losartan-potassium and gusperimus

Deoxyspergualin (DSG) is an immunosuppresive agent of proven effectiveness in the prevention and treatment of transplant rejection; its most frequent side effect is reversible bone marrow suppression. To clarify the mechanisms of bone marrow suppression induced by DSG, we monitored the numbers of peripheral blood and marrow stem cells in C3H/HeN mice receiving 14 days of DSG injections at a highly immunosuppressive dose of 10 mg/kg/day. In the peripheral blood cells, DSG induced severe anemia and mild leukopenia because of a decrease in granulocyte counts, although these phenomena were reversible. During DSG administration, nucleated cell counts in the femur also markedly decreased, whereas the absolute numbers of various stem cells and progenitor cells, except for erythroid colony-forming units (CFU-E), remained normal or increased; CD34- or c-kit-positive and lineage-negative cell levels markedly increased on the day DSG administration ceased. These findings indicate that DSG-induced anemia and leukopenia are not initiated by a generalized killing of these stem cells, but rather by a transient suppression of their ability to mature. Significantly, the severe anemia induced by DSG resembles pure red cell aplasia in humans, because there were marked decreases in peripheral reticulocytes, marrow CFU-E, and erythroblasts, with no decrease in renal erythropoietin mRNA expression. Furthermore, DSG-induced anemia was completely ameliorated by treatment with human recombinant erythropoietin.

Topics: Animals; Blood Cell Count; Bone Marrow Cells; Bone Marrow Transplantation; Cell Count; Drug Therapy, Combination; Erythropoietin; Female; Graft Rejection; Guanidines; Hematopoiesis; Hematopoietic Stem Cells; Immunosuppressive Agents; Kidney; Mice; Mice, Inbred C3H; Recombinant Proteins; Spleen; Time Factors

When 15-deoxyspergualin (DSG), a potent immunosuppressant, was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 14 to day 25, increased thrombopoiesis was induced on day 20 to day 33, accompanied by marked leukocytopenia and anemia. The mean platelet counts in DSG-treated and control [BALB/c-->C3H/He] bone marrow chimeras on day 25 were (114.1 +/- 0.5) x 10(4)/microliter versus (58.6 +/- 2.6) x 10(4)/microliter (1.9-fold increase). Colony-forming units-megakaryocyte (CFU-Meg) were not significantly increased in DSG-treated bone marrow chimeras. Colony-forming units-granulocyte/macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E) were decreased during DSG-treatment whereas CFU-Mix colony formations were rather increased, and more primitive hematopoietic progenitor cells (highly proliferative potential colony-forming units [CFU-HPP]) were not decreased in the same time period. Since CFU-GM and BFU-E colony formations were increased immediately after the cessation of DSG treatment, followed by the rebound of leukocyte counts and the recovery of hemoglobin (Hb) levels, the leukocytopenia and anemia appeared to be induced by a cytostatic effect of DSG. The adverse effect of DSG was partly reversed by the simultaneous administration of granulocyte colony-stimulating factor (G-CSF) and/or erythropoietin (EPO), suggesting the need for the administration of these cytokines in the case of bone marrow transplants treated with DSG. Furthermore, it was of note that DSG modulated hematopoiesis and stimulated the production of thrombopoietin (TPO)-like cytokine(s) as well as interleukin-3 (IL-3).

Topics: Anemia; Animals; Blood Cell Count; Blood Platelets; Bone Marrow Transplantation; Erythropoietin; Granulocyte Colony-Stimulating Factor; Guanidines; Hematopoiesis; Immunosuppressive Agents; Interleukin-3; Leukopenia; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Thrombopoietin; Transplantation Chimera