paroxetine, Paxil
Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets.

Plenge P, Mellerup ET, Laursen H.

Neuropsychiatry Institute, University of Copenhagen, Rigshospitalet, Denmark.

The dissociations of [3H]imipramine, [3H]paroxetine and [3H]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the microM range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains. Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [3H]imipramine, [3H]paroxetine and [3H]citalopram. For example, 5-HT markedly attenuated the dissociation of [3H]imipramine, had a moderate effect on [3H]paroxetine and very little effect on [3H]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter. [3H]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [3H]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1830276&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Concentration-response relationship in paroxetine treatment of diabetic neuropathy symptoms: a patient-blinded dose-escalation study.

Sindrup SH, Grodum E, Gram LF, Beck-Nielsen H.

Department of Clinical Pharmacology, Odense University, Denmark.

A single-blind dose-escalation study with the selective serotonin reuptake inhibitor paroxetine was conducted in 19 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by self-rating using visual analog scales. After an initial placebo period, paroxetine doses were increased from 10 mg/day in 10 mg steps, until the dose was 30-70 mg/day. In all except four patients, there was a marked relief of symptoms. Plasma concentrations of paroxetine above 300-400 nM were required to insure maximal relief in the majority of patients responding on paroxetine, but a considerable interindividual variation was observed (10-800 nM, median of 195 nM). The therapeutic effect appeared to increase gradually as the plasma concentration increased. The great interindividual variation in the pharmacokinetics of paroxetine was confirmed, but as the effect is maximal within approximately 1 week, and the drug is nontoxic, it may be clinically feasible simply to titrate the dose from 20 mg/day until the maximal effect is achieved. However, it is advised that titration to an effect, in diabetic neuropathy using doses above 50 mg/day, be undertaken with care as there is limited experience with doses above this level in any population. The beneficial effect of paroxetine appeared to be maintained unaltered during an additional 1 month open-label treatment on optimal paroxetine doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1835549&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Platelet 3H-paroxetine binding to the serotonin transporter is insensitive to changes in central serotonergic innervation in the rat.

Moret C, Briley M.

Department of Neuropharmacology, Pierre Fabre Research Center, Castres, France.

The serotonin transporter labeled in platelets by 3H-imipramine or 3H-paroxetine binding has been suggested to be a peripheral marker for changes in serotonin uptake in the brain that may be related to depression. The present study was designed to determine whether major changes in central serotonergic innervation modify the platelet serotonin transporter as labeled by 3H-paroxetine binding. Fifteen days after the intracerebroventricular administration of 5,7-dihydroxytryptamine (250 micrograms/animal) to rats to lesion central serotonergic neurons, serotonergic innervation was reduced by 82% in the cortex and 98% in the hippocampus as determined by endogenous serotonin levels. The maximum binding of 3H-paroxetine was reduced by 55% in the cortex and was undetectable in the hippocampus. Serotonin levels and 3H-paroxetine binding in platelets were not, however, significantly modified in the same animals. Thus, following a major serotonergic lesion in the brain, changes in the platelet serotonin transporter do not parallel serotonergic changes in the brain. The hypothesis that binding to the platelet serotonin transporter is a state-dependent marker of brain serotonergic activity therefore appears to be unlikely.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1836639&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
3H-paroxetine binding in brains of alcoholics.

Chen HT, Casanova MF, Kleinman JE, Zito M, Goldman D, Linnoila M.

Laboratory of Clinical Studies, DICBR, National Institute of Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD.

High affinity 3H-paroxetine binding was studied in human frontal cortex and hippocampus obtained from normal controls and alcoholics. On the basis of Scatchard analyses, a significant decrease in the maximal number of binding sites (Bmax) was found in the hippocampus of alcoholics (n = 8) as compared with that of controls (n = 10) (mean +/- SD = 63 +/- 35 vs. 114 +/- 70 fmoles/mg protein). There was no significant difference in the dissociation constants (Kd) between the two groups. The presumed effect of chronic alcohol abuse on 3H-paroxetine binding may be region-specific since no significant difference in either Bmax or Kd for 3H-paroxetine binding was found in the frontal cortex between normal controls and alcoholics. No significant correlation of 3H-paroxetine binding with age or postmortem interval was observed. The decrease in 3H-paroxetine binding in the hippocampus of alcoholics is probably indicative of reduced density of serotonergic nerve terminals either as a preexisting condition or as a result of neuronal damage caused by ethanol or the sequelae of alcoholism, such as nutritional deficiencies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1836640&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat.

Chaput Y, de Montigny C, Blier P.

Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839498&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Pharmacokinetics of paroxetine in patients with cirrhosis.

Dalhoff K, Almdal TP, Bjerrum K, Keiding S, Mengel H, Lund J.

Department of Medicine A, Rigshospitalet, Copenhagen, Denmark.

In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20-30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSSmin) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng.ml-1 per mg paroxetine and 89 vs 43 h (ng).ml-1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1839532&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Laminar distributions of muscarinic acetylcholine, serotonin, GABA and opioid receptors in human posterior cingulate cortex.

Vogt BA, Plager MD, Crino PB, Bird ED.

Department of Anatomy, Boston University School of Medicine, MA 02118.

Experimental animal studies have demonstrated a number of receptor localizations on specific cortical afferents and neurons. The present study of human posterior cingulate cortex evaluates the laminar distributions of particular receptors and their likely association with components of the neuropil. Coverslip autoradiographic and single grain counting techniques were used followed by heterogeneity analysis in which the layer of peak binding and an index of heterogeneity were determined for each ligand. The index was calculated by determining specific binding by layer as a percentage of binding in all layers. The differences from an absolutely homogeneous distribution, i.e. 11.1% for each of nine layers, were subtracted and the absolute laminar differences summed to form the index. High indices of over 15 reflected heterogeneous binding patterns in neocortex. The binding of ligands for muscarinic acetylcholine, serotonin, opioid, GABA and beta adrenoceptors was evaluated. Pirenzepine binding peaked in layer II of area 23a but was extremely homogeneous with an index of heterogeneity of 8.9. In contrast, oxotremorine-M binding had a peak in layer IIIc and an index of 16.4, while AF-DX 116 binding peaked in layer IIIa-b and had an index of 30.6. Of the ligands for serotonin uptake and receptor binding paroxetine binding was evenly distributed in layers I-III and had a low index of heterogeneity of 9.8. Ketanserin binding was also homogeneous and, since it had an index of 8.9, this pattern was virtually the same as that for paroxetine. In contrast, serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin binding peaked in layer II and had very high indices of 20.8 and 50.3, respectively, suggesting only a limited association with that of the paroxetine distribution. Finally, there were three layers which contained peaks in binding for ligands for opioid, GABA and beta adrenoceptors. Firstly, layer Ia had peak dynorphin-A binding, the latter of which had an index of 22.6. Secondly, Tyr-D-Ala-Gly-MePhe-Gly-ol and 2-D-penicillamine-5-D-penicillamine-enkephalin binding peaked in layer II and had indices of 8.6 and 17.4, respectively. Thirdly, muscimol and (-)-cyanopindolol binding peaked in layer IIIa-b and had indices of 29.6 and 11.1, respectively. When viewed in the context of experimental animal studies, it is likely that heterogeneities in oxotremorine-M and paroxetine binding are associated with the termination of the thalamic and raphe nuclei, respectively. While serotonin 2 receptors are co-distributed with serotonin uptake sites, serotonin 1A receptors have a significant mismatch with these sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1977100&dopt=Abstract paroxetine, Paxil, Paxil CR