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Fluoxetine in the treatment of depression in Asian (Chinese and Indian) patients in Singapore.

Tsoi WF, Tan CT, Kok LP.

Department of Psychological Medicine, National University Hospital, Singapore.

The aim of this paper is to study the efficacy and side-effects of fluoxetine. Fluoxetine is a specific serotonin reuptake inhibitor. Nineteen Asian (Chinese and Indian) patients who satisfied the DSM-3R criteria for major depressive episode were treated with fluoxetine 20 mg daily for 12 weeks. They were monitored two weekly. The results showed that during the period of treatment there was significant improvement in depressive symptoms and no serious side-effects. There were no significant changes in weight, temperature, blood pressure and pulse rate throughout the 12 weeks. This study showed that fluoxetine was well-tolerated and relieved the symptoms of depression effectively. Most of the results are supported by other studies.

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A murine model of adenomyosis: the effects of hyperprolactinemia induced by fluoxetine hydrochloride, a selective serotonin reuptake inhibitor, on adenomyosis induction in Wistar albino rats.

Ficicioglu C, Tekin HI, Arioglu PF, Okar I.

Department of Obstetrics and Gynecology, Zeynep Kamil Women and Children's Hospital, Istanbul, Turkey.

OBJECTIVE: The aim of this study was to investigate whether fluoxetine given to castrated and noncastrated rats caused hyperprolactinemia and its effects with respect to adenomyosis. DESIGN: Fluoxetine, a serotonin reuptake inhibitor, was given to Wistar Albino rats for 98 days to produce hyperprolactinemia. The drug was given to two groups consisting of castrated and noncastrated rats and compared to two groups of castrated and noncastrated controls. Prolactin levels were measured and the uteri of the rats were removed for histopathological analysis at the end of 98 days. SETTING: Marmara University School of Medicine, Department of Histology and Embryology, Zeynep Kamil Women and Children's Hospital. MAIN OUTCOME MEASURES: Serum prolactin levels, uterine histopathology. RESULTS: The prolactin levels of castrated and noncastrated groups treated with fluoxetine were statistically significantly higher when compared to their respective control groups. Histological studies revealed 11 cases of adenomyosis, all within the noncastrated group receiving fluoxetine. CONCLUSION: It was suggested that high serum prolactin levels cause degeneration of myometrial cells in the presence of ovarian steroids that results in a myometrial invasion by endometrial stroma. This invasion eventually progresses to adenomyosis.

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Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo.

Fuller RW, Snoddy HD, Krushinski JH, Robertson DW.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.

Norfluoxetine, the N-desmethyl metabolite of fluoxetine, has been reported to resemble fluoxetine in being a potent and selective inhibitor of the serotonin uptake carrier. The enantiomers of norfluoxetine have now been compared as serotonin uptake inhibitors in vivo, based on their antagonism of p-chloroamphetamine-induced depletion of serotonin in brain and their lowering of concentrations of the metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in brain. In rats, S-norfluoxetine (ED50 3.8 mg/kg) was more potent than R-norfluoxetine (ED50 > 20 mg/kg) in blocking the depletion of serotonin by p-chloroamphetamine after intraperitoneal administration. The S enantiomer decreased concentrations of 5-HIAA in whole brain after doses of 2.5-20 mg/kg, whereas the R enantiomer did not. The concentrations of both enantiomers in brain increased in proportion to dose and the R enantiomer disappeared from the brain at a slightly slower rate than the S enantiomer. The relative inability of the R enantiomer to block the uptake of serotonin was therefore not a result of smaller concentrations of drug in the brain. In mice, S-norfluoxetine was also more potent than R-norfluoxetine in blocking depletion of serotonin by p-chloroamphetamine (ED50 values 0.82 and 8.3 mg/kg, respectively). Thus, in contrast to the relatively similar potencies of the enantiomers of fluoxetine in blocking the uptake of serotonin, the enantiomers of norfluoxetine have markedly different potencies as inhibitors of the uptake of serotonin.

