Official internet pharmacy in Sydney where you can buy propecia australia online. Para compra cialis puede ser visto como un desafío. Aumenta Smomenta, y todos los que se poco a poco abrumado, como es lógico, cada vez más hombres están diagnosticados con disfunción eréctil.


Effect of fluvoxamine on plasma risperidone concentrations Concetta D’Arrigo , Gaetana Migliardi , Vincenza Santoro , Letterio Morgante , Maria Rosaria Muscatello , Maria Ancione , Edoardo Spina a Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Policlinico Universitario di Messina, Via Consolare Valeria, 98125 Messina, Italy b Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina, Messina, Italy c Centers of Mental Health, Azienda USL 5, Messina, Italy Abstract
The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day,was administered for 4 weeks to patients stabilized on risperidone (3–6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidoneand the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administrationwith fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initialfluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of fivesubjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developedextrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significantchanges in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a resultof a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.
Keywords: Risperidone; 9-Hydroxyrisperidone; Fluvoxamine; Drug interaction; CYP2D6; CYP3A4 1. Introduction
vivo and in vitro studies, cytochrome P450 (CYP) enzymesCYP2D6 and, to a lesser extent, CYP3A4 are responsible for Risperidone is a second-generation antipsychotic drug the 9-hydroxylation of risperidone As 9-OH-risperidone with potent antagonistic properties at serotonin 5-HT2A and is approximately equipotent with the parent drug in terms of dopamine D2 receptors agent is effective in the treat- dopamine receptor affinity, the total risperidone active moiety ment of both positive and negative symptoms and, possibly, (risperidone plus 9-OH-risperidone) is regarded to contribute other symptom dimensions in schizophrenia and has a lower to the overall antipsychotic effect It is well documented potential to cause extrapyramidal symptoms compared with that co-administration of CYP2D6 inhibitors or CYP3A4 conventional antipsychotics However, like first-generation inhibitors/inducers may affect total plasma risperidone concen- antipsychotics, risperidone can induce an increase in serum pro- trations with potential clinical implications n this respect, it has been reported that concomitant treatment with fluoxetine or Risperidone is extensively metabolized in the liver, pri- paroxetine, selective serotonin reuptake inhibitors (SSRIs) with marily by 9-hydroxylation, yielding an active metabolite 9- potent inhibitory activity on CYP2D6, may cause a significant hydroxyrisperidone (9-OH-risperidone) According to in elevation in the plasma concentrations of the active fraction ofrisperidone, possibly associated with occurrence or worseningof extrapyramidal side effects ∗ Corresponding author. Tel.: +39 090 2213647; fax: +39 090 2213300.
Fluvoxamine is a selective serotonin reuptake inhibitor E-mail address: (E. Spina).
(SSRI) widely used in the treatment of depression and other psy- chiatric disorders e other SSRIs, fluvoxamine may be co-administered with antipsychotics in schizophrenic patientswith concomitant depressive or negative symptoms Flu- Steady-state plasma concentrations of risperidone and 9-OH- voxamine interacts with several CYP isoenzymes in vitro: it risperidone were measured by HPLC according to the method is a potent inhibitor of CYP1A2 and CYP2C19 and a mod- of Avenoso et al. The limit of quantification of the assay erate inhibitor of CYP2C9 and CYP3A4, while it affects was 2 ng/mL for both analytes. As analytical method allows co- only slightly CYP2D6 activity Due to this non- extraction of fluvoxamine, its detection in the chromatogram selective inhibition of various CYP isoenzymes, fluvoxamine was used as a measure of compliance.
has a high potential for metabolic drug interactions in vivo Aim of the present study was to investigate the effect of fluvoxamine on steady-state plasma concentrations of risperi- Plasma concentrations of risperidone, 9-OH-risperidone and done and 9-OH-risperidone in patients with schizophrenia given their sum (active moiety) before and during fluvoxamine admin- fluvoxamine in addition to an ongoing treatment with risperi- istration were compared by the Student’s t-test with Bonfer- roni’s correction for multiple comparisons. Changes in plasmarisperidone/9-OH-risperidone ratio and in SAS scores before 2. Patients and methods
and during fluvoxamine treatment were compared by theWilcoxon signed-rank test. Results are given in the text as mean ± S.D. A P-value < 0.05 was regarded as statistically sig-nificant.
