Drugs online research references
J Pharm Biomed Anal. 2003 Feb 5;31(1):63-74.
Utilizing capillary gas chromatography mass spectrometry to determine 4-benzotrifluoride t-butyl ether as a reaction by-product in fluoxetine synthesized using potassium t-butoxide as base.
Robbins DK, Dodson PN, Buccilli LA, Mitchell D.
Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Fluoxetine hydrochloride has been prepared using two similar synthetic routes, both of which rely upon an ether formation reaction mediated by a base. The base used can affect the impurity profile of this reaction. It was proposed that the synthesis of fluoxetine carried out using potassium t-butoxide as base and 4-chlorobenzotrifluoride (or 4-fluorobenzotrifluoride) in the ether formation step may result in the formation of 4-benzotrifluoride t-butyl ether as a reaction by-product. To test this hypothesis, capillary gas chromatography-mass spectrometry (GC/MS) was utilized to evaluate samples of free base fluoxetine synthesized using sodium hydride (NaH) or potassium t-butoxide as the base. Assay conditions using selected ion monitoring (SIM) were developed, which allowed detection of trace levels (parts per million, ppm) of 4-benzotrifluoride t-butyl ether in fluoxetine free base sample matrix. Response linearity, precision, and standard spike recovery were examined during development, and were found to be suitable. Comparisons of fluoxetine samples generated from both NaH and potassium t-butoxide processes were performed using the GC/MS assay.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12560050&dopt=Abstract
note: kwd match prozac online literature
Control Clin Trials. 1999 Aug;20(4):328-42.
Randomized play-the-winner clinical trials: review and recommendations.
Rosenberger WF.
Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore 21250, USA.
The randomized play-the-winner rule is an adaptive randomized design, based on an urn model, that is used occasionally in clinical trials. This paper discusses practical and theoretical issues arising from its use, including stratification, delayed response, operating characteristics, selection of urn parameters, and inference. The paper also discusses recent experience with adaptive clinical trials within the pharmaceutical industry. The author concludes that the randomized play-the-winner rule is appropriate for some clinical trials, but intense and thoughtful planning must take place in the design phase. Such planning should incorporate considerations of variability, power, and appropriate techniques.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10440560&dopt=Abstract
note: kwd match prozac online literature
Exp Toxicol Pathol. 1999 Jul;51(4-5):309-14.
The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies.
Daniel WA, Syrek M, Haduch A, Wojcikowski J.
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Krakow.
Due to its psychotropic profile, thioridazine is a neuroleptic suitable for a combination with antidepressants in a number of complex psychiatric illnesses. However, because of its serious side-effects, such a combination with selective serotonin reuptake inhibitors (SSRIs) which inhibit cytochrome P-450 may be dangerous. The aim of the present study was to investigate a possible impact of SSRIs on the pharmacokinetics and metabolism of thioridazine in a steady state in rats. Thioridazine (10 mg/kg) was injected intraperitoneally, twice a day, for two weeks, alone or jointly with one of the antidepressants (fluoxetine, fluvoxamine or sertraline). Concentrations of thioridazine and its main metabolites (2-sulfoxide = mesoridazine; 2-sulfone = sulforidazine; 5-sulfoxide = ring sulfoxide and N-desmethylthiorid-azine) were assessed in the blood plasma and brain at 30 min, 6 and 12 h after the last dose of the drugs using an HPLC method. Fluoxetine potently increased (up to 13 times!) the concentrations of thioridazine and its metabolites in the plasma, especially after 6 and 12 h. Moreover, an increase in the sum of concentrations of tioridazine + metabolites and thioridazine/metabolite ratios was observed. In vitro studies with control liver microsomes, as well as with microsomes of rats treated chronically with fluoxetine show that the changes in the thioridazine pharmacokinetics may be attributed to the competitive (N-demethylation, Ki = 23 microM) and mixed inhibition (2- and 5-sulfoxidation, Ki = 60 microM and 34 microM, respectively) of thioridazine metabolism by fluoxetine, and to the adaptive changes produced by chronic administration of fluoxetine, as reflected by inhibition of N-demethylation and formation of sulforidazine. Sertraline seemed to have a tendency to decrease thioridazine concentration in vivo, though in vitro studies showed that - like fluoxetine - it competitively or via mixed mechanism inhibited the three metabolic pathways of thioridazine (Ki = 41 microM, 64 microM and 47 microM, respectively). Chronic treatment with sertraline stimulated thioridazine 2- and 5-sulfoxidation, which may be responsible for the observed tendency of sertraline to decrease concentrations of the neuroleptic. In the case of fluvoxamine, a tendency to increase the thioridazine level was observed, which may be connected with the competitive or mixed inhibition of thioridazine N-demethylation and 2-sulfoxidation by the antidepressant (Ki = 17 microM and 167 microM, respectively). Repeated administration of fluvoxamine did not produce any changes in the activity of thioridazine-metabolizing enzymes. In conclusion, of the SSRIs studied, only fluoxetine produces a substantial increase in the thioridazine level in the plasma and brain. In the case of fluvoxamine, a tendency to increase the thioridazine level should be considered. Coadministration of thioridazine and sertraline seems to be safe, though a tendency to decrease the thioridazine level may be expected.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10445388&dopt=Abstract
note: kwd match prozac online literature
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