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Biomedical subjects

E S Vesell

Publications and source records attributed to E S Vesell.

At least 19 recordsLinked to original sources
PubMed1992

Do histocompatibility antigens influence the risk of head and neck carcinoma?

Associations were sought between specific histocompatibility antigens (HLA) of the human major histocompatibility complex and the incidence of head and neck squamous cell carcinoma (SqCC). Seventy sequential patients with SqCC and 217 control subjects from the same geographic region were typed for HLA-A, HLA-B, and HLA-DR loci. These results were compared. Multivariate statistical analysis using stepwise logistic regression revealed significant associations between the incidence of SqCC and HLA-B14, HLA-DR3, and HLA-DR4 as well as smoking and the sex-smoking interaction. The authors concluded that certain host factors, including genetic constitution, and behavioral characteristics (i.e., smoking) as well as tumor biology, can influence the development of SqCC. The mechanism(s) of these associations may involve as yet undefined relationships between HLA region genes and the immune response.

Carcinoma, Squamous Cell↗
PubMed1992

Hormonal and immunological regulation of 2', 5'-oligoadenylate synthetase activity in human peripheral blood mononuclear cells.

A newly developed method for assaying 2', 5'-oligoadenylate (2, 5A) synthetase activity by polyacrylamide gel electrophoresis was applied to peripheral blood mononuclear cells (PBMC) from normal subjects, HIV-positive subjects, and renal cell carcinoma (RCC) patients. Sex differences were observed in 2, 5A synthetase activity of PBMC from normal young adults, males having eightfold higher activities of this enzyme than females. Moreover, compared to values for postmenopausal (PM) females receiving estrogen replacement, untreated PM females had higher activities. Collectively, these results suggest that estrogen downregulates 2, 5A synthetase activity. Activities of 2, 5A synthetase were investigated in two disease states associated with altered immune function. In one patient with AIDS-related Kaposi's sarcoma, interferon-alpha (IFN-alpha) therapy increased 2, 5A synthetase activity twofold. In addition, combined therapy with interleukin-2 (IL-2) and IFN-alpha increased 2, 5A synthetase activities in eight of nine patients with RCC. Therefore, in patients receiving immunotherapy with IL-2 and IFN-alpha, our new assay could contribute to evaluation of immune stimulation. In general, studies in vitro confirmed these observations; however, exposure of PBMC from RCC patients revealed that in vitro IL-2 failed to induce this enzyme activity as it did in PBMC from normal volunteers.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Inhibition of urea transport across renal tubules by pyrazinoylguanidine and analogs.

In addition to glomerular filtration and passive back diffusion of urea, there occurs across the renal tubule bidirectional transport of urea inhibitable in one or both directions by specific analogs of pyrazinoylguanidine (PZG). Effect of PZG on the profiles of sodium and urea concentrations along the tubule (stop flow) are consistent with their independent transport. Inhibition of urea and sodium reabsorption by PZG is dose dependent. PZG does not inhibit potassium excretion.

Amiloride↗
PubMed1992

Pharmacokinetics of pyrazinoyl-guanidine, 3-aminopyrazinoyl-guanidine and their corresponding pyrazinoic acid metabolites in humans and dogs.

Pyrazinoylguanidine (PZG), 3-aminopyrazinoylguanidine (NH2PZG) and their pyrazinoic acid metabolites were measured by a new reverse-phase HPLC method in the serum of dogs and humans after administration of PZG, NH2PZG or 2-pyrazinoic acid (PZA). Kinetic properties of PZG and its principal metabolite, PZA, were studied in normal humans and also in azotemic patients, since PZG acts on renal tubules of patients with kidney failure to increase urea elimination. In humans and dogs, PZG was rapidly hydrolyzed to PZA. The serum half-life (t1/2) of PZG was 1 h. In turn, PZA was metabolized to 5-hydroxy-PZA, but no evidence appeared for conjugation of PZA with glycine. The apparent volume of distribution of PZG and its 3-amino analog, NH2PZG, exceeded that of total body water. In the dog the serum t1/2 for NH2PZG was twice that of PZG. Compared to PZG, NH2PZG and its metabolite, 3-aminopyrazinoic acid, were much stabler in vitro in serum and water.

Animals↗
PubMed1992

Pyrazinoylguanidine: antihypertensive, hypocholesterolemic, and renin effects.

In a single-blind, placebo-controlled study of 12 subjects diagnosed as having mild to moderate hypertension and hypercholesterolemia, pyrazinoylguanidine (PZG) in a dose of 600 mg twice daily for 4 weeks reduced systolic blood pressure and heart rate. Pyrazinoylguanidine also reduced diastolic pressures, but to a lesser extent. Pyrazinoylguanidine reduced total serum cholesterol and low-density lipoprotein (LDL). Regression analysis indicated a dose-dependent reduction of both total cholesterol and LDL by PZG, i.e., the higher the presenting serum concentration, the greater the reduction by PZG. The extent of the reductions produced by PZG in elevated cholesterols and LDLs was highly correlated (r = .949). Normal high-density lipoprotein levels were unchanged by PZG. Pyrazinoylguanidine increased 24-hour urine volume and urinary excretion of sodium. Serum Na+, K+, or Cl- concentrations were unaltered. Means for plasma aldosterone and renin activities tended to decrease, but these trends did not attain statistical significance. Pyrazinoylguanidine was well tolerated. An activity profile that includes antihypertensive effects as well as reduction in hypercholesterolemia without major impact on serum renin or electrolyte balance makes PZG an attractive candidate for the management of hypertension.

