Actas Esp Psiquiatr. 1999 Sep-Oct;27(5):321-4.
[Fluoxetine (FX) efficacy in the treatment of cocaine dependence methadone maintenance patients. Interaction with plasma levels]

[Article in Spanish]

Bano MD, Agujetas M, Lopez ML, Tena T, Rodriguez A, Lora-Tamayo C, Guillen JL.

Programa Municipal de Drogas, Majadahonda, Madrid, 28220, Espana.

OBJECTIVES: The objective of this study was to assess the efficacy of fluoxetine (FX) treatment in cocaine dependent methadone (MTD) maintenance patients, to assess decrease or interruption of cocaine use and pharmacokinetic interaction between fluoxetine an methadone plasma levels. MATERIAL AND METHODS: The sample was composed of 11 patients with DSM IV criteria for opioid and cocaine dependence. We added Fluoxetine (20 mg per day) during 9 weeks in Majadahonda Drug Program. All patients were in methadone program a mean of 7.5 months. We made a psychiatry interview and the baseline severity of the mood disorder was assessed with the Clinical Global Impression ICG for therapeutic improvement. Cocaine use and fluoxetine treatment was measured in urine analysis and pharmacokinetic interaction between FX-MTD were measured with plasma levels of methadone. RESULTS: Fluoxetine was well tolerated combined with methadone. FX-MTD interaction didn't occur, resulting in no increased of MTD plasma level to dose before and after fluoxetine treatment. After fluoxetine treatment decreased cocaine use, changed cocaine tract from injected to smoked and improvement depressive symptoms.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10545663&dopt=Abstract fluoxetine

public1.ptt.js.cn

OBJECTIVE: To determine the effect of 20 mg/day fluoxetine on the pharmacokinetics of propafenone enantiomers and CYP2D6 activity by phenotyping with dextromethorphan. METHODS: Nine healthy Chinese volunteers (seven men and two women) were included in a two-phase study. Dextromethorphan (20 mg) was given before and after subjects took 20 mg/day fluoxetine for 10 days, and the dextromethorphan metabolic ratio was calculated to determine CYP2D6 phenotype. Pharmacokinetic studies of propafenone enantiomers after a single oral 400 mg dose before and after pretreatment with 20 mg/day fluoxetine for 10 days were also conducted in these subjects. Reversed-phase HPLC with precolumn derivatization was used to determine enantiomeric concentrations of propafenone in plasma. RESULTS: Mean CYP2D6 dextromethorphan metabolic ratios before and after fluoxetine therapy were 0.028 +/- 0.031 and 0.080 +/- 0.058, respectively (P = .001), indicating that a strong inhibition of CYP2D6 by fluoxetine activity was observed in Chinese subjects. Propafenone metabolism was also impaired significantly after fluoxetine treatment. The elimination half-life, peak concentration, and area under the curve from 0 hours to infinity of two enantiomers after fluoxetine therapy were significantly increased compared with those at baseline (P < .01), whereas oral clearance decreased from 75.01 +/- 17.69 L/h to 49.36 +/- 8.62 L/h for S-propafenone (P = .005) and from 107.62 +/- 33.82 L/h to 70.60 +/- 12.42 L/h for R-propafenone (P = .027). In addition, fluoxetine increased the peak concentration of S-propafenone by 39% and that of R-propafenone by 71% (P < .05). A

health.wa.gov.au

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. METHODS: Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg-1 day-1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20-252 microgram l-1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17-187 microgram l-1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. CONCLUSIONS: The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in




Pharmacol Res. 2000 Jan;41(1):39-45.
Fluoxetine modulates norepinephrine contractile effect on rat vas deferens.

Busch L, Wald M, Sterin-Borda L, Borda E.

Department of Pharmacology, School of Dentistry, University of Buenos Aires, Marcelo T. de Alvear 2142, Buenos Aires, 1122, Argentina.

The aim of this study was to evaluate whether the antidepressant drug fluoxetine could modify rat vas deferens response to norepinephrine (NE), and to compare its effect with that of desipramine and cocaine. Results showed that 10(-5)m fluoxetine produced a super-sensibility of vas deferens to NE. This result was the same as those obtained for 10(-6)m desipramine or cocaine. Since the effect was Na(+)- and Cl(-)-dependent, an inhibitory mechanism of neuronal NE transport was suggested. Fluoxetine did not modify [(3)H]prazosin K(d) or B(max) in rat vas deferens, reinforcing the hypothesis of a pre-synaptic site of action. On the other hand fluoxetine inhibited NE maximal effect. This inhibitory effect could be related to an antagonism of calcium entry through the voltage-dependent calcium channel, since it was partially reverted by increasing calcium concentration and, besides, the drug was able to inhibit the calcium concentration-response curve also. Contractions induced by 5-hydroxytryptamine (5-HT) were not modified in the presence of fluoxetine. It is concluded that fluoxetine modulates rat vas deferens response to low NE concentrations in the same manner as the selective inhibitor of NE neuronal uptake desipramine. This peripheral effect could participate in the modulation of the male reproductive tract observed by these drugs when used in clinical trials. Copyright 2000 Academic Press.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10600268&dopt=Abstract fluoxetine




Br J Pharmacol. 1999 Dec;128(7):1609-15.
Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine.

Yeung SY, Millar JA, Mathie A.

Department of Pharmacology, Medawar Building, University College London, Gower Street, London WC1E 6BT.

