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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
PubMed1999

Studies on pyrazinoylguanidine. 7. Effects of single oral doses in normal human subjects.

In a three-phase study, single oral doses of placebo, followed in 1 week by pyrazinoylguanidine (PZG; 900 mg), followed in 3 weeks by pyrazinoic acid (PZA; 300 mg) were given to 8 normal male subjects. Blood analyses performed 0, 2 and 4 h after administration of placebo or drug revealed that compared to mean 0 h values, PZG and also PZA, but not placebo, decreased mean values for serum glucose, insulin, C-peptide, triglycerides and free fatty acids. In all groups, serum potassium, urea, fibrinogen, high-density lipoprotein and low-density lipoprotein were unchanged. PZA, but not PZG, increased serum uric acid. PZG significantly reduced very-low-density lipoprotein whereas PZA only tended to do so. PZG was well tolerated and without any side effect, but in 7 of the 8 normal volunteers, PZA produced a variable vasomotor response over the blush area of the face and neck lasting from 30 min in 3 subjects to 4 h in 1 subject. Collectively, these results suggest generally similar metabolic responses of normal subjects to PZG and PZA after only a single oral dose of each. Previously, it was unrecognized that acute administration of PZG and PZA could produce such rapid metabolic changes.

Adult↗
PubMed1999

Metabolism and disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in rhesus monkeys.

Metabolism and disposition of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent rodent lung carcinogen, were studied in rhesus monkeys. In three males receiving a single i.v. dose of [5-3H]NNK (0.72 mCi; 4.6-9.8 microg/kg), urine was collected for 10 days. Within the first 24 h, 86.0 +/- 0.7% of the dose was excreted. NNK-derived radioactivity was still detectable in urine 10 days after dosing (total excretion, 92.7 +/- 0.7%). Decay of urinary radioactivity was biexponential with half-lives of 1.7 and 42 h. Metabolite patterns in urine from the first 6 h closely resembled those reported previously for patas monkeys; end products of metabolic NNK activation represented more than 50% of total radioactivity. At later time points, the pattern shifted in favor of NNK detoxification products (60-70% of total radioactivity in urine), mainly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide conjugates. One female rhesus monkey received a single i.v. dose of [5-3H]NNK (1.72 mCi; 28.4 microg/kg) under isoflurane anesthesia; biliary excretion over 6 h (0.6% of the dose) was 10 times less than predicted by our previously reported rat model. No preferential excretion of NNAL glucuronide was observed in monkey bile. Collectively, these results suggest that the rhesus monkey could be a useful model for NNK metabolism and disposition in humans.

Animals↗
PubMed1998

Pedigree analysis of a subject with abnormally slow renal elimination of 6-hydroxychlorzoxazone.

The family of an unusual subject was studied. When tested with chlorzoxazone (CX; 250 mg p.o.) on four separate occasions 5 years ago, this subject showed abnormally slow renal elimination of 6-hydroxychlorzoxazone (HCX), the primary CX metabolite. Since rates of CX biotransformation to HCX have served as a probe of the important cytochrome P450 isozyme, CYP 2E1, it was of interest that this unusual subject had normal conversion of CX to HCX. The present study revealed that over the past 5 years this subject accelerated his renal rate of HCX elimination which now lies at the slow end of the curve for normal subjects. His wife and 5 children all had more rapid rates than he for renal HCX elimination.

Adult↗
PubMed1998

Pyrazinoylguanidine in end-stage renal disease: a prospective, placebo-controlled pilot study.

Cardiovascular disease is the leading cause of mortality in end-stage renal disease (ESRD) patients receiving dialysis. In these patients, hypertriglyceridemia appears to increase the risk of accelerated atherosclerosis. The present placebo-controlled study evaluated prospectively lipid-lowering effects of pyrazinoylguanidine (PZG) in 6 ESRD patients undergoing maintenance hemodialysis. The design of the study entailed a placebo phase of 1 week followed by 3 weeks of PZG, 400 mg three times a day. Compared to placebo, PZG reduced serum triglycerides (PZG vs. placebo 370 +/- 171 vs. 414 +/- 182 mg/dl; p = 0.01). PZG also tended to decrease total cholesterol. In addition, PZG selectively lowered blood glucose in hyperglycemic patients. PZG was well tolerated; it did not interfere with hemodynamic parameters or alter liver function tests, nutritional parameters or dialysis clearance.

Administration, Oral↗
PubMed1997

Acetylator phenotype in relation to age and gender in the Baltimore Longitudinal Study of Aging.

