paroxetine, Paxil
Synthesis of the major metabolites of paroxetine.

Segura M, Roura L, de la Torre R, Joglar J.

Pharmacology Research Unit, IMIM, 08003 Barcelona, Spain.

Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12818234&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Quantitative determination of paroxetine and its 4-hydroxy-3-methoxy metabolite in plasma by high-performance liquid chromatography/electrospray ion trap mass spectrometry: application to pharmacokinetic studies.

Segura M, Ortuno J, Farre M, Pacifici R, Pichini S, Joglar J, Segura J, de la Torre R.

Institut Municipal d'Investigacio Medica (IMIM), Barcelona, Spain.

A high-performance liquid chromatography (HPLC) method with tandem mass spectrometric detection is described for the determination of paroxetine, an antidepressant drug, and its metabolite (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine (HM paroxetine) in human plasma. Plasma samples were hydrolysed with hydrochloric acid and then analytes were extracted with ethyl acetate at alkaline pH. Extracts were analysed by HPLC coupled to an atmospheric pressure ionisation-electrospray (ESI) interface and an ion trap mass spectrometer. Chromatography was performed on a reversed-phase column using acetonitrile/0.02% formic acid (66:34, v/v) as a mobile phase. The mass spectrometer was operated in the multiple reaction monitoring mode. The method was validated over concentration ranges of 0.75-100 microg/L and 5-100 microg/L for paroxetine and HM paroxetine, respectively. Mean recoveries of 77% for paroxetine and 76% for HM paroxetine were found, with precision always better than 15%. The limits of detection and quantification were 0.20 and 0.70 microg/L for paroxetine, and 0.70 and 2.20 microg/L for its metabolite. The method was applied to the analysis of plasma samples obtained from nine healthy male volunteers administered with a single oral dose of 20 mg paroxetine. After the 20-mg dose, the mean peak plasma concentration was 8.60 microg/L for paroxetine and 92.40 microg/L for HM paroxetine showing a tenfold ratio between the metabolite and the parent drug along the entire time-concentration curve. Copyright 2003 John Wiley & Sons, Ltd.

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paroxetine, Paxil
Paroxetine: new indication. In generalised anxiety: uncertain efficacy.

[No authors listed]

(1) Generalised anxiety is defined as overwhelming anxiety lasting at least 6 months. (2) Psychological treatment should be tried first. When the patient fails to cope the first-line drug is a benzodiazepine such as diazepam, prescribed for a short period. (3) In France, generalised anxiety has now been added to the licensed indications of paroxetine, a "selective" serotonin reuptake inhibitor antidepressant. Two placebo-controlled trials lasting 8 weeks showed a moderate improvement on the Hamilton anxiety score. Another trial showed no significant difference between the paroxetine and placebo groups. The clinical relevance of this improvement is unclear, however, and the trials suffered from methodological biases. Paroxetine has not been reliably compared with benzodiazepines, psychotherapy or buspirone in patients with generalised anxiety. (4) One trial showed 11% relapse in the paroxetine group and 40% in the placebo group during the 6 months following paroxetine withdrawal, among patients who had initially responded; once again, however, methodological flaws undermine these data. (5) The adverse effect profile of paroxetine in generalised anxiety is similar to its profile in other patients: in particular potentially serious drug interactions and withdrawal symptoms when treatment is stopped abruptly. (6) In practice, the standard drug therapy for generalised anxiety is a benzodiazepine such as diazepam. Paroxetine, whose clinical efficacy remains to be established in this setting, offers no tangible therapeutic advance.

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paroxetine, Paxil
Serotonin transporter and MAO-B levels in monoamine nuclei of the human brainstem are normal in major depression.

Klimek V, Roberson G, Stockmeier CA, Ordway GA.

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216, USA.

