paroxetine, Paxil
Evaluation of [3H]paroxetine as an in vivo ligand for serotonin uptake sites: a quantitative autoradiographic study in the rat brain.

Biegon A, Mathis C.

Division of Research Medicine and Radiation Biophysics, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

Paroxetine, a selective inhibitor of serotonin uptake and an antidepressant, was used in conjunction with quantitative ex vivo autoradiography to study the feasibility of imaging serotonin terminals in the living brain. Tritiated paroxetine was injected in the rat tail vein, and the brain was processed for quantitative autoradiography 3 hours later. Animals received either [3H]paroxetine alone (100 microCi/animal) or a mixture of labeled paroxetine (100 microCi) and an excess of unlabeled drug (0.5 or 2 mg/kg intravenously [i.v.]). Computerized image analysis of the resulting autoradiograms revealed high densities of radioactivity in brain regions known to contain high densities of serotonergic terminals and high specific binding of [3H] paroxetine in vitro, such as the raphe nuclei, interpeduncular nucleus, basolateral amygdala, substantia nigra, and some hypothalamic nuclei. Radioactivity uptake in these brain regions was effectively blocked (50-72%) by coadministration of excess unlabeled paroxetine. However, cortical and hippocampal binding of paroxetine in vivo was moderately high, in contrast to the relatively sparse serotonergic innervation in these regions. Only a relatively small proportion of cortical and hippocampal binding (20-40%) could be blocked by excess unlabeled paroxetine, indicating that most of the radioactivity in these regions is not associated with serotonin terminals or uptake sites. The usefulness of [3H]paroxetine as an in vivo ligand for imaging serotonin terminals in the human brain is limited by these nonserotonergic binding sites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8427010&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Autoradiographic analyses of the effects of estradiol benzoate on [3H]paroxetine binding in the cerebral cortex and dorsal hippocampus of gonadectomized male and female rats.

Mendelson SD, McKittrick CR, McEwen BS.

Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021.

Effects of estradiol benzoate (EB) on [3H]paroxetine binding in dorsal hippocampus and cerebral cortex of gonadectomized male and female rats were evaluated by quantitative autoradiography. EB significantly decreased [3H]paroxetine binding in male and female rats in the oriens layers of CA1-CA4, and in the radiata/lacunosum moleculare layers of CA2 and CA3. Sex differences were also noted, with binding of [3H]paroxetine being significantly lower in female rats in the radiata/lacunosum moleculare layers of CA2 and CA4, and in the suprapyramidal dentate. No significant effects of either EB or sex were noted in the cortex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8431776&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Central serotonergic uptake mechanisms in hypertensive rats: effects of clonidine and centhaquin.

Gulati A, Arora RC, Crayton J.

Department of Pharmacodynamics (m/c 865), University of Illinois, Chicago 60612.

The binding of a highly specific ligand for serotonin (5-HT) uptake sites, [3H]paroxetine, was studied in brain regions of normotensive Wistar-Kyoto rats (WKY) and spontaneous hypertensive rats (SHR). [3H]Paroxetine bound to a single, high affinity binding site in the brain. In midbrain, the density (Bmax values) of [3H]paroxetine binding were significantly reduced (27.16%) in SHR as compared to WKY. The affinity (Kd values) were found to be similar in SHR and WKY. The Kd and Bmax values of [3H]paroxetine binding were found to be similar in spinal cord, pons and medulla and cerebral cortex of WKY and SHR. The effect of centrally acting hypotensive agents, clonidine and centhaquin, on [3H]paroxetine binding was also determined and compared with imipramine, a known 5-HT uptake inhibitor. Clonidine did not displace [3H]paroxetine binding at any concentration (10(-4) to 10(-7) M). On the other hand, centhaquin, which produces hypotension similar to clonidine, could displace [3H]paroxetine binding in a concentration dependent manner. In cerebral cortex and brainstem (midbrain, pons and medulla) membranes, the IC50 values of imipramine and centhaquin for [3H]paroxetine binding were found to be similar in WKY and SHR. The IC50 of centhaquin in displacing paroxetine from 5-HT uptake sites, was 10 times lower in the cerebral cortex and 4 times lower in the brainstem membranes when compared to imipramine. Clonidine had no effect on 5-HT uptake sites. The results indicate that (1) the density of 5-HT uptake sites is reduced in the midbrain of hypertensive rats, and (2) centhaquin, a centrally acting hypotensive agent, acts on 5-HT transporter sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8453971&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine.

Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF.

Department of Clinical Pharmacology, Odense University, Denmark.

