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T N Thompson

Publications and source records attributed to T N Thompson.

At least 19 recordsLinked to original sources
PubMed2004

Measurement of the flux of ultrahigh energy cosmic rays from monocular observations by the High Resolution Fly's Eye experiment.

We have measured the cosmic ray spectrum above 10(17.2) eV using the two air-fluorescence detectors of the High Resolution Fly's Eye observatory operating in monocular mode. We describe the detector, phototube, and atmospheric calibrations, as well as the analysis techniques for the two detectors. We fit the spectrum to a model consisting of galactic and extragalactic sources.

Journal Article↗
PubMed2001

Observation of polarization in bottomonium production at square root of s = 38.8 GeV.

We present a measurement of the polarization observed for bottomonium states produced in p-Cu collisions at square root of s = 38.8 GeV. The angular distribution of the decay dimuons of the Upsilon(1S) state shows no polarization at small values of the fractional longitudinal momentum x(F) and transverse momentum p(T) but significant positive transverse production polarization for either p(T)>1.8 GeV/c or for x(F)>0.35. The Upsilon(2S+3S) (unresolved) states show a large transverse production polarization at all values of x(F) and p(T) measured. These observations challenge NRQCD calculations of the polarization expected in the hadronic production of bottomonium states.

Journal Article↗
PubMed2001

Optimization of metabolic stability as a goal of modern drug design.

Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high-throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called "early ADME" studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as "metabolic stability" studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half-life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

Amidohydrolases↗
PubMed2000

Early ADME in support of drug discovery: the role of metabolic stability studies.

The area of Drug Discovery has undergone an amazing evolution in the past decade. This evolution is typified by the development of automated combinatorial synthesis and high throughput pharmacological testing. This, in turn, has lead to the ability to create and mine extensive databases and then model this new information. The overall result is a substantial increase in the rate of target identification, generation of new leads, and finally, optimization of those leads into clinical candidates. ADME studies have always played a critical role in helping to optimize the pharmacokinetic (PK) properties of new drugs thereby increasing their success rate. As a consequence of the increased throughput of drug discovery, ADME studies have evolved to keep pace. These so-called "early ADME" studies, are characterized by parallel processing and higher throughput than before. A primary concern of medicinal chemists is to design molecules that will have not only the desired activity, but also suitable potency and duration of action, which is influenced by pharmacokinetic properties such as bioavailability and half-life. This article focuses on a particular subset of eADME studies known as "metabolic stability", which can be an important contributor for a good pharmacokinetic profile. Metabolic stability studies represent the adaptation of more complex metabolism rate studies to a minimized system suitable for parallel processing of large numbers of compounds. The theoretical basis for metabolic stability lies in its relationship to the concept of metabolic intrinsic clearance. Typical metabolic stability protocols are discussed with respect to their relation to drug design. How metabolic stability studies have evolved to keep pace with advances in drug discovery is also discussed. Several case studies of the role of metabolic stability in drug design over the past few years are summarized to exemplify the utility of this kind of study. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.

Animals↗
PubMed1997

Mass balance of 14C-bismuth sucrose octasulfate in Sprague-Dawley rats: evidence for dissociation of bismuth from sucrose octasulfate.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague-Dawley rats after single oral doses of 1.0 g kg-1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95.8 +/- 5.30% bismuth dose, while 99.2 +/- 3.63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0.051 +/- 0.028% bismuth dose, and 1.83 +/- 1.08% radioactive dose. Biliary excretion of bismuth averaged 0.0003 +/- 0.0006% bismuth dose, and 0.026 +/- 0.030% radiolabeled dose. An average 0.005 +/- 0.002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57.3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110 +/- 55.4 micrograms eq mL-1, while for bismuth it was 26.1 +/- 10.3 ng mL-1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.

Absorption↗
PubMed1997

Experimental models for evaluating enzyme induction potential of new drug candidates in animals and humans and a strategy for their use.

Experimental models that have application for evaluating enzyme induction potential have been described in order of increasing complexity. The main focus was on models that have had wide application thus far. However, many new models are currently being developed that may have future applications in evaluating enzyme induction potential. A strategy to evaluate the enzyme induction potential of drug candidates was outlined. This scheme uses a combination of new and established techniques to evaluate data in a stepwise manner that is appropriate to the drug's current stage of development.

Animals↗
PubMed1995

The effects of hepatic microsomal enzyme inducers on the pharmacokinetics of ouabain after portal and systemic administration to rats.

