Physical and theoretical models of vascular and anatomical systems are being used in our laboratory to study a variety of phenomena such as the distribution of anti-HIV drugs, hemodynamic effects in vascular disease, and transport of drugs into visceral tissues and the eye. Several projects have been emphasized this past year. (1) We have developed a physiologic pharmacokinetic model of the distribution of a pro-drug, F-ddA, for treating HIV infection in the central nervous system of AIDS patients. The model will guide the design of more effective drugs that will be better absorbed in the gastrointestinal tract after oral doses, and will also penetrate adequately into the brain and cerebral spinal fluid. (2) We are studying the interrelationship between blood flow patterns and the mass transport of macromolecules into the arterial wall as a possible explanation of lesion site preferences associated with atherosclerosis. We have fabricated a mechanical model of a branching flow system that is made of semi-permeable wall material to study convection / diffusion through the wall. We are theoretically simulating flow and transport in model arteries to corroborate our experiments. (3) Selective delivery of therapeutic agents to targeted hepatobiliary and renal tissues would make possible safer, more effective treatments by optimizing doses and reducing systemic toxicity. We are developing an infusion system for delivering drugs and gene vectors to the liver, gall bladder and urinary bladder under well-controlled and monitored conditions of pressure and flow. Pharmacokinetic studies will be performed, and infusate distribution will be measured in blood, liver and bladder. (4) A number of inflammatory and neoplastic diseases of the eye are now treated by repeated intravitreal drug injection. We are developing sustained drug release devices for intravitreal implantation that could release drugs for periods as long as five years. These would eliminate the need for frequent invasive intervention. A number of different drugs and device configurations are being evaluated. Mathematical models that incorporate the geometry and physical properties of the device, physico-chemical properties of the drug, and physiology of the eye are being developed to assist in design of the devices. (This is a continuation of Intramural Research Project Z01-RR- 10324-09 BEI.) - pharmacokinetic models, hemodynamics, regional drug delivery, sustained drug release
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