CONTROLLING THE ACUTE HEMODYNAMIC-EFFECTS ASSOCIATED WITH IV ADMINISTRATION OF PARTICULATE DRUG DISPERSIONS IN DOGS

Therapeutic and diagnostic agents can be formulated into colloidal or particulate dispersions to enhance their utility and possibly to modif y their pharmacodynamics. Since certain of these agents are intended f or intravenous administration, it is imperative that the cardiovascula r safety profile be clarified. The objectives of the present study wer e 1) to assess a variety of modes of administration and formulations w hich may affect the acute cardiovascular safety profile, 2) to identif y the mechanism of the hemodynamic effect and 3) to identify a method( s) to prevent the effect. Polystyrene nanospheres were used as a model dispersion which was administered intravenously to anesthetized dogs while blood pressure and heart rate were being continuously monitored. The effect of varying the concentration and rate of infusion of the d ispersions was evaluated while the actual dose was kept constant at 0. 1 ml/kg body weight. Infusion of a 5% particulate suspension at 1 ml/m in resulted in all dogs experiencing an acute hypotensive effect which peaked 2.5 min postdosing; animals fully recovered over a 60 min peri od. Reducing the concentration to 1% and the infusion rate to 0.5 ml/m in eliminated the response. Systemic hypotension was more consistently associated with 200 nm diameter particles than with 100 nm particles and was totally absent with 50 nm particles. Plasma histamine levels w ere consistently elevated, acutely, by 10-100-fold in those dogs that experienced hypotension. Pretreatment with antihistamines totally bloc ked the hypotension and acute splenectomy reduced the magnitude of the response by 50%. These studies represent the first report of the card iovascular effects of dispersions of nanometer-sized particles. The re sults of these studies suggest that these dispersions can be safely ad ministered intravenously to animals by controlling the rate of adminis tration, reducing particle size and, if necessary, by pretreating with antihistamines. (C) 1996 Wiley-Liss, Inc.