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Key Points Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may involve pseudohyperkalemia and perinatal edema. This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.

The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

We have investigated the interaction of clotrimazole (CLT) and related compounds with the erythroid Ca2"-activated K+ channel, a mediator of sickle cell dehydration. We measured K+ transport, membrane potential, and cell volume upon activation of this pathway in sickle erythrocytes. CLT blocked almost completely Ca2"-activated K+ transport in homozygous hemoglobin S cells, with IC5o values of 29±15 nM in isotonic 20 mM salt solution and 51±15 nM in normal saline (n = 3). The inhibition of K+ transport by CLT was caused by a specific interaction with the Ca2"-activated K+ channel of human red cells, since it displaced bound 125I-Charybdotoxin, a specific ligand of the Gardos channel, with an IC50 (12±4 nM in isotonic 20 mM) similar to the IC50 values for flux inhibition. When homozygous hemoglobin S cells were dehydrated by incubation in the presence of 100 ,gM CaCI2 and the ionophore A23187, or by exposure to cycles of oxygenation and deoxygenation, CLT effectively inhibited cell dehydration and K+ loss. The IC50 of CLT for inhibition of Ca2+-activated K+ transport in sickle cells is significantly lower than plasma concentrations of CLT achievable after nontoxic oral doses. We therefore propose that oral administration of CLT may prevent red cell dehydration in patients with sickle cell anemia. (J. Clin. Invest. 1993. 92:520-526.)