Advertisement

Research Article Free access | 10.1172/JCI118537

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

C Brugnara, B Gee, C C Armsby, S Kurth, M Sakamoto, N Rifai, S L Alper, and O S Platt

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Brugnara, C. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Gee, B. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Armsby, C. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Kurth, S. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Sakamoto, M. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Rifai, N. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Alper, S. in: JCI | PubMed | Google Scholar

Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu

Find articles by Platt, O. in: JCI | PubMed | Google Scholar

Published March 1, 1996 - More info

Published in Volume 97, Issue 5 on March 1, 1996
J Clin Invest. 1996;97(5):1227–1234. https://doi.org/10.1172/JCI118537.
© 1996 The American Society for Clinical Investigation
Published March 1, 1996 - Version history
View PDF
Abstract

Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca2+-activated K+ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K+ and water loss via this channel could be a potential therapy in vivo. We treated five subjects who have sickle cell anemia with oral clotrimazole, a specific Gardos channel inhibitor. Patients were started on a dose of 10 mg clotrimazole/kg/d for one week. Protocol design allowed the daily dose to be escalated by 10 mg/kg each week until significant changes in erythrocyte density and K+ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K+ transport. At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K+ content, and somewhat increased hemoglobin levels. Adverse effects were limited to mild/moderate dysuria in all subjects, and a reversible increase in plasma alanine transaminase and aspartic transaminase levels in two subjects treated with 30 mg clotrimazole/kg/d. This is the first in vivo evidence that the Gardos channel causes dehydration of sickle erythrocytes, and that its pharmacologic inhibition provides a realistic antisickling strategy.

Version history
  • Version 1 (March 1, 1996): No description
Advertisement
Advertisement