Nine extensive metabolizers (EMs) and eight poor metabolizers (PMs) of sparteine took a single oral dose of 100 mg of desipramine HCI before and while taking paroxetine 20 mg per day. Before paroxetine, the median of the total desipramine clearance was 7 times higher in EMs than in PMs (102 and 15 l.h-1 respectively). This confirms that desipramine is extensively metabolized via the sparteine/debrisoquine oxidation polymorphism i.e. by CYP2D6. During paroxetine, the median clearances were 22 l.h-1 and 18 l.h-1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l.h-1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l.h-1 respectively). The increase in this clearance in PMs suggests that paroxetine is an inducer of the alternative, unidentified P450(s) which catalyze(s) the formation of 2-OH-desipramine in this phenotype. Before paroxetine, the median amounts of 2-OH-desipramine glucuronide recovered in urine were 69% and 68% of the total recovery of 2-OH-desipramine in urine in EMs and PMs respectively. During paroxetine, the corresponding values were 77% and 84%.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8513845&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine, a selective serotonin reuptake inhibitor, reduces depressive symptoms and subjective handicaps in patients with dizziness.

Horii A, Mitani K, Kitahara T, Uno A, Takeda N, Kubo T.

Department of Otolaryngology, Osaka University Medical School, Suita, Japan. ahorii ent.med.osaka-u.ac.jp

OBJECTIVE AND STUDY DESIGN: When treating dizzy patients, the psychiatric aspect should be carefully addressed regardless of whether a well-defined organic disease is present. In this prospective study, we aimed to elucidate the role of paroxetine, a selective serotonin reuptake inhibitor, in the treatment of dizziness. SETTING AND PATIENTS: Forty-seven patients who complained of dizziness were treated with 20 mg of paroxetine per day. The depressive state of the patient was evaluated by the Zung Self-Rating Depression Scale (SDS). Treatment outcomes were measured with self-assessment of subjective handicaps in daily life using a dizziness and unsteadiness questionnaire. The questionnaire consisted of five factors related to emotional or bodily dysfunction that could be affected by dizziness. Changes in Self-Rating Depression Scale scores and subjective handicaps were assessed at 4 and 8 weeks after the start of paroxetine. RESULTS: In patients having well-defined organic diseases with high Self-Rating Depression Scale scores, paroxetine improved all five subjective handicap factors as well as Self-Rating Depression Scale scores. The decline in Self-Rating Depression Scale scores showed a significant correlation with improvement of subjective handicaps, which was related to emotional problems but not factors related to bodily dysfunction. Paroxetine was also effective for an improvement of factors related to emotional problems and Self-Rating Depression Scale scores in patients not having organic diseases but with high Self-Rating Depression Scale scores. In patients either with or without organic diseases with low Self-Rating Depression Scale scores, paroxetine had no effect on any subjective handicap factors and Self-Rating Depression Scale scores. CONCLUSION: In the treatment of dizzy patients, paroxetine was effective at relieving subjective handicaps caused by dizziness, specifically, in patients with high Self-Rating Depression Scale scores.

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paroxetine, Paxil
Paroxetine in the treatment of generalised anxiety disorder.

Snyderman SH, Rynn MA, Bellew K, Rickels K.

Mood & Anxiety Disorders Section, Department of Psychiatry, University of Pennsylvania School of Medicine, 3535 Market Street, Suite 670, Philadelphia, PA 19104, USA. steven.snyderman verizon.net

Paroxetine is a selective serotonin re-uptake inhibitor useful in the treatment of a wide range of psychiatric disorders. Generalised anxiety disorder (GAD) is characterised by excessive persistent anxiety and worry about a number of events and activities occurring on more days than not for at least 6 months. GAD is the most common anxiety disorder in primary care settings. Paroxetine was the second antidepressant to receive an FDA indication for the treatment of GAD. In contrast to benzodiazepines, which had been the mainstay of treatment for anxiety disorders for many years, antidepressants, such as paroxetine, are more effective for the psychic symptoms of anxiety, which include worry, tension, irritability and concentration difficulties, and carry a more tolerable and safe side effect profile.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15264994&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
NMR studies of the inclusion complex between beta-cyclodextrin and paroxetine.

Bernini A, Spiga O, Ciutti A, Scarselli M, Bottoni G, Mascagni P, Niccolai N.

Biomolecular Structure Research Center and Department of Molecular Biology, University of Siena, via Fiorentina 1, 53100 Siena, Italy. andrea.bernini unisi.it

A 1H and 13C NMR study on the inclusion complex of paroxetine with beta-cyclodextrin was carried out in order to define the stoichiometry of the association and its strength. Proton and carbon chemical shift measurements of paroxetine and beta-cyclodextrin were performed at several molar ratios and temperatures, allowing the determination of a 1:1 stoichiometry and an association constant value of the order of 2 x 10(3) for the paroxetine-beta-cyclodextrin complex. Overhauser effects in the rotating frame were also measured, and the experimental interproton distance constraints have been used for molecular model building of the complex. The obtained model indicates that the benzodioxolyl moiety of paroxetine is deeply inserted in the cavity of the cylindrical structure of beta-cyclodextrin, while the fluoro-phenyl ring lays above the wider rim.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15265514&dopt=Abstract paroxetine, Paxil, Paxil CR