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Christoph Hiemke - One of the best experts on this subject based on the ideXlab platform.

  • Differential effects of Fluvoxamine and other antidepressants on the biotransformation of melatonin
    Journal of clinical psychopharmacology, 2001
    Co-Authors: Sebastian Härtter, Ximing Wang, Harald Weigmann, Thomas Friedberg, Michael Arand, Franz Oesch, Christoph Hiemke
    Abstract:

    Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by Fluvoxamine, but not by other serotonin reuptake inhibitors. Because Fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of Fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and N-acetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by Fluvoxamine, with a Ki of 0.02 microM for the formation of 6-hydroxymelatonin and 0.05 microM for the formation of N-acetylserotonin. Other than Fluvoxamine, fluoxetine, paroxetine, citalopram, imipramine, and desipramine were also tested at 2 and 20 microM. Among the other antidepressants, only paroxetine was able to affect the metabolism of melatonin at supratherapeutic concentrations of 20 microM, which did not reach by far the magnitude of the inhibitory potency of Fluvoxamine. The authors concluded that Fluvoxamine is a potent inhibitor of melatonin degradation. Because this inhibitory action is also found in vivo, Fluvoxamine might be used as an enhancer of melatonin, which might offer new therapeutic possibilities of Fluvoxamine.

  • Increased bioavailability of oral melatonin after Fluvoxamine coadministration.
    Clinical pharmacology and therapeutics, 2000
    Co-Authors: Sebastian Härtter, Harald Weigmann, Michael Grözinger, Joachim Röschke, Christoph Hiemke
    Abstract:

    Background Fluvoxamine, a selective serotonin reuptake inhibitor, is known to elevate melatonin serum concentrations. It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin. The latter hypothesis was tested by this study. Methods Five healthy male volunteers (one CYP2D6 poor metabolizer) received 5 mg melatonin either with or without coadministration of 50 mg Fluvoxamine. Serum concentrations of melatonin and Fluvoxamine were assessed from 0 to 28 hours after melatonin intake. Results Coadministration of Fluvoxamine, on average, led to an 17-fold higher (P

  • Nonlinear pharmacokinetics of Fluvoxamine and gender differences.
    Therapeutic drug monitoring, 1998
    Co-Authors: Sebastian Härtter, E. Hammes, Herman Wetzel, Massud Torkzadeh, Christoph Hiemke
    Abstract:

    This prospective study assessed Fluvoxamine serum concentrations under two different fixed doses. The study included 15 male and female patients who met the DSM-III-R criteria for major depression. They were prescribed 50 mg Fluvoxamine twice a day for 2 weeks and 100 mg twice a day thereafter. Drug monitoring was carried out on days 14 and 28. Fluvoxamine serum concentrations were highly variable between patients. After the dose was doubled, the serum concentrations of Fluvoxamine increased disproportionately (mean, 3.4-fold), and there was a significantly (p < 0.05) more pronounced increase in men (4.6-fold) than in women (2.4-fold). These results provide evidence of nonlinear, sex-dependent pharmacokinetics of Fluvoxamine.

  • Inhibition of antidepressant demethylation and hydroxylation by Fluvoxamine in depressed patients
    Psychopharmacology, 1993
    Co-Authors: Sebastian Härtter, Hermann Wetzel, E. Hammes, Christoph Hiemke
    Abstract:

    Bidirectional drug interactions between Fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of Fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that Fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under Fluvoxamine monotherapy before comedication, plasma concentrations of Fluvoxamine increased after administration of a tricyclic antidepressant, thus indicating bidirectional drug interactions. The inhibitory effects of Fluvoxamine on the metabolism of classical antidepressants disappeared after discontinuation of concomitant Fluvoxamine treatment within at least 1–2 weeks. The reported alterations in drug metabolism observed in depressed patients who were under Fluvoxamine/tricyclic antidepressant comedication suggested that careful supervision and regular drug monitoring are necessary in such patients.

Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.

  • sigma 1 receptors and selective serotonin reuptake inhibitors clinical implications of their relationship
    Central nervous system agents in medicinal chemistry, 2009
    Co-Authors: Kenji Hashimoto
    Abstract:

