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PubMed1998

Efficacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients.

The effects of once-daily venlafaxine extended release (XR) 75-225 mg/day on symptoms of anxiety in depressed outpatients were assessed in two randomized, double-blind, placebo-controlled trials. In study 1, venlafaxine XR was significantly (p < or = 0.05) more effective than placebo by week 4 in relieving anxiety symptoms among patients with moderate or greater anxiety (anxiety-psychic item score > or = 2) at baseline. Among patients with severe (anxiety-psychic item score > or = 3) anxiety, venlafaxine XR was significantly (p < or = 0.05) more effective than placebo beginning at week 6. In study 2, among patients with moderate or greater anxiety (score > or = 2) at baseline, a significant reduction (p < or = 0.05- < or = 0.001) in HAM-D anxiety-psychic item scores was noted with venlafaxine XR compared with placebo from weeks 1 to 8. Among patients with severe anxiety (score > or = 3) at baseline, venlafaxine XR produced a significant reduction (p < or = 0.05- < or = 0.001) in the anxiety-psychic item score compared with placebo from weeks 1 to 8. Discontinuation for adverse events occurred in 11% of patients on venlafaxine XR, and the most common adverse events were nausea, dizziness, insomnia, somnolence and dry mouth. These results indicate that once-daily venlafaxine XR is effective for the treatment of anxiety symptoms associated with major depression in doses ranging from 75 to 225 mg/day.

Adult↗
PubMed1997

Long-term treatment of geropsychiatric depressed patients with venlafaxine.

Twenty-eight psychiatric patients older than 65 years with major depression with high probability of recurrence were enrolled in a 24-month open label clinical trial aimed at evaluating the long-term efficacy and safety of venlafaxine. All patients completed the acute phase of the study; 21 were responders and entered the follow-up period. During the continuation phase no relapse was observed. During the maintenance period, 20% of the patients had a single new recurrence. No significant side effects were observed. The results demonstrate that venlafaxine is both effective and safe in the long-term treatment of major depression in geropsychiatric patients.

Adrenergic Uptake Inhibitors↗
PubMed1998

Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion.

Tricyclic antidepressants have multiple sites of pharmacological actions which are responsible for their tolerability and toxicological problems as well as their efficacy. That fact has prompted the search for antidepressants with fewer sites of action. That search resulted in the serotonin selective reuptake inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs are safer and better tolerated than the TCAs, a significant percentage of patients do not benefit from SSRIs. A group of "atypical antidepressants" including bupropion, nefazodone, and venlafaxine are known to have multiple sites of antidepressant action but do not interact at sites associated with side effects or tolerance. Thus this group of antidepressants present an important alternative to the SSRIs in the pharmacological therapy of depression. The basic pharmacological properties of bupropion, nefazodone, and venlafaxine are presented along with clinical profiles and the role of these three antidepressants in the pharmacotherapy of depression is discussed.

Antidepressive Agents, Second-Generation↗
PubMed1999

A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression.

BACKGROUND: We compared the efficacy and tolerability of venlafaxine XR with that of fluoxetine in a multicenter, randomized, double-blind, placebo-controlled study in depressed outpatients. METHODS: Outpatients, 18 years and older, who met DSM-IV criteria for major depressive disorder were included (n = 301 randomized; 232 completed). Patients were randomly assigned to eight weeks of treatment with either venlafaxine XR 75-225 mg/day (n = 100), fluoxetine 20-60 mg/day (n = 103), or placebo (n = 98). The primary efficacy outcome measures were the final ratings on the Hamilton Rating Scale for Depression (HAM-D21) total score, HAM-D21 depressed mood item, Montgomery-Asberg Depression Rating Scale total score, and Clinical Global Impressions Scale. RESULTS: Withdrawal from the study due to adverse events occurred in 6% of the patients in the venlafaxine XR group and 9% of the patients in the fluoxetine group. Patients treated with venlafaxine XR, but only rarely those treated with fluoxetine, had statistically significant improvements in their depression ratings compared with placebo at the end of the study. The percentages of patients who achieved full remission of their depression (HAM-D21 total score < or = 7) at the end of treatment were 37%, 22% and 18% for the venlafaxine XR, fluoxetine and placebo groups, respectively. The differences in remission rates between venlafaxine XR and the other groups were statistically significant (p < 0.05). LIMITATIONS: The superior remission outcome observed with venlafaxine XR treatment needs to be replicated in additional studies. CONCLUSION: Venlafaxine XR is a well-tolerated and efficacious treatment for depression. The results of this study suggest that venlafaxine XR is as well-tolerated as fluoxetine but may have some efficacy advantages over fluoxetine.