Eleven outpatients (seven men and four women, aged 26–51 years) participated in the study. They had a diagnosis of 3. Results
schizophrenia according to DSM IV and were stabilized onrisperidone. The protocol was approved by a local Ethics Com- Demographic data of the patients participating to the study mittee and written informed consent was obtained from the and individual plasma concentrations of risperidone, 9-OH- risperidone and active moiety before and during fluvoxamineaugmentation are reported in After 4 weeks of fixed fluvoxamine dose, six patients were maintained on the flu-voxamine dose of 100 mg/day, while the dose was increased All patients, stabilized on risperidone, at a constant dosage to 200 mg/day in the other five subjects. Mean plasma con- (3–6 mg/day, given as two divided daily administrations) for at centrations of risperidone, 9-OH-risperidone and active moi- least 4 weeks, received adjunctive fluvoxamine to treat resid- ety were not significantly modified during the first 4 weeks ual negative symptoms, concomitant depression or both. Flu- of fluvoxamine coadministration (with all patients receiving voxamine was administered at a dose of 100 mg/day orally the dose of 100 mg/day). At week 8, in the six patients sta- in the evening for 4 consecutive weeks. At the end of week bilized on 100 mg/day, plasma concentrations of risperidone 4, the dose of fluvoxamine could be adjusted by the treat- and metabolically derived 9-OH-risperidone did not differ from ing physician on the basis of the individual response and then values at baseline and at week 4, so that levels of the active maintained until the end of week 8. The dosage of risperi- moiety remained unchanged. In the five patients on a final done was kept constant throughout the duration of the study, dose of 200 mg/day, mean plasma concentrations of risperi- and use of other drugs known to act as inhibitors or induc- done increased significantly (P < 0.05) from 7 ± 2 ng/mL at ers of risperidone metabolism was not allowed. Concomitant baseline to 9 ± 2 ng/mL at week 4, and to 13 ± 4 ng/mL at treatment with other medication, when present, also remained week 8, whereas levels of 9-OH-risperidone were not signif- icantly affected. As a consequence, mean concentrations of Blood samples for pharmacokinetic evaluations were drawn risperidone active moiety increased significantly (P < 0.05) from into heparinized tubes at 8:00 a.m. (12–13 h after the last dose 46 ± 6 ng/mL at baseline to 50 ± 5 ng/mL at week 4, and to of risperidone and fluvoxamine and immediately before the 58 ± 11 ng/mL at week 8 of fluvoxamine co-administration.
morning risperidone dose) in the week before starting flu- Moreover, in this subgroup of subjects, plasma risperidone/9- voxamine (baseline) and after 4 and 8 weeks of fluvoxamine OH-risperidone ratios increased significantly (P < 0.05) dur- co-administration. The plasma was separated immediately and ing fluvoxamine cotreatment from 0.16 ± 0.05 at baseline to Tolerability was assessed by interview and a medical exam- No symptoms ascribed to risperidone toxicity were observed ination at baseline and after 4 and 8 weeks of combination throughout the overall study period. No patient developed therapy, while extrapyramidal side effects were specifically eval- extrapyramidal side effects during adjunctive fluvoxamine treat- uated at the same times by using the Simpson and Angus Scale ment and SAS scores remained substantially unchanged during (SAS) Because of the uncontrolled design, the small and adjunctive therapy. Two patients complained of oversedation and heterogeneous sample, the clinical efficacy of the combination one of mild nausea during the first few days of fluvoxamine Table 1Demographic data and plasma concentrations of risperidone, 9-OH-risperidone and active moiety before and during fluvoxamine treatment in 11 patients withschizophrenia b Mean values at week 8 were not reported as patients were receving different fluvoxamine daily doses.
