Drugs online research references
Brain Res Bull. 1998;45(2):203-8.
Feedback stimulation of somatodendritic serotonin release: a 5-HT3 receptor-mediated effect in the raphe nuclei of the rat.
Bagdy E, Solyom S, Harsing LG Jr.
Institute for Drug Research, Budapest, Hungary.
Slices from rat midbrain containing the raphe nuclei and from hippocampus were prepared, loaded with [3H]5-HT and superfused and the resting and the electrically stimulated [3H]5-HT release was measured. The 5-HT3 receptor agonist 2-methyl-5-HT (1 to 10 micromol/l) increased the resting tritium outflow in superfused raphe nuclei slices, EC50 5.3 micromol/l. The 2-methyl-5-HT-induced increase of tritium outflow was an external Ca2+-independent process and was not altered by reserpine pretreatment but it was reversed by addition of the 5-HT uptake inhibitor fluoxetine (1 micromol/l). The 5-HT3 receptor antagonists ondansetron and GYKI-46 903 (1 micromol/l) did not antagonize the stimulatory effect of 2-methyl-5-HT on resting tritium outflow. 2-Methyl-5-HT in lower concentration increased the electrically induced tritium overflow from raphe nuclei slices (EC50 0.56 micromol/l) and also from hippocampal slices preloaded with [3H]5-HT. These effects were reversed by 1 micromol/l of ondansetron and GYKI-46903. The 5-HT3 receptor antagonists (1 micromol/l) were without effects on depolarization-evoked [3H]5-HT release at 2 Hz stimulation, when 10 Hz stimulation was used, ondansetron and GYKI-46 903 reduced the tritium overflow from raphe nuclei slices. These data indicate that 5-HT3 receptors positively alter depolarization-induced somatodendritic 5-HT release in the raphe nuclei. They also show that 2-methyl-5-HT is able to evoke 5-HT release not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9443841&dopt=Abstract
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Drug Metab Dispos. 1998 Jan;26(1):20-4.
Pharmacokinetics and antidepressant activity of fluoxetine in transgenic mice with elevated serum alpha-1-acid glycoprotein levels.
Holladay JW, Dewey MJ, Yoo SD.
College of Pharmacy, Howard University, Washington, DC 20059, USA.
Fluoxetine, a novel selective serotonin reuptake inhibitor utilized in the treatment of depression, is avidly bound to serum albumin and alpha-1-acid glycoprotein (AAG). AAG is an acute phase protein, and its serum levels are elevated in a variety of pathophysiological conditions including inflammation, depression, cancer, and acquired autoimmune deficiency syndrome. Further, the pharmacokinetic disposition and pharmacological activity of several highly bound drugs have been reported to be significantly altered as a result of elevated serum AAG. We investigated the effects of elevated serum AAG levels on the pharmacokinetic disposition, antidepressant activity, and steady state profile of fluoxetine and its demethylated metabolite, norfluoxetine. This was approached utilizing a novel strain of transgenic mice that expressed genetically elevated serum AAG levels severalfold over those of control mice. Serum and brain drug concentrations were determined by HPLC after fluoxetine administration. In transgenic mice, the volume of distribution and the terminal elimination half-life of fluoxetine were significantly reduced. Further, significant reductions in brain-to-serum fluoxetine concentration ratios and antidepressant activity were observed in transgenic mice, despite having higher serum drug levels than control mice. This trend in the serum continued at steady state, and brain fluoxetine levels were significantly lower in transgenic mice. The results of this study provide valuable insights regarding the consequences of elevated serum AAG levels, often seen in several disease states, on the pharmacokinetic disposition of fluoxetine.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9443847&dopt=Abstract
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Prescrire Int. 1998 Apr;7(34):51-3.
Milnacipran: new preparation. Tricyclics remain first-line antidepressants.
[No authors listed]
Several placebo-controlled trials have shown that milnacipran, 100 mg/day in two doses, is an effective antidepressant in both the ambulatory and hospital settings. Comparative trials against tricyclic antidepressants (imipramine and clomipramine) failed to show that milnacipran was any more effective. Milnacipran has not been compared with specific or non specific MAOI antidepressants. As regards non tricyclic-non MAOI antidepressants, milnacipran has been compared only to two specific serotonin reuptake inhibitors, fluvoxamine and fluoxetine. The trials cannot convince us of a difference in efficacy between the two types of treatment. The claimed superiority of milnacipran over serotonin reuptake inhibitors is not based on firm evidence of better efficacy or fewer adverse effects. The overall tolerability of milnacipran is similar to that of fluoxetine and fluvoxamine. Relative to the tricyclic antidepressants, milnacipran has fewer atropinic effects (sedation and sweating). In contrast, it cause more dysuria, and cannot, therefore, replace tricyclics in elderly men with prostate disorders. Tricyclics remain the preferred first-line antidepressant drugs. When they are contraindicated or poorly tolerated, many other antidepressants with well-documented risk-benefit ratios are available.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10183385&dopt=Abstract
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