Administration, Oral↗
PubMed2000

Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features.

BACKGROUND: Depressive illness may be associated with immune and cytokine alterations. However, data are unavailable concerning functional immune changes associated with chronic, low-grade depression (dysthymia). Moreover, the contribution of the neurovegetative features of depression (e.g., altered sleep, eating) to the immune alterations remains to be determined. METHODS: Mitogen-stimulated cell proliferation was assessed in major depressive and dysthymic patients exhibiting either typical or atypical features. In a subset of patients, lymphocyte proliferation was also assessed before and after pharmacotherapy to determine whether alleviation of symptoms would be accompanied by normalization of immune functioning. RESULTS: Lymphocyte proliferation was reduced to a greater extent among dysthymic than among major depressive patients. Among dysthymic patients reduced cell proliferation was evident irrespective of symptom typicality; however, among major depressive patients the contribution of neurovegetative features varied with the specific mitogen used. Symptom alleviation following antidepressant treatment was not accompanied by normalization of cell proliferation. LIMITATIONS: Patients received 12 weeks of antidepressant treatment, and more sustained therapy may be required for normalization of immune activity. As well, conclusions concerning normalization of immune functioning in drug-treated major depressive patients requires that a greater number of patients be assessed. CONCLUSIONS: As the immune variations were more pronounced in dysthymia than in major depression, chronicity of illness may be a pertinent factor in promoting immune disturbances. This does not exclude the possibility that depression is associated with immune activation, which then provokes suppression of other aspects of immunity. As well, it is conceivable that immune alterations indirectly contribute to the symptoms accompanying depressive state, although it does not appear that variations of lymphocyte proliferation are associated with neurovegetative status.

Adult↗
PubMed2000

Venlafaxine monotherapy in women with bipolar II and unipolar major depression.

BACKGROUND: Women with bipolar (BP) disorder have more depressive episodes and drug-induced manic switches compared to men. Current guidelines suggest treating BP type I and type II major depressive episode (MDE) with both a mood-stabilizer and antidepressant. In a post hoc analysis, we examined the safety and efficacy of venlafaxine monotherapy in women with BP II MDE. METHODS: 15 women with BP II MDE (mean+/-SD age: 37+/-12 years) were compared to 17 women with unipolar (UP) MDE (41+/-12 years). Patients were randomized to double-blind treatment with once versus twice daily venlafaxine up to 225 mg for 6 weeks. Efficacy was measured using the HAM-D(21), MADRS and CGI scales. Drug-induced manic switch episodes characterized by agitation, irritability, euphoria or mood lability were assessed at each visit. RESULTS: No episodes of drug-induced hypomania or rapid cycling were observed during 6 weeks of venlafaxine monotherapy. Similar efficacy was observed in BP and UP depressed women (p=ns). LIMITATIONS: This study was retrospective in nature and limited in patient number. Only BP II women were included in this study, and it is possible that efficacy and the manic switch rate might have differed if BP I women were included. CONCLUSION: Short-term venlafaxine monotherapy may be a safe and effective antidepressant treatment in women with BP II MDE.

Adult↗
PubMed2000

Effect of venlafaxine on imipramine metabolism.

The present study was designed to determine the effect of venlafaxine on imipramine metabolism in an attempt to elucidate the potential for cytochrome P450 drug-drug interactions with venlafaxine. We examined the metabolism of a single 100-mg dose of imipramine before and after treatment with venlafaxine, 50 mg three times a day. Eight male subjects were phenotyped for CYP2D6 activity. Two subjects were poor metabolizers of dextromethophan, and data from the remaining six subjects (mean age=45.3+/-15) were analyzed. Venlafaxine increased imipramine C(max) and elevated AUC by 40%. Desipramine clearance and volume of distribution were reduced by 20% and 25%, respectively. These findings are consistent with a statistically significant, but clinically modest impact of venlafaxine on CYP2D6-metabolized substrates.

