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Biomedical subjects

T J Tucker

Publications and source records attributed to T J Tucker.

At least 19 recordsLinked to original sources
PubMed1998

Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.

Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.

Antithrombins↗
PubMed1998

Thyroid hormone concentrations in black bears (Ursus americanus): hibernation and pregnancy effects.

Previous studies on thyroid hormones in hibernating bears have used very few sampling periods, so that the time course of any change is poorly understood. In this study, plasma sampled from pregnant and nonpregnant black bears before and during hibernation (16 samples each at 10-day intervals) was assayed by radioimmunoassay for concentrations of thyroxine (T4) and triiodothyronine (T3). Only free T4 showed a difference (P = 0.019) between females that produced cubs and those that did not, but this appeared to be due to higher preimplantation values. Free T3, total T3, and free T4 varied (P = 0.001, 0.038, 0.002, respectively) among sampling periods: during December, bears had depressed concentrations. These lowered concentrations were maintained during hibernation for the free hormones. Our data confirm previous work showing that food restriction and/or physiological preparation for hibernation is coincident with depressed plasma concentrations of thyroid hormones. Hormonal changes associated with pregnancy were minor.

Analysis of Variance↗
PubMed1997

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Administration, Oral↗
PubMed1997

Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Animals↗
PubMed1997

Hepatitis C virus infection rate in volunteer blood donors from the Western Cape--comparison of screening tests and PCR.

INTRODUCTION: Hepatitis C virus (HCV) antibody seroprevalence studies overestimate the true infection rate. No data exist on the incidence of HCV or its clinical features in blood donors of sub-Saharan Africa. AIMS: To establish the true incidence of HCV infection in volunteer blood donors in the Western Cape, and compare risk factors and clinical and biochemical features of viraemic and non-viraemic subjects. METHODS: All donors attending the Western Province Blood Transfusion Service between December 1992 and August 1994 were screened prospectively for anti-HCV using the Abbott second-generation assay. Positive donors were evaluated clinically and biochemically. Their sera were examined for HCV-RNA by the polymerase chain reaction (PCR). RESULTS: Of 66314 donors screened, 275 (0.41%) were anti-HCV-positive. Of these 13.6% were PCR-positive (0.056% of all donors). PCR-positive patients had more risk factors for HCV acquisition (P < 0.01), symptoms of hepatitis (P = 0.02) and clinical signs of liver disease (P = 0.05) and higher alanine (P < 0.0001) and aspartate aminotransferase levels (P < 0.0001) than PCR-negative donors. However, clinical and biochemical features did not discriminate adequately between PCR-positive and negative donors. Liver biopsies performed in 9 of 13 PCR-positive cases showed mild inflammation, but no cirrhosis.

Blood Donors↗
PubMed1997

High prevalence of GBV-C hepatitis G virus infection in a rural South African population.

A novel virus, GBV-C/hepatitis G virus (GBV-C/HGV), has been cloned and characterised recently. GBV-C/HGV global epidemiology and risk factors for acquisition are currently unclear. We aimed to establish the determinants of this infection in a rural South African (SA) population. The study population included two samples, namely a community-based sample, and consenting persons from a nonspecialist outpatient department in the same district. A questionnaire regarding demographic details and putative risk factors was administered; blood samples were taken on which a polymerase chain reaction (PCR) was performed for both 5'NCR and NS5a regions of GBV-C/HGV using commercially available primers and probes. Two hundred and forty-nine people were studied with a mean GBV-C/HGV prevalence of 10.4%. Outpatient department and community prevalences differed significantly (18.0% and 6.3%, respectively, P = 0.004). GBV-C/HGV infection was associated with excessive alcohol consumption (P = 0.02; OR, 4.18) and a lack of waterborne sewerage (P = 0.04). PCR amplification of the NS5a region of all but two South African GBV-C/HGV positive samples showed poor reactivity. The prevalence of GBV-C/HGV in rural SA appears to be higher than that reported from Europe and North America. Infection appeared to be associated with excess alcohol intake and a history of previous blood transfusion. The discrepant NS5a and 5'NCR PCR sensitivity in this study raises the possibility of genetic differences in southern African GBV-C/HGV.

Adolescent↗
PubMed1996

Hepatitis E in South Africa: evidence for sporadic spread and increased seroprevalence in rural areas.

