title: Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.
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.
authors.affiliation: Department of Laboratory Medicine, Harvard Medical School, Boston, Massachusetts, USA. brugnara@a1.tch.harvard.edu
authors.forename: C
authors.initials: C
authors.lastname: Brugnara
authors.forename: B
authors.initials: B
authors.lastname: Gee
authors.forename: C C
authors.initials: CC
authors.lastname: Armsby
authors.forename: S
authors.initials: S
authors.lastname: Kurth
authors.forename: M
authors.initials: M
authors.lastname: Sakamoto
authors.forename: N
authors.initials: N
authors.lastname: Rifai
authors.forename: S L
authors.initials: SL
authors.lastname: Alper
authors.forename: O S
authors.initials: OS
authors.lastname: Platt
mesh_terms: D000284:Administration, Oral; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism; D000986:Antisickling Agents / Q000627:therapeutic use*; D003022:Clotrimazole / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D026902:Potassium Channel Blockers
chemical_list: D000986:Antisickling Agents; D026902:Potassium Channel Blockers; D003022:Clotrimazole