Adult↗
PubMed2001

Cannabinoids inhibit nitric oxide production in bone marrow derived feline macrophages.

Feline immunodeficiency virus (FIV) infection causes a widespread natural immunodeficiency syndrome in cats that is considered a suitable animal model for studying human immunodeficiency virus (HIV) infection and pathogenesis. Short term cultures of bone marrow derived feline macrophages stimulated with recombinant feline interferon-gamma (r-IFN-gamma) and lipopolysaccharide (LPS) were shown to produce nitric oxide. Feline macrophages were shown to express cannabinoid receptors, and nitric oxide production decreased after in vitro exposure to synthetic cannabinoid CP-55940. Both cannabinoid receptors, CB1 and CB2, were involved in this process, since the inhibition was reversed by selective cannabinoid antagonists for both of these receptors.

Animals↗
PubMed2002

Antinociceptive, behavioural and neuroendocrine effects of CP 55,940 in young rats.

The peripubertal period appears to be critical in relation to the abuse of cannabinoids and opioids in humans. However there is little information about the acute effects of cannabinoids and their interactions with opioids in young experimental animals. We have studied the effects of the cannabinoid agonist CP 55,940 (0.1, 0.2, 0.4 and 0.6 mg/kg) on the nociceptive responses (tail immersion test) and holeboard activity of 40-day-old rats, and the involvement of the CB(1) receptor (antagonism by SR 141716A, 3 mg/kg). The implication of the opioid system was evaluated using the opioid antagonist naloxone (1 mg/kg) and a combined treatment with subeffective doses of CP 55,940 (0.1 mg/kg) and morphine (1 mg/kg). The effects of CP 55,940 on the serum corticosterone levels (radioimmunoassay) and on the dopamine and DOPAC contents of discrete brain regions (high-performance liquid chromatography) were also assessed. The antinociceptive effect of CP 55,940 was of a similar magnitude at all the doses used. The results show the involvement of the CB(1) receptor. The cannabinoid agonist significantly depressed the holeboard activity in a dose-dependent manner. The results indicate that the CB(1) receptor is involved in the effects on motor activity but not in the effects on the exploratory activity. The behavioural effects of CP 55,940 were modulated by morphine. The cannabinoid agonist (0.6 mg/kg) induced a CB(1)-mediated increase in the serum corticosterone levels, but no effect on the dopaminergic systems of either the striatum or the limbic forebrain was found.

Analgesics↗
PubMed2000

In vivo and in vitro treatment with the synthetic cannabinoid CP55, 940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors.

Cannabinoids have been shown to affect immune responses, acting on different populations of immune cells. In the present paper we analyze the ability of in vivo and in vitro treatment with the potent synthetic cannabinoid CP55,940 to interfere with an important function of rat peritoneal macrophages, i.e. spontaneous migration and formyl-metionyl-leucine-phenylalanine (fMLP)-induced chemotaxis, that were assessed by the use of a Boyden-modified microchemotaxis chamber. When added in vitro, CP55,940 induced a significant and dose-dependent inhibition of both spontaneous migration and fMLP-induced chemotaxis. Both the Cannabinoid Receptor 1 (CB1) and the Cannabinoid Receptor 2 (CB2) antagonists were able to block the CP55,940-induced inhibition of spontaneous migration, although the CB2 antagonist was more potent and only the CB2 antagonist was able to reverse the effect of CP55,940 on fMLP-induced chemotaxis. Similarly, in the in vivo experiments, 1 h after the acute subcutaneous administration of 0.4 mg/kg of CP55,940, both spontaneous motility and chemotaxis were reduced. The pretreatment with the CB2 antagonist, but not with the CB1 antagonist, was able to prevent this effect. Our data confirm that cannabinoids can affect some macrophage functions, mainly throughout CB2 receptors, and suggest that the development of specific CB2 ligands may lead to an interesting new class of anti-inflammatory drugs.

