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Drugs for preventing red blood cell dehydration in people with sickle cell disease

  • Review
  • Intervention

Authors

  • Srikanth Nagalla,

    1. Thomas Jefferson University, Department of Medicine, Division of Hematology, Philadelphia, Pennsylvania, USA
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  • Samir K Ballas

    Corresponding author
    1. Jefferson Medical College, Thomas Jefferson University, Cardeza Foundation for Hematologic Research, Department of Medicine, Philadelphia, USA
    • Samir K Ballas, Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA. Samir.Ballas@jefferson.edu.

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Abstract

Background

Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs.

Objectives

To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register.

Last search of the Group's Trials Register: 25 October 2011.

Selection criteria

Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment.

Data collection and analysis

Both authors independently selected studies for inclusion, assessed study quality and extracted data.

Main results

Of the 51 studies identified, three met the inclusion criteria. The first study tested the effectiveness of zinc sulphate to prevent sickle cell-related crises in a total of 145 participants and showed a significant reduction in painful crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15). However, analysis was restricted due to limited statistical data. Changes to red cell parameters and blood counts were inconsistent. No serious adverse events were noted in the study.

The second study was a Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo. Compared to the placebo group the high dose senicapoc showed significant improvement in change in hemoglobin level, number and proportion of dense red blood cells, red blood cell count and indices and hematocrit. The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups. A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises.

Authors' conclusions

While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.

While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red cell survival (depending on dose), this did not lead to fewer painful crises.

Plain language summary

Drugs that aim to reduce the loss of water from red blood cells in people with sickle cell disease

Sickle cell disease is an inherited condition that causes red blood cells to become sickle shaped when they lose water. This leads to a high risk of the blood vessels becoming blocked. Such blockages can cause pain, stroke and damage to organs. Recent therapies aim to stop the cells becoming sickle shaped by preventing them losing water. This review included three studies, one with zinc sulphate and two with senicapoc. The study with zinc sulphate showed that this drug may be able to reduce the number of sickle cell crises without causing toxic effects. There were 145 participants in this study and results showed a significant reduction in the total number of serious sickle-related crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15). However, our analysis was limited since not all data were reported. Changes to red cell measurements and blood counts were not consistent. No serious adverse events were noted in the study. The two studies with senicapoc demonstrated that this drug increases the red blood survival and has a role in the prevention on red blood cell dehydration in people with sickle cell disease. The higher dose of the drug was more effective compared to the lower dose. But these changes in the red blood cells did not translate into positive clinical outcomes in terms of reduction in the number of sickle cell crises. Senicapoc had a favourable safety profile. More longer-term research is needed on these drugs and others that might prevent water loss in red blood cells.

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