sertraline, Zoloft
Sertraline attenuates hyperphagia in rats following nicotine withdrawal.

Levin ED, Briggs SJ, Christopher NC, Rose JE.

Department of Psychiatry, Duke University, Durham, NC 27710.

Chronic nicotine administration can decrease food consumption and body weight. Abrupt withdrawal from nicotine can cause the reverse effect, hyperphagia and rapid weight gain. In the current study, the efficacy of sertraline, a serotonin reuptake inhibitor, on nicotine withdrawal-induced hyperphagia and rapid weight gain was assessed in rats. Sertraline was found to be effective in reversing the increase in feeding that occurred after withdrawal from chronic nicotine administration. Sertraline caused a dose-related decrease in food consumption in control rats not given nicotine. Doses of 5 and 10 mg/kg/day caused significant decreases while 2.5 mg/kg/day caused a slight though nonsignificant decrease in food consumption. Rats in which nicotine was abruptly withdrawn after 3 weeks of administration showed a significant increase in food consumption relative to controls. This increase was eliminated by the high dose of sertraline (10 mg/kg/day), but not by the lower two doses (2.5 and 5 mg/kg/day). Water consumption was affected in a similar fashion. Body weight gain was also affected by sertraline. During the first week after nicotine withdrawal, rats rapidly gained weight, but sertraline attenuated this. The 10-mg/kg dose of sertraline significantly attenuated the nicotine withdrawal-induced weight gain. These results suggest that sertraline can counteract the hyperphagia and rapid weight gain associated with nicotine withdrawal, and might therefore be a useful adjunct to smoking cessation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8430129&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys.

Kleven MS, Woolverton WL.

Department of Pharmacological and Physiological Sciences, University of Chicago, Pritzker School of Medicine, IL 60637.

Rhesus monkeys (n = 6) were surgically prepared with double lumen i.v. catheters and the effects of continuous infusion of the monoamine reuptake blockers mazindol, sertraline and fluoxetine were examined on behavior maintained by food presentation or i.v. cocaine injections. Under baseline conditions, lever pressing was maintained under a three-component multiple schedule of reinforcement in which food (1-g banana-flavored pellets) was available for 600 s under a fixed-ratio 30 schedule in the first and third components. In the second component, the dose of cocaine that maintained maximum rates of responding (0.03 or 0.05 mg/kg per injection) was available for 1800 s under a fixed-ratio 30 schedule. There was a brief time-out after each reinforcer. When behavior was stable, mazindol (0.4-3.2 mg/kg per 24 h), sertraline (0.1-8.0 mg/kg per 24 h) or fluoxetine (0.4-3.2 mg/kg per 24 h) was administered continuously via the second lumen of the double lumen catheter. Mazindol was administered for the same number of sessions that were required for responding to decline to low levels when the monkeys were allowed to self-administer saline [5-13] while sertraline and fluoxetine were administered for a minimum of 21 days. Baseline conditions were reinstated between doses of each drug. Each drug decreased cocaine-maintained responding in a dose-related manner. In most cases, food-maintained responding was disrupted at doses equal to or lower than those that decreased cocaine-maintained responding. Additionally, the higher doses of each drug decreased food intake outside the daily sessions. These results suggest that monoamine uptake blockers with prominent effects on either dopamine or serotonin neurotransmission can decrease cocaine self-administration but only at doses that also affect behavior maintained by other reinforcers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8436060&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes.

Bolden-Watson C, Richelson E.

Mayo Clinic, Jacksonville, FL 32224.

We determined the uptake blockade produced by eight new antidepressant drugs (etoperidone, femoxetine, lofepramine, nefazodone, paroxetine, sertraline, tomoxetine, and venlafaxine), two metabolites of newer antidepressants (desmethylsertraline and norfluoxetine), seven previously reported antidepressants, and carbamazepine. Inhibitor constants (Kis) for uptake blockade were obtained from competitive uptake studies with [3H]norepinephrine, [3H]5-hydroxytryptamine, and [3H]dopamine in rat brain synaptosomes prepared from hippocampus, frontal cortex, and striatum, respectively. Among the newer compounds, tomoxetine (Ki = 0.7 nM) and lofepramine (Ki = 1.9 nM) were potent and selective [3H]norepinephrine uptake blockers; paroxetine (Ki = 0.73 nM), sertraline (Ki = 3.4 nM), and femoxetine (Ki = 22 nM) potently and selectively inhibited [3H]5-hydroxytryptamine uptake. Although none of the drugs was potent for [3H]dopamine uptake blockade, sertraline was the most potent (Ki = 260 nM). These data are useful in predicting adverse effects and drug-drug interactions of antidepressants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8445992&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Hemodialyzability of sertraline.

