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The increased mortality observed when human immunodeficiency virus (HIV)-infected individuals are treated with clarithromycin (CLA) as prophylaxis for disseminated infection with organisms of the Mycobacterium avium complex (MAC) suggests that CLA might possess immunosuppressive activities. To test this possibility, we assessed the immunological response of BALB/c mice following subchronic (28 days) oral administration of CLA alone or in combination with zidovudine (ZDV). Because normal hematopoiesis is needed to maintain the immune system, we also examined the effect of these drugs given individually or in combination on several hematological parameters. The major effect of administration of 500 mg/kg CLA was a marked decrease in the lymphocyte/neutrophil ratio, and the only evidence of hematotoxicity in mice treated with 240 mg/kg ZDV alone was mild macrocytic anemia. However, treatment with a combination of CLA and ZDV resulted in severe hematotoxicity, evidenced by a significant (p < 0.01) decrease in the number of circulating erythrocytes, neutrophils, and lymphocytes and a 67% drop in splenic cellularity (p < 0.01). Treatment with CLA or ZDV alone or both drugs in combination had no effect on lymphocyte function, determined by measuring the ex vivo proliferative activity of splenocytes in response to alloantigens or a B cell mitogen, lipopolysaccharide (LPS). However, because of the cellular depletion in the spleen, overall immune responses in this organ decreased significantly (p < 0.05) in mice treated with CLA plus ZDV. These data suggest that interactions between CLA and ZDV warrant further evaluation because these drugs are given in combination to persons with advanced HIV infection.

Pyrimethamine (Pyr) is commonly used for treatment of toxoplasmic encephalitis in AIDS patients; however, in two clinical studies, an increased number of deaths were observed when Pyr was coadministered with zidovudine (ZDV). The BALB/c mouse was chosen as a model to study the mechanism underlying the unexpected toxicity from coadministration of these drugs. Daily administration by oral gavage of 60 mg/kg Pyr and 240 mg/kg ZDV resulted in 100% lethality after 30 days. These dose levels produced no effect when the drugs were given individually for the same period. Administration of combinations of Pyr and ZDV resulted in macrocytic anemia and leukopenia with synergistic decreases in lymphocyte and neutrophil numbers. To examine the mechanism of this hematotoxicity at the cellular level, mouse bone marrow colony-forming unit (mCFU) assays were employed. A combination of ZDV with various concentrations of Pyr resulted in synergistic decreases in numbers of erythroid and granulocyte-macrophage precursors (mCFU-E and mCFU-GM). mCFU-GM precursors appeared more sensitive than erythroid precursors to combinations of Pyr and ZDV. Incorporation of (14)C-ZDV into cellular DNA was increased in a dose-dependent manner in the presence of increasing concentrations of Pyr in the mCFU-GM assay. This suggested that inhibition of dihydrofolate reductase by Pyr and accompanying inhibition of dTTP synthesis allows preferential incorporation of ZDV into DNA, with resulting strand breakage and cell death. (14)C-ZDV incorporation was also observed when human GM cultures were analyzed, however, incorporation was less and required higher concentrations of Pyr., ((c) 2002 Elsevier Science (USA).)

We investigated the immunohematoxicities of the antiparasitic drug dapsone (DDS) and the antiretroviral drug zidovudine (ZDV, AZT) given alone or in combination in BALB/c mice. DDS is used for prophylaxis and treatment of Pneumocystis carinii infection in AIDS patients. We examined the impact of concurrent administration of these drugs on the immune and hematopoietic systems because DDS causes hematotoxicity and ZDV therapy results in bone marrow toxicity. Daily oral administration of DDS at 25 and 50 mg/kg for 28 days caused a slight anemia, marked methemoglobinemia, reticulocytosis, and a moderate leukopenia (P < 0.01 for all parameters) but had no discernible effect on platelet count. In DDS-treated mice, the proliferative response of splenic T cells to concanavalin A was > or = 35% higher than that manifested by splenocytes from vehicle-treated control mice. ZDV at 240 and 480 mg/kg was not immunosuppressive but caused low-grade macrocytic anemia, thrombocytosis, and neutropenia; these effects were drug dose-dependent and statistically significant (P < 0.01). Concurrent administration of DDS and ZDV augmented the severity of ZDV-mediated macrocytic anemia, and 7 of 12 (58%) mice did not survive treatment with the high doses of DDS and ZDV (50 and 480 mg/kg, respectively). On the other hand, co-administration of ZDV mitigated DDS-induced methemoglobinemia and the DDS-associated elevation in lymphoproliferative response. These data suggest interaction between DDS and ZDV in mice and indicate a need for caution in using DDS as long-term therapy in AIDS patients receiving ZDV.

Trimethoprim-sulfamethoxazole (TMP-SMX), commonly used for prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS patients, often produces a high incidence of treatment-limiting reactions. We investigated the effect of oral administration of TMP-SMX alone or in combination with the antiretroviral drug zidovudine (ZDV) on hematopoiesis and cellular immunity in BALB/c mice. Daily treatment for 28 days with TMP-SMX (160:800 mg/kg) had no effect on hematopoiesis or the ex vivo proliferative response of splenic T lymphocytes to allogeneic tumor cells (EL-4) or to concanavalin A (ConA), or that of splenic B cells to lipopolysaccharide (LPS). ZDV at 240 mg/kg/day was not immunosuppressive but caused a mild macrocytic anemia. Combined treatment produced severe pancytopenia, a significant drop in splenic cellularity, and a 61% decrease in the percentage of splenic macrophages. The percentage of splenic CD3+ lymphocytes increased 150% in the TMP-SMX + ZDV group, but the ratios of T-cell subsets and the frequency of B cells remained unchanged. Combined drug treatment did not impair the proliferative response of B cells to LPS or that of T cells to EL-4 cells. In concert with the reduction in the percentage of macrophages, the proliferative response of T lymphocytes to ConA decreased significantly. Optimal ConA-induced T-cell proliferation requires the participation of accessory cells (AC) (e.g., macrophages); EL-4 cells are able to function as AC. These data indicate that ZDV synergizes with TMP-SMX, causing severe hematotoxicity and suppressing AC-dependent immune function, and suggest that this therapeutic regimen may contribute to the immune deterioration in AIDS patients.