citalopram escitalopram Lexapro
Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by the recombinant rat serotonin transporter SERT1.

Sur C, Betz H, Schloss P.

Department of Neurochemistry, Max-Planck-Institute for Brain Research, Frankfurt am Main, Germany.

Tricyclic and nontricyclic serotonin [5-hydroxytryptamine (5-HT)] uptake inhibitors are widely used for the treatment of depression. Here, we show that both the tricyclic antidepressant imipramine and the nontricyclic antidepressant citalopram competitively inhibit 5-HT transport mediated by the recombinant rat 5-HT transporter SERT1. For citalopram, the concentration producing half-maximal transport inhibition was in the same order of magnitude as its K(D) value determined by equilibrium binding. In contrast, the inhibitory potency of imipramine was more than one order of magnitude lower than its K(D) value. Our data are consistent with low-affinity imipramine binding occurring at or close to the substrate recognition site, which also binds citalopram. Occupation of the high-affinity imipramine binding site on SERT1 did not affect 5-HT transport but allosterically displaced citalopram from the substrate recognition site. Consequently, low concentrations of imipramine partially protected 5-HT transport from citalopram inhibition. This protection was only observed in the presence of Na+ because high-affinity imipramine binding is strictly sodium-dependent. Thus, depending on which of its binding sites on SERT1 is occupied, imipramine may exert distinct effects on 5-HT uptake mediated by the recombinant rat 5-HT transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9603221&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Simultaneous quantification of citalopram, clozapine, fluoxetine, norfluoxetine, maprotiline, desmethylmaprotiline and trazodone in human serum by HPLC analysis.

Waschgler R, Hubmann MR, Conca A, Moll W, Konig P.

Medical Central Laboratory, Feldkirch, Austria. rwaschgler mzl.at

We describe an analytical procedure for the simultaneous quantification of citalopram (seropram), clozapine (leponex), fluoxetine (fluctine), norfluoxetine, maprotiline (ludiomil), desmethylmaprotiline and trazodone (trittico) in human serum within a period of 11.5 minutes using reversed phase HPLC. After 2 liquid/liquid extractions in the sample preparation phase, the drugs and metabolites were separated on a C18 column using a mobile phase consisting of acetonitrile/buffer (30/70, v:v) at 70 degrees C, a flow rate of 1.5 m/min and haloperidol as internal standard. Absorption and native fluorescence signals of the eluted compounds were detected simultaneously at 260 nm and 227/300 nm (excitation/emission), respectively. The calibration ranges for citalopram, clozapine, fluoxetine, norfluoxetine, maprotiline, and desmethylmaprotiline ranged from 50-400 microg/l and for trazodone from 50-3,200 microg/l. The CVs varied between 0.6% and 5.5% (within-run) and between 3.2% and 7.1% (between-run). Recoveries were > 90% for all pharmaceuticals. We noticed no interferences from several commonly used drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12503813&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Citalopram concentrations in samples from autopsies and living persons.

Worm K, Dragsholt C, Simonsen K, Kringsholm B.

Institute of Forensic Medicine, Copenhagen O, Denmark.

Concentrations of citalopram in medicolegal samples from 92 autopsies and 27 living persons are described. In autopsy cases in which citalopram alone was the cause of death, concentrations ranged from 2.0 to 6.2 mg/kg whole blood. In autopsy cases in which citalopram together with other substances was considered to be the cause of death, the concentrations of citalopram ranged from 0.6 to 5.2 mg/kg whole blood. In autopsy cases toxic concentrations ranged from 0.4 to 0.9 mg/kg whole blood and therapeutic concentrations from 0.03 to 0.6 mg/kg whole blood. In samples from living persons the concentrations of citalopram in whole blood were 0.02 to 0.3 mg/kg.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9646161&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo.

Evans SG, Butkow N, Stilwell C, Berk M, Kirchmann N, Havlik I.

Department of Experimental and Clinical Pharmacology, University of the Witwatersrand, Parktown, South Africa.

Citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. Citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain--a pattern found with other reversal agents. Citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9655857&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
High affinity recognition of serotonin transporter antagonists defined by species-scanning mutagenesis. An aromatic residue in transmembrane domain I dictates species-selective recognition of citalopram and mazindol.

Barker EL, Perlman MA, Adkins EM, Houlihan WJ, Pristupa ZB, Niznik HB, Blakely RD.

Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, USA.

