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Biomedical subjects

K H Beyer

Publications and source records attributed to K H Beyer.

At least 19 recordsLinked to original sources
PubMed2000

Studies on pyrazinoylguanidine: a novel antihypertensive, hypoglycemic and lipolytic drug intended for adjunctive use in hypertensive patients with type 2 diabetes mellitus.

Herein are described the development and certain properties of a new drug, pyrazinoylguanidine (PZG), intended for use as an adjunct in the treatment of hypertensive patients with type 2 diabetes, formerly called noninsulin dependent diabetes mellitus. PZG is an analog of the potassium sparing diuretic, amiloride. However, in diabetic patients, amiloride exacerbates hyperglycemia and hyperlipidemia, whereas PZG reduces them. In several studies, PZG not only reduced elevated blood pressure in subjects with essential hypertension, but also downregulated the glucose fatty acid cycle in hypertensive patients with type 2 diabetes. PZG was well tolerated in all patients, as well as in normal subjects whose blood pressures and glucose metabolism were unaffected by PZG. However, in normal subjects made hyperglycemic by giving them hydrochlorothiazide, coadministration of PZG returned blood glucose concentrations to normal. Mechanisms for these effects of PZG in human subjects were investigated in both normal Sprague-Dawley rats and rats made diabetic with streptozotocin (STZ). In isolated rat adipocytes stimulated with theophylline, PZG downregulated both lipolysis and cyclic AMP concentrations. PZG, as well as insulin, increased adipose cyclic nucleotide phosphodiesterase activity, whereas theophylline reduced it. In perfused rat liver, PZG decreased gluconeogenesis and cyclic AMP concentrations. Collectively, these studies illustrate how the side effects (toxicity) of certain drugs, such as the tendency of thiazide diuretics to cause hyperglycemia and hyperlipidemia, can be modulated and even reversed by slight changes in the chemical structure of the molecule, specifically by removal of the 3,5-diamino and 6-chloro substituents on the benzene ring of amiloride to produce PZG.

Animals↗
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↗
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

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↗
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↗
PubMed1993

Effects of pyrazinoylguanidine on the glucose-fatty acid cycle in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Pyrazinoylguanidine (PZG) reduced the hyperglycemia, hyperinsulinemia, and hyperlipidemia of patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as of normal subjects receiving hydrochlorothiazide (HCTZ). Mechanisms are proposed by which PZG downregulated the elevated glucose-fatty acid cycle toward a more normal level in NIDDM patients and in non-diabetic subjects maintained on HCTZ. Despite maintenance of these NIDDM patients on their current antihypertensive medication, PZG reduced further their systolic and diastolic pressures. PZG was well tolerated by both normal and NIDDM patients.

Adult↗
PubMed1993

Contrasting effects of pyrazinoylguanidine and hydrochlorothiazide in patients with renal insufficiency.

A single blind crossover study with washout phases showed that pyrazinoylguanidine (PZG) reduced elevated serum concentrations of urea, triglycerides, and cholesterol in patients with renal insufficiency. Pyrazinoylguanidine was saluretic, without affecting serum potassium or glucose concentrations. The onset of PZG's antihypertensive effect occurred within 4 hours. In contrast, hydrochlorothiazide (HCTZ) increased serum concentrations of urea, triglycerides, and glucose, without affecting cholesterol.

Adult↗
PubMed1993

[Immunologic studies of barbiturates--the effect of structural characteristics on cross-reactivity].

Immunologic assay methods are widely used in chemico-toxicological analysis. Often test kits that are created for the detection of entire drug groups, e.g. barbiturates, are put into action. Within a drug-group the extent of the reaction with the test antiserum, the cross-reactivity, varies considerably. The influence of molecular structures on the cross-reactivity is examined for the ADX-test kit for the detection of barbiturates from urine. In order to obtain a result equal to or exceeding the threshold value (200 ng/ml secobarbital-equivalents) high barbiturate concentrations in urine are required in some cases.

Antibody Specificity↗
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↗