Fluoxetine HCl

Selective serotonin reuptake inhibitor. Binds to the human 5-HT transporter with a K_i of 0.9 nmol/l and is between 150- and 900- fold selective over 5-HT_1A, 5-HT_2A, H₁, α₁, α₂-a

Adsorption of fluoxetine HCl by activated charcoal.[Pubmed:9145393]

J Pharm Sci. 1997 May;86(5):642-4.

We studied the adsorption of Fluoxetine HCl (Prozac) by Norit USP XXIII activated charcoal in vitro, in simulated gastric fluid (USP; pH 1.2), and in simulated intestinal fluid (USP; pH 7.5). The data were fitted to both Langmuir and Freundlich equations. The Langmuir Qm values (maximal adsorption capacities) for pH 1.2 and 7.5 were 0.258 and 0.330 g drug/g charcoal, respectively. These excellent capacities suggest that oral charcoal therapy would be effective for fluoxetine overdose.

Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).[Pubmed:8394920]

J Pharmacol Exp Ther. 1993 Aug;266(2):836-44.

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

In utero exposure to fluoxetine HCl increases hematoma frequency at birth.[Pubmed:8415836]

Pharmacol Biochem Behav. 1993 Aug;45(4):959-62.

The present study was undertaken to determine if Fluoxetine HCl (Prozac, Dista Products Ltd., Liverpool, UK) might cause adverse vascular effects, such as hematomas, in rats exposed in utero. Gravid Sprague-Dawley rats were administered 5.62 mg/kg Fluoxetine HCl by oral gavage beginning on day 7 of gestation and ending the day of birth. A control group received distilled water by oral gavage during gestation. At birth, offspring of both groups were assessed for visible adverse vascular effects. Fluoxetine HCl-exposed offspring showed a statistically higher frequency of skin hematomas when compared to water controls. This result is consistent with known adverse effects of fluoxetine and lends support to a recently published report that attempted to link Fluoxetine HCl use to bleeding episodes in eight patients being treated for obsessive-compulsive disorder. The results of this study suggest caution in the prolonged use of this medication during pregnancy and in patients with predisposing conditions that may increase the chances of bleeding.

Evaluation of in vitro percutaneous absorption of olanzapine and fluoxetine HCl: enhancement properties of olanzapine.[Pubmed:21864096]

Drug Dev Ind Pharm. 2012 Feb;38(2):227-34.

The diffusion characteristics of Fluoxetine HCl (FLX HCl) and olanzapine (OLZ) alone and in combination with each other were studied to determine their in vitro permeation behavior across a series of gelling agents through a cellulose membrane and human cadaver skin. Klucel 0.5% was selected as the optimal formulation to study their diffusion through human cadaver skin. The release profiles of drugs acting alone and in combinations were identical in the case of the cellulose membrane. However, with human cadaver skin, the permeation of FLX HCl in combination with OLZ drastically increased (732 microg) compared with the release of FLX HCl alone (43.7 microg), while the release of OLZ remained the same whether alone or in combination with FLX HCl (183.7 microg). The results indicate that OLZ enhances the diffusion of FLX HCl through the cadaver skin. Follow-up studies with OLZ were conducted to further investigate this phenomenon and have shown that OLZ enhancement properties are skin reversible as well as concentration dependent. Also, a variety of experiments with different hydrophilic and lipophilic molecules were conducted, and it was found that OLZ enhances the permeation of hydrophilic compounds, while it has no influence on lipophilic compounds. Finally, a number of compounds structurally related to OLZ were investigated as enhancers, and it was determined that piperazine ring attached to the tricyclic system of OLZ is essential for enhancement of FLX HCl (1,837 microg).

Increased cellular turnover in response to fluoxetine in neuronal precursors derived from human embryonic stem cells.[Pubmed:19598107]

Int J Dev Biol. 2010;54(4):707-15.

Previous reports have shown that antidepressants increase neuronal cell proliferation and enhance neuroplasticity both in vivo and in vitro. This study investigated the direct effects of one such antidepressant, fluoxetine , on cell proliferation and on the production of neurotrophic factors in neuronal precursors derived from human embryonic stem cells (hESCs; H9). Fluoxetine induced the differentiation of neuronal precursors, strongly enhancing neuronal characteristics. The rate of proliferation was higher in fluoxetine -treated cells than in control cells, as determined by MTT [3(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay. The CPDL (cumulative population doubling level) of the fluoxetine-treated cells was significantly increased in comparison to that of control cells (p<.001). Bromodeoxyuridine incorporation and staurosporine-induced apoptosis assays were elevated in fluoxetine-treated cells. Quantitative RT-PCR analysis revealed no significant differences in the expression of neurotrophic factors, brain-derived neurotrophic factor (BDNF);glial-derived neurotrophic factor (GDNF) and cAMP-responsive element-binding protein (CREB) between cells treated with fluoxetine for two weeks and their untreated counterparts. These results may help elucidate the mechanism of action of fluoxetine as a therapeutic drug for the treatment of depression. Data presented herein provide more evidence that, in addition to having a direct chemical effect on serotonin levels, fluoxetine can influence hESC-derived neuronal cells by increasing cell proliferation, while allowing them to maintain their neuronal characteristics.

Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells.[Pubmed:9103487]

J Pharmacol Exp Ther. 1997 Apr;281(1):115-22.

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.

Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites.[Pubmed:9400006]

J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22.

Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand binding assays, we measured the affinity (Ki) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The Ki values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha-1 and alpha-2 receptors. These data are useful for predicting side effect profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a "dual uptake inhibitor", possesses weak affinity for the NET. We observed significant correlations in SERT (r = 0.965) or NET (r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha-1 and alpha-2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.

Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.[Pubmed:2878798]

Drugs. 1986 Dec;32(6):481-508.

Fluoxetine is a new antidepressant which enhances serotoninergic neurotransmission through potent and selective inhibition of neuronal reuptake of serotonin. Metabolism by N-desmethylation occurs in man yielding desmethylfluoxetine, which also inhibits serotonin reuptake. Both the parent compound and metabolite possess elimination half-lives of several days facilitating the maintenance of steady-state plasma concentrations during long term treatment. Fluoxetine has overall therapeutic efficacy comparable with imipramine, amitriptyline and doxepin in patients with unipolar depression treated for 5 to 6 weeks, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients. Geriatric patients also responded as well to fluoxetine as to doxepin. The symptomatic improvement in patients with unipolar depression during short term fluoxetine treatment has been satisfactorily maintained when therapy was extended for at least 6 months: the relapse rate was low and similar to that of imipramine. Preliminary data have shown that patients with bipolar depression gained similar therapeutic benefit from fluoxetine or imipramine. Other preliminary trials have indicated that fluoxetine may be useful in obsessive-compulsive disorders. Usual doses of fluoxetine cause significantly fewer anticholinergic-type side effects than tricyclic antidepressants. Nausea, nervousness and insomnia are the most frequently reported fluoxetine-related adverse effects, but these have usually not been severe. Therapeutic doses of fluoxetine do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease and fluoxetine has been relatively safe in the small number of patients who have taken overdoses. It has not been clearly established whether some types of depression may respond more readily to fluoxetine than other antidepressants, and its overall therapeutic efficacy has not been compared with other second generation antidepressants. Thus, with its different and perhaps improved side effect profile compared with older tricyclic antidepressants, fluoxetine offers properties that could be used to advantage in many patients with depression.