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Anorectic activity of fluoxetine and norfluoxetine in rats: relationship between brain concentrations and in-vitro potencies on monoaminergic mechanisms.

Caccia S, Bizzi A, Coltro G, Fracasso C, Frittoli E, Mennini T, Garattini S.

Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.

The present study was aimed at establishing the importance of brain monoamine uptake and release mechanisms in the anorectic activity of fluoxetine, relating them to the actual brain concentrations of the parent drug and its metabolite norfluoxetine after anorectic doses in rats. Both compounds showed anorectic activity when administered intraperitoneally, norfluoxetine being slightly more active (ED50 = 22.9 mumol kg-1) than fluoxetine (ED50 = 35.0 mumol kg-1) despite the fact that the metabolite is about ten times less potent than the parent drug in inhibiting 5-hydroxytryptamine (5-HT) uptake. Comparing the brain concentrations of norfluoxetine, in terms of maximum concentrations (Cmax) and area under the curve (AUC), after the ED50 of fluoxetine or synthetic norfluoxetine, it also appeared that the metabolite plays a major role in the anorectic effect of the parent drug in rats. Brain Cmax of fluoxetine (48.7 microM) and norfluoxetine (21.7 and 27.3 microM after metabolite and drug, respectively) were several times those blocking 5-HT uptake in-vitro (0.5 microM), making it unlikely that fluoxetine (directly or through its metabolite) reduces food intake by specifically blocking 5-HT neuronal uptake. Brain Cmax of fluoxetine but particularly norfluoxetine were more compatible with those capable in-vitro of affecting catecholaminergic mechanisms, such as inhibition of dopamine and noradrenaline uptake and enhancement of dopamine release. These results together with recent in-vitro findings that the parent compound and its active metabolite induce tritium release from hippocampal synaptosomes previously loaded with [3H]5-HT suggest that mechanisms other than inhibition of 5-HT uptake are involved in the anorectic action of these compounds in rats.

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Potentiation of 5-hydroxytryptamine-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.

Gruetter CA, Lemke SM, Anestis DK, Szarek JL, Valentovic MA.

Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.

This study examined the effects of chlorpheniramine, citalopram and fluoxetine on 5-hydroxytryptamine (5-HT)-induced contraction and 5-HT uptake in rat thoracic aortic rings in vitro. Chlorpheniramine and citalopram markedly potentiated 5-HT-induced contraction. Potentiation by fluoxetine was less pronounced. Chlorpheniramine (0.01-1 microM) and citalopram (0.1-1 microM) induced concentration-dependent parallel shifts to the left of the 5-HT concentration-response curves. The potentiation by chlorpheniramine was selective as chlorpheniramine (1 microM) did not potentiate phenylephrine-induced contraction. The potentiation did not depend upon the presence of endothelium, and was not related to H1 receptor antagonism as diphenhydramine and pyrilamine (1 microM) did not similarly enhance 5-HT-induced contractions. Whereas cocaine (1-10 microM) similarly potentiated 5-HT-induced contraction, imipramine (1-10 microM) inhibited, rather than enhanced, contraction elicited by 5-HT. In the presence of 10 microM cocaine, maximally effective concentrations of chlorpheniramine (1 microM) or citalopram (100 nM) did not induce any additional potentiation of 5-HT-induced contraction. Cooling (4 degrees C) markedly inhibited uptake of [3H]5-HT in rings with and without endothelium. Although less marked, imipramine (10 microM), cocaine (1 microM), chlorpheniramine (1 microM) and citalopram (100 nM) inhibited [3H]5-HT uptake in endothelium-intact and endothelium-denuded rings. Fluoxetine also inhibited [3H]5-HT uptake, but the inhibition was only statistically significant in endothelium-intact rings. The monoamine oxidase (MAO) inhibitor, pargyline (10-100 microM), did not significantly affect 5-HT-induced contraction. The results demonstrate that chlorpheniramine, citalopram and to a lesser extent, fluoxetine potentiate 5-HT-induced contraction in rat aorta in which neuronal 5-HT uptake is negligible. The data are consistent with inhibition of non-neuronal 5-HT uptake as at least one mechanism responsible for potentiation of 5-HT-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.

