Nitro-imidazole radiosensitizer-induced toxicity in cynomolgus monkeys.

Intravenously administered nitro-imidazole radiosensitizer and alkylating anticancer compound CI-1010, designated as (R)-alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide, causes multiorgan toxicity in rodents, including retinal degeneration. This study determined the potential of CI-1010 to induce similar effects in nonhuman primates. One male and 1 female cynomolgus monkey were given single daily doses of CI-1010 intravenously for 5 consecutive days each week for 3 wk. Doses were escalated from 5 mg per kilogram of body weight in week 1 to 40 and 60 mg/kg in week 3. Postdosing emesis occurred in both monkeys at 5 mg/kg, and clinical signs at 40 and 60 mg/kg included more pronounced emesis, reduced food consumption, pallor, weakness, and body weight loss. At study termination, both monkeys had markedly reduced peripheral blood lymphocytes and moderately lowered erythrocyte, hemoglobin, and hematocrit levels, which correlate with a decreased total nucleated bone marrow cell count. At necropsy, the monkeys had pancytic bone marrow hypocellularity, multiorgan lymphoid depletion, pancreatic acinar cell apoptosis, testicular seminiferous tubular degeneration, and bilateral multifocal retinal degeneration involving the photoreceptor and outer nuclear layers. Ultrastructurally, selected inner and outer retinal rod segments were swollen and fragmented, a state associated with cytoplasmic condensation and pyknosis of the outer nuclear cell layer. Thus, CI-1010 induced toxicity of hematopoietic/lymphoid organs, retina, testes, and pancreas in monkeys, findings similar to those of previous studies in rodents.

Arrhythmia prevalence during ambulatory electrocardiographic monitoring of beagles.

Ambulatory ECG, approximately 18 to 24 hours in duration, were obtained from 113 male and 115 female clinically normal, purpose-bred Beagles. The ECG analyzed semi-automatically (44 males, 46 females) were evaluated for heart rate, ventricular ectopic complexes (VEC), bradycardia, and sinus pause; those analyzed by visual inspection (69 males, 69 females) were evaluated for VEC, second-degree atrioventricular block, and supraventricular escape complexes. Mean heart rate was highest at times of maximal human contact (eg, feeding, cleaning) and lowest at periods of no human contact. Bradycardia was observed in 27 of 44 males (61.4%) and 18 of 46 females (39.1%). Sinus pause was identified in 33 of 44 males (75%) and 30 of 46 females (65.2%). Frequency of bradycardia and sinus pause tended to vary inversely with mean heart rate. Ventricular ectopic complexes were detected in 18.8 to 26.1% of the ECG analyzed by use of either method. Although VEC runs and bigeminy were observed, most VEC were single and occurred sporadically. Second-degree atrioventricular block was observed in 6 of 69 males (8.7%) and 14 of 69 females (20.3%); episodes often were single and occurred sporadically. Supraventricular escape complex occurred in 2 of 69 females (2.9%). Multiple types of abnormal complexes were observed in 2 of 69 males (2.9%) and 6 of 69 females (8.7%). Among clinically normal Beagles, ambulatory electrocardiography detects a higher percentage of dogs with VEC, second-degree atrioventricular block, and supraventricular ectopic complexes than does resting electrocardiography.

Renal morphology and function in dogs after treatment with the angiotensin-converting enzyme inhibitor quinapril.

Angiotensin-converting enzyme (ACE) inhibitors have proven to be effective therapeutic agents for treatment of hypertension and congestive heart failure (CHF). Because of the role the renin-angiotensin system (RAS) plays in maintaining renal homeostasis, the effect these compounds have on renal function has been of interest. We assessed the effect of toxicologically significant doses of the new ACE inhibitor, quinapril, on renal function and morphology in dogs. Groups of 3 male beagle dogs were administered quinapril orally at daily doses of 0, 25, 125, or 250 mg/kg for 13 weeks. After treatment, animals were anesthetized and assessed for clinical pathologic and renal functional disturbances under normal conditions and after volume expansion and diuresis. Renal histopathology was conducted on perfusion-fixed kidney. No adverse effects on sensitive measures of renal function were detected; changes observed were consistent with the pharmacologic consequences of ACE inhibition. Decreased serum Na+ and Cl- (< 10%) and hematocrit at 125 and 250 mg/kg, twofold increases in serum creatinine and blood urea nitrogen (BUN) at 250 mg/kg, and decreased arterial blood pressure (BP) (20%) were observed at all doses. Under baseline conditions, urine flow increased 81-123% in quinapril-treated animals as compared with controls and urine specific gravities decreased 16% relative to controls at 125 and 250 mg/kg. Microscopically, juxtaglomerular hypertrophy was observed at all doses. At 250 mg/kg, minimal, widely scattered cortical tubular alterations were observed; glomerular lesions were not. No significant adverse effects of quinapril on renal morphology or function were observed at doses approximately 250 times the therapeutic dose.