Aged↗
PubMed1991

Genetic and environmental factors causing variation in drug response.

Large pharmacokinetic variations, ranging in magnitude from 4- to 40-fold, often exist among the members of a given population. These variations create differences in risk of cancer by accelerating metabolic activation of certain environmental carcinogens in some subjects, while retarding such rates in other subjects. To identify specific genetic and environmental causes of large interindividual variations in these rates, several methods have been developed to probe hepatic cytochrome P-450 isozymes responsible for xenobiotic activation. In patients, dynamic interactions occur between genetic and environmental factors causing large interindividual variations in xenobiotic metabolism. Even the same patient can change dosage requirements with time and condition. Appropriate marker drugs can sensitively indicate pharmacokinetic capacity at any given time in a patient or normal volunteer. With respect to genetic factors, twin and family studies are the traditional methods used to test pharmacogenetic hypotheses. Representative examples are cited to illustrate how twin and family studies serve this purpose. Monogenic control of large interindividual variations in the activity of approx. 12 P-450 isozymes has been described. Individual metabolic pathways need to be investigated for drugs biotransformed by multiple pathways. Since many hepatic P-450 isozymes are extremely sensitive to perturbation by numerous environmental alterations, the critical role of selection criteria is stressed to assure that all subjects of twin and family studies are under as uniform environmental conditions as possible. Otherwise, the operation of genetic factors may be concealed or misinterpreted in studies that do not use gene cloning or protein sequence.

Biotransformation↗
PubMed1991

HLA antigens influence resistance to lung carcinoma.

The concept of genetic factors playing a role in the pathogenesis of lung cancer has gained increased attention. The present study was undertaken to reexamine the question of HLA antigen association with carcinoma of the lung. In a study of 90 patients, a significant association occurred between HLA-DR7 and resistance to lung cancer, after accounting for smoking status and sex. HLA class I antigens were also implicated. These results suggest that major histocompatibility complex loci affect carcinoma of the lung.

Carcinoma↗
PubMed1991

Genetic factors that regulate cytosolic epoxide hydrolase activity in normal human lymphocytes.

To determine whether genetic mechanisms control large variations in cytosolic epoxide hydrolase (cEH) activity of unstimulated lymphocytes from normal human subjects, cEH activity was measured in: a) 6 sets of monozygotic (MZ) twins and 6 sets of dizygotic (DZ) twins; b) 100 unrelated male subjects and c) 6 families. The twin study revealed predominantly genetic control (H2/1 = 0.95). Variability was markedly less within MZ (intrapair variance = 0.25) than DZ twins (intrapair variance = 6.33). In 100 unrelated male subjects the extent of interindividual variation was 11-fold. Unimodal distribution of values among 99 subjects encompassed a six-fold range. One outlier with very high activity clearly stood apart. Using the whole distribution curve we phenotyped members of 6 families. In the outlier's family, analysis of 3 generations suggested autosomal dominant transmission of high cEH activity. Analysis of the other 5 families and 12 sets of twins, all from the large unimodal distribution, was consistent with either monogenic or polygenic control of variations within this mode.

Cytosol↗
PubMed1991

Diet and cimetidine induce comparable changes in theophylline metabolism in normal subjects.

This study compared the effects of diet and cimetidine on theophylline metabolism and examined interactions between these effects. Twelve men received a high-protein diet for 15 days and at another time a high-carbohydrate diet also for 15 days. Cimetidine, 800 mg daily at bedtime, was administered on days 10 through 15 of each dietary period. Theophylline metabolism was studied after the administration of a single intravenous 3 mg/kg dose on days 8 and 15 of each dietary period. Changing from a high-protein to a high-carbohydrate diet decreased theophylline clearance by about the same extent (30% +/- 10%) as treatment with cimetidine (37% +/- 5% during a high-protein diet and 30% +/- 5% during a high-carbohydrate diet). Cimetidine did not significantly influence the effects of diet on theophylline clearance. Conversely, dietary composition did not influence the degree of inhibition of theophylline metabolism induced by cimetidine. Depending on the direction of the change in protein/carbohydrate ratio, the effects of diet and cimetidine treatment were either additive (theophylline clearance was most prolonged during the high-carbohydrate regimen with concurrent cimetidine administration) or counteractive (increasing the dietary protein/carbohydrate ratio at least partially counteracted the inhibitory effect of cimetidine). In individual subjects, effects of cimetidine on theophylline metabolism were somewhat more consistent than diet-induced changes. The results are further evidence that diet and drugs can have similar effects on hepatic drug metabolism rates in humans. Variations in diet over time and individual differences in responses to diet may provide the potential for considerable instability of drug metabolism rates in free-living subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