The microsomal enzyme inducers 3-methylcholanthrene, phenobarbitone and pregnenolone-16alpha-carbonitrile (PCN) are known to affect other aspects of hepato-biliary disposition in addition to metabolism. This study was designed to determine if presystemic elimination of the non-metabolized xenobiotic ouabain could be altered by these inducers. Male Sprague-Dawley rats were pretreated with inducers or saline for four days. A day later, ouabain (0.5 mg kg-1) was administered into either the ileocolic vein (portal administration) or the femoral vein (systemic administration). Blood and bile samples were collected for up to 90 min after ouabain administration. Biliary excretion rate and cumulative biliary excretion of ouabain were increased by pretreatment with PCN (75 mg kg-1 day-1) relative to controls. Phenobarbitone pretreatment (75 mg kg-1 day-1) also increased these parameters, but to a lesser extent than PCN. In contrast, 3-methylcholanthrene pretreatment (20 mg kg-1 day-1) had no effect on biliary excretion. Plasma concentrations of ouabain were much lower after PCN pretreatment relative to controls, whereas neither phenobarbitone nor 3-methylcholanthrene had any effect. Similarly, clearance (both biliary and total) and volume of distribution were increased by PCN, but not by phenobarbitone or 3-methylcholanthrene pretreatment. Interestingly, the magnitude of biliary and plasma effects induced by PCN appeared to be comparable whether ouabain was administered portally or systemically. Pretreatment of rats with PCN, but not phenobarbitone or 3-methylcholanthrene was shown to increase total clearance of ouabain, mainly via an increase in biliary clearance. Furthermore, because the enhanced clearance occurs after systemic as well as after portal administration of ouabain, a significant change in hepatic presystemic elimination was not detected.

Animals↗
PubMed1995

Pharmacological evaluation of selected, orally active, peptidyl inhibitors of human neutrophil elastase.

Human neutrophil elastase (HNE) is a serine proteinase capable of degrading a number of connective tissue macromolecules and has been implicated in the destructive processes associated with several chronic inflammatory diseases. A large series of peptidyl electrophilic ketones have been shown to be potent inhibitors of HNE in vitro and in vivo. We report the pharmacology and pharmacokinetics of selected inhibitors from this series. MDL 101, 146, MDL 102, 111, MDL 102,823 and MDL 100,948A are -Val-Pro-Val-pentafluoroethylketones with various amino-terminal protecting groups. Although their Ki values varied considerably, (25-170 nM), these compounds demonstrated similar ED50 values after oral administration in the HNE-induced hemorrhage model in hamsters and rats. The duration of action of MDL 102,111 was shorter than that of the other analogs in the HNE-induced pulmonary hemorrhage model in both species. The duration of action of all of the compounds was longer in the rat than in the hamster. Isolated sections of rat jejunum were used to determine the in situ absorption of these compounds. MDL 102,111 showed the greatest extent of absorption, with MDL 102,823, MDL 100,948A and MDL 101,146 following in descending rank order. The comparative metabolic stability of these analogs was measured over a 2-hr incubation period using rat liver homogenates. MDL 101,146 was the most stable, followed by MDL 102,823, MDL 102,111 and MDL 100,948A. MDL 101,146 was more stable in a liver homogenate from rats compared with a liver homogenate from hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Pharmacodynamic effects of cotinine in abstinent cigarette smokers.

The nicotine metabolite cotinine was administered to abstinent cigarette smokers to determine whether it has pharmacologic activity as assessed by various physiologic and subjective measurements. By means of a randomized, double-blind, placebo-controlled counterbalanced-order design, subjects received cotinine base (30 mg) intravenously after 48 hours of abstinence from cigarette smoking. Serum cotinine concentrations increased to levels commonly achieved during daily cigarette smoking, whereas no change in serum nicotine concentration was observed. Cotinine compared with placebo produced subjective differences in self-reported ratings of restlessness, anxiety and tension, insomnia, sedation, and pleasantness. Cotinine had minimal effects on cardiovascular measurements. These findings indicate that cotinine is behaviorally active in the setting of cigarette abstinence at blood concentrations similar to those commonly achieved through daily cigarette smoking.

Adult↗
PubMed1991

Determination of ML-1035 enantiomers in plasma by chiral high-performance liquid chromatography.

ML-1035, is a gastroprokinetic agent structurally related to metoclopramide. Because ML-1035 contains an asymmetric chiral sulphoxide moiety, a chiral HPLC method has been developed to separate and quantitate its R- and S-enantiomers in plasma. The ML-1035 enantiomers present in plasma are extracted with dichloroethane under alkaline conditions, the extract evaporated to dryness and reconstituted in the mobile phase. Samples are chromatographed on a Chiralcel OD HPLC column with hexane-absolute ethanol (1% TEA) (1:1, v/v) as the mobile phase. The enantiomers of the unchanged drug are determined by fluorescence measurement (ex: 310 nm, em: 350 nm). The method provides a linear response for both enantiomers over a concentration range of 25 (limit of determination) to 2500 ng ml-1 with correlation coefficients of 0.9987 or greater. The inter-assay precision is 9.5% or less and the accuracy ranges from 93.9 to 103.4% of the theoretical value. The method is used to determine the plasma concentrations of the R- and S-enantiomers following oral and intravenous administration of R- or S-enantiomers to dogs. The method is also adapted to measure enantiomer levels from in vitro reaction mixtures so that the possibility of metabolic inversion may be assessed. The data suggest that no significant level of inversion between the enantiomers occurred either in vivo or in vitro.

