paroxetine, Paxil
Comparison of some effects of paroxetine with amitriptyline on the cardiovascular system in animals.

Hamilton TC, Norton J, Poyser RH, Thormahlen D.

The effects of intravenous infusions of paroxetine, a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, amitriptyline, on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, paroxetine was less cardiotoxic than amitriptyline in both species. Thus, paroxetine has the advantage over amitriptyline of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than amitriptyline in tests for antidepressant activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2939838&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
High affinity binding of 3H-paroxetine and 3H-imipramine to rat neuronal membranes.

Mellerup ET, Plenge P.

Paroxetine is the most potent and one of the most specific serotonin uptake inhibitors. High-affinity 3H-paroxetine and 3H-imipramine binding was compared in rat neuronal membranes. The KD value for 3H-paroxetine binding to neuronal membranes was 0.08 nM, which is exactly the same value as with platelet membranes. The KD value for 3H-imipramine binding to neuronal membranes was about 4 nM, which is higher than the KD value for 3H-imipramine binding to platelet membranes (0.5 nM). The results indicated that the 3H-paroxetine binding site is identical in neuronal membranes and in platelet membranes; this binding site is probably located on the serotonin transport mechanism. In addition, part of the high-affinity 3H-imipramine binding to neuronal membranes is probably located on the serotonin transport mechanism, but another part is located elsewhere. Furthermore the polypeptides containing the 3H-imipramine binding sites may not be identical in neuronal and platelet membranes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2944152&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of chronic treatment with selective monoamine oxidase inhibitors and specific 5-hydroxytryptamine uptake inhibitors on [3H]paroxetine binding to cerebral cortical membranes of the rat.

Graham D, Tahraoui L, Langer SZ.

Department of Biology, Laboratoires d'Etudes et de Recherches Synthelabo (L.E.R.S.), Paris, France.

[3H]Paroxetine is a highly selective ligand for the 5-hydroxytryptamine transporter complex and the specific binding of this ligand to membrane fractions from cerebral cortex or hippocampus was studied in rats treated with specific inhibitors of the uptake of 5-hydroxytryptamine and monoamine oxidase inhibitors. The Kd and Bmax of the binding of [3H]paroxetine to cerebral cortical membranes of the rat was unaffected, compared to sham controls, by either acute or chronic administration with citalopram or chlorimipramine. Also, chronic treatment with chlorimipramine did not alter the parameters of the binding of [3H]paroxetine to hippocampal membranes from the rat compared to sham controls. Furthermore, chronic and acute treatments with clorgyline or deprenyl did not produce any significant changes in the Kd and Bmax of the binding of [3H]paroxetine to cerebral cortical membranes in the rat. These findings on the binding of [3H]paroxetine are discussed in light of previous equivocal results on the plasticity of neuronal binding sites for [3H]imipramine after various pharmacological treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2958720&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytryptamine uptake inhibitor.

Thomas DR, Nelson DR, Johnson AM.

Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.

Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine has little affinity for alpha 1, alpha 2 or beta adrenoceptors, dopamine (D2), 5-HT1, 5-HT2 or histamine (H1) receptors at concentrations below 1000 nM. Paroxetine demonstrated weak affinity for muscarinic receptors (Ki = 89 nM) but was at least 15 fold weaker than amitriptyline (Ki = 5.1 nM). Paroxetine, therefore, provides a useful pharmacological tool for investigating 5-HT systems and furthermore should be an antidepressant with reduced tricyclic-like side-effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2962217&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Cardiovascular effects of paroxetine, a newly developed antidepressant, in anesthetized dogs in comparison with those of imipramine, amitriptyline and clomipramine.

Yokota S, Ishikura Y, Ono H.

Department of Pharmacology and Toxicology, Hatano Research Institute, Kanagawa, Japan.

The cardiovascular effects of various antidepressant drugs including paroxetine, imipramine, amitriptyline and clomipramine, administered intravenously, have been assessed. Paroxetine, imipramine, amitriptyline or clomipramine potentiated the response to norepinephrine (0.1 microgram/kg, i.v.) on systemic blood pressure, while paroxetine, imipramine and amitriptyline weakened the response to tyramine (30 micrograms/kg, i.v.). A marked decrease in systemic blood pressure was observed after large doses of each drug (3 and 10 mg/kg of paroxetine; 1-10 mg/kg of imipramine, amitriptyline or clomipramine); and half of the animals died following administration of 10 mg/kg of imipramine, amitriptyline or clomipramine. Paroxetine did not show a marked effect on heart rate at a dose of up to 3 mg/kg, although 0.1-3 mg/kg of imipramine, amitriptyline or clomipramine dose-dependently caused tachycardia. ECG disturbances were observed in animals administered 10 mg/kg of imipramine, amitriptyline or clomipramine; but in contrast, 10 mg/kg of paroxetine caused only slight changes in the ECG. Prolongation of atrio-ventricular conduction time was observed with all the drugs. It was concluded that the effects of paroxetine on the canine heart are more mild in comparison with other tricyclic antidepressants used, although its pharmacological features are essentially similar to those of other drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2963926&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of the selective 5-hydroxytryptamine uptake inhibitors paroxetine and zimeldine on EEG sleep and waking stages in the rat.

Kleinlogel H, Burki HR.

Wander Research Institute, Wander Ltd., Bern, Switzerland.

The effects of oral paroxetine and zimeldine on EEG sleep-waking phases in the rat were investigated over a wide dose range. To ascertain that at the doses used for the EEG studies paroxetine and zimeldine selectively affect the serotoninergic system, their effects on brain 5-hydroxytryptamine (5-HT), dopamine and noradrenaline were determined. It was found that paroxetine and zimeldine at doses of 1-18 mg/kg dose-dependently prolonged waking and shortened slow-wave sleep and paradoxical sleep. In the same dose range cortical 5-HT turnover was significantly reduced, whereas the other aminergic systems were not influenced. These results suggest that 5-HT uptake inhibitors increase vigilance in rats at oral doses which selectively stimulate the serotoninergic system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2964564&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Characterization of [3H]paroxetine binding in rat brain.

Marcusson JO, Bergstrom M, Eriksson K, Ross SB.

Department of Geriatric Medicine, University of Umea, Sweden.

The binding of the 5-hydroxytryptamine (5-HT, serotonin) uptake inhibitor [3H]paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 microliter, the binding was optimized with an apparent dissociation constant (KD) of 0.03-0.05 nM. Competition experiments with 5-HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single-site binding model. Fluoxetine and imipramine revealed, in addition to a high-affinity (nanomolar) site, also a low-affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the [3H]paroxetine binding was emphasized by the fact that 5-HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5-HT- and fluoxetine-sensitive [3H]paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5-HT (100 microM) sensitive [3H]paroxetine binding were also consistent with a single-site binding model, and the binding was competitively inhibited by 5-HT and imipramine. The number of binding sites (Bmax) for 5-HT-sensitive [3H]paroxetine and [3H]imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p-chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a greater than 60% reduction in the striatum and hypothalamus, indicating a selective localization on 5-HT terminals. Together these findings suggest that [3H]paroxetine specifically and selectively labels the substrate recognition site for 5-HT uptake in rat brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2967349&dopt=Abstract paroxetine, Paxil, Paxil CR