Drugs online research references
Toxicol Appl Pharmacol. 1999 Jul 15;158(2):115-24.
The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions.
Daniel WA, Wojcikowski J.
Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, Krakow, 31-343, Poland.
The purpose of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slices of various rat tissues as a system with intact lysosomes. Thioridazine and antidepressants (5 microM) were incubated separately or jointly with the tissue slices in the absence or presence of "lysosomal inhibitors," i.e., ammonium chloride or monensin. The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is as important as phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive interactions between thioridazine and the investigated antidepressants at the level of cellular distribution. Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal inhibitors. In general, the observed interactions between thioridazine and antidepressants occurred only in those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) but were not observed in the presence of ammonium chloride. The above finding provides evidence that the interactions proceeded at the level of lysosomal trapping. In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those tissues were not the site of such an interaction. Since the organs and tissues involved in the distributive interactions constitute a major part of the organism and take up most of the total drug in the body, the interactions occurring in them may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the heart and muscles. An in vivo study into the thioridazine-imipramine interaction showed that joint administration of the drugs under study (10 mg/kg ip) increased drug concentration ratios of lysosome-poor tissue/plasma and lysosome-poor/lysosome-rich tissue. Considering serious side effects of thioridazine and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine-antidepressant combinations studied should be approached with respect to the appropriate dose adjustment. Copyright 1999 Academic Press.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10406926&dopt=Abstract
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Brain Res Mol Brain Res. 1999 Jul 23;71(1):120-6.
Molecular cloning, expression and characterization of a bovine serotonin transporter.
Mortensen OV, Kristensen AS, Rudnick G, Wiborg O.
Department of Biological Psychiatry, Psychiatric University Hospital, Skovagervej 2, 8240 Risskov, Denmark.
The serotonin transporter (SERT) is a member of a highly homologous family of sodium/chloride dependent neurotransmitter transporters responsible for reuptake of biogenic amines from the extracellular fluid. SERT constitutes the pharmacological target of several clinically important antidepressants. Here we report the molecular cloning of SERT from the bovine species. Translation of the nucleotide sequence revealed 44 amino acid differences compared to human SERT. When transiently expressed in HeLa cells and compared with rat and human SERTs the K(m) value for uptake was increased 2-fold. V(max) and B(max) were both increased about 4-fold indicating the turnover number is conserved. The pharmacological profile revealed a decreased sensitivity towards imipramine, desipramine, citalopram, fluoxetine and paroxetine compared with human SERT, while the sensitivity towards 3, 4-methylenedioxymethamphetamine (MDMA) was mainly unchanged. RT-PCR amplification of RNA from different tissues demonstrated expression of SERT in placenta, brain stem, bone marrow, kidney, lung, heart, adrenal gland, liver, parathyroid gland, thyroid gland, small intestine and pancreas. Copyright 1999 Elsevier Science B.V.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10407194&dopt=Abstract
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Stat Med. 1999 Jul 30;18(14):1757-67.
Bootstrap methods for adaptive designs.
Rosenberger WF, Hu F.
Department of Mathematics and Statistics, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
Adaptive designs generate dependent sequences of random variables that are not exchangeable. Therefore, it is not obvious how to employ a resampling scheme for confidence interval estimation. We propose a simple procedure where observed response rates from an adaptive experiment are input to a simulation program. The program then generates sequences from the adaptive sampling scheme. We compare, via simulation, three bootstrap confidence intervals with the asymptotic confidence interval for two adaptive designs useful for clinical trials. A simple ranking of simulated response rates yields a confidence interval approximation with coverage close to 1-alpha in most cases. The method allows us to incorporate such complexities as staggered entry and delayed response. We give an example of its utility on a clinical trial of fluoxetine in depression. Copyright 1999 John Wiley & Sons, Ltd.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10407246&dopt=Abstract
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