Animals↗
PubMed2001

Comparative characterization in the rat of the interaction between cannabinoids and opiates for their immunosuppressive and analgesic effects.

In the present work, we investigated in the rat the possibility of functional interaction between opiate and cannabinoid systems at immune level comparatively with the central nervous system (CNS). Moderate analgesic doses of the synthetic cannabinoid compound CP-55,940 (0.2 mg/kg, i.p.) and morphine (5 mg/kg, s.c.) significantly inhibited the ConA-induced splenocyte proliferation and natural killer (NK) cytolytic activity. The acute co-administration of the two drugs resulted in an enhancement of antinociception while they did not yield any additive inhibition of the immune parameters. The CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 3 mg/kg, i.p.) and the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethhyl bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 3 mg/kg, i.p.) did not block the central nor the immune effects of morphine; similarly, the opioid receptor antagonist naloxone did not attenuate CP-55,940-induced effects. Animals tolerant to CP-55,940-induced (0.2 mg/kg, i.p.; twice a day for 4 days) or morphine-induced analgesia (5 mg/kg, s.c.; twice a day for 6 days) also developed tolerance to their acute immunosuppressive effects. Concomitantly, animals became cross-resistant to the immunosuppressive effects while an asymmetric cross-tolerance developed for analgesia. Our data demonstrated the existence of an interaction between cannabinoids and opiates at the immune level that differs from the interaction present in the CNS.

Analgesics↗
PubMed1997

Regulation of immune functions in rat splenocytes after acute and chronic in vivo treatment with CP-55,940, a synthetic cannabinoid compound.

Changes in mitogen-induced splenocyte proliferation and NK activity were evaluated after acute (1 h) and chronic (6 d) in vivo treatment of rats with the synthetic cannabinoid compound CP-55,940. At a dose of 0.4 mg/kg i.p. it significantly inhibited the splenocyte proliferative response to PHA and NK activity but half this dose (0.2 mg/kg) had no effect on immune responses. Pretreatment of rats with the cannabinoid receptor CB1 antagonist SR141716A did not antagonize the CP-55,940-induced immunosuppression, excluding the activation of this receptor subtype in the mediation of this effect. When immune function studies were done on rats tolerant to CP-55,940-induced analgesia, full tolerance also developed for the inhibition of splenocyte proliferation and NK activity. The data provided indicate that CB1 cannabinoid receptors are not involved in mediating the acute and chronic effects of cannabinoids on the immune system and suggest a possible implication of CB2 receptor although other modalities of CP-55,940 action can not be ruled out.

Animals↗
PubMed1998

In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.

Tamoxifen is a highly lipophilic drug that is widely used in breast malignancies and also as a prophylactic therapy in women at high risk for the development of this disease. Recently, the terpenes have been reported to show an enhancement effect on percutaneous drug absorption. The effect of terpenes (e.g. carvone, 1,8-cineole, menthol, and thymol) was studied on the in vitro percutaneous absorption of tamoxifen through porcine epidermis. The above terpenes (5% w/v) in combination with 50% ethanol significantly (P < 0.01) increased the permeability coefficient of tamoxifen in comparison to the control (50% ethanol). The solubility of tamoxifen was determined in the control and enhancer solutions to correct the permeability enhancement by way of fractional solubility adjustment. Binding of tamoxifen to powdered stratum corneum from control and enhancer solutions was also determined. Binding studies reveal that the enhancement in the permeability coefficient of tamoxifen by menthol and thymol is due at least in part, to improvement in the partitioning of the drug to the stratum corneum. In conclusion, terpenes in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug tamoxifen.

Animals↗
PubMed1998

Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain.

