Morphine antinociception is enhanced in mdr1a gene-deficient mice.

Purpose: Previous studies have suggested that P-glycoprotein (P-gp) modulates opioid antinociception for selected mu-and delta-agonists. This study was undertaken to assess morphine antinociception in mice lacking the mdr1a gene for expression of P-gp in the CNS.

Methods: Morphine (n = 4-5/group) was administered as a single s.

Coagulation products and their uses.

The indications, pharmacokinetics, and therapeutic guidelines for available coagulation products are reviewed. Patients with hemophilia, von Willebrand's disease (VWD), or acquired inhibitors to antihemophilic factor (AHF) cannot spontaneously stop an acute hemorrhage. Coagulation products used to manage bleeding in patients with these disorders include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, anti-inhibitor coagulant complexes, and desmopressin acetate.

Pharmacokinetics of ibuprofen enantiomers in children with cystic fibrosis.

Chiral inversion of R(-)- to S(+)-ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2-13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean Cmax, AUC, apparent CL/F, and Varea/F of S-ibuprofen were significantly different from those of R-ibuprofen.

Rational combinatorial library design. 3. Simulated annealing guided evaluation (SAGE) of molecular diversity: a novel computational tool for universal library design and database mining.

We have developed a novel method for molecular diversity sampling called SAGE (simulated annealing guided evaluation of molecular diversity). Compounds in chemical databases or virtual combinatorial libraries are conventionally represented as points in multidimensional descriptor space. The SAGE algorithm selects a desired number of optimally diverse points (compounds) from a database.

Growth and geographic distribution of selected health professions, 1971-1996.

This article examines the growth and geographic distribution of selected health professions in a 26-year period. The health professionals investigated were physicians, dentists, pharmacists, registered nurses, other health practitioners, dieticians and therapists, medical technologists and technicians, and health service workers. Allied health professions are represented by the last three of these groups.

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor.

Enhanced antinociception of the model opioid peptide [D-penicillamine] enkephalin by P-glycoprotein modulation.

Purpose: This study was conducted to examine the influence of P-glycoprotein (P-gp) modulation on the pharmacodynamics of the model opioid peptide DPDPE.

Methods: Mice (n = 5-7/group) were pretreated with a single oral dose of the P-gp inhibitor GF120918 (25 or 250 mg/kg) or vehicle. 3H-DPDPE (10 mg/kg) or saline was administered 2.

Anti-AIDS agents. 32. Synthesis and anti-HIV activity of betulin derivatives.

Eleven betulin derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Compound 4 was found to be the most active with EC50 and TI values of 0.00066 microM and 21,515, respectively.

Bacterial complementation as a means to test enzyme-ligand interactions.

A bacterial complementation assay has been developed for the rapid screening of a large number of compounds to identify those that inhibit an enzyme target for structure-based inhibitor design. The target enzyme is the hypoxanthine phosphoribosyltransferase (HPRT). This enzyme has been proposed as a potential target for inhibitors that may be developed into drugs for the treatment of diseases caused by several parasites.

A single amino acid substitution in the human and a bacterial hypoxanthine phosphoribosyltransferase modulates specificity for the binding of guanine.

Early studies involving purine salvage in Salmonella typhimurium resulted in the isolation and identification of a mutant strain possessing a genetically modified hypoxanthine phosphoribosyl-transferase (HPRT) with enhanced substrate specificity for guanine [Benson, C. E., and Gots, J.

Influence of moderate haemodilution with fluosol or normal saline on carbaryl disposition in Sprague-Dawley rats.

In rats carbaryl undergoes extensive biotransformation involving both albumin-mediated hydrolysis and cytochrome P-450-mediated metabolism; studies have suggested that approximately one-half of a carbaryl dose is hydrolysed and one-half is metabolized. Fluosol is known to be an inducer of cytochrome P-450, and Fluosol haemodilution reduces plasma albumin concentrations. The disposition of carbaryl was, therefore, determined in rats for 72 h after 40 mL kg-1 haemodilution with Fluosol or normal saline (0.

A modified residual method to estimate the zero-order absorption rate constant in a one-compartment model.