Schwenk MH, Verga MA, Wagner JD.

St. John's University, College of Pharmacy and Allied Health Professions, Department of Clinical Pharmacy Practice, Jamaica, New York 11439, USA.

Sertraline is an antidepressant which selectively inhibits the neuronal uptake of serotonin in the central nervous system. The pharmacokinetics of sertraline in end-stage renal disease (ESRD) and the effect of hemodialysis on sertraline clearance is unknown. A dose of 100 mg sertraline was administered to two anuric hemodialysis patients after hemodialysis. During the next hemodialysis session, simultaneous pre- and post dialyzer blood samples were obtained at the start of and hourly throughout dialysis until completion. All spent dialysate was collected hourly, quantified and an aliquot retained. Additional blood samples were obtained approximately 20 hours after dialysis and prior to the next treatment. Serum and dialysate were assayed for sertraline by gas chromatography-mass spectroscopy. Initial sertraline serum concentrations were similar to those observed in subjects with normal renal function given the same sertraline dose, implying unaltered absorption and distribution. Sertraline was not detected in any dialysate sample. The elimination half-life was 42-92 h (normally 24-36 h), suggesting impaired clearance. Smaller doses of sertraline may be required in ESRD patients, yet post-hemodialysis supplementation is unnecessary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8529300&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effect of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline on human CYP3A catalyzed 1'-hydroxy midazolam formation in vitro.

Ring BJ, Binkley SN, Roskos L, Wrighton SA.

Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

The ability of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline to inhibit the CYP3A subfamily of cytochromes P450 was examined in vitro, using the formation of 1'-hydroxy midazolam as a probe for CYP3A catalytic activity. The inhibition observed with these four compounds was modeled using competitive, noncompetitive, uncompetitive and mixed competitive/noncompetitive relationships by nonlinear regression analysis. The best fit model of the inhibition of CYP3A-mediated 1'-hydroxy midazolam formation by all four compounds examined was determined to be mixed inhibition. The calculated Ki values were 65.7 +/- 12.0 microM for fluoxetine, 19.1 +/- 1.9 microM for norfluoxetine, 64.4 +/- 11.6 microM for sertraline and 48.1 +/- 11.6 microM for desmethyl sertraline. Steady-state plasma levels of fluoxetine and norfluoxetine can approach a concentration of 1 microM (approximately 350 ng/ml of plasma). Assuming an inhibitor concentration of 1 microM and a concentration of the substrate substantially below its Km (at least 10-fold lower), the results reported predict that fluoxetine and norfluoxetine together would inhibit CYP3A catalytic activity by less than 7% (less than 0.7% if the unbound plasma concentration of fluoxetine is considered). By using the same assumptions and concentrations for sertraline and desmethyl sertraline, these agents together would be predicted to inhibit the metabolic clearance of a coadministered CYP3A metabolized drug by less than 4%. The observations reported here suggest that fluoxetine and sertraline would have little effect on CYP3A-mediated clearance of coadministered drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8531073&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Carbonic anhydrase activators. The selective serotonin reuptake inhibitors fluoxetine, sertraline and citalopram are strong activators of isozymes I and II.

Casini A, Caccia S, Scozzafava A, Supuran CT.

Universita degli Studi di Firenze, Dipartimento di Chimica, Rm 188, Via della Lastruccia 3, I-50019 (Firenze), Sesto Fiorentino, Italy.

The selective serotonin reuptake inhibitors (SSRI) fluoxetine, sertraline and citalopram have been investigated for their ability to activate two carbonic anhydrase (CA) isozymes, hCA I and hCA II, in parallel with two standard activators for which the X-ray structure (in complex with isozyme II) has been resolved: histamine and phenylalanine. All three SSRI activated both isozymes with potencies comparable to that of the standards although the profile was different: for hCA I, best activators were fluoxetine and histamine, with citalopram and sertraline showing weaker activity. For hCA II, the best activators were phenylalanine and citalopram, and the weakest histamine and sertraline, whereas fluoxetine showed an intermediate behavior. These results suggest that SSRI efficacy in major depression complicating Alzheimer's disease may be partly due to their ability to activate CA isozymes and may lead to the development of potent activators for the therapy of diseases associated with significant decreases in brain CA activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12873510&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effects of serotoninergic agents on downregulation of beta-adrenoceptors by the selective serotonin reuptake inhibitor sertraline.

Koe BK, Lebel LA.

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

The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8540763&dopt=Abstract sertraline Zoloft