This study was designed to examine the interactions between the cannabinoid and enkephalinergic systems in the rat brain. To this aim, we have examined the effects of subchronic (5 days) administration (10 mg.kg-1.day-1; i.p.) of delta 9 -tetrahydrocannabinol (THC) or R-methanandamide (AM356) and chronic (18 days) administration with the synthetic cannabinoid receptor agonist CP-55,940 (1 mg.kg-1.day-1; i.p) on proenkephalin (PENK) mRNA levels in several brain regions of the rat. Twenty micrometer brain sections from striatum, nucleus accumbens, paraventricular nucleus, ventromedial nucleus, periaqueductal grey matter and mammillary nucleus were hybridized with an oligonucleotide probe complementary to PENK using in situ hybridization technique. Subchronic administration of THC or AM356 increased PENK mRNA levels in the ventromedial nucleus of the hypothalamus, (82%) and (39%), in the periaqueductal grey matter, (97%) and (49%), and mammillary nucleus, (43%) and (9%), respectively. In contrast, both drugs were without effect in the striatum and nucleus accumbens. On the other hand, chronic administration of CP-55,940 increased PENK mRNA levels in the striatum (44%), nucleus accumbens (25%), paraventricular (31%) and ventromedial nuclei of the hypothalamus (41%). These results revealed that chronic cannabinoid administration increases opioid gene expression in the rat central nervous system and suggest an interaction between the cannabinoid and enkephalinergic systems that may be part of a molecular integrative response to behavioral and neurochemical alterations that occur in cannabinoid drug abuse.

Animals↗
PubMed1996

New antidepressant drugs and the treatment of depression in the medically ill patient.

The advent of the SSRIs, venlafaxine, bupropion, and nefazodone, has greatly expanded pharmacologic treatment options for the depressed medically ill patient. Although the relatively benign side effects of these medications on cardiac conduction and blood pressure allow for more liberal use in the medically ill, these drugs nevertheless have different capacities for adverse drug interactions that must be considered. Nevertheless, such interactions can usually be avoided or managed by knowledgeable clinicians cognizant of the pharmacodynamic and pharmacokinetic principles outlined in this article.

Adjustment Disorders↗
PubMed1997

Seizures, ventricular tachycardia, and rhabdomyolysis as a result of ingestion of venlafaxine and lamotrigine.

Few cases of overdoses have been described involving venlafaxine, lamotrigine, or a combination of the two agents. We describe a combined venlafaxine and lamotrigine ingestion in a patient presenting with a seizure, ventricular tachycardia, and rhabdomyolysis. We conclude that patients with overdoses that involve venlafaxine can exhibit severe cardiac effects in addition to seizures, especially if venlafaxine is combined with other agents.

Adult↗
PubMed2001

Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study.

Tricyclic antidepressants and serotonin (5-HT) uptake inhibitors rapidly block uptake sites, or transporters; however, their therapeutic effects are only seen after 2-3 weeks of treatment. Thus, direct blockade of 5-HT and noradrenaline (NA) transporters cannot account entirely for their clinical efficacy, and other long-term changes may be involved. Adult Sprague-Dawley rats were treated for 21 days with daily injections of either desipramine, trimipramine, fluoxetine, or venlafaxine; a fifth group that was used as a control, received daily saline injections. Identified cortical areas, hippocampal divisions and nuclei raphe dorsalis, raphe medialis and locus coeruleus were examined by quantitative autoradiography using either [3H]citalopram to label 5-HT transporters, or [3H]nisoxetine for NA uptake sites. Increases in [3H]nisoxetine binding were found in the cingulate, frontal, parietal, agranular insular, entorhinal and perirhinal cortices as well as in the hippocampal divisions CA1, CA3, dentate gyrus and subiculum, and in nucleus raphe dorsalis of trimipramine-treated animals compared to the control rats. Also, densities of NA transporters decreased in temporal cortex, CA2 and nucleus raphe dorsalis in fluoxetine-treated rats as compared to the controls. Also, there was a decrease in NA transporters in the locus coeruleus of the desipramine-treated animals as compared to the densities measured in the control group. Chronic treatment with desipramine or trimipramine, which do not directly inhibit 5-HT uptake, compared to fluoxetine and venlafaxine, lead to increases in 5-HT transporter densities in cingulate, agranular insular and perirhinal cortices. The present study shows differential region-specific effects of antidepressants on 5-HT and NA transporters, leading to distinct consequences in forebrain areas.

Animals↗