sertraline, Zoloft
[3H] sertraline binding to rat brain membranes.

Koe BK, Lebel LA, Welch WM.

Central Research Division, Pfizer Inc., Groton, CT 06340.

Tritiated sertraline, a radiolabeled form of a potent and selective inhibitor of serotonin uptake, was found to bind with high affinity to rat whole brain membranes. Characterization studies showed that [3H] sertraline binding occurred at a single site with the following parameters: KD 0.57 nM, Bmax 821 fmol/mg protein, nH 1.06. This binding was reversible; the dissociation constant calculated from kinetic measurements (KD 0.81 nM) agreed with that determined by saturation binding experiments. [3H] Sertraline binding in the presence of serotonin, paroxetine, fluoxetine or imipramine suggested competitive inhibition of binding (large increase in KD with little change in Bmax). The rank order of potency of inhibition of [3H] sertraline binding was similar to that of inhibition of serotonin uptake for known uptake inhibitors and the 1-amino-4-phenyltetralin uptake blockers. A marked decrease in ex vivo [3H] sertraline binding in the brain of rats 7 days after treatment with p-chloroamphetamine was consistent with the loss of serotonin uptake sites induced by this agent. The results of our study indicated that [3H] sertraline labels serotonin uptake sites in rat brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2138796&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Behavioral mechanisms for the anorectic action of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting 5-HT agonists.

Simansky KJ, Vaidya AH.

Department of Pharmacology, Medical College of Pennsylvania, Eastern Pennsylvania Psychiatric Institute, Philadelphia 19129.

The 5-HT uptake inhibitor, sertraline (5-40 mumol/kg, IP) reduced the volume of milk consumed by food-deprived rats during a 30-min test (ID50 = 12 mumol/kg). Observations using a time-sampling method revealed that sertraline shortened meal duration (ID50 = 14 mumol/kg) by decreasing feeding and increasing resting without altering nonfeeding activity or the overall sequence of behavior that characterizes normal satiety. In separate experiments, analysis of videotapes demonstrated that sertraline (10 mumol/kg) decreased not only the time that rats fed but also their actual rate of intake. In comparison, doses of the direct 5-HT agonists, mCPP (1-[3-chlorophenyl]piperazine), RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), and DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-amino-propane) that produced similar anorectic effects altered either feeding time or rate but not both. DOI also disrupted the continuity of feeding and the 5-HT agonist, 8-OH-DPAT (8-hydroxy-di-N-propylamino tetralin) produced marked stereotypy at anorectic doses. Together, these results imply that stimulating a number of different serotonergic mechanisms can reduce food intake in rats. Sertraline appears to accelerate the onset of normal satiety, presumably by enhancing physiological actions of endogenous 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2149668&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The effect of combined administration of ethanol and sertraline, fluoxetine and citalopram on rabbit EEG.

Pietrzak B, Czarnecka E.

Department of Pharmacodynamics, Medical University of Lodz, Muszynskiego 1, 90-151, Lodz, Poland. bpietrzak pharm.am.lodz.pl

In this study we have decided to examine acute interaction of ethanol with some drugs that belong to selective serotonin inhibitor (SSRI) group. Therefore, the influence of sertraline, fluoxetine and citalopram on the effect of ethanol on EEG of rabbits (frontal cortex, hippocampus, MRF) was tested. Sertraline (10mg/kg i.p.), fluoxetine (10mg/kg i.p.) and citalopram (5mg/kg i.p.) were given 30min before ethanol injection in a dose 0.8g/kg i.v. Ethanol caused the increase of the slow frequencies (0.5-4cps) in the recording, as well as a marked decrease of the fastest frequencies (13-30 and 30-45cps). Sertraline, fluoxetine and citalopram (given before ethanol) prevented the increase in the slow frequencies (0.5-4cps) in the recordings from the frontal cortex and hippocampus, which indicates on antagonism inhibitory action of ethanol. These drugs administered together with ethanol may increase its influence on fast frequencies. This effect depends on brain structure and drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12742007&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The electrocardiogram as a tool for therapeutic monitoring: a critical analysis.

Guy S, Silke B.

Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.

