Trends in the use of selective serotonin reuptake inhibitors in nine Department of Veterans Affairs outpatient facilities. Daily fluoxetine administration impairs avoidance learning in the rat without altering sensory thresholds. Use of peptide combinatorial libraries in drug design: the identification of a potent serotonin reuptake inhibitor derived from a tripeptide cassette library. Rx drugs

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J Clin Psychol. 1999 Jan;55(1):129-33.
Trends in the use of selective serotonin reuptake inhibitors in nine Department of Veterans Affairs outpatient facilities.

Voris JC.

University of South Carolina, College of Pharmacy, Dorn Veterans Hospital, Columbia 29209-1639, USA.

The average daily dose and need for dose escalations for the drugs known as selective serotonin reuptake inhibitors (SSRIs) has frequently been a point of controversy. This study reports on the information gathered from nine Veterans Affairs hospitals over a two six-month periods. Average daily doses of fluoxetine, paroxetine, and sertraline started at 30.9 mg, 24.2 mg, and 87.8 mg and ended at 28.4 mg, 24.2 mg, and 89.8 mg, respectively. Cost, number of prescriptions, and dosage strength data is also presented.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10100839&dopt=Abstract

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Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):1043-57.
Daily fluoxetine administration impairs avoidance learning in the rat without altering sensory thresholds.

Nelson CJ, Jordan WP, Bohan RT.

Department of Psychology, St. Mary's College of Maryland, St. Mary's City, USA.

1. Male rats given daily intraperitoneal injections of fluoxetine (10 mg/kg) were slower to escape foot shock by jumping a low barrier. 2. When switched to a shuttle task requiring two crosses to terminate shock, the FLU-treated animals failed to learn in 55 trials. 3. A second experiment found FLU-treated animals could learn a one-way avoidance response, but were significantly slower to learn than control animals. 4. FLU-treated animals were no different than controls on tests of sensory thresholds for foot shock or heat. 5. Tests of motor behaviors revealed no differences in latency to traverse a narrow beam to reach a goal box, however FLU-treated animals were less active in an open field. 6. Several hypotheses can account for these data, the most promising being that a central motivational system (fear) is less active in FLU-treated animals.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9380787&dopt=Abstract

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Chem Biol. 1995 Jul;2(7):483-7.
Use of peptide combinatorial libraries in drug design: the identification of a potent serotonin reuptake inhibitor derived from a tripeptide cassette library.

Koppel G, Dodds C, Houchins B, Hunden D, Johnson D, Owens R, Chaney M, Usdin T, Hoffman B, Brownstein M.

CNS Division, Lilly Research Laboratories, Indianapolis, IN 46285, USA.

BACKGROUND: Medicinal chemistry traditionally requires the identification of biologically active molecules by synthesizing and screening each purified substrate. Further progress in drug discovery then requires definition of the structure-activity relationship of the lead compound. More recently, combinatorial chemistry has emerged as a way to examine structure-activity relationships by screening a large mixture of compounds synthesized in a predictably random manner, without the labor-intensive costs of molecular isolation and purification. We set out to use this approach to examine the structural requirements for peptide binding to serotonin and dopamine transporters. RESULTS: We screened a tripeptide cassette library for serotonin and dopamine reuptake inhibition using cloned transporter assay systems. The method has afforded a number of tripeptide pharmacophores with inhibitory IC50 values ranging from 10 microM to < 1 microM in the dopamine and serotonin reuptake systems. The conformation of one of these tripeptides, N-acetyl-D-Trp-L-Phe-D-Lys-CONH2 (which inhibits serotonin uptake with an IC50 of 10 microM) was compared to that of the serotonin uptake inhibitor s-fluoxetine, and was shown to be more similar in conformation to fluoxetine than was an analogous tripeptide containing L-Lys (IC50 > 50 microM). CONCLUSIONS: We have identified five tripeptides with inhibitory IC50 values of < 10 microM in the serotonin reuptake system. One tripeptide was predicted to have pharmacophore features similar to that of fluoxetine, a selective and potent non-peptide serotonin reuptake inhibitor. Our results suggest that tripeptides derived from combinatorial libraries will help to define the important structural elements of pharmacophores.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9383450&dopt=Abstract

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