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PubMed2003

Efficacy and safety of venlafaxine ER vs. amitriptyline ER in patients with major depression of moderate severity.

INTRODUCTION: A double-blind, randomized phase-III study was conducted with the aim to compare the efficacy and safety of venlafaxine ER (extended release) with that of amitriptyline ER in moderately depressed outpatients. METHODS: Patients with major depression of moderate severity, HAM-D (Hamilton Depression scale, 21 items) score 20-26, were given a six-week double-blind treatment with venlafaxine ER and amitriptyline ER in a dosis of 75 mg each, which could be increased to 150 mg, if necessary. Efficacy was assessed using HAM-D and CGI (clinical global impression) scores. Safety analysis was carried out using the HAM-D item 3 to assess suicidality, the d2 test to evaluate attention and drug screening for benzodiazepines. Adverse events were recorded at each visit. RESULTS: 160 patients were randomized. There were 151 patients available for analysis in the intent-to-treat (ITT) population. The according-to-protocol (ATP) population consisted of 117 patients, with 60 patients in the venlafaxine ER group and 57 in the amitriptyline ER (extended release) group. The non-inferiority of venlafaxine ER compared to amitriptyline ER with reference to the primary efficacy parameter, the change of HAM-D total score, could be proven in both the ITT population and the ATP population. There were no significant differences between groups in the HAM-D response rates and the CGI scores of items 1 (severity) and 2 (improvement). Venlafaxine ER showed a more favorable safety profile than amitriptyline ER: adverse drug reactions were less frequent under venlafaxine ER than under amitriptyline ER. Most of the discontinuations in the amitriptyline ER group were due to dry mouth. The d2 test showed greater improvement of performance under venlafaxine ER. DISCUSSION: In this study with patients treated for major depression of moderate severity, the non-inferiority of venlafaxine ER compared to amitriptyline ER with respect to the chosen efficacy parameter could be demonstrated. Venlafaxine ER showed a more favorable safety profile than amitriptyline ER.

Adult↗
PubMed2005

Relaxant effects of the essential oil of Eucalyptus tereticornis and its main constituent 1,8-cineole on guinea-pig tracheal smooth muscle.

The effects of the essential oil of Eucalyptus tereticornis Sm. (EOET) on guinea-pig tracheal smooth muscle were investigated. EOET (10 - 1000 microg/mL) relaxed the tracheal basal tonus with an EC (50) value of 125.3 [52.2 - 300.9] microg/mL. Its maximal relaxation (40 +/- 6 %) was significantly lower than that evoked by aminophylline (209 +/- 34 %). The K (+)-(60 mM)-induced contractions were significantly reduced by both EOET (200 - 1000 microg/mL) and its main constituent 1,8-cineole (600 - 1000 microg/mL). Acetylcholine (1 microgM)-induced contractions were significantly enhanced by 1,8-cineole (10 - 1000 microg/mL). However, they were significantly enhanced and reduced by lower (200 - 400 microg/mL) and higher (800 - 1000 microg/mL) concentrations of EOET, respectively. Electrical field stimulation-induced contractions were significantly increased by EOET (100 - 600 microg/mL). In conclusion, EOET produces myorelaxant effects on guinea-pig isolated trachea, an effect that seems to result from a complex interaction between its monoterpenoid constituents.

Animals↗
PubMed1997

A case of serotonin syndrome caused by venlafaxine and lithium.

Serotonin syndrome occurred under treatment with average dose of Venlafaxine and lithium in a 50 year-old female patient with a history of sensitiveness to SSRIs. Plasma levels of Venlafaxine and its metabolite were within reference range. Parmacogenetic evaluation indicated normal metabolic pathway.

Antidepressive Agents, Second-Generation↗
PubMed1996

Subchronic antidepressant treatment with venlafaxine or imipramine and effects on blood pressure and heart rate: assessment by automatic 24-hour monitoring.

Venlafaxine is a new nontricyclic antidepressant inhibiting the reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine without antagonizing cholinergic, histaminergic, or noradrenergic receptors. Significantly, in a first placebo-controlled safety and efficacy study, high doses of venlafaxine increased blood pressure in some study subjects. In order to investigate further the effect of subchronic antidepressant drug treatment on blood pressure and heart rate, the effects of a conventional tricyclic (imipramine) and a structurally different phenethylamine antidepressant (venlafaxine) were compared. Sixteen inpatients with major depression (melancholic type) were treated for six weeks with imipramine or venlafaxine in a randomized parallel double-blind design. Blood pressure was monitored for 24 hours before treatment and at days 14 and 28 by means of a portable, automatic blood-pressure monitoring system. Both compounds lowered systolic blood pressure by about 5% on average, while diastolic pressure was influenced neither by imipramine nor by venlafaxine. Imipramine treatment resulted in a significant 15% increase in heart rate on both day 14 and day 28, whereas heart rate tended to decrease under venlafaxine. When the data of individual patients were evaluated, a clinically significant increase in blood pressure was apparent in one venlafaxine-treated patient; a marked increase in blood pressure in one patient treated with imipramine proved to be reversible with continued treatment. Due to the relatively small sample sizes, the present data do not allow a definitive judgement as to whether venlafaxine may cause differential blood pressure alterations in comparison with imipramine. However, our results demonstrate that the blood pressure-increasing effect reported for venlafaxine from first clinical studies might be clinically significant in individual patients. Furthermore, our study shows that 24-hour monitoring of blood pressure and heart rate is a powerful tool in safety evaluations of new drugs, even in relatively small samples.