Hepatitis E virus (HEV) is a major cause of non-A, non-B hepatitis in developing countries. Factors influencing sporadic spread of hepatitis E are unclear. We examined anti-HEV seroprevalence and demographic data from 407 urban and 360 rural black South African adults living in formal housing, squatter camps, or mud huts. Anti-HEV sero-prevalence ranged from 5.8% to 19.1% (mean 10.7%) in the different regions. Mean urban and rural rates were 6.6% and 15.3%, respectively (P = 0.0001). Rural mud hut dwellers, using unchlorinated river water, were at greater risk (17.4%) than rural villagers (5.3%; P = 0.008). A linear relation was found between seroprevalence and age, suggesting sporadic spread. The high prevalence in mud hut dwellers suggests that contaminated water plays a major role in HEV spread in South Africa. Routine chlorination or boiling of river drinking water before consumption may reduce HEV infection.

Adult↗
PubMed1994

Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin -2(1H)-ones 4aa-l has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-l were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides. By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HIV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.

Cells, Cultured↗
PubMed1994

Hepatitis E.

Explore the source record for details and available documents.

Female↗
PubMed1992

A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity.

A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.

Amino Acid Sequence↗
PubMed1992

Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design.

By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.

Binding Sites↗
PubMed1988

Antigenic analysis of a major neutralization site of herpes simplex virus glycoprotein D, using deletion mutants and monoclonal antibody-resistant mutants.

Herpes simplex virus glycoprotein D is a component of the virion envelope and appears to be involved in attachment, penetration, and cell fusion. Monoclonal antibodies against this protein can be arranged in groups on the basis of a number of biological and biochemical properties. Group I antibodies are type common, have high complement-independent neutralization titers, and recognize discontinuous (conformational) epitopes; they are currently being used in several laboratories to study the functions of glycoprotein D. We have used a panel of neutralization-resistant mutants to examine the relationships between these antibodies in detail. We found that they can be divided into two subgroups, Ia and Ib, such that mutations selected with Ia antibodies have little or no effect on binding and neutralization by Ib antibodies and vice versa. In addition, Ia antibodies are able to bind deletion and truncation mutants of glycoprotein D that Ib antibodies do not recognize, suggesting that their epitopes are physically distinct. However, with one exception, Ia and Ib antibodies block each other strongly in binding assays with purified glycoprotein D, whereas antibodies from other groups have no effect. We have therefore defined the sum of the Ia and Ib epitopes as antigenic site 1.

Antibodies, Monoclonal↗
PubMed1987

Vitamin and proximate composition of fast-food fried chicken.

As part of the USDA's effort to obtain accurate data for nutrient composition handbooks, we determined proximate composition and vitamin (thiamin, riboflavin, niacin, folacin, pantothenic acid, and vitamins B-6 and B-12) content of fast-food fried chicken. Ninety-four samples were purchased from six chains in 10 cities throughout the United States. Vitamin content of breast and thigh meat portions differed, and slight differences in composition among brands were noted. Thiamin values for breast and thigh muscle, respectively, ranged from 0.062 to 0.136 and from 0.078 to 0.122 mg/100 gm; riboflavin, from 0.176 to 0.205 and 0.249 to 0.328 mg/100 gm; niacin, from 6.32 to 8.46 and 3.86 to 5.57 mg/100 gm; vitamin B-6, from 0.315 to 0.390 and 0.189 to 0.271 mg/100 gm; folacin, from 4.2 to 6.9 and 5.00 to 8.00 micrograms/100 gm; vitamin B-12, from 0.331 to 0.459 and 0.382 to 0.596 micrograms/100 gm; and pantothenic acid, from 1.48 to 1.68 and 1.58 to 1.77 mg/100 gm. Pressure-fried samples tended to have higher percentage moisture and lower percentage fat than crispy, open-vat fried samples. Fat ranged from about 15% to 20%.

Animals↗
PubMed1985

Gastric emptying in exercised mice.

Male adult mice were fasted for 8-10 hr, given a 1% phenol red marker solution, and exercised on a treadmill. Mice exercised at 0.50 mph had significantly faster gastric emptying rates after 15 min of exercise than non-exercised mice; however differences were not significant for longer periods of time. Mice exercised at 0.25 mph did not have significantly different gastric emptying rates at any time interval studied. Larger volumes empty faster than smaller volumes from stomachs of exercised mice.

Animals↗