Prozac
Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus.

Norris S, Zhang X, Avenell A, Gregg E, Schmid Ch, Lau J.

Division of Diabetes Translation, National Center for Chronic Disease Prevention & Health Promotion, Centers for Control and Prevention, 4774 Buford Highway NE, Mail Stop K-10, Atlanta, GA, USA, 30341.

BACKGROUND: Obesity is closely related to type 2 diabetes and long-term weight reduction is an important part of the care delivered to obese persons with diabetes. OBJECTIVES: To assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. SEARCH STRATEGY: Computerized searches were performed of MEDLINE (January 1966 to May 2004), EMBASE (January 1974 to May 2004, Web of Science (January 1981 to May 2004, and other electronic bibliographic databases, supplemented with hand searches of reference lists and selected journals. SELECTION CRITERIA: Randomized, controlled trials were included where pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished literature in any language and with any study design was included. DATA COLLECTION AND ANALYSIS: Two reviewers abstracted data and the quality of included studies was evaluated by assessing potential attrition, as well as selection and measurement bias, and a Jadad score was obtained. Effects were combined using a random effects model. MAIN RESULTS: A sufficient number of studies were available for a quantitative synthesis for fluoxetine, orlistat, and sibutramine. Twenty two randomized controlled trials were included in the review, with a total of 296 participants for fluoxitine, 2036 for orlistat, and 1047 for sibutramine. Pharmacotherapy produced modest reductions in weight for fluoxetine (5.1 kg (95% confidence interval [CI], 3.3 - 6.9) at 24 to 26 weeks follow up; orlistat 2.0 kg (CI, 1.3 - 2.8) at 12 to 57 weeks follow-up, and sibutramine 5.1 kg (CI, 3.2 - 7.0) at 12 to 52 weeks follow-up. Glycated hemoglobin also modestly and significantly reduced for fluoxetine and orlistat. Gastrointestinal side effects were common with orlistat; tremor, somnolence and sweating with fluoxetine; and palpitations with sibutramine. Some studies, using a variety of study designs, were available on other drugs and a significant decrease in weight was noted in three studies of mazindol, one of phenmetrazine, two of phentermine. No studies were identified that fit inclusion criteria for pseudophedrine, ephedra, sertraline, yohimbine, amphetamine or its derivatives, bupropion, topiramate, benzocaine, threachlorocitric acid, sertraline, and bromocriptine. AUTHORS' CONCLUSIONS: Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 12 to 57 weeks. The magnitude of weight loss is modest, however, and the long-term health benefits remain unclear. The safety of sibutramine is uncertain. There is a paucity of data on other drugs for weight loss or control in persons with type 2 diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15674929&dopt=Abstract fluoxetine Prozac



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Spiroxatrine augments fluoxetine-induced reduction of ethanol intake by the P line of rats.

McBride WJ, Murphy JM, Lumeng L, Li TK.

Department of Psychiatry, R. L. Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202.

The present study was undertaken to determine if spiroxatrine, a reported 5-HT1A antagonist, could block the attenuating effects of fluoxetine (a 5-HT uptake inhibitor) on voluntary ethanol intake by the selectively bred alcohol-preferring P line of rats. Fluoxetine (10 mg/kg, IP) significantly reduced the intake of 10% ethanol by P rats approximately 50% during the 4-hour period of alcohol availability. Spiroxatrine (4 mg/kg, IP) was without effect on ethanol intake when given alone. However, when given 5 minutes before fluoxetine (10 mg/kg, IP), this dose of spiroxatrine augmented the reduction of ethanol intake to approximately 15% of control values after 4 hours. Similar experiments conducted with 1 mg/kg (IP) 8-hydroxy-2(di-N-propylamino) tetralin (DPAT) demonstrated that this 5-HT1A agonist also enhanced the attenuating effects of fluoxetine on ethanol intake. Likewise, spiroxatrine augmented the DPAT reduction of alcohol intake. Spiroxatrine enhanced the effect of DPAT and fluoxetine on food intake as it did on ethanol intake. The results suggest that spiroxatrine behaved as a partial agonist and/or modulator and not as an antagonist at 5-HT1A receptors under the present experimental conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2533688&dopt=Abstract fluoxetine Prozac



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Effect of fluoxetine pretreatment on plasma and tissue concentrations of desipramine in rats.

Fuller RW, Perry KW.

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.

