Prozac
Chronic antidepressant treatment alters serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons.

Zhong P, Yan Z.

Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, 124 Sherman Hall, Buffalo, NY 14214, USA.

The serotonin system is highly involved in the pathophysiology of mood disorders such as depression and anxiety. Currently, the most widely used treatment for these illnesses is selective serotonin (5-HT)reuptake inhibitors, such as fluoxetine. Because of the multiplicity of 5-HT receptors and their different adaptive properties, the chronic effects of fluoxetine have remained unclear. In this study, we investigated the alteration of 5-HT functions by long-term antidepressant treatment in pyramidal neurons of prefrontal cortex (PFC), a brain region crucial for the control of emotion and cognition. One prominent function of serotonin in PFC is to regulate GABAergic inhibitory transmission. Application of 5-HT induced a large, desensitizing enhancement of the amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSC), as well as a potent reduction of electrically evoked IPSC (eIPSC). Chronic fluoxetine treatment did not alter basal sIPSC, but reduced eIPSC in response to different stimulus strengths. Moreover, chronic (but not acute) fluoxetine treatment caused a much faster desensitization of the 5-HT effect on sIPSC, and significantly attenuated the 5-HT effect on eIPSC. Application of a 5-HT(2) receptor agonist produced similar effects as 5-HT on sIPSC and eIPSC, and these effects were similarly altered by long-term fluoxetine treatment. These electrophysiological results suggest that chronic antidepressant treatment resulted in a down-regulation of the synaptic function of forebrain 5-HT(2) receptors. Given the key role of GABAergic inhibitory transmission in controlling PFC functions, its altered regulation by serotonin after chronic fluoxetine treatment may provide a mechanism underlying the therapeutic action of antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15489029&dopt=Abstract fluoxetine Prozac



Prozac
Automated HPLC assay of fluoxetine and norfluoxetine in serum.

Nichols JH, Charlson JR, Lawson GM.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.

This automated assay determines the concentration of the antidepressant fluoxetine (Prozac) and its active metabolite norfluoxetine in serum by reversed-phase HPLC with spectrophotometric detection. Extraction, injection, and quantification are performed by the Gilson Aspec automated sample handler. The patient's specimen, with added protriptyline as internal standard, is extracted with solid-phase and liquid-liquid methods. Separation is conducted isocratically on a 5-microns (particle size) Supelcosil LC-8-DB reversed-phase column with a triethylamine acetate:acetonitrile mobile phase. The detection limit is 10 micrograms/L and absorbance varies linearly with concentration between 20 and 1,000 micrograms/L for both compounds. Mean recovery was 62% for fluoxetine and 70% for norfluoxetine over linear limits. Within-run and day-to-day imprecision (CV), evaluated at three concentrations (50, 200, and 500 micrograms/L), ranged from 2% to 7%. An extensive interference study of 108 drugs was conducted. Results (n = 58) by the automated method (y) correlated well with those by a manual HPLC method (x): y = 0.96x + 10.20 (r = 0.951, Sylx = 42.9) for fluoxetine, and y = 0.95x - 1.37 (r = 0.917, Sylx = 47.2) for norfluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8013105&dopt=Abstract fluoxetine Prozac



Prozac
Comparison of stimulus properties of fluoxetine and 5-HT receptor agonists in a conditioned taste aversion procedure.

Berendsen HH, Broekkamp CL.

Neuropharmacology Department, Organon International B.V., Oss, Netherlands.

Pre-exposure to 5-hydroxytryptamine (5-HT) receptor agonists in conditioned taste aversion experiments was used to characterize the stimulus properties of fluoxetine. The taste aversion induced by fluoxetine (10 mg/kg) was completely prevented when mice were pre-exposed to fluoxetine or when they were pre-exposed to the preferential 5-HT1C receptor agonist MK 212. Pre-exposure to MK 212 also prevented the conditioned taste aversion induced by another serotonin uptake inhibitor, paroxetine. A partial attenuation of fluoxetine-induced conditioned taste aversion was seen after pre-exposure to a high dose of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1 mg/kg), but not to lower doses. No familiarization for the fluoxetine stimulus was obtained by pre-exposure to treatments with the mixed 5-HT1C/2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). With the reversed sequence, pre-exposure to fluoxetine prevented the conditioned taste aversion induced by MK 212 or 8-OH-DPAT and reduced that induced by DOI. It is concluded that the acute stimulus properties of fluoxetine mostly resemble those of a 5-HT1C receptor agonist. This supports the suggestion that the 5-HT1C receptor can play an important role in the therapeutic effect of 5-HT reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8013551&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine in family practice patients.

