INHIBITORS AND IMMUNOASSAY FOR SEPTIC SHOCK/DIC

DISSEMINATED INTRAVASCULAR COAGULATION (DIC) IS AN UNDERLYING PTHOGENETIC MECHANISM IN CASES OF VIREMIA (INCLUDING DENGUE HEMMORHAGIC FEVER) AND SEPTICEMIA. THE DEVELOPMENT OF THERAPY AND DECISIVE DIAGNOSTIC TECHNIQUES TO MONITOR THE PROGRESS OF THERAPY ARE IMPORTANT FOR INDIVIDUALS WITH SEPTIC SHOCK DUE TO THERMAL INJURY OR BIOLOGICAL WARFARE WHERE INFECTIONS RESULT IN A HIGH MORBIDITY AND MORTALITY. WE PROPOSE TO DEVELOP NOVEL PEPIDYL CHLOROMETHYL KETONES (CMKS) OF THERAPEUTIC UTILITY TO INTERRUPT ONE OF THE FUNDAMENTAL PATHOGENETIC MECHANISMS IN SEVERE LIFE-THREATING DIC, SEPTIC SHOCK, THROMBOTIC AND RELATED COMPLICATIONS IN WHICH THE INTRAVASCULAR ACTIVATION OF COAGULATION PLAYS A SIGNIFICANT ROLE. IRREVERSIBLE INHIBITORS ARE PREDICTED TO BE OF THERAPEUTIC VALUE BASED ON THE SPECIFIC BINDING TO THE SERINE PROTEASE CATALYTIC SITE OF THE TISSUE FACTOR (TF):FACTOR VII/VIIA DELLURLAR INITIATING COMPLEX OF COAGULATION AND THE SUBSEQUENT IRREVERSIBLE INHIBITION THEREOF. IMMUNOASSAYS OF PEPTIDES RELEASED UPON ACTIVATION OF ZYMOGENS IN THE CLOTTING CASCADE PROVIDE QUANTITATION AND ARE USEFUL DIAGNOSTIC INDICATORS OF ENZYMATIC ACTIVITY. THEREFORE, IN CONJUNCTION WITH A SPECIFIC INHIBITOR OF FACTOR VII/VIIA, WE ARE PROPOSING TO DEVELOP A SPECIFIC IMMUNOASSAY FOR FACTOR X ACTIVATION PEPTIDE WHICH WOULD MONITOR TF:FACTOR VII/VIIA ACTIVITY IN VITRO AND IN VIVO, FACILITATINGTHERAPEUTIC DECISION MAKING.