From: Doug Skrecky (oberon@vcn.bc.ca)
Date: Tue Dec 22 1998 - 15:56:26 MST
Citations: 1-9
<1>
Authors
Ahsan N. Korsunsky Z. Beyer KH Jr. Vesell ES.
Institution
Department of Medicine, The Milton S. Hershey Medical Center, Pennsylvania
State University College of Medicine, Hershey, PA 17033, USA.
Title
Pyrazinoylguanidine in end-stage renal disease: a
prospective, placebo-controlled pilot study.
Source
Pharmacology. 57(2):96-103, 1998 Aug.
Abstract
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.
<2>
Authors
A-Rahim YI. Beyer KH Jr. Vesell ES.
Institution
Department of Pharmacology, Pennsylvania State University, College of
Medicine, Hershey 17033, USA.
Title
Studies on pyrazinoylguanidine. 2. Comparative drug and dose
effects on glucose and lipid metabolism in streptozotocin-induced diabetic
rats.
Source
Pharmacology. 52(3):145-52, 1996 Mar.
Abstract
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.
<3>
Authors
Follansbee MH. Beyer KH Jr. Vesell ES.
Institution
Department of Pharmacology, Pennsylvania State University College of
Medicine, Hershey 17033, USA.
Title
Studies on pyrazinoylguanidine. 6. Prevention of cataracts
in STZ-diabetic rats.
Source
Pharmacology. 54(5):256-60, 1997 May.
Abstract
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.
<4>
Authors
Follansbee MH. Beyer KH Jr. Griffith JW. Vesell ES.
Institution
Department of Pharmacology, Pennsylvania State University, College of
Medicine, Hershey 17033, USA.
Title
Studies on pyrazinoylguanidine. 5. Temporal effects over 24
weeks demonstrating attenuation of diabetic nephropathy in STZ-diabetic rats.
Source
Pharmacology. 54(5):241-55, 1997 May.
Abstract
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.
<5>
Authors
A-Rahim YI. Beyer KH Jr. Vesell ES.
Institution
Department of Pharmacology, Pennsylvania State University College of
Medicine, Hershey 17033, USA.
Title
Studies on pyrazinoylguanidine. 1. Characterization of
metabolic effects in diabetic rats.
Source
Pharmacology. 52(3):135-44, 1996 Mar.
Abstract
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.
<6>
Authors
Vesell ES. Chambers CE. Seaton TD. Passananti GT. Demers LM. Beyer KH
Jr.
Institution
Department of Pharmacology, Pennsylvania State University College of
Medicine, Hershey 17033.
Title
Pyrazinoylguanidine downregulates the glucose fatty-acid
cycle in hypertensive, hyperinsulinemic diabetic patients.
Source
Journal of Clinical Pharmacology. 34(12):1234-45, 1994 Dec.
Abstract
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.
<7>
Authors
Vesell ES. Chambers CE. Passananti GT. Demers LM. Beyer KH Jr.
Institution
Department of Pharmacology, Pennsylvania State University College of
Medicine, Hershey 17033.
Title
Effects of pyrazinoylguanidine on the glucose-fatty acid
cycle in normal subjects and patients with non-insulin-dependent diabetes
mellitus.
Source
Journal of Clinical Pharmacology. 33(9):823-31, 1993 Sep.
Abstract
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.
<8>
Authors
Beyer KH Jr. Ward TD. Vary JE. Gelarden RT. Knutson DW. Vesell ES.
Institution
Department of Pharmacology, Pennsylvania State University College of
Medicine, Hershey 17033.
Title
Contrasting effects of pyrazinoylguanidine and
hydrochlorothiazide in patients with renal insufficiency.
Source
Journal of Clinical Pharmacology. 33(6):554-61, 1993 Jun.
Abstract
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.
<9>
Authors
Chambers CE. Vesell ES. Helm C. Passananti GT. Beyer KH Jr.
Institution
Department of Medicine, Pennsylvania State University College of Medicine,
Hershey 17033.
Title
Pyrazinoylguanidine: antihypertensive, hypocholesterolemic,
and renin effects.
Source
Journal of Clinical Pharmacology. 32(12):1128-34, 1992 Dec.
Abstract
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.
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