There is experimental and clinical evidence that iv injection of the first 7 mm serum half-life of BTH was 2.1±0.2 mm (n= bovine testicular hyaluronidase(BTH) reduces the extent of 8), but increased to 9.4 mm in later serum samples. After the necrosis during myocardial infarction. The fate of iv adminis- injection of ‘25l-labeled BTH into the rat, protein-bound 1251 tered BTH has not been described. In this study, serum kinetics disappeared from serum with a half-life(3.4 mm) that is similar of BTH enzyme activity in dogs, rats and humans were deter- to the serum half-life of BTH enzyme activity (3.2 mm). Twenty mined. Tissue distribution of BTH was determined with an 1251 minutes after injection of 125l-labeled BTH, 30% of the label labeled preparation of purified BTH. Serum BTH activity initially was recovered in the liver. It is concluded that BTH activity has decreased exponentially with half-life 2.0±0.1 mm in dogs a short serum half-life of less than 1 0 mm in dogs, rats and with coronary artery occlusion(n= 8; 500 U of BTH/kg); 3.2 humans. In the rat model, the disappearance of serum BTH mm in humans with acute myocardial infarction(n= 2; 500 U activity results from physical removal of circulating BTH mole-of BTH/kg); and 3.2±0.3 mm in rats (n= 5; 5,000 U of BTH/ cules rather than serum inhibition or inactivation of BTH enzykg). In dogs BTH disappearance showed two distinct phases. matic activity. After injection of high dose BTH (5,000 U of BTH/kg), during

The first clinical application of iv BTH was reported in 1954 ied in a double-blind randomized clinical trial called the Mulwhen it was used for the treatment of cerebral edema (SaEarp, ticenter Investigation of the Limitation of Infarct Size (MILlS). 1954). In 1959, BTH was administered iv to patients with Despite 28 years ofexperimental and clinical experience with acute myocardial infarction and was reported to cause rapid iv BTH, very little is known about the basic pharmacologic resolution of electrocardiographic signs of ischemia(deOliveira properties of this agent. Data on the serum kinetics of BTH are et at., 1959), although no control patients were presented for important for understanding the mechanism of the BTH myocomparison. In 1972, iv BTH was shown to reduce myocardial cardial protective effect because iv BTH therapy limited to necrosis in a dog model of myocardial infarction(Maroko et al., the first 24 hr after coronary occlusion in the dog provides 1972), and this observation has been confirmed in a number of salvage of ischemic myocardium lasting at least 3 weeks after subsequent animal studies (Braunwald and Maroko, 1976; Mac- coronary occlusion(Kioner et at., 1978). lean et at., 1976; Kioner et al., 1977; Hillis et at., 1977). Two Measurement ofBTH activity is complicated by the presence controlled clinical trials of iv BTH in acute myocardial infarc- in mammalian serum of substantial amounts of naturally octions suggest that BTH can reduce human myocardial necrosis curring hyaluronidase activity(Bollet et at., 1963; DeSalegui as assessed by electrocardiographic techniques(Maroko et al., and Pigman, 1967) and of a circulating inhibitor of BTH(Ma-1975; Maroko et at., 1977). A recent report of a double-blind thews and Dorfman, 1955; Northup et at., 1973). Previous randomized trial of BTH in acute myocardial infarction de-studies of the serum kinetics of hyaluronidase have yielded scribed a trend toward lower mortality in the BTH-treated conflicting data (Duran-Reynolds, 1933; Seifter, 1950; Salkie, group of patients(DeGiovanni et al., 1981). Intravenous BTH 1980), perhaps due to the limitations of the assays available. In therapy of acute myocardial infarction is currently being stud- the …