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  • Title: High and constant plasma levels of tissue plasminogen activator and PEG-hirudin can be achieved by subcutaneous delivery.
    Author: Humphries J, Lattimer C, Smith A, McGuinness CL, Whitton C, Gaffney PJ, Burnand KG.
    Journal: Thromb Res; 1997 Jul 01; 87(1):123-9. PubMed ID: 9253807.
    Abstract:
    Intramural thrombosis is a consistent finding in the arteries of patients who die following coronary angioplasty. This thrombosis is thought to have a role in restenosis, which is a common complication of coronary angioplasty. It has been hypothesised that antithrombotics such as hirudin or tissue-type plasminogen activator (tPA), may be therapeutically useful following angioplasty. This report describes the bioavailability of both agents following subcutaneous (sc) injection in cholesterol-fed rabbits. Intravenously delivered tPA has a half-life of 3-5 minutes. The half-life of intravenously administered hirudin is less than one hour in many species. In order to prolong the duration of action recombinant hirudin was conjugated to polyethylene glycol (PEG). Polyethylene glycol conjugated recombinant hirudin (PEG-rH) (0.7 mg/kg) antigen and activity were measurable after just 1 hr, reaching a maximum (663 and 884 ng/ml respectively) at 12 hours. Significant levels were present in rabbit plasma 24 hours after injection. Subcutaneously delivered recombinant (r-tPA) (1 mg/kg) was present in significant amounts 1 hr after injection, reaching a maximum (92 IU/ml) at 2 hours. Levels of tPA at 9 hours were approximately 80x normal circulating levels. High and constant levels of functional activity of both PEG-rH and r-tPA in rabbit plasma are achieved by subcutaneous delivery.
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