Abstract
Continuous intravenous infusion allows the intended clinical dosing regime to be better evaluated during preclinical studies. Depending on the test material and vehicle, infusion for up to 6 months in primates and 12 months in beagle dogs is possible, but 28 days is the most frequent duration. Under general anesthesia, medical grade catheters are placed in the vena cava via the femoral vein, passed subcutaneously, and exteriorized between the scapulae. A jacket and tether system are used to connect the catheter to an external pump for dosing and the animals are allowed to move freely within the cages. Dosing usually commences after a 1-week recovery period. Body weight gain, food intake, and general observations indicate that the procedure does not adversely affect the normal laboratory behavior of the animals. Test article infusion periods from a few minutes up to 24 h a day, 7 days a week are used; a low infusion rate ofsaline is used for the balance of the 24-h period. Dosage volumes up to 120 ml/kg/day can be infused for 28 days and larger volumes for shorter periods. Up to three separate catheters can be inserted to allow coadministration of compounds for assessment of potential interactions. Body weight, ophthalmoscopy, blood sampling, electrocardiography, and indirect blood pressure measurement can be performed during infusion. Histopathologic common changes in all species include thrombosis, proliferation of vascular intima, and various local inflammatory changes at the infusion site in the vicinity of the catheter tip. These generally are considered to be due to physical irritation by the catheter. Secondary changes include pulmonary microemboli or thrombosis and histiocytosis in hepatic sinusoids often with erythrophago-cytosis. The main findings associated with infusion of very large volumes are reticulocytosis and increased hematopoiesis. These spontaneous findings must be distinguished from those possibly related to administration of the test material and/or vehicle.