The preclinical toxicology of anisoylated plasminogen streptokinase activator complex.
The preclinical toxicological evaluation of anisoylated plasminogen streptokinase activator complex (APSAC) was designed with specific regard to the potential for immunogenic effects in animals arising from the high molecular weight of the complex. Animals were treated with multiples of the human dose by use of a dose regimen spanning that proposed clinically and in conventional repeat dose toxicity studies employing the maximum practicable dose level and duration. Few adverse effects were noted, despite the large doses administered with respect to the clinical dose. The thrombolytic activity of APSAC resulted in pronounced acute effects on blood coagulation times and fibrinogen levels in rats and dogs but there was little evidence of clinically relevant systemic toxicity in either species. Evidence of a possible effect on the liver was seen 24 hours after single doses much higher than the proposed human dose in the rat (40-fold higher) and dog (9-fold higher). No hepatic effects were apparent following repeated administration. The main adverse effect was focal acute myocarditis, which was seen only in rats of the Sprague Dawley strain. Administration of human plasminogen alone or in combination with streptokinase also produced this lesion, suggesting that plasminogen may play a central role in its appearance. Experiments in anaesthetised dogs showed APSAC to be devoid of undesirable haemodynamic effects. An intravenous acute toxicity study in rats with p-anisic acid, which is released on deacylation of APSAC, showed the levels of p-anisic acid which occur in humans to be of no toxicological significance. Finally, in a series of tests designed to investigate potential genetic toxicity, no mutagenic activity was detected.
Artus
J A
JA
Beecham Pharmaceuticals Research Division, Department of Toxicology and Pathology, Stock.
Cockburn
A
A
Fuller
J
J
McMurdo
A S
AS
White
D J
DJ
D000818:Animals; D016255:Anistreplase; D002319:Cardiovascular System / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000633:toxicity*; D062425:Hydroxybenzoate Ethers; D062385:Hydroxybenzoates / Q000633:toxicity; D051379:Mice; D009153:Mutagens; D010958:Plasminogen / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects; D013300:Streptokinase / Q000633:toxicity*
D005343:Fibrinolytic Agents; D062425:Hydroxybenzoate Ethers; D062385:Hydroxybenzoates; D009153:Mutagens; C004520:4-anisic acid; D016255:Anistreplase; D010958:Plasminogen; D013300:Streptokinase