Physical and theoretical models of anatomical and physiological systems are being used in our laboratory to study a variety of phenomena such as the transport of drugs into visceral organs and into the eye, the distribution of anti-HIV drugs, and hemodynamic phenomona in vascular systems. The following four projects are reported for this year: (1) A number of inflammatory and neoplastic diseases of the eye are currently 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 months. These would eliminate the need for frequent invasive intervention. A number of different drugs and device configurations are being evaluated in vitro. Finite element mathematical models that incorporate the geometry and physical properties of the device, the physico-chemical properties of the drug, and the physiology of the eye have been developed to assist in design of the devices. We are also developing non-invasive methods with MRI to study transport of drug surrogates in the eye compartments using MRI tracers. (2) We have developed a preliminary physiologic pharmacokinetic model of the distribution of a pro-drug, FddA, for treating HIV infection in the central nervous system of AIDS patients. The initial model is based on data from mice experiments. The model can be extended to other species, including monkey and humans. Such models are useful in guiding the design of more effective drugs that will be better absorbed in the gastrointestinal tract after oral doses, and also will penetrate adequately into the brain and cerebral spinal fluid. (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 have developed a localized 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. We have determined the infusate flow rate into mouse liver during retrograde intrabiliary infusions of solutions of molecules of molecular weights ranging from 342 to 2 million as a function of infusion pressure. Pharmacokinetic studies for sucrose have been performed in rabbits, comparing the distribution and clearance by iv, intrabiliary constant flow rate and intrabiliary constant pressure infusions. (4) We are investigating the use of magnetic resonance angiography (MRA) for making hemodynamic measurements in vascular systems, such as carotid arteries. We have fabricated plastic and glass flow models of normal and stenosed human carotid arteries and are characterizing the flow patterns and velocity fields in these """"""""phantoms"""""""" by means of particle image velocimetry (PIV) techniques. Finite element models of the carotid flow system will be used to corroborate the experimental results. With the well-characterized flow models, we can validate the flow measurements made by MRA in these in vitro phantoms at identical flow conditions. MRA is being studied as a non-invasive means of making hydrodynamic measurements in patients for detecting vascular pathologies such as stenosis.
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