Safety of irbesartan in the treatment of mild to moderate systemic hypertension.

Nine multicenter, randomized, placebo-controlled studies were conducted to evaluate the safety and tolerability of the angiotensin II subtype 1 receptor blocker (AT1 blocker) irbesartan for the treatment of mild to moderate hypertension. After a 4- to 5-week placebo lead-in phase, patients were randomized to 4 to 12 weeks of double-blind therapy with either placebo (n = 641) or irbesartan (n = 1,965) at doses of 1 to 900 mg orally. All doses of irbesartan were well tolerated with no evidence of dose-related adverse effects.

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.

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.

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.

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.

Active transport of urea by mammalian kidney.

With the aid of three basic organic compounds, 2-pyrazinoylguanidine, 3-amino-2-pyrazinoylguanidine, and 3,5-diamino-6-fluoro-2-pyrazinoylguanidine, urea was shown to be secreted by the renal tubules of the dog both from the lumen and into the lumen independent of urine flow.

Hydrochlorothiazide-induced 131I excretion facilitated by salt and water.

Salt intake is restricted under clinical conditions for which thiazide diuretics are customarily used. Dietary iodide intake offsets any effect of thiazide on iodide loss. However, our correlation coefficients relating Na+ to Cl- to I- excretion indicate that as thiazide administration or sodium chloride intake increases renal Na+ and Cl- excretion, I- reabsorption by the nephron coordinately decreases.

Renal concentration gradients of salicylic acid and its metabolic congeners in the dog.

Salicylic acid and its principal metabolic product, salicyluric acid, are ultrafiltered at the glomeruli, secreted by the proximal segment and undergo back diffusion; the net effect being an accumulation of salicylates in the cortex. The back diffusion of salicylate is pH-sensitive (salicylurate is not) and its secretion is less sensitive than that of salicylurate to depression by probenecid. There was an increasing concentration gradient of these salicylates from outer cortex to innermost medulla.

Functional characteristics of the renal tubular secretion of amprolium, a quaternary organic base.

Amprolium [1-(4-amino-2-propyl-5-pyrimidinemethyl)-2-methyl-pyridinium chloride hydrochloridel is a basic (quaternary) organic compound. At very low plasma concentration, it is cleared by the kidney at a rate approximating renal plasma flow in the dog. Its renal clearance is not depressed by organic acids (p-aminohippurate or probenecid) but is reduced by the quaternary base, mepiperphenidol.