1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3. Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent. 6. It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10602343&dopt=Abstract fluoxetine

mlib.cnr.it

A capillary electrophoresis method was optimized for the stereoselective analysis of the antidepressant drug fluoxetine and its main demethylated metabolite norfluoxetine using a cyclodextrin-modified sodium phosphate buffer at pH 2.5. The combination of a neutral and a negatively charged cyclodextrin, dimethylated-beta- and phosphated-gamma-respectively, provided the baseline enantiomeric separation of the two compounds. The very low concentrations of chiral selectors employed together with the use of a high sensitivity detection cell of special design (zeta-shaped) in a diode array UV detector allowed us to reach a limit of detection of 0.005 and 0.01 microg/mL for fluoxetine and norfluoxetine, respectively. Analysis of fluoxetine and norfluoxetine standard mixtures showed a reproducibility of migration times and peak area and linearity in the concentration range of 0.1-2.0 microg/mL. The optimized method was applied to the analysis of clinical serum and plasma samples of patients under depression therapy. In all the analyzed samples the enantiomeric forms of fluoxetine and norfluoxetine were easily identified. The fluoxetine and metabolite enantiomeric ratio confirmed the stereoselectivity of the metabolic process of the fluoxetine drug in accordance with the literature data.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10608711&dopt=Abstract fluoxetine




Arthritis Rheum. 1999 Dec;42(12):2561-8.
Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.

Yaron I, Shirazi I, Judovich R, Levartovsky D, Caspi D, Yaron M.

Ichilov Hospital, Tel Aviv University, Israel.

OBJECTIVE: To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. METHODS: Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation. RESULTS: Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1alpha (IL-1alpha; 1 ng/ml) plus tumor necrosis factor alpha (TNFalpha; 30 ng/ml). Amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1alpha plus TNFalpha, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) and amitriptyline (1 microg/ml and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) also significantly (P<0.05) inhibited HA production by human synovial cells in the presence of IL-1beta plus TNFalpha. Fluoxetine and amitriptyline (1 microg/ml) partially reversed IL-1beta-induced inhibition of 35S-GAG synthesis by human cartilage cult




Pharmacol Biochem Behav. 1999 Jul;63(3):377-85.
Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic fluoxetine in female rats.

Heisler LK, Kanarek RB, Homoleski B.

Department of Psychology, Tufts University, Medford, MA 02155, USA.

Fluoxetine hydrochloride, a selective serotonin reuptake inhibitor, leads to reductions in food intake and body weight and is under investigation as a possible treatment for obesity. Additionally, it has been suggested that fluoxetine administration could lead to a selective suppression in carbohydrate consumption. Because women more often than men seek weight reduction treatment, the present study examined the acute and chronic effects of fluoxetine on food intake, macronutrient selection, body weight, estrous cycle, and motor activity in female rats. Female Long-Evans rats were provided with separate sources of protein, fat and carbohydrate, and nutrient intakes were recorded following single (5.0, 10.0, and 20.0 mg/kg, IP) and chronic daily (10 mg/kg for 28 days) injections of fluoxetine. Acute and chronic administration of fluoxetine significantly reduced total caloric intake when compared to vehicle treatment. Moreover, fluoxetine significantly suppressed fat and protein intakes, but not carbohydrate intake following both acute and chronic drug administration. Animals chronically treated with fluoxetine gained significantly less weight than animals treated with vehicle. Chronic fluoxetine treatment did not significantly alter estrous cycle. However, in both fluoxetine- and vehicle-treated animals, total caloric intake, and carbohydrate and protein intakes were reduced and fat intake was increased when estrogen levels were high. Fluoxetine significantly reduced motor activity up to 4 h postinjection, and increased motor activity 24 h postinjection.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10418777&dopt=Abstract fluoxetine




Brain Res. 2000 Feb 7;855(1):58-66.
Long-term fluoxetine produces behavioral anxiolytic effects without inhibiting neuroendocrine responses to conditioned stress in rats.

Zhang Y, Raap DK, Garcia F, Serres F, Ma Q, Battaglia G, Van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Maywood, IL 60153, USA.

The aim of the present study was to investigate the anxiolytic effects of long-term treatment with fluoxetine in rats. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are used to treat anxiety and panic disorders, in addition to treating depression. A major concern with SSRIs is a 2-3-week delay in their therapeutic effects. SSRIs share with anxiolytic 5-HT(1A) agonists the ability to produce desensitization of post-synaptic 5-HT(1A) receptors. To investigate the anxiolytic effects of fluoxetine, rats were treated for 14 days with fluoxetine (10 mg kg(-1) day(-1), i.p. ). The rats were stressed using a conditioned stress procedure and tested one day after the last fluoxetine injection. Fluoxetine decreased stress-induced defecation (by 60%), reversed the stress-induced suppression of exploring behavior (by 59%) and shortened the duration of stress-induced freezing behavior (by 11. 5%). However, the stress-induced increase in plasma levels of ACTH, corticosterone, oxytocin, prolactin and renin were not inhibited by fluoxetine treatment. These findings suggest that neuroadaptive changes induced by sustained inhibition of serotonin (5-HT) reuptake, contribute to the mechanism of the anxiolytic effects of fluoxetine. In contrast, the neuroendocrine responses to conditioned stress are not affected by these neuroadaptive changes.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10650130&dopt=Abstract fluoxetine