    Abstract Endoplasmic protein sigma-1 receptors represent unique binding sites in the brain, and they exert a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that sigma-1 receptors play roles in the pathophysiology of psychiatric diseases, as well as in the active mechanisms of some selective serotonin reuptake inhibitors (SSRIs). Interestingly, we reported that some SSRIs possess moderate to high affinities at sigma-1 receptors in the brain. Among them, the order of affinity for sigma-1 receptors was as follows: Fluvoxamine > sertraline > fluoxetine > citalopram " paroxetine. In a cell culture system, we demonstrated that Fluvoxamine, but not sertraline or paroxetine, significantly potentiated nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, and that the effect of Fluvoxamine on NGF-induced neurite outgrowth was significantly antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, we reported that phencyclidine (PCP)-induced cognitive deficits in mice were significantly improved by subsequent subchronic administration of Fluvoxamine, but not sertraline and paroxetine, and that the effect of Fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of NE-100. Moreover, a recent study using the specific sigma-1 receptor ligand [(11)C] SA4503 and positron emission tomography (PET) have demonstrated that an oral administration of Fluvoxamine, but not paroxetine, could bind to sigma-1 receptors in the healthy human brain, in a dose-dependent manner. These findings suggest that sigma-1 receptors might be implicated in the active mechanisms of Fluvoxamine. In this article, the author would like to discuss the novel role of sigma-1 receptors in the active mechanisms of some SSRIs including Fluvoxamine.

Toshio Matsuda - One of the best experts on this subject based on the ideXlab platform.

  • Antidepressant-like effect of coadministration of sulpiride and Fluvoxamine in mice.
    European journal of pharmacology, 2005
    Co-Authors: Toshiya Harasawa, Soichi Itoh, Shigeo Nakamura, Akemichi Baba, Toshio Matsuda
    Abstract:

    We have recently reported that coadministration of sulpiride, an antipsychotic drug, and Fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, selectively increases in vivo dopamine release in the prefrontal cortex. This study examined the effects of coadministration of these drugs on duration of immobility in the tail suspension test using mice. Neither sulpiride (3 or 10 mg/kg) nor Fluvoxamine (10 or 20 mg/kg) alone affected immobility time, whereas coadministration significantly reduced immobility time. WAY 100635, a 5-HT(1A) receptor antagonist, did not affect the effects of sulpiride and Fluvoxamine coadministration, but reduced immobility time in combination with Fluvoxamine (20 mg/kg). A high dose of Fluvoxamine alone (60 mg/kg) also reduced immobility time. These results suggest that the antidepressant-like effects of Fluvoxamine in combination with sulpiride or WAY 100635 in the tail suspension test are mediated by the activation of dopamine or 5-HT systems, respectively.

  • Sulpiride in Combination with Fluvoxamine Increases in vivo Dopamine Release Selectively in Rat Prefrontal Cortex
    Neuropsychopharmacology, 2005
    Co-Authors: Shigeo Nakamura, Akemichi Baba, Toshio Matsuda
    Abstract:

    Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) enhances the release of monoamines such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the prefrontal cortex. To clarify the role of DA-D_2/3 receptors in the combination effect, we examined the effects of coadministration of the selective DA-D_2/3 antagonist sulpiride and the SSRI Fluvoxamine on amine neurotransmitter release in rat prefrontal cortex. Sulpiride (10 mg/kg, i.p.) and Fluvoxamine (10 mg/kg, i.p.) alone did not affect extracellular DA levels, while their coadministration caused a significant increase in DA levels. Sulpiride alone did not affect extracellular levels of 5-HT and NE in the prefrontal cortex, while Fluvoxamine alone caused a marked increase in 5-HT levels and a slight increase in NE levels. Sulpiride did not affect the Fluvoxamine-induced increases in extracellular levels of 5-HT and NE. The DA-D_2/3 antagonist haloperidol (0.1 mg/kg) in combination with Fluvoxamine also caused a selective increase in extracellular DA levels in the cortex. Coadministration of sulpiride and Fluvoxamine did not affect extracellular DA levels in the striatum. Combination of systemic sulpiride and local Fluvoxamine did not increase the DA levels, but that of systemic Fluvoxamine with local sulpiride increased. The combination effect in increasing prefrontal DA levels was antagonized systemically, but not locally, by the 5-HT_1A antagonist WAY100635 at a low dose. These findings suggest that the combination of prefrontal DA-D_2/3 receptor blockade and 5-HT_1A receptor activation in regions other than the cortex plays an important role in sulpiride and Fluvoxamine-induced increase in prefrontal DA release.

Jun Nakamura - One of the best experts on this subject based on the ideXlab platform.