Adult↗
PubMed1984

[On-demand analgesia with tramadol in bilateral multiple rib fractures].

A 41-year-old woman sustained bilaterally multiple rib fractures in a severe car accident. She developed severe pain-related dyspnoea. On-demand analgesia with tramadol (by pressing a button the patient could self-administer single doses of 20 mg) rapidly decreased the pain and respiration became almost normal. Daily doses of about 400 mg were sufficient. The ability to self-administer the analgesic clearly was an important psychological factor in the good response to the usually relatively weakly effective opioid.

Adult↗
PubMed2006

Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.

BACKGROUND: After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another. METHODS: We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores). RESULTS: Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events. CONCLUSIONS: After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).

Adult↗
PubMed2001

Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans.

BACKGROUND: Tricyclic antidepressants relieve neuropathic pain, and the analgesic properties of tricyclic antidepressants are substantiated in human experimental pain models. It has been speculated that drugs with a selective inhibition of presynaptic reuptake of both serotonin and noradrenaline could have an analgesic effect comparable to the analgesic effect of tricyclic antidepressants. OBJECTIVE: Our objective was to evaluate the analgesic effect of the serotonin-noradrenaline reuptake inhibitor venlafaxine in human experimental pain models. METHOD: The study was carried out as a randomized, placebo-controlled, double-blind, crossover experiment that included 16 healthy volunteers. A 37.5-mg dose of venlafaxine was given orally 4 times with 12-hour intervals, and pain tests were performed before and 3 hours after the second and fourth doses. Pain tests included the determination of pain detection and tolerance thresholds to pressure, pain detection and tolerance thresholds on single electrical transcutaneous stimulation of the sural nerve, pain temporal summation on repetitive electrical sural nerve stimulation, and pain experienced during the cold pressor test. RESULTS: Venlafaxine increased thresholds for pain tolerance after single electrical stimulation (P =.005) and pain summation (P =.01) on repetitive stimulation but did not alter the thresholds for pain detection after single electrical sural nerve stimulation. Venlafaxine did not alter pain experienced during the cold pressor test or increase the pressure pain thresholds. CONCLUSION: Venlafaxine increases the pain tolerance threshold to electrical sural nerve stimulation and the threshold at which pain increases (pain summation). The impact of venlafaxine on pain summation in this experimental pain model on repetitive stimulation may indicate a potential analgesic effect for clinical neuropathic pain.

Adult↗
PubMed1995

Temporal competition between odorants: effect of different time intervals on the perception of monorhinic and dichorhinic binary mixtures.

Backward masking and its possible connection with the perception of odour mixtures has been investigated. Temporal competition between odorants in a binary mixture was tested by artificially creating a delay between one odour (the target) and a second, stronger, odour (the mask) during a single natural sniff. To test the influence of central versus peripheral competition, the same mixture was presented either monorhinically or dichorhinically. The delay (100 to 400 ms) did not influence intensity perception, indicating that intensities are integrated during the sniff irrespective of the temporal arrangement. In contrast, the number of qualities perceived was influenced by the delay: delays of 200 to 400 ms gave significant increases in the frequency of detection of a mixture, whereas synchronous mixtures favoured the perception of a single odour. Masking was also significantly stronger in dichorhinic mixtures. These effects are discussed in terms of retroactive masking which seems to be enhanced by dichorhinic mixtures, suggesting that masking has an important central component.

Adult↗
PubMed2005

The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins.

