Controlling the acute hemodynamic effects associated with IV administration of particulate drug dispersions in dogs
✍ Scribed by Lawrence de Garavilla; Nancy Peltier; Elaine Merisko-Liversidge
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 946 KB
- Volume
- 37
- Category
- Article
- ISSN
- 0272-4391
No coin nor oath required. For personal study only.
✦ Synopsis
Therapeutic and diagnostic agents can be formulated into colloidal or particulate dispersions to enhance their utility and possibly to modify their pharmacodynamics. Since certain of these agents are intended for intravenous administration, it is imperative that the cardiovascular safety profile be clarified. The objectives of the present study were I) to assess a variety of modes of administration and formulations which may affect the acute cardiovascular safety profile, 2 ) to identify 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 dispersions 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/min resulted in all dogs experiencing an acute hypotensive effect which peaked 2.5 min postdosing; animals fully recovered over a 60 min period. Reducing the concentration to 1% and the infusion rate to 0.5 mlimin 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 were consistently elevated, acutely, by I& 100-fold in those dogs that experienced hypotension. Pretreatment with antihistamines totally blocked the hypotension and acute splenectomy reduced the magnitude of the response by 50%. These studies represent the first report of the cardiovascular effects of dispersions of nanometersized particles. The results of these studies suggest that these dispersions can be safely administered intravenously to animals by controlling the rate of administration, reducing particle size and, if necessary, by pretreating with antihistamines.