4. Discussion
trations needs to be investigated by a complete pharmacokineticstudy.
Augmentation of SSRIs to risperidone is relatively com- The results of the present investigation are substantially mon and proposed for the treatment of depressive and negative in line with previous findings indicating that fluvoxamine, at symptoms of schizophrenia Moreover, risperidone may its usually effective dose of 100 mg/day, has a low poten- be added to SSRIs to improve response in patients with major tial for CYP2D6-mediated drug interactions In this depression or obsessive-compulsive disorder owever, respect, in vitro research has demonstrated that fluvoxam- these combinations may result in clinically relevant pharmacoki- ine has a weaker inhibitory effect on CYP2D6 activity as netic interactions as a consequence of the differential inhibitory compared to other SSRIs such as fluoxetine, norfluoxetine effects of SSRIs on CYP enzymes n this respect, formal and paroxetine Consistent with this, fluvoxamine, kinetic studies in patients with schizophrenia have reported that 100 mg/day, has been reported to have relatively modest in paroxetine and fluoxetine increased plasma concentrations of vivo effects on CYP2D6 substrates such as dextromethorphan risperidone active moiety by 45 and 75%, respectively, sertraline desipramine To explain the minimal elevation caused a minimal, dose-dependent elevation of total risperidone in total plasma risperidone levels and the associated increase concentrations, while citalopram did not modify significantly in risperidone/9-OH-risperidone ratio in the subgroup of sub- the plasma levels of risperidone and its metabolite jects receiving the highest fluvoxamine dose, it can be specu- With regard to other newer antidepressants, reboxetine and mir- lated a dose-dependent inhibitory effect of fluvoxamine on the tazapine do not cause significant modifications of plasma con- 9-hydroxylation of risperidone, presumably mediated by inhi- centrations of risperidone active fraction bition of CYP2D6 and/or CYP3A4. In fact, fluvoxamine is a In the current study, a 4-week addition of fluvoxamine, at moderate inhibitor of CYP3A4 which plays a role in the doses of 100 mg/day, to pre-existing risperidone therapy was biotransformation of risperidone On the other hand, the associated with no significant changes in plasma concentrations observation that in these subjects the levels of 9-OH-metabolite of risperidone, 9-OH-risperidone and the active moiety. How- did not decrease as a result of the interaction may be explained ever, while in the six patients stabilized on 100 mg/day plasma by assuming that fluvoxamine also inhibited the further bio- levels of risperidone and its metabolite were still unchanged transformation of 9-OH-risperidone and/or affected alternative at week 8, in the five patients receiving the highest dose of routes of risperidone metabolism, such as N-dealkylation or 7- fluvoxamine, 200 mg/day, plasma concentrations of risperidone were almost doubled at final evaluation as compared to baseline, While fluvoxamine appears to affect minimally and in a dose- while levels of the metabolite were substantially unchanged. As dependent manner the elimination of risperidone, it should be a result, a slight, but significant increase (by a mean 26%) in pointed out that this agent, already at the dose of 100 mg/day, plasma concentration of risperidone active fraction was observed may cause a significant elevation of plasma concentration of var- in this subgroup of patients at week 8 as compared to pretreat- ious antipsychotics, such as haloperidol (1.8–4.2-fold increase), ment values. However, due to the limited number of patients clozapine (up to 5–10-fold) and olanzapine (up to 2-fold), due treated with the highest fluvoxamine dose, our findings can be to its potent inhibitory effect on CYP1A2, CYP2C19 and, to a regarded as preliminary and the reported evidence of a dose- lesser extent, CYP3A4, the major CYP isoforms involved in the dependent effect of fluvoxamine on plasma risperidone concen- The combination risperidone-fluvoxamine was safe and well [13] Wilde MI, Plosker GL, Benfield P. Fluvoxamine: an updated review tolerated and no patient experienced extrapyramidal symptoms.
