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Combination therapy of erythropoietin, hydroxyurea, and clotrimazole in a beta thalassemic mouse: a model for human therapy.

Abstract

beta thalassemia (beta thal) in DBA/2J mice is a consequence of the spontaneous and complete deletion of the beta major globin gene. Homozygous beta thal mice have clinical and biological features similar to those observed in human beta thal intermedia. Erythrocytes in human beta thal are characterized by a relative cell dehydration and reduced K+ content. The role of this erythrocyte dehydration in the reduced erythrocyte survival, which typifies the disease, has not previously been evaluated. We examined for 1 month the effects on the anemia and the erythrocyte characteristics of beta thal mice of daily treatment with either clotrimazole (CLT), an inhibitor of red blood cell (RBC) dehydration via the Gardos channel, or human recombinant erythropoietin (r-HuEPO), or hydroxyurea (HU). The use of either r-HuEPO or HU induced a significant increase in hemoglobin (Hb), hematocrit (Hct), erythrocyte K+ and a decrease in percent reticulocytes, suggesting improved erythrocyte survival. CLT alone decreased only mean corpuscular hemoglobin concentration (MCHC) and cell density and increased cell K+. Thus, though the Gardos channel plays a major role in cell dehydration of murine beta thal erythrocyte survival. Combination therapy with r-HuEPO plus HU produced no incremental benefit beyond those of single drug therapy. However, addition of CLT to r-HuEPO, to HU, or to combined r-HuEPO plus HU led to statistically significant increase in Hb, Hct, and erythrocyte K+ compared with any of the regimens without CLT. These results suggest that CLT not only inhibits erythrocyte dehydration, but also potentiates the erythropoietic and cellular survival responses to r-HuEPO and HU.

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  • Authors+Show Affiliations

    ,

    Department of Internal Medicine, University of Verona, Italy.

    , , , ,

    Source

    Blood 87:3 1996 Feb 01 pg 1188-95

    MeSH

    Animals
    Body Water
    Calcimycin
    Calcium
    Calcium Channel Blockers
    Chlorides
    Clotrimazole
    Disease Models, Animal
    Drug Synergism
    Drug Therapy, Combination
    Erythrocyte Aging
    Erythrocyte Count
    Erythrocyte Deformability
    Erythrocytes, Abnormal
    Erythropoietin
    Female
    Gene Deletion
    Globins
    Hematocrit
    Humans
    Hydroxyurea
    Intracellular Fluid
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Inbred DBA
    Mice, Mutant Strains
    Potassium
    Potassium Channels
    Recombinant Proteins
    Reticulocytes
    Rubidium
    beta-Thalassemia

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    8562946

    Citation

    de Franceschi, L, et al. "Combination Therapy of Erythropoietin, Hydroxyurea, and Clotrimazole in a Beta Thalassemic Mouse: a Model for Human Therapy." Blood, vol. 87, no. 3, 1996, pp. 1188-95.
    de Franceschi L, Rouyer-Fessard P, Alper SL, et al. Combination therapy of erythropoietin, hydroxyurea, and clotrimazole in a beta thalassemic mouse: a model for human therapy. Blood. 1996;87(3):1188-95.
    de Franceschi, L., Rouyer-Fessard, P., Alper, S. L., Jouault, H., Brugnara, C., & Beuzard, Y. (1996). Combination therapy of erythropoietin, hydroxyurea, and clotrimazole in a beta thalassemic mouse: a model for human therapy. Blood, 87(3), pp. 1188-95.
    de Franceschi L, et al. Combination Therapy of Erythropoietin, Hydroxyurea, and Clotrimazole in a Beta Thalassemic Mouse: a Model for Human Therapy. Blood. 1996 Feb 1;87(3):1188-95. PubMed PMID: 8562946.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Combination therapy of erythropoietin, hydroxyurea, and clotrimazole in a beta thalassemic mouse: a model for human therapy. AU - de Franceschi,L, AU - Rouyer-Fessard,P, AU - Alper,S L, AU - Jouault,H, AU - Brugnara,C, AU - Beuzard,Y, PY - 1996/2/1/pubmed PY - 1996/2/1/medline PY - 1996/2/1/entrez SP - 1188 EP - 95 JF - Blood JO - Blood VL - 87 IS - 3 N2 - beta thalassemia (beta thal) in DBA/2J mice is a consequence of the spontaneous and complete deletion of the beta major globin gene. Homozygous beta thal mice have clinical and biological features similar to those observed in human beta thal intermedia. Erythrocytes in human beta thal are characterized by a relative cell dehydration and reduced K+ content. The role of this erythrocyte dehydration in the reduced erythrocyte survival, which typifies the disease, has not previously been evaluated. We examined for 1 month the effects on the anemia and the erythrocyte characteristics of beta thal mice of daily treatment with either clotrimazole (CLT), an inhibitor of red blood cell (RBC) dehydration via the Gardos channel, or human recombinant erythropoietin (r-HuEPO), or hydroxyurea (HU). The use of either r-HuEPO or HU induced a significant increase in hemoglobin (Hb), hematocrit (Hct), erythrocyte K+ and a decrease in percent reticulocytes, suggesting improved erythrocyte survival. CLT alone decreased only mean corpuscular hemoglobin concentration (MCHC) and cell density and increased cell K+. Thus, though the Gardos channel plays a major role in cell dehydration of murine beta thal erythrocyte survival. Combination therapy with r-HuEPO plus HU produced no incremental benefit beyond those of single drug therapy. However, addition of CLT to r-HuEPO, to HU, or to combined r-HuEPO plus HU led to statistically significant increase in Hb, Hct, and erythrocyte K+ compared with any of the regimens without CLT. These results suggest that CLT not only inhibits erythrocyte dehydration, but also potentiates the erythropoietic and cellular survival responses to r-HuEPO and HU. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/8562946/Combination_therapy_of_erythropoietin_hydroxyurea_and_clotrimazole_in_a_beta_thalassemic_mouse:_a_model_for_human_therapy_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=8562946 DB - PRIME DP - Unbound Medicine ER -