Taylor AT, Wagner PJ, Pritchard DC, Tollison JW.

Department of Pharmacy Practice, University of Georgia College of Pharmacy, Athens.

BACKGROUND. Many patients with depression are seen only by family physicians, yet it is unknown how their physicians prescribe newer antidepressants. METHODS. Charts of family practice patients receiving fluoxetine were reviewed using a standardized format. Information reviewed included patient demographics, diagnosis, prescriptions, and course of treatment. RESULTS. Depression was documented in 92.5% of the 40 patients studied. There were significantly more female patients in the fluoxetine sample than in the base sample of depressed patients (P < .04). Fluoxetine patients weighed significantly more than the base sample, with a mean difference of 20.8 pounds (P < .03). Side effects were documented in the charts of 12 (30%) patients. Prescription practice was considered optimal in 43% of patients who were told to take fluoxetine in the morning. No differences in improvement or side effects were found based on optimal prescribing behavior. Improvement was documented in 68% of patients. Fluoxetine was discontinued in 6 (15%) cases because of adverse side effects. CONCLUSIONS. An improvement rate of 68% among patients taking 20 to 40 mg of fluoxetine per day indicates that an adequate response can be achieved without the risk of side effects that typically accompany higher doses. In this study, fluoxetine was prescribed more often to obese patients. This prescribing pattern may indicate that primary care physicians perceive overweight patients as good candidates for fluoxetine regardless of inconclusive evidence about the effectiveness of this drug for weight loss.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8027732&dopt=Abstract fluoxetine Prozac



Prozac
Na(+)-dependent, fluoxetine-sensitive serotonin uptake by astrocytes tissue-printed from rat cerebral cortex.

Dave V, Kimelberg HK.

Division of Neurosurgery, Albany Medical College, New York 12208.

Previous studies have established that rat primary astrocyte cultures prepared from several brain regions of 1-4-d-old rats exhibit high-affinity, Na(+)-dependent and fluoxetine-sensitive serotonin (5-HT) uptake with a Km for 5-HT of 0.4 microM and a Ki for fluoxetine of 23 nM, which correspond to the characteristics for this transport for other brain preparations. However, it is not known whether astrocytes in situ show such uptake. We addressed this question by performing 3H-5-HT uptake experiments on cortical astrocytes, within 4 hr of isolating them from 6- and 21-d-old rats by the tissue-print technique. Quantitative autoradiography was combined with GFAP and neurofilament (NF) immunocytochemistry to distinguish astrocytic from neuronal 3H-5-HT uptake. In composition, the tissue-printed (TP) cells and processes were 60-70% GFAP (+) and 10-15% NF(+). 3H-5-HT uptake (0.3 microM 5-HT, 3.4 microCi/ml) in both tissue-printed GFAP(+) astrocytes and NF(+) structures was sensitive to 1 microM fluoxetine and was also Na+ dependent. More than 90% of TP astrocytes from 6- and 21-d-old rats and 100% of NF(+) structures from 21-d-old rats showed positive 3H-5-HT uptake (defined as > or = 31 grains/10(3) microns2). The highest level of uptake (> or = 191 grains/10(3) microns2) was never observed in TP astrocytes but was exhibited by about half of the NF(+) structures. In other experiments were found that 3H-5-HT uptake by 6-d-old TP astrocytes was comparable to uptake by postnatal age-matched primary cultured astrocytes that were grown in fetal bovine serum (FBS). However, primary cultured astrocytes grown in horse serum showed lower uptake than that observed with FBS, a finding similar to previous results in cultures where 3H-5-HT uptake was measured per milligram of cell protein. These results imply that high-affinity, Na(+)-dependent and fluoxetine-sensitive 5-HT uptake occurs in rat cortical astrocytes in situ.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8046464&dopt=Abstract fluoxetine Prozac



Prozac
Selective serotonin reuptake inhibitor dose titration in the naturalistic setting.

