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Cardiac and Pulmonary Effects of High Doses of Cyclophosphamide and Isophosphamide¹

Wellcome Laboratories of Experimental Pathology, Variety Club Research Wing, St. Mary's Hospital Medical School, London, W2 1PG, United Kingdom

It has been reported that patients given 240 mg cyclophosphamide per kg over a 4-day period have shown electrocardiographic abnormalities, and 2 deaths accompanied by myocardial necrosis have been recorded. In view of these reports, dogs were given 500 mg cyclophosphamide per kg (an approximately equivalent dose on a surface area basis) in a single injection. They showed electrocardiographic evidence of myocardial damage (falling ventricular voltage and prolonged Q-T interval) and died in 4 to 6 hr of acute pulmonary edema. Postmortem examination showed early hemorrhagic myocarditis.

Dogs given isophosphamide died between 4.5 and 18 hr later with evidence of myocardial damage but without pulmonary edema. The absence of pulmonary edema with isophosphamide may be due to the fact that its metabolism differs quantitatively from that of cyclophosphamide or to failure to form a specific edema-producing product.

¹ Supported by grants from the Medical Research Council, the Cancer Research Campaign, and the Nuffield Foundation.

² To whom reprint requests should be addressed. Supported by USPHS Grant GM 1559-07. Present address: Department of Surgery, School of Medicine, Center for the Health Sciences, University of California, Los Angeles, Calif. 90024.

Received 11/ 5/73. Accepted 3/22/74.