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

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. This is an updated version of a previously published review.

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. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group's Haemoglobinopathies Trials Register: 08 October 2018.

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, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). 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 (low-quality evidence). 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 blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Division of Hematology and Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, USA, 75390.

    Source

    MeSH

    Acetamides
    Anemia, Sickle Cell
    Antisickling Agents
    Clinical Trials, Phase II as Topic
    Clinical Trials, Phase III as Topic
    Dehydration
    Early Termination of Clinical Trials
    Erythrocyte Aging
    Erythrocytes
    Humans
    Piracetam
    Quality of Life
    Randomized Controlled Trials as Topic
    Trityl Compounds
    Zinc Sulfate

    Pub Type(s)

    Journal Article
    Meta-Analysis
    Research Support, Non-U.S. Gov't
    Systematic Review

    Language

    eng

    PubMed ID

    30338520

    Citation

    Nagalla, Srikanth, and Samir K. Ballas. "Drugs for Preventing Red Blood Cell Dehydration in People With Sickle Cell Disease." The Cochrane Database of Systematic Reviews, vol. 10, 2018, p. CD003426.
    Nagalla S, Ballas SK. Drugs for preventing red blood cell dehydration in people with sickle cell disease. Cochrane Database Syst Rev. 2018;10:CD003426.
    Nagalla, S., & Ballas, S. K. (2018). Drugs for preventing red blood cell dehydration in people with sickle cell disease. The Cochrane Database of Systematic Reviews, 10, p. CD003426. doi:10.1002/14651858.CD003426.pub6.
    Nagalla S, Ballas SK. Drugs for Preventing Red Blood Cell Dehydration in People With Sickle Cell Disease. Cochrane Database Syst Rev. 2018 10 19;10:CD003426. PubMed PMID: 30338520.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Drugs for preventing red blood cell dehydration in people with sickle cell disease. AU - Nagalla,Srikanth, AU - Ballas,Samir K, Y1 - 2018/10/19/ PY - 2019/10/19/pmc-release PY - 2018/10/20/pubmed PY - 2019/2/9/medline PY - 2018/10/20/entrez SP - CD003426 EP - CD003426 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev VL - 10 N2 - 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. This is an updated version of a previously published review. 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. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group's Haemoglobinopathies Trials Register: 08 October 2018. 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, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). 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 (low-quality evidence). 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 blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/30338520/Drugs_for_preventing_red_blood_cell_dehydration_in_people_with_sickle_cell_disease_ L2 - https://doi.org/10.1002/14651858.CD003426.pub6 DB - PRIME DP - Unbound Medicine ER -