The tubular handling of gentamicin (G) and its intrarenal distribution were determined to elucidate the mechanism of G accumulation in the kidney. At a serum level of 11.1 ± 0.5 μg/ml (10 animals), as maintained by constant infusion for 5 h, serum Na + and K + , arterial pressure, effective renal plasma flow and glomerular filtration rate remained undisturbed. The clearance values in milliliters per minute for G, inulin, and p -aminohippuric acid were 40.3 ± 1.8, 49.9 ± 2.8, and 132 ± 14, respectively. The ratio of clearance of G to clearance of inulin was 0.82 ± 0.04 ( P < 0.005), suggesting net reabsorption of G by the renal tubules. The renal cortex/serum ratio for G was 11.9 ± 2.1, and the medulla/serum ratio was 2.7 ± 0.4, indicating greater uptake of G by the cortex. The extraction ratio of p -aminohippuric acid was 0.74 ± 0.03. In contrast, the extraction ratio of G was 0.20 ± 0.03, which was significantly lower than that of inulin (0.30 ± 0.04). It is concluded that the accumulation of G in the cortex was due to tubular reabsorption. Probably some of the reabsorbed G became trapped in the epithelial cells after crossing the luminal membrane, whereas some returned to the circulation.

A series of 9-[(aminoalkyl)thio]-9H-xanthenes (3-6) and 5-[(aminoalkyl)thio]-5H-[1]benzopyrano[2,3-b]pyridines (7-10) possessing gastric antisecretory activity in the rat and dog is described Many of the compounds possessed good activity in the pylorus-ligated rat and several inhibited histamine-stimulated gastric acid secretion in the dog. The mechanism of acid secretion inhibition is not related to anticholinergic or histamine (H2) receptor antagonism.

Investigation of the interrelationship between structure, antiulcer activity, and toxicology screening data derived from a series of compounds selected from structure-activity studies directed toward identifying a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (1), has identified 3-(cyanomethyl)-2,7-dimethyl-8-(phenylmethoxy)imidazo[1,2 -a]pyridine (5), 3-amino-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine (6), and 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine (7). These analogues exhibit a combination of antisecretory and cytoprotective activity in animal models, while eliminating the adverse effects of the prototype 1. One of these, 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyrazine, Sch 32651 (7), has a profile meeting all criteria.

Netilmicin (Sch 20569), a new semisynthetic aminoglycoside, was studied for its effects on kidney function and mechanisms by which it is handled by the kidneys. Measurements of glomerular filtration rate (GFR) and urinalysis in chronic rat studies indicated that the nephrotoxicity of netilmicin was remarkably less than that of gentamicin. Gentamicin caused a dose-related reduction in GFR in association with glucosuria and elevated fractional excretion of K+. By contrast, high doses of netilmicin produced only slight reduction in GFR with increased fractional excretion of K+ but without glucosuria. In separate experiments, rats were shown to excrete 71 to 90%o of netilmicin or gentamicin in 24 h after daily intramuscular administration of doses of 20 or 40 mg/kg for 4 days. In acute experiments on anesthetized dogs, GFR and renal plasma flow were unaffected at serum levels of 11.0 + 0.6 ug/ml maintained by constant infusion of netilmicin for 5 h. The renal clearance of netilmicin was significantly correlated with GFR. The urinary output of netilmicin was 80.0 ± 4.2% ofthe infusion rate and was independent of urine flow over the range of 0.04 to 0.33 ml/kg per min. Preferential accumulation of netilmicin occurred in the renal cortex; the cortex-serum and medulla-serum ratios were 9.9 ± 1.2 and 4.2 + 0.6, respectively. In addition, the extraction ratio of netilmicin, which was lower than that of inulin, suggested that netilmicin reabsorption occurs in the proximal tubule and results in cortical accumulation. It is concluded that netilmicin, like gentamicin, is excreted by the dog kidney by glomerular filtration plus limited reabsorption. However, the new drug is characterized by low intrinsic nephrotoxicity in rats.Netilmicin (Sch 20569) is a newly described semisynthetic aminoglycoside (18). Its effect on kidney function was evaluated in comparison with gentamicin in rats chronically treated with the drugs. In addition, urinary excretion of the drugs was measured after repeated administration. The renal handling of netilmicin was investigated in acute dog experiments to determine the method of drug excretion. The intrarenal distribution was studied to determine the extent and location of drug accumulation in the dog.(This work was presented in part at the 16th Interscience Conference of Antimicrobial Agents and Chemotherapy, Chicago, 1976.) MATERIALS AND METHODS Renal function study in rats. Seventy-eight male Sprague-Dawley rats (180 to 200 g) were divided into 13 groups of six each. They were injected intramuscularly (i.m.) with saline, gentamicin (batch no. GMC-4M-6231), or netilmicin (batch no. 7733-15) according to the dosing schedule listed in Table 1.Twenty-four hours after administration of the last dose, the animals were anesthetized by intraperitoneal injection of 100 mg of thiobarbital (Inactin) per kg. Body temperature was maintained at 38°C. After tracheostomy, the left jugular vein was cannulated for blood sampling and the right femoral vein was cannulated for fluid infusion. Carotid arterial bloo...

Gastric necrosis was induced in the rat by oral administration of absolute ethanol. Carbenoxolone sodium, administered orally, but not intravenously, reduced the severity of ethanol-induced lesions in a dose-responsive manner. Maximum inhibition of lesion formation occurred when carbenoxolone was administered 15 min before ethanol. Our results suggest that carbenoxolone, like prostaglandins, is cytoprotective to the rat gastric mucosa. Similarities in the time response for cytoprotection by these two compounds suggest that they exert their effect by a common mechanism.