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.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Intramural Research (Z01)
Project #
1Z01OD010324-04
Application #
6548615
Study Section
(BEPS)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Office of the Director, NIH
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Robinson, Michael R; Lee, Susan S; Kim, Hyuncheol et al. (2006) A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp Eye Res 82:479-87
Kim, Hyuncheol; Csaky, Karl G; Gravlin, Luisa et al. (2006) Safety and pharmacokinetics of a preservative-free triamcinolone acetonide formulation for intravitreal administration. Retina 26:523-30
Kim, Hyuncheol; Csaky, Karl G; Chan, Chi-Chao et al. (2006) The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res 82:760-6
Kim, Hyuncheol; Lizak, Martin J; Tansey, Ginger et al. (2005) Study of ocular transport of drugs released from an intravitreal implant using magnetic resonance imaging. Ann Biomed Eng 33:150-64
Amaral, Juan; Fariss, Robert N; Campos, Maria M et al. (2005) Transscleral-RPE permeability of PEDF and ovalbumin proteins: implications for subconjunctival protein delivery. Invest Ophthalmol Vis Sci 46:4383-92
Park, Juyoung; Bungay, Peter M; Lutz, Robert J et al. (2005) Evaluation of coupled convective-diffusive transport of drugs administered by intravitreal injection and controlled release implant. J Control Release 105:279-95
Kim, Hyuncheol; Csaky, Karl G; Gilger, Brian C et al. (2005) Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease. Invest Ophthalmol Vis Sci 46:655-62
Kim, Hyuncheol; Robinson, Michael R; Lizak, Martin J et al. (2004) Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging. Invest Ophthalmol Vis Sci 45:2722-31
Yim, Peter J; Cebral, Juan R; Weaver, Ashley et al. (2004) Estimation of the differential pressure at renal artery stenoses. Magn Reson Med 51:969-77
Lutz, Robert J; Warren, Kathy; Balis, Frank et al. (2002) Mixing during intravertebral arterial infusions in an in vitro model. J Neurooncol 58:95-106

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