Gregor KJ, Overhage JM, Coons SJ, McDonald RC.

Center for Pharmaceutical Economics, College of Pharmacy, University of Arizona, Tucson.

Little information exists regarding the use of selective serotonin reuptake inhibitors (SSRIs) in the naturalistic setting. The Regenstrief Medical Record System was used to analyze the dosing of SSRIs in the outpatient population of an urban teaching hospital. A cohort of 3350 patients was extracted, of whom 2859 had received fluoxetine and 460 sertraline. This cohort received 21,079 prescriptions. (The 31 patients who were prescribed paroxetine were eliminated from further analysis.) The mean daily dose for all patients receiving fluoxetine was 21 +/- 6 mg for the first prescription dispensed and 25 +/- 11 mg for the ninth. For fluoxetine-treated patients with depression included on their computerized medical problem list, the mean daily dose was 21 +/- 6 mg for the first prescription and 26 +/- 12 mg for the ninth. A mean of 5.0% of all patients continuing fluoxetine therapy had their daily dose increased with each prescription refill during the first nine prescriptions. The mean daily dose for all patients receiving sertraline was 59 +/- 28 mg for the first prescription and 117 +/- 66 mg for the ninth. For sertraline-treated patients with depression included on their computerized medical problem list, the mean daily dose was 57 +/- 25 mg for the first prescription and 110 +/- 65 mg for the ninth. A mean of 14.9% of all patients continuing sertraline therapy had their daily dose increased with each prescription refill during the first nine prescriptions. The frequency of sertraline dose increases was 2 to 3 times the rate for fluoxetine. Because increases in daily doses typically result from inadequate control of symptoms of depression, these findings may reflect fluoxetine's greater effectiveness in controlling symptoms during the initial stages of therapy in the naturalistic setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8062324&dopt=Abstract fluoxetine Prozac



Prozac
Effect of fluoxetine on rat liver mitochondria.

Souza ME, Polizello AC, Uyemura SA, Castro-Silva O, Curti C.

Departamento de Fisica e Quimica, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Brasil.

The in vitro and in vivo effects of fluoxetine (and its active metabolite norfluoxetine) on mitochondrial respiration and F0F1-ATPase were studied, respectively, in mitochondria and submitochondrial particles isolated from rat liver. Fluoxetine in vitro inhibited state 3 mitochondrial respiration for alpha-ketoglutarate and succinate oxidations (50% of effect at 0.25 and 0.35 mM drug concentrations, respectively); stimulated state 4 for succinate; and induced a decrease in the respiratory control ratio (RCR) for both oxidizable substrates. The F0F1-ATPase activity was determined at various pH levels in the absence and presence of Triton X-100. The solubilized form was not affected markedly, but an inhibition, apparently non-competitive, was observed for the membrane-bound enzyme, with 50% of the effect at a 0.06 mM drug concentration in pH 7.4. These results suggest that fluoxetine in vitro acts on F0F1-ATPase through direct interaction with the membrane F0 component (similar to oligomycin), or first with mitochondrial membrane and then affecting F0. A very similar behavior concerning the respiratory parameters and F0F1-ATPase properties was observed with norfluoxetine. The in vivo studies with fluoxetine showed stimulation of mitochondrial respiration in state 4 for alpha-ketoglutarate or succinate oxidations in acute or prolonged treatments (1 hr after a single i.p. dose of 20 mg of drug/kg of body weight, and 22 hr after 12 days of treatment with a daily dose of 10 mg/kg of body weight, respectively), indicating uncoupling of oxidative phosphorylation. Pronounced changes were not observed in the K0.5 values of F0F1-ATPase catalytic sites, but the Vmax decreased during the prolonged treatment. The results show that fluoxetine (as well as norfluoxetine) has multiple effects on the energy metabolism of rat liver mitochondria, being potentially toxic in high doses. The drug effects seem to be a consequence of the drug and/or metabolite solubilization in the inner membrane of the mitochondria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8068040&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models.

Peer D, Dekel Y, Melikhov D, Margalit R.

Department of Biochemistry, the George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv, Israel.

Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15492283&dopt=Abstract fluoxetine Prozac