Animals↗
PubMed1989

Perturbation of red blood cell flow in small tubes by white blood cells.

The flow of blood in the microcirculation is facilitated by the dynamic reduction in viscosity (Fahraeus-Lindquist effect) resulting from the axial flow of deforming erythrocytes (RBCs) and from the decrease in the ratio of cell to vessel diameter. RBC velocity exceeds that of average fluid velocity; however the slower moving white blood cells (WBC) perturb flow velocity and the ratio of cell to vessel diameter by obstructing red cell flow through formation of "trains" of red cells collecting behind the white cell. This effect of white cells was studied quantitatively in a model in vitro tubes less than 10 microns in diameter with the demonstration that flow resistance increases linearly with white cell numbers up to 1,000 WBC/mm3 at tube hematocrit of 17.7%. The increase in resistance exceeds the flow resistance of WBC and appears to relate directly to train formation. A mechanical model of train formation developed to predict WBC influence in flow resistance over the range of WBC studied reasonably fits observed WBC effects.

Biophysical Phenomena↗
PubMed1989

CGS 20625, a novel pyrazolopyridine anxiolytic.

CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocyclohepta[b]pyrazolo-[3,4-d]pyridin-3-one) is a potent and selective ligand for the central benzodiazepine receptor (IC50 = 1.3 nM), with little or no affinity to several other neurotransmitter receptor binding sites in vitro. CGS 20625 had a gamma-aminobutyric acid ratio of 0.9 and increased t-[35S]butylbicyclophosphorothionate binding by 20% in vitro, a profile indicative of a partial agonist or mixed agonist/antagonist. In vivo, CGS 20625 blocked a pentylenetetrazol discriminative cue with an ED50 = 1.7 mg/kg p.o. The compound selectively increased conflict responding in the Cook-Davidson paradigm with a minimal effective dose of 0.3 mg/kg p.o., as compared with 3.0 mg/kg p.o. for diazepam. At doses as high as 100 mg/kg p.o., CGS 20625 had no effect on variable interval responding, suggesting minimal sedation. Unlike diazepam, CGS 20625 had no effect on rotorod performance at doses up to 100 mg/kg p.o. indicating no overt muscle relaxation, and did not potentiate the action of ethanol in this behavioral paradigm. Also, CGS 20625 had no marked effect on locomotor behavior, did not potentiate hexobarbital sleep time and had no sedative activity at doses up to 300 mg/kg p.o. CGS 20625 was efficacious in preventing pentylenetetrazol-induced seizures (ED50 = 0.7 mg/kg p.o.), had less efficacy with no clear dose-response relationship against picrotoxin-induced seizures and had no effect on either strychnine or electroshock-induced convulsions at doses up to 300 mg/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pentopril-cimetidine interaction caused by a reduction in hepatic blood flow.

The interactive effects of the coadministration of steady-state cimetidine and single-dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to be caused by a reduction in liver blood flow probably mediated through H2 receptor blockade. Meanwhile pentopril induced the oral clearance of cimetidine by 21%, presumably by a reduction in the bioavailable fraction of cimetidine. The mechanism of this interaction is unknown.

Administration, Oral↗
PubMed1985

Hepatic presystemic elimination of diethylstilbestrol by rats and effect of pretreatment with inducers of UDP-glucuronosyltransferase.

In order to determine if the synthetic estrogen diethylstilbestrol (DES) undergoes hepatic presystemic elimination, male Sprague-Dawley rats were administered [3H]DES (0.005, 0.05, 0.5 mg/kg) into either the ileocolic (portal administration) or femoral (systemic administration) vein. Plasma and bile samples were collected and the concentrations of both DES and DES glucuronide fractions were determined. The concentration of the DES fraction was lower and the proportion of glucuronides was higher after portal than after systemic administration of all three doses. Comparison of the areas under the curve (AUC) of plasma concentration versus time for the DES fraction indicates that the liver diminishes this fraction by 50-70%. Biliary excretion of DES also showed route-dependent differences, in that it was higher for 10-20 min after portal than after systemic administration. To determine if these effects could be enhanced by induction of UDP-glucuronosyltransferase, rats were pretreated for 4 d with phenobarbital, 3-methylcholanthrene, or pregnenolone-16 alpha-carbonitrile and then administered DES (0.5 mg/kg) by the portal or systemic route. 3-Methylcholanthrene and pregnenolone-16 alpha-carbonitrile enhanced the plasma disappearance of the DES fraction to a greater extent after portal than systemic administration and thus further increased the apparent hepatic presystemic elimination. This effect does not appear to involve increased glucuronidation or biliary excretion. These data provide evidence that hepatic presystemic elimination of DES occurs in rats, and this effect can be enhanced by some microsomal enzyme inducers.