This study investigated in healthy Caucasians the possible occurrence of age and gender-associated differences in NAT2 acetylator phenotype. Acetylator phenotype was determined after a single oral dose of 100 mg dapsone during testing of oral glucose tolerance in 510 Caucasian volunteers aged from 19 to 93 years, 339 men and 171 women, from the Baltimore Longitudinal Study of Aging. Participants were classified as slow or rapid acetylators according to the ratio of monoacetyldapsone to dapsone concentration in plasma. The ratio dividing the two groups, 0.30, was chosen after inspection of a probit plot and histogram of the monoacetyldapsone/dapsone ratios. Fifty-one percent of the participants were slow acetylators and 49% were rapid acetylators. Because there was no significant difference between the sexes in the monoacetyl-dapsone/dapsone ratios, all 510 participants were pooled into a single group for further analysis. In the combined analysis, there was a small decline in the prevalence of the slow acetylator phenotype with age, but this age effect accounted for less than 1% of the total variance in the monoacetyldapsone/dapsone ratio (r2 = 0.009). Also, it was shown in a group of 20 participants that administration of glucose with dapsone does not influence the determination of acetylator phenotype. In a large healthy Caucasian. American population, there was no biologically important effect of age or sex on the distribution of NAT2 acetylator phenotype.

Adult↗
PubMed1997

Studies on pyrazinoylguanidine. 5. Temporal effects over 24 weeks demonstrating attenuation of diabetic nephropathy in STZ-diabetic rats.

This study was designed to determine whether pyrazinoylguanidine (PZG) can attenuate diabetic nephropathy in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced within 1 week after a single intraperitoneal dose of STZ (45 mg/kg in 0.05 mol/l sodium citrate buffer). Diabetic rats were divided into five groups. Each group received by gavage for 24 weeks one of the following: vehicle (saline 10 ml/kg, b.i.d.), PZG (35 mg/kg, b.i.d.), captopril (15 mg/kg, b.i.d.), or hydrochlorothiazide (HCTZ, 20 mg/kg, b.i.d.). Insulin (NPH 7.5 U/day) was given subcutaneously. PZG treatment for 24 weeks reduced mortality and attenuated diabetic nephropathy, as indicated by reduced urinary excretion of total protein (79% of control), low-molecular-weight protein (12% of control), and albumin (60% of control). PZG also preserved renal structure and function. Compared to HCTZ or vehicle-treated rats, STZ-diabetic rats receiving either captopril or insulin exhibited decreased excretion of total protein, low-molecular-weight protein, and albumin, as well as amelioration of renal pathology. Collectively, these results indicate that PZG, as well as captopril and insulin, improved longevity and several indices of diabetic nephropathy in STZ-diabetic rats.

Analysis of Variance↗
PubMed1997

Studies on pyrazinoylguanidine. 6. Prevention of cataracts in STZ-diabetic rats.

This study was designed to determine whether pyrazinoylguanidine (PZG) can attenuate cataract development in streptozotocin (STZ)-induced diabetic rats. After a single, intraperitoneal dose of STZ (45 mg/kg in 0.05 mol/l sodium citrate buffer), Sprague-Dawley rats (250-260 g) were divided into three groups. Beginning a week later, each group of diabetic rats received twice daily for 24 weeks by gavage one of the following: vehicle (saline 10 ml/kg), PZG (35 mg/kg), or captopril (15 mg/kg). PZG treatment prevented the development of diabetic cataracts (p = 0.0009 compared to vehicle). In contrast to PZG, 38% of vehicle-treated rats exhibited cataracts after 12 weeks, increasing to 89% after 16 weeks. At week 16, 22% of captopril-treated rats exhibited cataracts, a 75% reduction from vehicle-treated rats (p = 0.4289 compared to vehicle; p = 0.0571 compared to PZG). These results indicate that captopril can attenuate cataract formation in STZ-diabetic rats, whereas PZG completely suppresses it.

Animals↗
PubMed1996

Studies on pyrazinoylguanidine. 1. Characterization of metabolic effects in diabetic rats.

Pyrazinoylguanidine (PZG) is a new antihyperglycemic, antihyperlipidemic drug. The current study reports on the development of an animal model in which the favorable metabolic effects of PZG, previously described in diabetic patients, could be reproduced and investigated. Adult male as well as female Sprague-Dawley rats received a single intraperitoneal dose (50 mg/kg) of streptozotocin (STZ). One week later, they received PZG (50 mg/kg i.p.) twice daily for a week. Compared to vehicle (saline-treated controls), PZG reduced plasma concentrations of glucose by 33-70%, triglycerides by 50-70%, nonesterified fatty acids by 17-27%, cholesterol by 10-50%, and glucagon by 18-20%. Hydrochlorothiazide given in a dose of 20 mg/kg i.p. b.i.d for 1 week induced metabolic effects opposite to those of PZG. In the Zucker fatty rat, PZG also lowered plasma glucose and lipid concentrations. These results indicate that PZG ameliorated the abnormalities of plasma glucose and lipid that characterize STZ-diabetic and Zucker fatty rats.

Analysis of Variance↗
PubMed1996

Studies on pyrazinoylguanidine. 2. Comparative drug and dose effects on glucose and lipid metabolism in streptozotocin-induced diabetic rats.