of its pharmacology, and therapeutic use in depressive illness. Drugs However, it should be underlined that the concentrations of [14] Silver H. Selective serotonin reuptake inhibitor augmentation in the treat- risperidone active fraction reached at final evaluation by one of ment of negative symptoms in schizophrenia. Int Clin Psychopharmacol the patients on the highest fluvoxamine dose were close to the threshold values (around 70–80 ng/mL) more frequently associ- [15] Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 In conclusion, our findings indicate that augmentation (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol1992;34:262–5.
of risperidone therapy with fluvoxamine at dosages up to [16] Brosen K, Skielbo E, Rasmussen BB, Poulson HE, Loft S. Fluvoxam- 100 mg/day is not associated with clinically significant changes ine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol in plasma risperidone concentrations. However, in consideration of a dose-dependent elevation of total risperidone levels, careful [17] Xu ZH, Xie HG, Zhoou HH. In vivo inhibition of CYP2C19 but not clinical observation and monitoring of plasma risperidone levels CYP2D6 by fluvoxamine. Br J Clin Pharmacol 1996;42:518–21.
[18] Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Shader RI. Inhi- may be of value in the management of patients receiving higher bition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylaton. Br J Clin Pharmacol 1997;44:495–8.
[19] Shad MU, Preskorn SH. Antidepressants. In: Levy RH, Thummel KE, Acknowledgement
Trager WF, Hansten PD, Eichelbaum M, editors. Metabolic drug inter-actions. Philadelphia: Lippincott Williams & Wilkins; 2000. p. 563– Supported by grants from the University of Messina (PRA [20] Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol 2003;17:517–38.
[21] Simpson GM, Angus JWS. Drug-induced extrapyramidal disorders. Acta References
Psychiatr Scand 1970;212(Suppl.):11–9.
[22] Avenoso A, Facciol`a G, Salemi M, Spina E. Determination of risperi- [1] Chouinard G, Arnott W. Clinical review of risperidone. Can J Psychiatry done and its major metabolite 9-hydroxyrisperidone in human plasma by reversed-phase liquid chromatography with ultraviolet detection. J [2] Brunelleschi S, Zeppegno P, Risso F, Cattaneo CI, Torre E. Risperidone- associated hyperprolactinemia: evaluation in twenty psychiatric outpa- [23] Ostroff RB, Nelson JC. Risperidone augmentation of selective sero- tients. Pharmacol Res 2003;48:405–9.
tonin reuptake inhibitors in major depression. J Clin Psychiatry 1999; [3] Mannens G, Huang ML, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J. Absorption, metabolism and excretion of risperidone in [24] McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A humans. Drug Metab Dispos 1993;21:1134–41.
double-blind, placebo-controlled study of risperidone addition in sero- [4] Huang ML, van Peer A, Woestenborghs R, De Coster R, Heykants J, tonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Jansen AA, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharma- [25] Lane RM. Pharmacokinetic drug interaction potential of selective sero- tonin reuptake inhibitors. Int Clin Psychopharmacol 1996;11(Suppl.
[5] Scordo MG, Spina E, Facciol`a G, Avenoso A, Johansson I, Dahl ML. Cytochrome P450 2D6 genotype and steady-state plasma levels [26] Spina E, D’Arrigo C, Migliardi G, et al. Plasma risperidone concen- of risperidone and 9-hydroxyrisperidone. Psychopharmacology 1999; trations during combined treatment with sertraline. Ther Drug Monit [6] Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9- [27] Avenoso A, Facciol`a G, Scordo MG, Gitto C, Drago Ferrante G, Madia hydroxyrisperidone by human cytochrome P450 2D6 and 3A4. Naunyn- A, et al. No effect of citalopram on plasma levels of clozapine, risperi- Schmiederberg’s Arch Pharmacol 1999;359:147–51.
done and their active metabolites in patients with chronic schizophrenia.