  • Grapefruit juice-Fluvoxamine interaction--is it risky or not?
    Journal of clinical psychopharmacology, 2003
    Co-Authors: Hiroko Hori, Reiji Yoshimura, Nobuhisa Ueda, Koji Shinkai, Takeshi Terao, Seiji Eto, Shinichi Sakata, Osamu Ohmori, Jun Nakamura
    Abstract:

    To the Editors:One of the selective serotonin reuptake inhibitors, Fluvoxamine, is eliminated predominantly by oxidation through cytochrome P 450 (CYP). 1 Because Fluvoxamine exhibits nonlinear kinetics, it is possible that the disposition of Fluvoxamine is involved in a complex metabolic pathway. 2

  • Interaction between Fluvoxamine and cotinine or caffeine.
    Neuropsychobiology, 2002
    Co-Authors: Reiji Yoshimura, Nobuhisa Ueda, Jun Nakamura, Seiji Eto, Masakazu Matsushita
    Abstract:

    We examined the relationships between plasma Fluvoxamine concentrations and plasma levels of cotinine and caffeine, respectively, under steady-state conditions in 30 patients who met DSM-IV criteria for a major depressive disorder and who were being treated with Fluvoxamine. The daily dosages of Fluvoxamine ranged from 50 to 200 mg (mean ± SD 108 ± 42 mg). Eleven patients were smokers and the remaining 19 were nonsmokers. The plasma Fluvoxamine concentrations were significantly higher in nonsmokers (0.92 ± 0.40 ng/ml/mg) than in smokers (0.56 ± 0.28 ng/ml/mg); in addition, a trend towards negative correlations was observed between the plasma Fluvoxamine concentrations and the plasma cotinine levels, although it was not significant. Significant positive correlations were found between the plasma Fluvoxamine concentrations and the plasma caffeine levels. These findings are compatible with those in earlier reports that cytochrome P450 1A2 plays a major role in Fluvoxamine metabolism.

  • Characteristics of Fluvoxamine-induced nausea.
    Psychiatry research, 2001
    Co-Authors: Nobuhisa Ueda, Reiji Yoshimura, Koji Shinkai, Takeshi Terao, Jun Nakamura
    Abstract:

    Abstract We investigated the association between Fluvoxamine and nausea from various viewpoints. The incidence of nausea induced by Fluvoxamine was 29% (12/41). Plasma 5-hydroxyindoleacetic acid (p5-HIAA) levels after Fluvoxamine administration were significantly higher in patients with nausea (6.6±3.4 ng/ml) than in those without nausea (3.5±2.7 ng/ml). On the other hand, no significant differences were found between patients with and patients without nausea in terms of sex, age, initial and maximum dosages of Fluvoxamine and its plasma concentrations, and clinical response to Fluvoxamine. However, the incidence of nausea in patients who were initially administered Fluvoxamine at under 50 mg/day was significantly lower than in those who were started at above 50 mg/day. In addition, mosapride, a member of the benzamide family, was effective in alleviating Fluvoxamine-induced nausea. These results suggest that Fluvoxamine-induced nausea is associated with hyperactivity in serotonergic neurons.

  • Increased libido in a woman treated with Fluvoxamine: a case report.
    Acta psychiatrica Scandinavica, 2001
    Co-Authors: Hiroko Hori, Reiji Yoshimura, Jun Nakamura
    Abstract:

    Objective: The aim of this paper is to describe a case of increased libido during Fluvoxamine therapy. Method: Single case report. Results: The patient, a 27-year-old married Japanese woman with borderline personality disorder, developed an increased libido with the administration of Fluvoxamine. The increased libido disappeared after Fluvoxamine was discontinued. Conclusion: The present findings suggest that Fluvoxamine can cause increased libido in some patients.

  • low dosage of levomepromazine did not increase plasma concentrations of Fluvoxamine
    International Clinical Psychopharmacology, 2000
    Co-Authors: Reiji Yoshimura, Nobuhisa Ueda, Jun Nakamura
    Abstract:

    : The cytochrome enzyme P450 2D6 (CYP2D6) is thought to play a role in the human metabolism of Fluvoxamine. Levomepromazine is a potent inhibitor of CYP2D6. We coadministered a low dosage of levomepromazine and Fluvoxamine in 15 patients and found that the low dosage of levomepromazine was effective in counteracting the Fluvoxamine-induced insomnia and did not increase plasma Fluvoxamine levels. These results suggest that the inhibition of CYP2D6 by levomepromazine has little effect on Fluvoxamine metabolism. Therefore, a low dosage of levomepromazine, used as a hypnotic agent, appears to be effective and safe when coadministered with Fluvoxamine. Since this was a pilot study without a placebo control, a double-blind placebo-controlled study is needed to confirm our preliminary findings.

Rene H Levy - One of the best experts on this subject based on the ideXlab platform.

