Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca 2 ϩ -activated K ϩ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K ϩ 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 ϩ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K ϩ transport. At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K ϩ 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. ( J. Clin. Invest. 1996. 97:1227-1234.)

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An electroretinographic (ERG) study was undertaken to test the hypothesis that scotopic retinal function is altered in transfused thalassemics on chronic Deferoxamine (DFO). ERG a- and b-wave responses and dark adapted visual thresholds were obtained from 11 patients with beta-thalassemia major, ages 7 to 38 (median 17) years. A quantitative model of the activation of phototransduction was fitted to the a-waves to estimate the gain of the transduction processes and the saturated amplitude of the rod photoresponse. From b-wave stimulus/response functions. the saturated b-wave amplitude and an index of b-wave sensitivity (log sigma ) were calculated. The patients' data were compared to those of normal subjects. The relations of the ERG parameters to age. average ferritin level, and duration of transfusion without DFO as well as other clinical parameters were examined. Longitudinal measures of b-wave responses and dark adapted visual thresholds. available for nine of the patients, were examined for significant change over time. For all patients both the gain and saturated amplitude of the rod response are normal. In two patients log sigma is below the 99% prediction interval for normal. One has low scotopic visual sensitivity. The duration of transfusion therapy unprotected by DFO chelation therapy was correlated with log a. These results suggest iron accumulation rather than DFO toxicity underlies scotopic dysfunction in older thalassemics. some of whom may have had extended periods of transfusion without the protection of chelation. Thus, monitoring of retinal function is recommended in such patients.

Währungskrisen der ersten Generation sind eng mit einer expansiven Geldpolitik verknüpft. Die inkonsistente Wirtschaftspolitik, bestehend aus einer Bindung des Wechselkurses und der monetären Expansion, führt zu einem Wettbewerb der Spekulanten um die Währungsreserven der Zentralbank. In einem Währungskrisen-Modell der ersten Generation wird dieser Zusammenhang deutlich. In einem zweiten Schritt wird das Modell erweitert, indem die Parameter einer selbsterfüllenden Währungskrise implementiert werden.