The objective of this work was to develop a simple residual method to estimate the rate constant for actual or apparent zero-order absorption into a one-compartment model. The method is based on the fact that, in theory, a plot of residuals versus e-Kt is linear for a zero-order absorption process, where K represents the elimination rate constant governing the terminal phase of the concentration-time profile. The apparent absorption rate constant (K0) can be calculated from the slope and intercept of the residual plot.

Extensive biliary excretion of the model opioid peptide [D-PEN2,5] enkephalin in rats.

Purpose: This study was designed to test the hypothesis that the enzymatically stable opioid peptide, [D-pen2,5] enkephalin (DPDPE), is excreted extensively into bile.

Methods: Following an i.v.

Developing a medical achievement reading test to evaluate patient literacy skills: a preliminary study.

A medical terminology achievement reading test (MART) administered to patients was developed for health care practitioners and researchers. In this study, 405 respondents from five populations (nursing home patients, college students, high school students, adult basic education students, and shopping mall customers) took both the MART and the Wide Range Achievement Test (WRAT). Cronbach's reliability test alpha indicated a high level (alpha = 0.

Comparative toxicokinetics of methanol in pregnant and nonpregnant rodents.

Methanol toxicokinetics were examined in pregnant Sprague-Dawley rats and CD-1 mice to explore the possibility of gestational-associated alterations in metabolism and disposition. In vitro biotransformation of methanol in rat and mouse fetal livers also was examined to assess the capability of the near-term rodent fetus to metabolize methanol. In the in vivo studies, rats received a single dose (100 or 2,500 mg/kg) of methanol either orally (by gavage) or intravenously; mice received a single oral or intravenous 2500-mg/kg dose.

Evidence for reversible sequestration of morphine in rat liver.

The residence of morphine in the systemic circulation is prolonged despite a high systemic clearance, suggestive of significant extravascular sequestration. The present study was conducted to test the hypothesis that morphine binds significantly in tissues, and that the liver plays an important role in morphine binding. [14C]Morphine was administered to male Sprague-Dawley rats 55 min before unlabeled morphine or saline.

Synthesis and pharmacological studies of 3-amino-2-methyl-1-phenyl-propanones as hypolipidemic agents in rodents.

A series of 3-amino-2-methyl-1-phenylpropanones were synthesized and proven to have potent hypolipidemic activity in rodents by lowering both serum cholesterol and triglyceride levels at 8 mg/kg/day, i.p. and orally.

Development of a capillary zone electrophoresis assay to examine the disposition of [D-pen2,5]enkephalin in rats.

A novel capillary zone electrophoresis (CZE) assay method was developed to evaluate the systemic disposition of [D-pen2,5]enkephalin (DPDPE) in rats. DPDPE was recovered from serum samples (200 microliters) by solid-phase extraction. Complete resolution of DPDPE and the internal standard ([D-ser2]leucine-enkephalin; DSLET) from other serum components was achieved within 15 min on a 50-microns I.

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.

Objective: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine.

Methods: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5.

Age-related changes in valproic acid binding to rat serum proteins in vitro.

The effect of age on the in vitro binding of valproic acid (VPA) to serum proteins was investigated in rats ranging in age from 14 days (preweaning) to 24 months (senescent). The influence of free fatty acid (FFA) and total protein (TP) concentrations on age-related changes in binding was examined. The protein binding of VPA was altered during development and aging.

Pharmacokinetic and pharmacodynamic drug interactions with polypharmacotherapy of treatment-resistant affective and obsessive-compulsive disorders.

The concomitant use of multiple therapeutic agents in the treatment of resistant affective and obsessive-compulsive disorders increases the likelihood of a patient experiencing a drug-drug interaction at either the pharmacokinetic or pharmacodynamic level. Recent developments in molecular biology and pharmacogenetics have allowed the identification of which psychotropic agents are substrates, inducers, or inhibitors of specific hepatic cytochrome P450 isozymes. This increases the predictability of which drug combinations may lead to kinetic interactions.

Comparative toxicokinetics of inhaled methanol in the female CD-1 mouse and Sprague-Dawley rat.

Female CD-1 mice were exposed for 8 hr, both individually and in groups of eight to nine, to 2500, 5000, and 10,000 ppm methanol vapor in a flowthrough exposure chamber. The ventilation of individually exposed mice and the absorption of methanol from the chamber airstream were measured. The extraction of methanol from the airstream and the blood methanol concentration at various time points during and following exposure were determined for the group-exposed mice.