A Toxicity Study Of Norvancomycin Ydrochloride In Beagle Dogs

The objective of this study was to evaluate the potential toxicity of norvancomycinhydrochloride in Beagle dogs, to identify the possible target organs and reversibility of thetoxicity induced by the test article, to establish a lowest or no observed adverse effect level,and provided a basic reference for clinical use.Total 24 Beagle dogs were randomly assigned to three dose groups (27mg/kg, 54mg/kg,162mg/kg→108mg/kg) and one control group. Norvacomycin hydrochloride wasadministrated by daily iv drop to Beagle dogs, 6 times per week for consecutive 6 weekswith a 4 weeks recovery period. During the study, a general clinical observation wasconducted in all animals for morbidity and mortality. ECG, heamatology, clinical chemistry,urinalysis, fecal occult blood test and glomerular filtration rate (GFR) were conducted atscheduled period, Gross necropsy, microscopic examination and ultrastructure observationof the kidney were performed at the end of the administration and at the end of the recoveryperiod, respectively.Some changes were obvious, especially in high dose group. The body weights ofanimals were declined compared with the control group. Food consumption was alsodecreased, but they were generally comparable with those of the controls after 4 weeksrecovery, blood urea nitrogen (BUN), creatinine value increased significantly, but did notgo back to the control level after 4 weeks recovery. The amount of red blood cell andprotein in urine were increased significantly, cell and protein cast as well as inflammatorycell were also observed. Fecal occult blood test appeared positive in high dose group, GFRreduced significantly, it was improved to some extent after 4 weeks recovery.In histopathological examination, degeneration and necrosis of epithelium in proximaltubular and casts in renal tubular were detected in high and mid dose group. Stomachmucosa edema and ulceration and hemorrhage in intestine were observed. Seminiferoustubular partialy degeneration in testes of the male dogs were detected. Under transmission electron microscopy, mitochondria were swelled with broken ridges,increased autolysosome and interstitial fibrosis in tubular cell of kidney were noted,especially in high dose group. Some cell showed apopototic appearence and nucleuspyknosis. Most of changes indicated renal damage in these dogs.Conclusion: Norvacomycin hydrochloride could induce renal function injury, whichdeveloped into renal failure furthermore. Gastrointestinal injury detected was a secondaryreaction related to the renal function failure.The main target organ for toxicity was kidney under the conditional of this study.Nephrotoxicity caused by norvacomycin hydrochloride tend to be reversible after aobservation period of 4 weeks. At dose level of 162mg/kg/d animal death occured. Arelatively safe level of dosage was 27mg/kg/d.According to the results of toxicity study in beagle dogs, vitro tests of norvancomycinhydrochloride in human renal tubular epithelial cell line (HK-2) were conducted by cell HEstaining and MTT assay. The results of first stage showed that norvancomycinhydrochloride could lead morphological changes and proliferative inhibition in HK-2 cell tosome extent.