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.

Novel multivalent effects of pyrazinoylguanidine in patients with azotemia.

In patients with azotemia, urea excretion, urea clearance, and urea/creatinine clearance ratio were increased by pyrazinoylguanidine in a dose-related manner. Urine volume and excretion of sodium greater than chloride greater than potassium tended to increase during administration of pyrazinoylguanidine. Systemic arterial pressure declined while pyrazinoylguanidine was given at 300 or 600 mg b.i.d. for 3 days. At both doses pyrazinoylguanidine reduced plasma renin activity during the first 2 hours. Between days 1 and 3 only the high dose of pyrazinoylguanidine decreased plasma renin activity and plasma aldosterone levels. These findings with pyrazinoylguanidine are consistent with those of secretion of urea in human subjects across the renal tubules and indicate that this process is susceptible to pharmacologic alteration, even in the presence of severe renal insufficiency.

A sensitive gas-chromatographic assay using a nitrogen-phosphorus detector for determination of antipyrine and aminopyrine in biological fluids.

A method using gas chromatography with organic nitrogen-sensitive detection is described for measurement of antipyrine and aminopyrine concentrations in biological fluids. The analysis was performed isothermally on 3% SP-2250 DB after alkalinized saliva was extracted into chloroform. Phenacetin served as internal standard. Low oral doses of antipyrine (1.0-1.8 mg/kg) and/or aminopyrine (2 mg/kg) were measured accurately in saliva of normal human subjects. The standard curves for antipyrine and aminopyrine were linear from 0 to 10 microgram/ml. The coefficient of variation, determined at a salivary concentration of 2 microgram/ml, was 1.7% for antipyrine and 2.4% for aminopyrine. Saliva concentrations obtained by this method in normal human subjects after either an oral dose of antipyrine (18 mg/kg) or aminopyrine (9 mg/kg) agreed closely with those determined by the flame ionization gas-chromatographic method used to measure higher concentrations of antipyrine and aminopyrine. Antipyrine (1.8 mg/kg) administered concomitantly with aminopyrine (1 mg/kg or 2 mg/kg) to normal male volunteers prolonged mean saliva antipyrine half-life by about 25-33% compared to values obtained when these same subjects received the same dose of antipyrine alone.

Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man.

The mean half-life of antipyrine in the plasma of four sets of identical and four sets of fraternal twins after a single oral dose of 16 mg/kg of antipyrine was 12.7 +/-(SD) 3.3 hr. After 2 wk on sodium phenobarbital (2 mg/kg daily) the half-life of antipyrine in the plasma of these twins was reduced to 8.0 +/-(SD) 1.5 hr. Shortening of the plasma antipyrine half-life occurred in all but one of these 16 normal, adult volunteers, but there was considerable variation in the extent of reduction which ranged from 0 to 69%. Phenobarbital administration decreased individual variations in antipyrine metabolism as indicated by the smaller standard deviation of the plasma antipyrine half-lives after phenobarbital than observed initially and by the narrowed range of variation in plasma antipyrine half-lives from 2.8-fold initially to 1.8-fold after phenobarbital. These results suggest that some inducing agents may be used to minimize individual variations in drug metabolism where such variations create therapeutic problems by exposing patients who slowly metabolize certain drugs to toxicity and other patients who rapidly metabolize some drugs to undertreatment. During the course of phenobarbital administration blood levels were determined. Phenobarbital blood levels correlated neither with the final values for plasma antipyrine half-lives nor with the per cent reduction in plasma antipyrine half-life produced by phenobarbital treatment. There was a direct relationship between initial antipyrine half-lives and the per cent shortening of antipyrine half-life produced by phenobarbital administration: the shorter the initial antipyrine half-life, the less the reduction caused by phenobarbital treatment. Larger intrapair variances in fraternal than in identical twins indicate genetic, rather than environmental, control of phenobarbital-induced alterations in plasma antipyrine half-life.

Genetic control of dicumarol levels in man.

The mean half-life of dicumarol in the plasma of seven sets of identical and seven sets of fraternal twins after a single oral dose of 4 mg/kg was 43.6+/-SD 17.9 hr. Half-lives ranged from 7 to 74 hr in these 28 normal adults not receiving other drugs for 2 wk preceding dicumarol administration. Large differences among unrelated individuals in dicumarol half-life disappeared almost completely in identical twins, but persisted to some extent in most sets of fraternal twins. These results indicate that marked differences among subjects in dicumarol half-life are under genetic rather than environmental control. Reproducibility of values for dicumarol half-life was demonstrated. A direct relationship between the dose and the half-life of dicumarol occurred in unrelated volunteers administered progressively larger doses at 10-day intervals. Dose dependence of the half-life of a drug results in increased variability of half-life and hence in greater risks of toxicity on long-term therapy. Risks of toxicity on the one hand and of failure to anticoagulate adequately on the other can be reduced by determining dicumarol half-life before starting long-term therapy. Half-lives for dicumarol and phenylbutzone tended to be correlated in the 28 twins, but no correlation occurred between dicumarol and antipyrine half-lives.