Factors affecting urine reagent strip blood results in dogs and nonhuman primates and interpretation of urinalysis in preclinical toxicology studies: a Multi-Institution Contract Research Organization and BioPharmaceutical Company Perspective.

BACKGROUND: Urinalysis data in preclinical toxicology studies can be influenced by preanalytic and analytic factors which have the potential to confound interpretation. There is a paucity of information regarding positive reagent strip urinary blood reactions in healthy nonhuman primates (NHP) and Beagle dogs used in preclinical toxicology studies. OBJECTIVES: The objectives were (1) to establish historical control data for reagent strip urinary blood reactions in healthy NHP and Beagle dogs, (2) to determine the incidence of positive urinary blood reactions during predose and dosing phases, and (3) to determine if collection practice was a relevant parameter. METHODS: Historical control data from 2 institutions in the biopharmaceutical industry were retrospectively analyzed for reagent strip urinary blood reactions in healthy NHP and Beagles. The incidence of positive results between the 2 institutions with different urine collection practices and between males and females was compared. RESULTS: The incidence of positive urinary blood reactions in NHP was comparable between institutions (≤ 14% in males; ≤ 33% in females), while the incidence of positive urinary blood reactions in Beagles was more variable (≤ 77% in males; ≤ 69% in females), and higher in females during the dosing phase. CONCLUSIONS: Positive urinary blood results that could potentially be misinterpreted as toxicologically relevant were identified in healthy NHP and Beagles during predose and dosing phases. Different incidences of positive results between the 2 institutions were likely related to collection practices. Strategies to reduce feces and food contamination of collected urine samples should help minimize false-positive urinary blood reactions.

Comparison of cardiac troponin I and T, including the evaluation of an ultrasensitive assay, as indicators of doxorubicin-induced cardiotoxicity.

Cardiac troponin (cTn) has been utilized to assess acute myocardial injury, but the cTn response in active/ongoing chronic injury is not well documented. The purpose of this study was to characterize the cardiac troponin I (cTnI), cardiac troponin T (cTnT), high-sensitivity cTnI, hematology, and clinical chemistry responses in rats treated with doxorubicin. Rats treated with 1, 2, or 3 mg/kg/week (wk) of doxorubicin for 2, 4, or 6 wks were sacrificed after 0, 2, or 4 wks of recovery and compared to untreated controls and animals treated with doxorubicin/dexrazoxane (50 mg/kg/wk) or etoposide (1 and 3 mg/kg/wk). The incidence and mean magnitude of cTn response increased with increasing dose and/or duration of doxorubicin treatment. Conversely, dexrazoxane/doxorubicin was partially protective for cardiotoxicity, and minimal cardiotoxicity occurred with etoposide treatment. Both cTnI and cTnT effectively identified doxorubicin-induced injury as indicated by vacuolation of cardiomyocytes of the atria/ventricles. The association between the cTn responses and histological changes was greater at the higher total exposures, but the magnitude of cTn response did not match closely with histologic grade. The high-sensitivity cTnI assay was also effective in identifying cardiac injury. Alterations occurred in the hematology and clinical chemistry parameters and reflected both dose and duration of doxorubicin treatment.