Because of clinical reports that fluoxetine co-administration has led to increased blood concentrations of desipramine and adverse clinical effects in depressed patients treated with desipramine, we investigated the effect of fluoxetine on desipramine metabolism by rat liver microsomes in vitro and on blood and brain concentrations of desipramine in rats treated with desipramine. Fluoxetine caused a concentration-dependent inhibition of the 2-hydroxylation and N-demethylation of desipramine in vitro. Fluoxetine increased blood and brain concentrations of desipramine and prolonged the half-life of desipramine in blood and brain in rats in vivo. The inhibition of desipramine metabolism by fluoxetine probably led to the increased blood levels of desipramine in the clinical cases and may have contributed to the acceleration of cortical beta adrenoreceptor downregulation reported in rats when desipramine and fluoxetine were co-administered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2609015&dopt=Abstract fluoxetine Prozac



Prozac
Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors.

Hirano K, Kimura R, Sugimoto Y, Yamada J, Uchida S, Kato Y, Hashimoto H, Yamada S.

1Department of Biopharmaceutical Sciences and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in K(D) for specific [(3)H]paroxetine binding, and the in vivo SERT-binding potency was in the order of paroxetine>>fluoxetine, sertraline>fluvoxamine.The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long-lasting binding activity of brain SERT after the fluoxetine administration.Oral administration of each SSRI suppressed significantly the marble-burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble-burying behaviour correlated significantly with their brain SERT binding activities.In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT-binding characteristics is closely associated with the pharmacokinetics and inhibition of marble-burying behaviour.British Journal of Pharmacology advance online publication, 24 January 2005; doi:10.1038/sj.bjp.0706108.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15678084&dopt=Abstract fluoxetine Prozac



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Anticonvulsant effects of acute and repeated fluoxetine treatment in unstressed and stressed mice.

Pericic D, Lazic J, Svob Strac D.

Laboratory for Molecular Neuropharmacology, Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka cesta 54, P.O. Box 180, 10002 Zagreb, Croatia. pericic irb.hr

Comorbidity of epilepsy and depression is not rare. Stress can affect both depression and seizures. Therefore, it is important to know whether an antidepressant drug has pro- or anticonvulsant properties and whether these properties will be modified by stress. We tested the effects of the antidepressant drug fluoxetine on the seizure threshold for picrotoxin in unstressed and swim-stressed mice. The mice were, prior to exposure to swim stress and the intravenous infusion of picrotoxin (a non-competitive GABA(A) receptor antagonist), pretreated with fluoxetine (a selective serotonin reuptake inhibitor), either acutely or repeatedly (5 days), and the latency to the onset of two convulsant signs and death was registered. The convulsant signs were running/bouncing clonus and tonic hindlimb extension. As expected, swim stress enhanced the seizure threshold for picrotoxin. Fluoxetine (20 mg/kg ip) given acutely increased in unstressed and swim-stressed mice the dose of picrotoxin producing tonic hindlimb extension and in unstressed mice the dose of picrotoxin producing death. Neither 10 nor 20 mg/kg of fluoxetine affected doses of picrotoxin needed to produce running bouncing/clonus. Repeated treatment with fluoxetine (20 mg/kg ip) enhanced significantly in unstressed and swim-stressed mice doses of picrotoxin needed to produce tonic hindlimb extension and death, and in stressed mice also the dose of picrotoxin producing running/bouncing clonus. The results demonstrate that the antidepressant drug fluoxetine, given acutely or repeatedly, shows anticonvulsant properties against convulsions induced in unstressed and swim-stressed mice by antagonist of GABA(A) receptors, picrotoxin. Swim stress failed to modify the anticonvulsant properties of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15680343&dopt=Abstract fluoxetine Prozac



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The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway.

Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E.

Department of Psychiatry, University Hospital of Maastricht, Vijverdal P.O. Box 88, 6200 AB Maastricht, The Netherlands.

