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The objective of the study was to evaluate the cardiovascular and pulmonary safety of CuATSM/H2ATSM (NSC-D729307) when administered as a single intravenous bolus dose in beagle dogs. CuATSM is a positron emission tomography (PET) agent for imaging hypoxia, as well as, a potential therapeutic agent. This study was undertaken to determine the safety of Cu-ATSM. The formulation of the imaging drug primarily consists of Cu-ATSM and the parent ligand H2ATSM, which was the formulation used for testing. Doses of 0 (vehicle) and 0.3 mg/kg were administered. Each dose group utilized two male and two female dogs. Clinical observations, body temperatures, body weights, clinical pathology, cardiovascular data (systemic arterial blood pressures, heart rate, ECG waveforms and ECG interval measurements) and pulmonary data (respiratory rate, tidal volume and minute volume) were all evaluated. There were no test article-related changes associated with the clinical observations, body temperatures, body weights or clinical pathology. The hemodynamic parameters, systemic arterial blood pressures (systolic, diastolic, and mean) and heart rate, appeared to increase for the first 10-minute post-dosing period for all animals in both test article and vehicle groups. The 10-minute average pressures increased 10 to 15 mmHg and heart rates increased 15 to 30 BPM as compared to baseline. Pressures returned to near baseline by the second 10-minute interval whereas heart rates returned towards baseline slower. Similar pressure and rate increases in both test article and vehicle groups indicate that a component present in the vehicle was responsible for these elevations. When both sexes were considered, there were no differences between the test article and vehicle groups for first 4.5 hours when the animals were “in-slings” for simultaneous pulmonary determinations. Following the 4.5 hours post-dosing period, animals were returned to their home cages and cardiovascular monitoring continued until 72 hours post-dosing. For the 6 to 72 hour “in-cage” post-dosing period, there were no statistically significant differences between the test article and vehicle groups. No alterations in ECG intervals, rhythm or morphology were noted that could be attributed to the test article. No statistically significant alterations in the pulmonary parameters (respiratory rate, tidal volume, and minute volume) were observed. There were no alterations in the blood pressure, heart rate, ECG or pulmonary parameters that could be attributed to the administration of CuATSM/H2ATSM. The acute blood pressure and heart alterations seen in both test article and vehicle groups, are likely a response to the DMSO component of the formulations (Supported by NCI contract N01-CM-87028 and N01-CM-42200)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]