Assessment of acute respiratory and cardiovascular toxicity of casiopeinas in anaesthetized dogs

Abstract

The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas((R)) in dogs was calculated to be 200 mg/m(2) for casiopeina III-ia and 160 mg/m(2) for casiopeina IIgly. Considering therapeutic dose ranges from 3.6 to 18 mg/m(2) for the former and 1.2 to 3 mg/m(2) for the latter, true therapeutic margin of safety varies from 4.7 to 23.6 mg/m(2) and from 20 to 50 mg/m(2), respectively. For both casiopeinas intravenous administration of the corresponding lethal dose in 100 ml of 5% dextrose solution in a time period of 30 min. induced death after an almost uneventful latency time period of 30-50 min. Then, after an apparently sudden onset, changes in blood gases indicated respiratory distress (PO(2) from 82.5% to 26.5% for casiopeina III-ia and from 88.6% to 37.5% for casiopeina IIgly; end-tidal CO(2) from 38 to 8.1 mmHg for the first and from 35.1 to 11.2 mmHg for the second, this was almost simultaneously confirmed by the onset of tachypnoea (from 16 to almost 60 breaths/min. for both casiopeinas) and by a drop in arterial blood pressure (from 117 to 51 mmHg for casiopeina III-ia and from 108 to 49 mmHg for casiopeina IIgly). Reflex tachycardia occurs at the beginning of intravenous administration followed by bradycardia a few minutes later (from 158 to 63 beats/min. for casiopeina III-ia and from 148 to 56 beats/min. for casiopeina IIgly). Finally, cardiac arrest occurred no later than 25 min. towards the end of these events lung oedema appeared as fluid dripping from the endotracheal tube. Death occurred in a mean of 15 +/- 5 min. S.D. from the beginning of the end of the latency period. For both casiopeina's data allow the speculation that lung oedema is caused by a joined toxicity to the lung capillary bed, and particularly to the heart. Carvedilol premedication for 8 days delayed the outcome of lung oedema by approximately 8 hr but could not prevent it.