Animals↗
PubMed1984

Oxidative and conjugative metabolism of xenobiotics by livers of cattle, sheep, swine and rats.

Homogenate preparations from fresh livers of cattle, sheep, swine and rats were assayed for microsomal cytochrome P-450 content, for mixed-function oxidase activities and for a wide array of conjugative activities using numerous xenobiotic substrates. Results show that hepatic enzymatic capabilities toward xenobiotics do not parallel phylogenetic classifications, thus strengthening the view that most of the comparative data available at present is more descriptive than predictive of relationships among species. Livestock species differed widely from rats in having lower activities of benzo(alpha)pyrene hydroxylase, glutathione S-transferase and acetyltransferase toward isoniazid and sulfamethazine and UDP-glucuronosyl-transferase toward bilirubin. Acetyltransferase activities toward beta-naphthylamine and 2-aminofluorene were not detected in livers of livestock species studied. Cattle livers were remarkably high in activities of styrene oxide hydrolase, ethoxyresorufin O-deethylase, 2-naphthol sulfotransferase and p-aminobenzoic acid acetyltransferase; but notably low in activity of glutathione-S-transferase toward sulfobromophthalein and 1,2-dichloro-4-nitrobenzene. Swine livers had low activity of glutathione-S-transferase toward four of six substrates and low acetyltransferase activity toward four of five substrates. Sheep livers generally were higher than cattle livers in sulfo- and UDP-glucuronsyltransferase activities and lower in acetyl- and glutathionyl-S-transferase. Findings emphasize the risk of error in extra-polations among species and in extrapolations among substrates.

Acetyltransferases↗
PubMed1983

Hepatic phase I and phase II biotransformations in quail and trout: comparison to other species commonly used in toxicity testing.

The ability of quail and trout to perform a number of representative phase I and phase II biotransformations was examined. To facilitate interspecies comparisons, metabolism of the same substrates was examined simultaneously under uniform conditions for rat, mouse, rabbit, guinea pig, cat, and dog. Both nonmammalian species can metabolize four representative substrates of phase I mixed-function oxidases and one substrate of epoxide hydrolase, though activity tended to be lower than that of the mammals. Important differences in the conjugative pathways were also noted. Among these differences were the quail's relative deficiency in glutathione conjugation and the trout's low ability to conjugate sulfate compounds. Trout liver UDP-glucuronosyltransferase activity was remarkably high toward testosterone and bilirubin, while quail liver formed glucuronides of naphthol, p-nitrophenol, and digitoxigenin-monodigitoxoside. Also noteworthy was the high N-acetyltransferase activity of both quail and trout toward isoniazid, beta-naphthylamine, and 2-aminofluorene. Differences in substrate specificity for a given enzymatic pathway may be an indication that multiple forms of drug metabolizing systems also occur in these nonmammalian species. Observation of several hundred- or even thousand-fold differences between species in their enzyme activities for certain substrates under uniform conditions re-emphasizes the need for caution in extrapolation of xenobiotic metabolism from one species to another.

Acetylation↗
PubMed1983

Disposition of metals after portal and systemic administration to rats.

To determine if metals undergo significant hepatic presystemic elimination, male Sprague-Dawley rats were administered solutions of ionic 109Cd, 64Cu, 203Hg and CH3 203Hg, 210Pb, and 113Sn at 1.0 mumol metal/kg into either the ileocolic (portal administration) or femoral vein (systemic administration). Serial blood and bile samples were obtained for 90 min after administration. Whereas the area under the blood concentration vs time curve after portal administration was not less than that following systemic administration or any metal, route-dependent differences in distribution did occur. Portal, in comparison to systemic administration, resulted in a higher blood/plasma concentration ratio for mercury and lower ratio for lead. These data suggest that the liver may play a role in the distribution of these metals within the blood. In addition, the biliary excretion of mercury, methylmercury, cadmium, and lead was higher after portal than after systemic administration. These route-dependent differences in disposition suggest that some degree of hepatic presystemic elimination occurs for several metals.

Animals↗