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Anorectic activity of fluoxetine and norfluoxetine in mice, rats and guinea-pigs.

Anelli M, Bizzi A, Caccia S, Codegoni AM, Fracasso C, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 39.1, 34.7 and 21.7 mumol kg-1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24.3, 22.9 and 19.1 mumol kg-1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0-90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50-60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.

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Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain.

Caccia S, Fracasso C, Garattini S, Guiso G, Sarati S.

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

The effects of repeated doses of fluoxetine over time and dose-responses of the content of indoles and catecholamines and metabolism, were examined in rats in relation to the concentrations of the parent compound and its active metabolite norfluoxetine in brain. Brains were removed for assays of the regional content of monoamines and concentrations of drugs 24 hr after the last dose on days 1, 7 and 21 of a twice-daily schedule of fluoxetine (15 mg/kg, i.p.). Measurements were also taken 1 week after the last dose (7.5 and 15 mg/kg, b.i.d.) of the 21-day regimen. On day 1 fluoxetine did not change the content of serotonin (5-HT) but reduced the concentrations of 5-hydroxyindolacetic acid (5-HIAA) in the hippocampus and cortex, compatible with the action of a blocker of the uptake of 5-HT. Continued injections of fluoxetine, however, significantly reduced 5-HT in the brain of the rat, the depletion being significant on days 7 and 21 in the hippocampus and cortex, respectively. The content of indoles remained significantly decreased for at least a week after the last dose of fluoxetine in the 21-day regimen, although the concentrations of 5-HIAA (but not 5-HT) totally recovered at the smaller dose (7.5 mg/kg) in all regions of the brain (cortex, hippocampus and striatum). In spite of slight changes in the concentrations and metabolism of dopamine (DA) in the striatum, 24 hr after the last dose (15 mg/kg), treatment with drug had no significant long-term effects on the content of catecholamines in these regions of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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Involvement of 5-HT1, 5-HT2, and 5-HT3 receptors in the mediation of the prolactin response to serotonin and 5-hydroxytryptophan.

Jorgensen H, Knigge U, Warberg J.

Department of Medical Physiology C, Panum Institute, University of Copenhagen, Denmark.

Serotonin (5-HT) is involved in the neuroendocrine regulation of prolactin (PRL) secretion as a stimulator. Within the last decade several 5-HT receptor types have been identified, but their individual role in the mediation of the PRL response to 5-HT is only partly understood. We investigated in conscious male rats the effect of different 5-HT1, 5-HT2, and 5-HT3 receptor antagonists on the PRL response to 5-HT or to the 5-HT precursor 5-hydroxytrytophan (5-HTP) which was administered in combination with the 5-HT reuptake inhibitor fluoxetine. 5-HT (0.5-5.0 mg/kg BW i.v.) or 5-HTP (25-100 mg/kg i.p.) in combination with saline or fluoxetine (10 mg/kg i.p.) increased the plasma PRL concentration dose-dependently. Pretreatment with the 5-HT1+2 receptor antagonist methysergide (2.5 mg/kg i.p.) prevented the stimulatory effect of 5-HT or 5-HTP + fluoxetine. Pretreatment with the 5-HT2 receptor antagonists ketanserin or LY 53857 (2.5 mg/kg i.p.) inhibited the PRL response to 5-HT by approximately 80% and to 5-HTP + fluoxetine approximately 100%. A higher dose (10 mg/kg) of the 5-HT2 receptor antagonists possessed only 50% inhibitory effect. Pretreatment with the 5-HT3 receptor antagonists ICS 205-930 or GR 38032F (0.05-2.5 mg/kg i.p.) inhibited the PRL response induced by 5-HT or by 5-HTP + fluoxetine. The maximal inhibitory effect (approximately 80%) was obtained by a dose of 0.1 mg/kg of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

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