Four-week oral toxicity studies of the new quinolone antibacterial agent cetefloxacin tosylate in rats and marmoset monkeys.

Four-week oral toxicity studies with cetefloxacin tosylate ((-)-7[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-1-(2,4- difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid tosylate, CAS 141725-88-4 (base), E-4868.Ts) a new quinolone antibacterial agent, were performed in Sprague-Dawley rats and marmoset monkeys at doses of 100, 450, 2000 mg/kg/d and 25, 50, 125, 300 mg/kg/d, respectively. In rats, due to its toxicity the high dose was decreased to 1000 mg/kg/d after 3 days of treatment. Mortality was recorded among high dose rats receiving 2000 or 1000 mg/kg/d. Rats receiving dosages of 450 or 2000/1000 mg/kg/d showed less activated mandibular lymph nodes, cortical lymphocyte depletion of mandibular and/or mesenteric lymph nodes, atrophy of the white pulp of the spleen, cortical atrophy of thymus and thymic apoptosis. Enlarged caeca, increased water consumption and variations in plasma electrolyte levels were observed in animals receiving these dosages and in male rats receiving 100 mg/kg/d. Low neutrophil counts were observed in rats receiving dosages of 100 or 450 mg/kg/d, and increased alkaline phosphatase and alanine transaminase plasma levels and slightly decreased plasma protein levels in females receiving 450 or 2000/1000 mg/kg/d. Marmosets receiving dosages of 50 mg/kg/d and above displayed several clinical signs which included emesis, diarrhoea, ptosis, occasional episodes of under- and overactivity, and excessive scratching activity. Skin reddening was observed during the first week of treatment in marmosets receiving 300 mg/kg/d. On the basis of the results obtained it can be concluded that the non-toxic doses of E-4868. Ts after 4-week oral administration in rats and marmoset monkeys were 100 and 25 mg/kg/d, respectively.

Subchronic toxicity of the new quinolone antibacterial agent irloxacin in beagle dogs.

The subchronic oral toxicity of the new quinolone antibacterial agent irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone- 3-carboxylic acid, CAS 91524-15-1) in Beagle dogs was investigated in studies of 4 and 29 weeks of duration. In both studies animals received dosages of 10, 120 and 1400 mg/kg/d. Pale coloured faeces were seen on animals receiving 1400 mg/kg/d. Animals receiving 1400 mg/kg/d for 29 weeks showed an increased incidence of wax in the ears during the latter half of the treatment period, and one male and one female experienced transitory locomotive difficulties at the end of the first week of treatment. The liver was identified as the target organ for toxicity with presence of lipofuscin in the hepatocytes of animals receiving 120 or 1400 mg/kg/d for 29 weeks. Slight increases in liver weights were observed in animals receiving 120 or 1400 mg/kg/d for 4 weeks, and in all groups receiving irloxacin for 29 weeks. However, no histopathological findings were observed in the liver of animals receiving irloxacin for 4 weeks or those receiving 10 mg/kg/d for 29 weeks. Other relevant findings observed in the 29 week study were increased triglyceride, phospholipid and cholesterol levels in males receiving 120 mg/kg/d and animals receiving 1400 mg/kg/d, increased albumin and decreased beta-globulin concentrations in females receiving 1400 mg/kg/d, and prolonged activated partial thromboplastin time in animals receiving 1400 mg/kg/d. On the basis of the results obtained it is concluded that 10 mg/kg/d can be considered as the non-toxic dose after 29 week oral administration of irloxacin in dogs.

Acute and subchronic toxicity studies of the new quinolone antibacterial agent irloxacin in rodents.

Irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1, 4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS 91524-15-1), a new quinolone antibacterial agent, was administered as a single dose to rats and mice both by oral and intraperitoneal route in oder to study its acute toxicity. Its oral subchronic toxicity was also assessed by treating rats for 4 and 13 weeks. The results obtained showed that irloxacin was well tolerated after single administration in mice and rats, with LD50 values above 2000 and 5000 mg/kg for intraperitoneal and oral administration, respectively. In the oral subchronic toxicity studies, the histopathological examination performed after the 13-week treatment period confirmed the kidney as the target organ for toxicity. Increased presence of lipofuscin in the kidneys was observed in animals receiving 2000 or 450 mg/kg/d, and degeneration and/or dilatation of proximal renal tubules and chronic interstitial nephritis in males receiving these dosages. No histopathological findings were observed in the kidneys of animals receiving 100 mg/kg/d for 13 weeks. Other relevant findings were, presence of dark or cloudy urine with slightly lower pH in animals receiving dosages of 450 mg/kg/d and above, increased urinary protein concentration in animals receiving 2000 or 450 mg/kg/d, and increased plasma urea concentration in those receiving 2000 mg/kg/d. Moreover, increased plasma phospholipids and total cholesterol concentration, and increased liver and kidney weights were observed among treated animals. As a summary, the results have shown that irloxacin has a low acute toxicity in both mice and rats. For repeat oral administration in rats, 100 mg/kg can be considered as the non-toxic effect level after a treatment period of 13 weeks.

A study of reference parameters in the CFY (remote Sprague-Dawley) rat.

The reference parameters for 10- and 19-week old CFY (remote Sprague-Dawley) rats fed powdered feed have been studied: growth curves, food consumption, ophthalmoscopy, results of urinalyses and hematological and biochemical assays, and absolute and relative organ weights. Detailed information is given of instrumentation and methods employed, of the animals, strain and environment, and of blood-sampling technique. In general, the results obtained were similar to those previously reported in literature.

Acute, subacute and subchronic toxicity of besulpamide.

The acute oral and intraperitoneal toxicity of besulpamide has been studied in the rat and mouse, together with the subacute and subchronic oral toxicity in the rat at doses of 0, 125, 500 and 2000 mg/kg/day. The LD50 is in excess of 12,800 mg/kg by the oral route and in excess of 5,000 mg/kg intraperitoneally. Toxic signs were very slight and autopsy did not reveal lesions which could be attributed to the test substance. In the subacute and subchronic toxicities the characteristic effects of the diuretic activity were observed. In the subchronic toxicity study significant, although not dose-related, increases were observed in calcium, alkaline phosphatase, GPT and GOT levels. A decrease in liver-weight of the female animals with respect to controls was also noted. Histopathological studies did not reveal any changes which could be attributed to administration of the test substance. Besulpamide has demonstrated the typical effects of diuretics which are derivatives of 3-sulfamoyl-4-chlorobenzoic acid and in acute, subacute and subchronic tests by the oral route in the rat it has shown itself to be a substance of very low toxicity.