A collaborative, double-blind randomized study of cetiedil citrate in sickle cell crisis

Abstract

We have recently completed a double-blind, placebo-controlled, noncrossover study, the goal of which was to determine whether cetiedil citrate (cetiedil) could affect the course of vaso-occlusive crises in sickle cell disease. Patients, who presented to the emergency room at least 4 but no more than 24 hours after the onset of a painful vasoocclusive crisis severe enough to require hospitalization, were considered candidates for the study. Each patient received either placebo or cetiedil at one of the following three dosages: 0.2, 0.3, or 0.4 mg/kg body weight. The assigned drug dosage was given as a 30 minute intravenous infusion every 8 hours for 4 consecutive days. A total of 67 patients was enrolled in the study. Cetiedil, at its highest dosage (0.4 mg/kg body weight), was found to be significantly superior to placebo both in reducing the number of painful sites present on all 4 treatment days and in shortening the total time in crisis. No serious adverse reactions were observed during the course of the study. We conclude that cetiedil, given at a dosage of 0.4 mg/kg body weight, is therapeutically advantageous for sickle cell crisis.

Bepridil protects sickle cells against the adverse rheological effects of cyclical deoxygenation

“…198 7) and reduces slightly the severity of vaso-occlusive sickle crises (Cabannes et a/. 1983;Benjamin et al, 1986). Both cetiedil citrate and bepridil inhibit the binding of calmodulin to erythrocyte membranes (Agre et a], 1984) and bepridil has recently been found to inhibit the Gardos channel (Stuart et al, 1989).…”

Cellular effects of hydroxyurea in Hb SC disease

“…Osmotic swelling of Hb SC cells reduces their oxygen affinity, rate of sickling, deoxygenation-induced K þ efflux, and mean cell haemoglobin concentration (MCHC) (Fabry et al, 1982;Lawrence et al, 1991;, suggesting that decreasing the density of these cells might alleviate the pathology associated with this disease (Fabry et al, 1982). Membrane-active drugs have been considered as therapy in sickle cell disease (Clark et al, 1982;Orringer et al, 1991b;Berkowitz & Orringer, 1981;Wolff et al, 1988;Brugnara et al, 1993Brugnara et al, , 1995Benjamin et al, 1986). Because of the unique pathophysiology of Hb SC disease, this class of agents might be especially useful for its treatment.…”

The trials and hopes for drug development in sickle cell disease

“…Multiple drugs have been evaluated as treatments to either prevent acute pain episodes (Table I) or shorten the duration of such episodes in SCD (Table II) (Cooperative Urea Trials Group, 1974;Gillette et al, 1974;Harkness & Roth, 1975;Greenberg et al, 1983;Cabannes et al, 1984;Zago et al, 1984;Benjamin et al, 1986;Griffin et al, 1994;Charache et al, 1995;Orringer et al, 2001;Qari et al, 2007;Ataga et al, 2011;Gladwin et al, 2011;Morris et al, 2013;Telen et al, 2015;Niihara et al, 2014). However, the majority of these treatments have exhibited only minimal clinical efficacy or were too toxic (Cooperative Urea Trials Group, 1974;Peterson et al, 1974;Nicholson et al, 1976;Greenberg et al, 1983;Zago et al, 1984;Griffin et al, 1994;Ataga et al, 2011;Gladwin et al, 2011).…”

“…Despite these initial promising results, the development of sodium cyanate was not pursued further due to subsequent evidence of its toxicity Nicholson et al, 1976). Cetiedil, a vasodilator and blocker of the Gardos channel (Berkowitz & Orringer, 1982), has been reported to shorten the duration of painful episodes in patients with SCD (Benjamin et al, 1986). Despite the apparent beneficial effect of cetiedil, further development of this drug was not pursued in SCD.…”