IMPROVED THERAPY FOR CNS TOXOPLASMOSIS

CEREBRAL TOXOPLASMOSIS IS THE MOST COMMON OPPORTUNISTIC DISEASE AFFECTING THE BRAIN OF PATIENTS WITH ACQUIRED IMMUNEDEFICIENCY SYNDROME (AIDS). SULFONAMIDE TREATMENT IS INITIALLY EFFECTIVE IN TREATING THE INFECTION, BUT THE REGIMEN OFTEN CAUSES SIDE EFFECTS THAT LIMIT THERAPY, SUBSEQUENTLY PROVOKING RELAPSE. THIS RESEARCH SEEKS TO DEVELOP BRAIN-TARGETED DELIVERY FORMS OF THE ACTIVE ANTITOXOPLASMA AGENTS SUCH AS SULFADIAZINE. THE METHOD CHOSEN TO ACHIEVE SELECTIVITY IS A DIHYDROPYRIDINE = PYRIDINIUM SALT, REDOX-TYPE CHEMICAL DELIVERY SYSTEM (CDS). VARIOUS TYPES OF CDS'S WILL BE APPLIED TO THE SELECTED SULFA DRUGS. ANALYTICAL METHODOLOGIES WILL BE DEVELOPED FOR THE SYNTHESIZED COMPOUNDS. IN VITRO EXAMINATIONS, INCLUDING LIPOPHILICITY DETERMINATION AND COMPOUND STABILITY BOTH IN CHEMICAL OXIDANTS AND IN BIOLOGICAL MATRICES, WILL HELP TO SELECT A CDS FOR IN VIVO EXPERIMENTATION. A DISTRIBUTION STUDY IN RATS WILL INDICATE WHETHER THE CDS SATISFACTORILY PERFORMED ITS FUNCTION AS MEASURED BY BRAIN RETENTION OF SULFONAMIDE ANTIBIOTIC RELATIVE TO PERIPHERAL RETENTION. PROPERLY DEVELOPED, A CDS FOR SULFONAMIDE COULD IMPROVE THE THERAPY OF TOXOPLASMOSIS BY DIVERTING A LARGER PORTION OF THE ADMINISTERED DOSE TO THE SITE OF INFECTION AND REDUCE TOXICITIES THAT ARE OFTEN DOSE LIMITING.