Rapid simple high-performance liquid chromatographic determination of paroxetine in human plasma. Variations in [3H]imipramine and 5-HT2A but not [3H]paroxetine binding sites in suicide brains. The selective norepinephrine reuptake inhibitor, LY368975, reduces food consumption in animal models of feeding. Rx drugs

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J Chromatogr B Biomed Sci Appl. 1998 Aug 25;713(2):452-6.
Rapid simple high-performance liquid chromatographic determination of paroxetine in human plasma.

Shin JG, Kim KA, Yoon YR, Cha IJ, Kim YH, Shin SG.

Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital, South Korea.

A rapid, simple method for the measurement of paroxetine in human plasma by reversed-phase high-performance liquid chromatography (HPLC) with fluorescence detection is described. This method includes only one-step extraction of paroxetine and dibucaine, an internal standard, with chloroform. Their recoveries were around 90%. The mobile phase, 10 mM phosphate buffer-acetonitrile (40:60, v/v) was eluted isocratically. Between- and within-day coefficients of variation were in the range of 1.9-9.4% and 2.3-13.3%, respectively. The detection limit was 0.2 ng/ml. The method we describe can be easily applied to the measurement of plasma paroxetine concentration for pharmacokinetic studies as well as for therapeutic drug monitoring in patients taking paroxetine.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9746264&dopt=Abstract

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Psychiatry Res. 1998 Jun 30;82(3):161-70.
Variations in [3H]imipramine and 5-HT2A but not [3H]paroxetine binding sites in suicide brains.

Rosel P, Arranz B, Vallejo J, Oros M, Crespo JM, Menchon JM, Navarro MA.

Department of Clinical Chemistry, Hospital Princeps D'Espanya, Barcelona, Spain.

Both the [3H]imipramine and [3H]paroxetine binding sites and the 5-HT2A receptor were simultaneously determined in frontal cortex, cingulate cortex, hippocampus and amygdala from 17 control subjects and 17 depressed suicide victims. A significant decrease in the maximum binding (Bmax) of [3H]imipramine was observed in the hippocampus of suicide victims as compared to control subjects (160 +/- 25 vs. 328 +/- 52 fmol/mg protein; P = 0.007) without changes in the apparent affinity constant (Kd). Furthermore, a significant decrease in the number of 5-HT2A binding sites, together with a significantly lower Kd, was also observed in the hippocampus of suicides as compared to control subjects (129 +/- 18 vs. 225 +/- 32 fmol/mg protein; P = 0.02 and 0.91 +/- 0.07 vs. 1.38 +/- 0.08 nM, respectively; P = 0.006). [3H]Paroxetine binding did not display modifications between the two groups in either Bmax or Kd from any of the brain regions studied. When all four brain regions were taken together, a down-regulation was noted between presynaptic [3H]imipramine binding and the postsynaptic 5-HT2A receptor (r = -0.40; P = 0.0013) in the control group. This correlation did not appear in the suicide group. No correlation was observed between [3H]paroxetine binding and the 5-HT2A receptor in either control subjects or suicides. Taken together, these results suggest that the 5-HT uptake site measured with [3H]imipramine and the 5-HT2A receptors are reliable markers of serotonergic dysfunction.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9754440&dopt=Abstract

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J Pharmacol Exp Ther. 1998 Oct;287(1):122-7.
The selective norepinephrine reuptake inhibitor, LY368975, reduces food consumption in animal models of feeding.

Gehlert DR, Dreshfield L, Tinsley F, Benvenga MJ, Gleason S, Fuller RW, Wong DT, Hemrick-Luecke SK.

Neuroscience and Endocrine Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.

The compound, LY368975 ((R)-thionisoxetine) is a potent and selective inhibitor of the norepinephrine (NE) reuptake site. We evaluated the in vivo properties of LY368975 in various animal models. In mice, LY368975 prevented heart NE depletion by 6-hydroxydopamine with an ED50 of 1.22 mg/kg. In rats, orally administered LY368975 inhibited 3H-NE uptake into hypothalamic synaptosomes ex vivo with an ED50 of 2.5 mg/kg and 3H-tomoxetine binding to the NE transporter with an ED50 of 2.7 mg/kg. When rats were deprived of food for 18 hr, 10 mg/kg LY368975 was able to suppress food intake 1, 2 and 4 hr after reintroduction of the feed. In nonfasted rats trained to drink sweetened condensed milk, LY368975 produced a dose-dependent reduction in consumption with a 44% decrease at 3 mg/kg. At doses up to 10 mg/kg p.o., LY368975 produced no significant effects on locomotor activity suggesting the compound does not activate or sedate the animals at pharmacologically relevant doses. Therefore, LY368975 is an orally available and centrally active NE reuptake inhibitor that is capable of reducing food consumption in rodents. Compounds of this class may have use in the treatment of obesity and eating disorders.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9765330&dopt=Abstract

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