In streptozotocin (STZ)-induced diabetic rats, pyrazinoylguanidine (PZG) markedly reduced elevated fasting concentrations of plasma glucose, triglycerides, and cholesterol. In contrast, these parameters were unaffected by a sulfonylurea, glyburide, or by a biguanide, metformin. PZG's glucose- and lipid-lowering effects were dose-dependent. These metabolic effects were also investigated after: (a) pyrazinoic acid (PZA), a metabolite of PZG; (b) 3-amino-PZG, an analog of PZG, and (c) 3-amino-PZA, a hydrolytic product of 3-amino-PZG. PZA moderately reduced elevated fasting glucose and lipid concentrations in STZ-diabetic rats, suggesting partial medication of PZG's antidiabetic actions by PZA. Neither 3-amino-PZG nor 3-amino-PZA exerted any glucose- or lipid-lowering effect in STZ-diabetic rats.

Analysis of Variance↗
PubMed1996

Studies on pyrazinoylguanidine. 3. Downregulation of lipolysis in isolated adipocytes.

The effects of pyrazinoylguanidine (PZG) on lipolysis and intracellular cyclic AMP concentrations were investigated in isolated rat adipocytes. PZG reduced basal cyclic AMP concentrations and blocked in a concentration-dependent manner forskolin (1 mumol/l) and isoproterenol (1 mumol/l) stimulatory effects on intracellular cyclic AMP production and lipolysis. PZG's effects on hormone-sensitive lipase were investigated in the presence and absence of glucagon (1 mumol/l) or isoproterenol (1 mumol/l). PZG inhibited uncompetitively the induction of hormone-sensitive lipase by either glucagon or isoproterenol. PZG's antilipolytic effects appeared to result from downregulation of intracellular cyclic AMP concentrations. In adipose tissue, cyclic AMP controls lipolysis through hormone-sensitive lipase. PZG's downregulation of lipolysis and cyclic AMP concentrations was unaffected by adenosine deaminase or pertussis toxin, suggesting that PZG did not activate Gi, the inhibitory guanyl nucleotide regulatory protein.

Adipocytes↗
PubMed1996

Studies on pyrazinoylguanidine. 4. Upregulation of phosphodiesterase activity in rat adipose tissue and downregulation of gluconeogenesis and adenosine 3',5'-monophosphate concentrations in perfused rat liver.

In isolated rat adipocytes stimulated with theophylline (1 mmol/l), pyrazinoylguanidine (PZG) downregulated both lipolysis and cyclic AMP concentrations, raising the possibility that PZG stimulates adipose insulin-sensitive phosphodiesterase. To investigate this directly, we measured PZG's effects on phosphodiesterase activity in rat adipocytes. PZG (10 mumol/l) as well as insulin (0.1-1 mU) increased adipose phosphodiesterase activity, whereas theophylline reduced it. Also investigated were PZG's effects on gluconeogenesis and cyclic AMP in perfused rat liver where PZG decreased gluconeogenesis and cyclic AMP concentrations.

Adipocytes↗
PubMed1996

Reflections from distant cuvettes.

The main events described in this essay occurred between 30 and 40 years ago. Care has been exercised to describe these events as accurately as possible. I have confined myself to the facts as best I can recollect them now. I have also attempted to recapture the spirit and ambiance of the individual laboratories, their directors, and the scientists working there, leaving philosophical interpretations to others. I feel privileged to have been permitted to work in these laboratories and with these scientists. Despite present difficulties besetting those who desire to devote their lives to scientific research, I encourage these hardy souls to pursue their vision and wish for them the good fortune I had in being associated with so many supportive, brilliant, and interesting researchers.

Animals↗
PubMed1994

Pyrazinoylguanidine downregulates the glucose fatty-acid cycle in hypertensive, hyperinsulinemic diabetic patients.

Eight hypertensive patients with noninsulin dependent diabetes mellitus (NIDDM) were administered the experimental drug pyrazinoylguanidine (PZG) either alone or in combination with calcium-channel or beta-blockers. This treatment appeared to "downregulate" the glucose fatty acid cycle and reduced both systolic and diastolic blood pressures and mean body weight. Patients served as their own controls in this dose-escalation study, which included placebo treatment (baseline) 3 weeks, 300 mg PZG for 3 weeks and 600 mg for 3 weeks. PZG reduced increased serum concentrations of free fatty acids (FFA), glucose, and triglycerides (TG). TG concentrations correlated inversely with serum HDL-cholesterol concentrations. The beta-blockers used by several patients increased their FFA, glucose, insulin and TG concentrations, as well as blunting their response to PZG. The calcium-channel blockers exerted these effects to a much lesser extent. PZG reduced or abolished glycosuria, related to PZG's capacity to decrease hyperglycemia. Withdrawal of PZG restored glycosuria, as blood sugar increased. PZG was well tolerated. No patient reported any adverse effect or missed a weekly clinic visit (12 weeks). PZG deserves further study as supplementary and/or replacement therapy in NIDDM patients who are hypertensive and hyperlipidemic.

Adult↗