open-label treatment of premenstrual dysphoric disorder with venlafaxine.

Various studies have demonstrated the efficacy of selective serotonergic re-uptake inhibitors in the treatment of premenstrual dysphoric disorder (PMDD). But the effectiveness of novel antidepressant, venlafaxine, in PMDD has been reported in only one Western study. The purpose of the present open-label study was to provide preliminary data on the effectiveness of venlafaxine for Asian women with PMDD. Thirty women with PMDD were enrolled and treated with a flexible dosage of venlafaxine for two menstrual cycles. Responses were assessed every 2 weeks. Outcome measures included the scores of the Prospective Record of the Impact and Severity of Menstrual Symptomatology (PRISM) calendar, self-rating Zung Depressive Scale (Zung), State and Trait Anxiety Inventory (STAI), Hamilton Rating Scale for Depression/Anxiety (HAM-D/HAM-A), and the Clinical Global Impression scale (CGI). Twenty patients completed the trial. All patients had significant improvement of the mood and behavior components in the PRISM calendar. The effects of active treatment were marked by the first active cycle of menstruation. Venlafaxine at a mean dose of 60.1 +/- 29.1 mg per day was effective in reducing PMDD symptoms. The results of the present open trial indicated that venlafaxine is effective in the treatment of ethnic Taiwanese women with PMDD.

Administration, Oral↗
PubMed2000

Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations.

Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.

Action Potentials↗
PubMed2003

Odorant specificity of three oscillations and the DC signal in the turtle olfactory bulb.

The odour-induced population response in the in vivo turtle (Terepene sp.) olfactory bulb consists of three oscillatory components (rostral, middle and caudal) that ride on top of a DC signal. In an initial step to determine the functional role of these four signals, we compared the signals elicited by different odorants. Most experiments compared isoamyl acetate and cineole, odorants which have very different maps of input to olfactory bulb glomeruli in the turtle and a different perceptual quality for humans. We found substantial differences in the response to the two odours in the rise-time of the DC signal and in the latency of the middle oscillation. The rate of rise for cineole was twice as fast as that for isoamyl acetate. Similarly, the latency for the middle oscillation was about twice as long for isoamyl acetate as it was for cineole. On the other hand, a number of characteristics of the signals were not substantially different for the two odorants. These included the latency of the rostral and caudal oscillation, the frequency and envelope of all three oscillations and their locations and spatial extents. A smaller number of experiments were carried out with hexanone and hexanal; the oscillations elicited by these odorants did not appear to be different from those elicited by isoamyl acetate and cineole. Qualitative differences between the oscillations in the turtle and those in two invertebrate phyla suggest that different odour processing strategies may be used.

Animals↗