There is data to suggest an immunologic mechanism for some of the adverse reactions seen in AIDS and normal patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis carinii pneumonia. We propose to investigate a role of antibodies directed against SMX, TMP or their metabolites in the causation of these adverse reactions. Pilot studies have developed an ELISA which detects human IgM antibody against sulfamethoxazole utilizing a synthetic sulfamethoxazole-human serum albumin conjugate. We propose to optimize the new ELISA and use it to screen, mostly in a prospective manner, the sera of AIDS and nonAIDS patients who demonstrate adverse reactions to TMP-SMX, for the presence of antibodies to SMX and its metabolites. Comparable studies will be undertaken with trimethoprim. To optimize the ELISA, the active conjugate will be modified synthetically with respect to epitope density, protein carrier and length of the spacer arm between the drug and the protein carrier. Protein conjugates of oxidized metabolites will be synthesized and evaluated as antigens in the ELISA. A variety of substances including other sulfonamide drugs, metabolites and currently proposed clinical substitutes for sulfamethoxazole (sulfadoxine, dapsone) will be evaluated for immunological cross- ractivity with sulfamethoxazole by competition ELISA. A chromatographic antigenic profile will be developed for TMP-SMX serum metabolites that may uncover relevant differences for the adverse reactor based on metabolism/detoxification. This study may lead to an understanding of the immunological mechanism of adverse reactions to TMP-SMX with an additional insight into drug reactions in general. It would enable one to discriminate between the 2 components of TMP-SMX as the active antigen and enable the use of TMP and SMX separately or in combinations (eg, TMP-dapsone). In special instances, the ELISA could be used as a screening test to identify patients with sensitivity specifically to SMX, TMP or their metabolites. We believe this will affect not only the management, but also the survival of AIDS and nonAIDS patients.
| Ressler, C; Tatake, J G (1996) N epsilon-cyclosuccinyllysine: synthesis and formation from hemisuccinylated polylysine and its hapten conjugates with sulfamethoxazole during acid hydrolysis. Bioconjug Chem 7:82-7 |
| Tatake, J G; Knapp, M M; Ressler, C (1991) Synthesis and characterization of protein and polylysine conjugates of sulfamethoxazole and sulfanilic acid for investigation of sulfonamide drug allergy. Bioconjug Chem 2:124-32 |