  • comparison of in vitro and in vivo inhibition potencies of Fluvoxamine toward cyp2c19
    Drug Metabolism and Disposition, 2003
    Co-Authors: Caiping Yao, Kent L Kunze, William F Trager, Evan D Kharasch, Rene H Levy
    Abstract:

    A previous study suggested that Fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by Fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (Ki) values of Fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe.Ki values based on total added Fluvoxamine concentration (Ki,total) and unbound Fluvoxamine concentration (Ki,ub) were calculated, and interindividual variability inKi values was examined in six nonfatty livers. Ki,total values varied with microsomal protein concentration, whereas the correspondingKi,ub values were within a narrow range (70–80 nM). In vivo inhibition constants (Kiiv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving Fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with Fluvoxamine average steady-state concentration with an intercept of 0.85 (r2 = 0.88,p

  • Fluvoxamine theophylline interaction gap between in vitro and in vivo inhibition constants toward cytochrome p4501a2
    Clinical Pharmacology & Therapeutics, 2001
    Co-Authors: Caiping Yao, Isabelle Ragueneau, Kent L Kunze, William F Trager, Evan D Kharasch, Yi Wang, Rene H Levy
    Abstract:

    Objective Several reports indicate that Fluvoxamine decreases the clearance of cytochrome P4501A2 (CYP1A2) substrates. This study compared in vitro and in vivo inhibition potencies of Fluvoxamine toward CYP1A2 with an approach based on inhibition constants (Ki) determined in vitro and in vivo. Methods In vitro inhibition constant values were determined with human liver microsomes and complementary deoxyribonucleic acid-expressed CYP1A2 (supersomes). Fluvoxamine in vivo inhibition constants (Kiiv) for CYP1A2 were obtained from an investigation of single-dose theophylline (250 mg) disposition in 9 healthy volunteers receiving steady-state (9 days) Fluvoxamine at 3 doses (0, 25, or 75 mg/d) in a randomized crossover design. Results In vitro Ki values based on total inhibitor concentrations were 177 ±56 nmol/L, 121 ±21 nmol/L, and 52 ±13 nmol/L in human liver microsomes with 1 mg/ml protein and 0.5 mg/ml protein and in supersomes with 0.3 mg/ml protein, respectively. The corresponding in vitro Ki values based on unbound Fluvoxamine concentrations were 35 nmol/L, 36 nmol/L, and 36 nmol/L. The ratio of 1-methyluric acid formation clearances (control/inhibited) in 8 subjects was positively correlated with Fluvoxamine concentration (r2 = 0.87; P < .001) with an intercept near 1. Mean values for Kiiv based on total and unbound plasma concentrations at steady state were 25.3 nmol/L (range, 14–39 nmol/L) and 3.6 nmol/L (range, 2.4–5.9 nmol/L), respectively. Conclusion Comparison of in vitro and in vivo Ki values based on unbound Fluvoxamine concentrations suggests that Fluvoxamine inhibition potency is approximately 10 times greater in vivo than in vitro. Clinical Pharmacology & Therapeutics (2001) 70, 415–424; doi: 10.1016/S0009-9236(01)62844-3

  • Fluvoxamine-theophylline interaction
    Clinical pharmacology and therapeutics, 2001
    Co-Authors: Caiping Yao, Isabelle Ragueneau, Kent L Kunze, William F Trager, Evan D Kharasch, Yi Wang, Rene H Levy
    Abstract:

    Objective Several reports indicate that Fluvoxamine decreases the clearance of cytochrome P4501A2 (CYP1A2) substrates. This study compared in vitro and in vivo inhibition potencies of Fluvoxamine toward CYP1A2 with an approach based on inhibition constants (Ki) determined in vitro and in vivo. Methods In vitro inhibition constant values were determined with human liver microsomes and complementary deoxyribonucleic acid-expressed CYP1A2 (supersomes). Fluvoxamine in vivo inhibition constants (Kiiv) for CYP1A2 were obtained from an investigation of single-dose theophylline (250 mg) disposition in 9 healthy volunteers receiving steady-state (9 days) Fluvoxamine at 3 doses (0, 25, or 75 mg/d) in a randomized crossover design. Results In vitro Ki values based on total inhibitor concentrations were 177 ±56 nmol/L, 121 ±21 nmol/L, and 52 ±13 nmol/L in human liver microsomes with 1 mg/ml protein and 0.5 mg/ml protein and in supersomes with 0.3 mg/ml protein, respectively. The corresponding in vitro Ki values based on unbound Fluvoxamine concentrations were 35 nmol/L, 36 nmol/L, and 36 nmol/L. The ratio of 1-methyluric acid formation clearances (control/inhibited) in 8 subjects was positively correlated with Fluvoxamine concentration (r2 = 0.87; P < .001) with an intercept near 1. Mean values for Kiiv based on total and unbound plasma concentrations at steady state were 25.3 nmol/L (range, 14–39 nmol/L) and 3.6 nmol/L (range, 2.4–5.9 nmol/L), respectively. Conclusion Comparison of in vitro and in vivo Ki values based on unbound Fluvoxamine concentrations suggests that Fluvoxamine inhibition potency is approximately 10 times greater in vivo than in vitro. Clinical Pharmacology & Therapeutics (2001) 70, 415–424; doi: 10.1016/S0009-9236(01)62844-3