Recently, we have shown that various types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, have negative immunoregulatory effects. These antidepressants suppress the interferon-gamma (IFN-gamma)/interleukin-10 (IL-10) production ratio, which is of critical importance for the determination of the capacity of immunocytes to inhibit or activate monocytic/lymphocytic functions. Since cyclic adenosine monophosphate (cAMP) production is stimulated by some antidepressants, and since cAMP inhibits IFN-gamma and stimulates IL-10 production, we postulate that the negative immunoregulatory effects of antidepressants result from their effects on the cAMP-dependent protein kinase A (PKA) pathway. The aim of the present study was to determine whether the negative immunoregulatory effects of fluoxetine may be blocked by antagonists of the cAMP-dependent PKA pathway, such as, e.g., SQ 22536, an adenylate cyclase inhibitor, and Rp-8-Br-cAMPs (Rp-isomer of 8-bromo-adenosine-3',5'-monophosphorothioate), a PKA antagonist. To this end, diluted whole blood collected from 17 normal volunteers was incubated with fluoxetine (10(-6) and 10(-5) M), with or without SQ 22536 (10(-6) and 10(-4) M) and Rp-8-Br-cAMPs (10(-6) and 10(-4) M), afterwards, IFN-gamma, IL-10 and the tumor necrosis factor alpha (TNF-alpha) were determined. Fluoxetine, 10(-6) and 10(-5) M, significantly reduced the production of IFN-gamma and TNF-alpha, and significantly decreased the IFN-gamma/IL-10 production ratio. SQ 22536 and Rp-8-Br-cAMPs were unable to block the suppressant effects of fluoxetine on the IFN-gamma/IL-10 ratio. Rp-8-Br-cAMPs, 10(-4), but not 10(-6) M, normalized the fluoxetine-induced suppression of TNF-alpha production. It is concluded that the suppressant effect of fluoxetine on the IFN-gamma/IL-10 production ratio is probably not related to the induction of the cAMP-dependent PKA pathway, whereas the suppressant effect on TNF-alpha may be related to the induction of PKA. The obtained results suggest that increased activation of the PKA-dependent pathway may constitute an important molecular basis for some (suppression of TNF-alpha production), but not all (suppression of IFN-gamma production), negative immunoregulatory effects of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15683856&dopt=Abstract fluoxetine Prozac



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Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine.

Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A.

1Blackett Laboratory, Biophysics Section, Department of Biological Sciences, Imperial College London, Exhibition Road, London SW7 2AZ.

Block of the human two-pore domain potassium (2-PK) channel TREK-1 by fluoxetine (Prozac(R)) and its active metabolite, norfluoxetine, was investigated using whole-cell patch-clamp recording of currents through recombinant channels in tsA 201 cells.Fluoxetine produced a concentration-dependent inhibition of TREK-1 current that was reversible on wash. The IC(50) for block was 19 muM. Block by fluoxetine was voltage-independent. Fluoxetine (100 muM) produced an 84% inhibition of TREK-1 currents, but only a 31% block of currents through a related 2-PK channel, TASK-3.Norfluoxetine was a more potent inhibitor of TREK-1 currents with an IC(50) of 9 muM. Block by norfluoxetine was also voltage-independent.Truncation of the C-terminus of TREK-1 (Delta89) resulted in a loss of channel function, which could be restored by intracellular acidification or the mutation E306A. The mutation E306A alone increased basal TREK-1 current and resulted in a loss of the slow phase of TREK-1 activation.Progressive deletion of the C-terminus of TREK-1 had no effect on the inhibition of the channel by fluoxetine. The E306A mutation, on the other hand, reduced the magnitude of fluoxetine inhibition, with 100 muM producing only a 40% inhibition.It is concluded that fluoxetine and norfluoxetine are potent inhibitors of TREK-1. Block of TREK-1 by fluoxetine may have important consequences when the drug is used clinically in the treatment of depression.British Journal of Pharmacology advance online publication, 31 January 2005; doi:10.1038/sj.bjp.0706068.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15685212&dopt=Abstract fluoxetine Prozac



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QTc Prolongation Associated with Combination Therapy of Levofloxacin, Imipramine, and Fluoxetine.

Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG.

Department of Clinical and Administrative Sciences, Mercer School of Pharmacy, Atlanta, GA.

OBJECTIVE: To report QTc interval prolongation associated with combination therapy including levofloxacin, imipramine, and fluoxetine. CASE SUMMARY: A 49-year-old white female presented to the emergency department with fever, aches, and pains for the past 3 days. She was diagnosed and treated for pyelonephritis in the hospital. Therapy included intravenous levofloxacin 500 mg every 24 hours and ceftriaxone 2 g every 24 hours, along with her medications upon admission, including imipramine 50 mg at bedtime and fluoxetine 10 mg/day. She was discharged after 5 days and returned the next day with chest tightness and shortness of breath. Upon the second admission, a 12-lead electrocardiogram showed a QTc interval of 509 msec. Levofloxacin was discontinued and the QTc interval fell to 403 msec. The patient was discharged 3 days later and instructed to consult with her primary care physician about discontinuing imipramine. DISCUSSION: This adverse drug reaction is thought to be a pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Fluoxetine is a potent inhibitor of CYP2D6, and imipramine is metabolized by CYP2D6. Therefore, fluoxetine is able to increase the plasma concentrations of imipramine, leading to QT interval prolongation. Taken with imipramine, levofloxacin can lead to even greater prolongation of the QT interval. Based on the Naranjo probability scale, levofloxacin was possibly associated with cardiac arrhythmias in our patient. CONCLUSIONS: The use of levofloxacin alone, or more often in concomitant therapy with other medications that are known to prolong the QT interval, may cause QT interval prolongation; however, additional studies/case reports are needed to validate this conclusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15687478&dopt=Abstract fluoxetine Prozac