Neurochemical imbalance between noradrenergic and serotonergic systems has been postulated to underlie the pathophysiology of psychiatric illnesses involving mood disorders. The present study was designed to examined the possibility that serotonergic innervation of the locus coeruleus (LC) is abnormal in major depression, by measuring two proteins expressed by serotonergic neurons, but not by noradrenergic neurons, in the region of the LC. The specific binding of [(3)H]paroxetine to serotonin transporter (SERT) and of [(3)H]lazabemide to monoamine oxidase (MAO-B) were measured autoradiographically in tissue sections cut transversely at multiple levels along the rostro-caudal extent of the LC, as well as in the caudal portion of the dorsal raphe nucleus, from psychiatrically normal subjects and age-matched subjects with major depression. Under the conditions of the assays, [(3)H]paroxetine binding in the LC was specific for the SERT, based on the rank order of affinity of compounds for inhibiting [(3)H]paroxetine binding in the LC, i.e. citalopram > imipramine > desipramine > mazindol. The binding of [(3)H]paroxetine to SERT and [(3)H]lazabemide to MAO-B were higher in the raphe nuclei than in the LC. Comparison of control subjects to major depressive subjects revealed no differences in the amount of [(3)H]paroxetine binding to SERT and [(3)H]lazabemide to MAO-B in the LC, as well as in the raphe nuclei. These findings imply that serotonergic innervation of the LC is intact in major depression.

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paroxetine, Paxil
Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats.

Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E.

Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Krakow, Poland.

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.

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paroxetine, Paxil
Effect of combined treatment with paroxetine and transcranial magnetic stimulation (TMS) on the mitogen-induced proliferative response of rat lymphocytes.

Roman A, Vetulani J, Nalepa I.

Laboratory of Intracellular Signalling, Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Krakow, Poland. roman if-pan.krakow.pl

Depression is associated with abnormal functions of the immune system. In this study, we investigated how two modem antidepressant therapies, chronic treatment with transcranial magnetic stimulation (TMS) and administration of an antidepressant belonging to selective serotonin reuptake inhibitors (SSRI), paroxetine, affect the proliferative response of thymocytes and splenocytes stimulated in vitro with various mitogens. Paroxetine (10 mg/kg) and TMS (B = 1.2 T, f = 30 Hz, t = 330 s) were applied once daily for 12 consecutive days, while, if given jointly paroxetine was injected 30 min before TMS. The mitogens used were: concanavalin A (Con A), pokeweed mitogen (PWM) or lipopolysaccharide (LPS). While either treatment applied alone had no effect on proliferative response, the joint application of paroxetine and TMS significantly depressed it. The literature data suggest that pulsed magnetic field may directly inhibit mitogen-activated lymphocyte proliferation, which is also inhibited by the presence of high level of serotonin. The present results suggest that both effects are additive, and because of that application of both treatments, whose effects alone are insufficient to prompt the reaction, possibly because adaptive changes during chronic treatment, results in a significant inhibition of lymphocyte proliferation.

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paroxetine, Paxil
Pindolol and the acceleration of the antidepressant response.

Plenge P, Mellerup ET.

Laboratory of Neuropsychiatry, Righospitalet-6102, DK-2100, Copenhagen, Denmark. pp6102 rh.dk

BACKGROUND: It has been suggested that treatment with selective serotonin reuptake inhibitors (SSRIs) in combination with pindolol, a partial agonist at the 5-HT(1A) receptor, may produce a fast antidepressant response. However, inconsistent results have been obtained in clinical studies with combination of the two drugs. Some studies, most using paroxetine, show an acceleration of the antidepressant response, whereas studies with other SSRIs find no marked latency reduction. METHODS: The free SSRI concentration in patients either receiving the first dose, or in steady state treatment with the five different SSRIs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline was estimated using pharmacokinetic data for the individual drugs. RESULTS: Due to differences between the drugs regarding protein binding, distribution volume and affinity for the 5-HT transporter (5-HTT), the 5-HT uptake inhibition obtained with clinically relevant doses differs markedly among the SSRIs. CONCLUSIONS: A nearly complete blockade of the 5-HTT is obtained already after the first dose only with paroxetine, explaining why the latency reducing effect of pindolol preferentially is seen when pindolol is combined with paroxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12880941&dopt=Abstract paroxetine, Paxil, Paxil CR