[7] Yasui-Furukori N, Hidestrand M, Spina E, Facciol`a G, Scordo MG, Tybring G. Different enantioselective 9-hydroxylation of risperidone by [28] Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Levita A.
the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos No effect of reboxetine on plasma concentrations of clozapine, risperi- done and their active metabolites. Ther Drug Monit 2001;23:675– [8] Megens AA, Awouters FH, Schotte A, Meert TF, Dugovic C, Niemegeers CJ, et al. Survey on pharmacodynamics of the new antipsy- [29] Zoccali R, Muscatello MR, La Torre D, Malara G, Canale A, Crucitti D, chotic risperidone. Psychopharmacology 1994;114:9–23.
et al. Lack of pharmacokinetic interaction between mirtazapine and the [9] DeVane CL, Nemeroff CB. An evaluation of risperidone drug interac- newer antipsychotics clozapine, risperidone and olanzapine in patients tions. J Clin Psychopharmacol 2001;21:408–16.
with chronic schizophrenia. Pharmacol Res 2003;48:411–4.
[10] Spina E, Avenoso A, Facciol`a G, Scordo MG, Ancione M, Madia [30] Alfaro CL, Lam YW, Simpson J, Ereshefsky L. CYP2D6 status of exten- A. Plasma concentrations of risperidone and 9-hydroxyrisperidone dur- sive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, ing combined treatment with paroxetine. Ther Drug Monit 2001;23: or sertraline. J Clin Psychopharmacol 1999;19:155–63.
[31] Spina E, Pollicino AM, Avenoso A, Campo GM, Caputi AP, Perucca [11] Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, et E. Effect of fluvoxamine on the pharmacokinetics of imipramine al. Inhibition of risperidone metabolism by fluoxetine in patients with and desipramine in healthy subjects. Ther Drug Monit 1993;15:243– schizophrenia: a clinically relevant pharmacokinetic drug interaction. J Clin Psychopharmacol 2002;22:419–23.
[32] Daniel DG, Randolph C, Jaskiw G, Handel S, Williams T, Abi-Dargham [12] Bondolfi G, Eap CB, Bertschy G, Zullino D, Vermeulen A, Bau- A, et al. Coadministration of fluvoxamine increases serum concentrations mann P. The effect of fluoxetine on the pharmacokinetics and safety of haloperidol. J Clin Psychopharmacol 1994;14:340–3.
of risperidone in psychotic patients. Pharmacopsychiatry 2002;35:50– [33] Jerling M, Lindstrom L, Bondesson U, Bertilsson L. Fluvoxamine inhi- bition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit pharmacokinetic interactions and clinical effects. J Clin Psychopharma- [34] Hiemke C, Weighmann H, Hartter S, Dahmen N, Wetzel H, Muller H.
[36] Spina E, Avenoso A, Facciol`a G, Salemi M, Scordo MG, Ancione M, et Elevated serum levels of clozapine after addition of fluvoxamine. J Clin al. Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psy- [35] Hiemke C, Avi P, Jabarin M, Hadjez J, Weigmann H, Hartter S, et al. Fluvoxamine augmentation of olanzapine in chronic schizophrenia :


REPRODUCED FROM IMS PHARMA PRICING & REIMBURSEMENT, AUGUST 2009 I n n ova t i ve Pricing Ag reements to Enhance Access Pro s p e c t s IN THE FACE OF RISING DEMAND FOR INCREASINGLY“In some count r ie s, risk-sharing is becoming popular becauseEXPENSIVE HEALTHCARE PRODUCTS AND SERVICES,there is a common desire to make sure that patients getaccess to the medicines they need. As th

J Epidemiol Community Health 2000; 54 :79–80 Treatment with ivermectin: what works in onecommunity may not work in anotherO E Onwujekwe, E N Shu, C C Ndum, P O OkonkwoNigeria is highly endemic for onchocerciasis, Study design and seven million people are infected, 40million at risk of infection and 0.2 million blindstudy sites with an estimated total populationfrom the disease.1 Disea

Copyright © 2010-2014 PDF pharmacy articles