Human and Drosophila melanogaster serotonin (5-HT) transporters (SERTs) exhibit similar 5-HT transport kinetics and can be distinguished pharmacologically by many, but not all, biogenic amine transporter antagonists. By using human and Drosophila SERT chimeras, major determinants of potencies of two transporter antagonists, mazindol and citalopram, were tracked to the amino-terminal domains encompassing transmembrane domains I and II. Species-scanning mutagenesis, whereby amino acid substitutions are made switching residues from one species to another, was employed on the eight amino acids that differ between human and Drosophila SERTs in this region, and antagonist potencies were reassessed in 5-HT uptake assays. A single mutation in transmembrane domain I of human SERT, Y95F, shifted both citalopram and mazindol to Drosophila SERT-like potencies. Strikingly, these potency changes were in opposite directions suggesting Tyr95 contributes both positive and negative determinants of antagonist potency. To gain insight into how the Y95F mutant might influence mazindol potency, we determined how structural variants of mazindol responded to the mutation. Our studies demonstrate the importance of the hydroxyl group on the heterocyclic nucleus of mazindol for maintaining species-selective recognition of mazindol and suggest that transmembrane domain I participates in the formation of antagonist-binding sites for amine transporters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9677366&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Simultaneous determination of human plasma levels of citalopram, paroxetine, sertraline, and their metabolites by gas chromatography-mass spectrometry.

Eap CB, Bouchoux G, Amey M, Cochard N, Savary L, Baumann P.

Departement Universitaire de Psychiatrie Adulte, Hopital de Cery, Prilly-Lausanne, Switzerland. Chin.Eap inst.hospvd.ch

A gas chromatography-mass spectrometry method is presented which allows the simultaneous determination of the plasma concentrations of the selective serotonin reuptake inhibitors citalopram, paroxetine, sertraline, and their pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline) after derivatization with the reagent N-methyl-bis(trifluoroacetamide). No interferences from endogenous compounds are observed following the extraction of plasma samples from six different human subjects. The standard curves are linear over a working range of 10-500 ng/mL for citalopram, 10-300 ng/mL for desmethylcitalopram, 5-60 ng/mL for didesmethylcitalopram, 20-400 ng/mL for sertraline and desmethylsertraline, and 10-200 ng/mL for paroxetine. Recoveries measured at three concentrations range from 81 to 118% for the tertiary amines (citalopram and the internal standard methylmaprotiline), 73 to 95% for the secondary amines (desmethylcitalopram, paroxetine and sertraline), and 39 to 66% for the primary amines (didesmethylcitalopram and desmethylsertraline). Intra- and interday coefficients of variation determined at three concentrations range from 3 to 11% for citalopram and its metabolites, 4 to 15% for paroxetine, and 5 to 13% for sertraline and desmethylsertraline. The limits of quantitation of the method are 2 ng/mL for citalopram and paroxetine, 1 ng/mL for sertraline, and 0.5 ng/mL for desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline. No interferences are noted from 20 other psychotropic drugs. This sensitive and specific method can be used for single-dose pharmacokinetics. It is also useful for therapeutic drug monitoring of these three drugs and could possibly be adapted for the quantitation of the two other selective serotonin reuptake inhibitors on the market, namely fluoxetine and fluvoxamine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9679303&dopt=Abstract citalopram escitalopram Lexapro



citalopram escitalopram Lexapro
Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents.

Marona-Lewicka D, Nichols DE.

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907, USA.

MMAI (5-methoxy-6-methyl-2-aminoindan) is a nonneurotoxic, highly selective neuronal serotonin (5-HT) releasing agent. MMAI and other 5-HT releasing agents produce a robust discriminative cue in drug discrimination (DD) studies. The selective serotonin reuptake inhibitors (SSRIs) sertraline and citalopram may also serve as discriminative stimuli, but acquisition of their discrimination required almost twice as much time as for MMAI. In vitro, 5-HT release by MMAI can be blocked by selective SSRIs. However, in the present DD studies, pretreatment with fluoxetine, sertraline, or citalopram 60 min before the training drugs MMAI or (+)-MBDB produced only partial inhibition of the discriminative cue. In substitution tests, sertraline and citalopram partially mimicked the training drugs, whereas only 40% substitution occurred with fluoxetine in MMAI or (+)-MBDB trained rats. In generalization tests, the tricyclic antidepressants imipramine and clomipramine partly substituted for the sertraline, citalopram, and MMAI stimuli. The increase in extracellular 5-HT produced by SSRIs leads to a subtle or feeble drug cue that is apparently difficult for an animal to recognize. This observation contrasts with the 5-HT releasing agents, which clearly produce robust cues that are easily recognized by the animals. However, mechanism(s) responsible for the discriminative stimulus effects of SSRIs and 5-HT releasing agents seem to be similar, at least in part.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9694528&dopt=Abstract citalopram escitalopram Lexapro