Central nervous system responses to cannabis are primarily mediated by CB(1) receptors, which couple preferentially to G(i/o) G proteins. Here, we used calcium photometry to monitor the effect of CB(1) activation on intracellular calcium concentration. Perfusion with 5 microM CB(1) aminoalkylindole agonist, WIN55,212-2 (WIN), increased intracellular calcium by several hundred nanomolar in human embryonic kidney 293 cells stably expressing CB(1) and in cultured hippocampal neurons. The increase was blocked by coincubation with the CB(1) antagonist, SR141716A, and was absent in nontransfected human embryonic kidney 293 cells. The calcium rise was WIN-specific, being essentially absent in cells treated with other classes of cannabinoid agonists, including Delta(9)-tetrahydrocannabinol, HU-210, CP55,940, 2-arachidonoylglycerol, methanandamide, and cannabidiol. The increase in calcium elicited by WIN was independent of G(i/o), because it was present in pertussis toxin-treated cells. Indeed, pertussis toxin pretreatment enhanced the potency and efficacy of WIN to increase intracellular calcium. The calcium increases appeared to be mediated by G(q) G proteins and phospholipase C, because they were markedly attenuated in cells expressing dominant-negative G(q) or treated with the phospholipase C inhibitors U73122 and ET-18-OCH(3) and were accompanied by an increase in inositol phosphates. The calcium increase was blocked by the sarco/endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin, the inositol trisphosphate receptor inhibitor xestospongin D, and the ryanodine receptor inhibitors dantrolene and 1,1'-diheptyl-4,4'-bipyridinium dibromide, but not by removal of extracellular calcium, showing that WIN releases calcium from intracellular stores. In summary, these results suggest that WIN stabilizes CB(1) receptors in a conformation that enables G(q) signaling, thus shifting the G protein specificity of the receptor.

Analgesics↗
PubMed1990

Cannabinoid receptor localization in brain.

[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

Animals↗
PubMed1991

Odorant-sensitive adenylate cyclase: rapid, potent activation and desensitization in primary olfactory neuronal cultures.

Using primary olfactory neuronal cultures, we have demonstrated rapid, potent increases in cAMP levels and adenylate cyclase [AC; ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity in response to odorants. Isobutyl-methoxypyrazine is active at 1 nM. Odorant enhancement is dependent on Ca2+ concentration with maximal effects at 10-100 microM. Biphasic temporal and concentration-related effects occur with all odorants. All odorants examined elicit desensitization with AC responses abolished when odorants are reapplied immediately after removal. When reapplied 1 min after removal, odorants elicit an AC response greater than on first exposure, implying a cellular "memory" for odorants.

Adenylyl Cyclases↗
PubMed1993

Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction.

Arachidonylethanolamide (anandamide), a candidate endogenous cannabinoid ligand, has recently been isolated from porcine brain and displayed cannabinoid-like binding activity to synaptosomal membrane preparations and mimicked cannabinoid-induced inhibition of the twitch response in isolated murine vas deferens. In this study, anandamide and several congeners were evaluated as cannabinoid agonists by examining their ability to bind to the cloned cannabinoid receptor, inhibit forskolin-stimulated cAMP accumulation, inhibit N-type calcium channels, and stimulate one or more functional second messenger responses. Synthetic anandamide, and all but one congener, competed for [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the rat cannabinoid receptor. The ability of anandamide to activate receptor-mediated signal transduction was evaluated in Chinese hamster ovary (CHO) cells expressing the human cannabinoid receptor (HCR, termed CHO-HCR cells) and compared to control CHO cells expressing the muscarinic m5 receptor (CHOm5 cells). Anandamide inhibited forskolin-stimulated cAMP accumulation in CHO-HCR cells, but not in CHOm5 cells, and this response was blocked with pertussis toxin. N-type calcium channels were inhibited by anandamide and several active congeners in N18 neuroblastoma cells. Anandamide stimulated arachidonic acid and intracellular calcium release in both CHOm5 and CHO-HCR cells and had no effect on the release of inositol phosphates or phosphatidylethanol, generated after activation of phospholipase C and D, respectively. Anandamide appears to exhibit the essential criteria required to be classified as a cannabinoid/anandamide receptor agonist and shares similar nonreceptor effects on arachidonic acid and intracellular calcium release as other cannabinoid agonists.

Amides↗
PubMed1999

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice.

Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor.

Animals↗
PubMed1995

Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells.

The recent isolation and cloning of the G protein-coupled central cannabinoid receptor (CB1) from brain tissue has provided a molecular basis to elucidate how cannabinoid compounds may mediate their psychoactive effects. Here we report the high expression of cannabinoid receptors in human astrocytoma tumors of different grades, in the astrocytoma cell lines U373 MG and GL-15, as well as in normal astrocytes. From an analysis of the coupling mechanisms of functional CB1 receptors in U373 MG, we show that, in addition to the inhibition of adenylyl cyclase, activation by the cannabinoid agonist CP-55940 induces the expression of the immediate-early gene krox-24, also known as NGFI-A, zif/268, egr-1, and TIS8. The amount of Krox-24 protein and the level of Krox-24 DNA binding activity, as measured by Western blot and electrophoretic mobility shift assay, respectively, were also increased by the addition of CP-55940. These effects were blocked by incubation with pertussis toxin but not by treatment with hydrolysis-resistant cAMP analogues, suggesting that the transduction pathway between the cannabinoid receptor and krox-24 involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. The specific involvement of CB1 in Krox-24 induction was demonstrated in Chinese hamster ovary cells transfected with the human CB1 receptor and also in experiments using the CB1-selective cannabinoid antagonist SR 141716A.

Animals↗