The authors review the scientific value of electrocardiographic studies and discuss the limitations that arise from variability in technology and in standards of recording and interpretation. A consistent recording procedure and objective assessment using standardized diagnostic criteria are required, particularly in multicenter studies. Tricyclic antidepressants depress cardiac conduction at therapeutic concentrations; therefore a comparison with the electrocardiographic profile of sertraline, a specific serotonin reuptake inhibitor with antidepressant activity, was made. In four studies, sertraline was compared with placebo, with amitriptyline or placebo, and with amitriptyline alone. There were decreases in RR interval and increases in PR, QRS, and QTC intervals with amitriptyline but no effect with sertraline. Thus, sertraline had no demonstrable effects on intraventricular conduction or electrocardiographic time intervals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2258381&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The radiosynthesis of [N-methyl-11C]-sertraline.

Lasne MC, Pike VW, Turton DR.

MRC Cyclotron Unit, Hammersmith Hospital, London, U.K.

[N-methyl-11C]Sertraline, a potential agent for the study of the serotonergic system in vivo with positron emission tomography, was prepared by N-methylation of the corresponding norcompound with [11C]iodomethane, which was itself prepared from cyclotron-produced [11C]carbon dioxide. Under the best conditions found [norsertraline free base (20 mM) in DMF (0.70 mL), 120 degrees C for 8 min] [N-methyl-11C]-sertraline can be prepared in 43% radiochemical yield from [11C]iodomethane (decay-corrected), corresponding to 20% overall radiochemical yield from [11C]carbon dioxide (decay-corrected), with high specific radioactivity. Preparations can be ready for i.v. injection 50 min from the end of radionuclide production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2541104&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Sertraline-induced desensitization of the serotonin 5HT-2 receptor transmembrane signaling system.

Sanders-Bush E, Breeding M, Knoth K, Tsutsumi M.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Sertraline is a new, selective serotonin (5HT) uptake inhibitor with antidepressant activity. The effect of chronic administration of sertraline on 5HT-2 receptors in rat cortex was compared with that of the tricyclic antidepressant, amitriptyline. 5HT-2 receptors were evaluated in binding assays using [3H]-ketanserin and in functional assays of transmembrane signaling, hydrolysis of phosphoinositides. The daily injection of 17 mg/kg sertraline induced a desensitization of 5HT-2-mediated phosphoinositide hydrolysis after 28, but not 21, days. The administration of 1.2 mg/kg/day via continuous release pumps caused a more rapid desensitization. Amitriptyline administered chronically also produced a desensitization of the 5HT-2-mediated phosphoinositide hydrolysis response. A decrease in the density of 5HT-2 binding sites accompanies the functional desensitization after amitriptyline, but changes in 5HT-2 binding sites were not detected after chronic sertraline administration. Studies of the mechanism of action of sertraline show that the desensitization of the phosphoinositide hydrolysis response is homologous in nature, and that it is not secondary to changes in the synthesis of precursor lipids. Other possibilities such as alterations in coupling efficiency or in the activity of effector enzymes are currently being considered. The present results suggest a new postsynaptic action of antidepressant drugs at central 5HT-2 receptors (i.e., changes in 5HT-2 signal transduction at a site distal to the cell surface binding site) and illustrate the importance of studies of receptor signaling pathways to complement radioligand binding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2550988&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Characterization of a carbamic acid ester glucuronide of the secondary amine sertraline.

Tremaine LM, Stroh JG, Ronfeld RA.

Drug Metabolism Department, Central Research, Pfizer, Inc. Groton, CT 06340.

In the dog, the major excretory metabolite of the antidepressant sertraline was characterized as sertraline carbamoyl-O-glucuronide. The intact conjugate was isolated from bile by HPLC. The metabolite was labile to beta-glucuronidase and produced sertraline as the single hydrolytic product, based on HPLC and GC-MS analyses. By fast atom bombardment MS analysis, [M+H]+ and [M+Na]+ ions at m/z 526 and 548 were observed, as were the proton and sodium adducts of the aglycone (m/z 350 and 372) due to cleavage of the glycosidic bond and elimination of the glucuronic acid moiety (176 amu). The observed mass of the aglycone was 44 amu greater than sertraline, indicating that a carbamic acid of this secondary amine was conjugated with glucuronic acid. These data suggest that sertraline in solution reversibly associates with CO2 before formation of sertraline carbamoyl-O-glucuronide. This novel amine glucuronide was also identified in human plasma after the oral administration of sertraline to each of seven subjects. The glucuronide was stable in plasma at both acidic and basic pH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2566471&dopt=Abstract sertraline Zoloft