© 2007 The Authors Doi: 10.1111/j.1742-7843.2006.00038.x Journal compilation © 2007 Nordic Pharmacological Society . Basic & Clinical Pharmacology & Toxicology , 101, 151–158 Blackwell Publishing, Ltd. Assessment of Acute Respiratory and Cardiovascular Toxicity of Casiopeinas in Anaesthetized Dogs Marco Leal-García 1 , Luis García-Ortuño 2 , Lena Ruiz-Azuara 3 , Isabel Gracia-Mora 3 , Jorge Luna-delVillar 4 and Héctor Sumano 1 1 Department of Physiology and Pharmacology and 2 Department of Pathology, School of Veterinary Medicine, National Autonomous University of Mexico, 3 Department of Inorganic Chemistry, School of Chemistry, National Autonomous University of Mexico, and 4 Clinic for Small Species, School of Veterinary Medicine, National Autonomous University of Mexico, Mexico City, México (Received August 28, 2006; Accepted November 9, 2006) Abstract: The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas ® 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 begin- ning 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. Casiopeinas are a new group of coordination compounds with a copper core and high antineoplastic activity in vitro versus various tumour cell lines [1,2]. More than 100 deriv- atives with demonstrated antineoplastic activity have been patented (Ruiz Ramírez L. U.S. Patent A 21, 1992. Number 51,027,005. U.S. Patent Re 35,458 February 18, 1997. U.S. Patent November 19, 1996. Number 5,576,326. 407,543 SECOFI; 1993). Its mechanism of action has not been fully defined; yet, it has been shown that casiopeinas uncouple the cell respirat- ory chain by interacting with succinate and 2-oxoglutarate dehydrogenases [3,4]. Also, these drugs are known to bind to DNA through formation of adducts with nitrogen moieties [5]. Particularly, casiopeina III-ia and casiopeina IIgly have so far shown the best in vitro activity and for this reason they have been chosen for this study. It has been postulated that casiopeinas may be less toxic than other antineoplastic drugs, based on the fact that copper participates in normal metabolic reactions [6] and that some of them appear to possess a superoxide dismutase activity [7]. A similar coordination compound, cisplatin, has well-defined ototoxic and nephrotoxic side effects [8,9], which have not been described for casiopeinas. In contrast, cardiotoxic side effects of cisplatin are regarded as moderate [10], but may be important for casiopeinas [11]. Observations in rodents to assess acute toxicity of casio- peinas have shown that the toxicity is directly linked to the rate at which the drug is injected [12]. Evidence from in vitro rat heart preparations suggests that toxic concentrations of casiopeina III-ia induce cardiac arrythmias, decrease in cardiac output and a drop in heart rate [13]. Acute toxicity in rats and mice as well as some clinical evidence from dogs suggest that approximately ten times the therapeutic dose (200 mg/m 2 for casiopeina III-ia ‘casIII-ia’ and 160 mg/m 2 for casiopeina IIgly ‘casIIgly’) induce either fatal pulmonary and/or cardiac toxicity [4,12]. Yet, actual measurements of cardiovascular or respiratory variables are not available at this moment. Hence, this study was carried out to establish the 99 lethal dose (LD 99 ) of two casiopeinas (fig. 1) (casio- peina III-ia, [(4,4-dimethyl-2,2-bipyridine) (acetylacetonate) copper II nitrate], 200 mg/m 2 ; and casiopeina IIgly, [(4,7- dimethyl-1,10-phenanthroline) (glycinate) copper II nitrate]), 160 mg/m 2 and to assess the cardiovascular and respiratory responses to LD 99 doses of these drugs. Such doses were chosen because they may confer dependable sequences of physiopathological events, necessary to project their poten- tial use in the target species. Author for correspondence: Héctor Sumano, Av. Universidad 3000, Coyoacán, México City, 04510, México (fax +52 55 56 22 59 80, e-mail sumano@servidor.unam.mx).