Effect of <i>N</i>‐acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial

Sins, Joep W. R.; Fijnvandraat, Karin; Rijneveld, Anita W.; Boom, Martine B.; Kerkhoffs, Jean-Louis; Meurs, Alfred; Groot, Marco R. de; Heijboer, H.; Dresse, Marie-Françoise; Lê, Phu Quoc; Hermans, Philippe; Vanderfaeillie, Anna; Neste, Eric W Van Den; Benghiat, Fleur Samantha; Kesse‐Adu, Rachel; Delannoy, André; Efira, André; Azerad, Marie‐Agnès; Borgie, Corianne A de; Biemond, Bart J.

doi:10.1111/bjh.14809

Cited by 27 publications

(13 citation statements)

References 9 publications

(10 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the recent study of Sins et al. ( 55 ) failed to clearly detect any clinical impact of NAC treatment in SCA. One possible explanation of this disappointing result could be that adherence to NAC treatment was very low in this study.…”

Section: Discussionmentioning

confidence: 95%

“…Interestingly, the findings of Sins et al. showed that rates of vaso-occlusive crisis (VOC) were decreased in adherent patients ( 55 ). NAC is a precursor of reduced glutathione (GSH), an endogenous antioxidant, and GSH has been shown to be reduced in RBCs of SCA patients ( 57 , 58 ).…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism would lead to endothelial cell activation, cell adhesion, and a pro-inflammatory environment that supports vascular dysfunction. IL-1β and IL-6 can activate platelets and leukocytes, promote their adhesiveness ( 55 ), and damage the endothelium itself ( 68 ). IL-1β has been associated with stroke in SCA ( 69 ), and it has been suggested that IL-6 could be related to the development of pulmonary hypertension in SCA children ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

et al. 2020

View full text Add to dashboard Cite

Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals . In-vitro experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In an open-label pilot trial of oral N-acetylcysteine (NAC), treatment with either 1,200 mg or 2,400 mg daily for 6 weeks increased whole blood glutathione levels and decreased erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation products, and cell-free hemoglobin in both groups 91 . A randomized, placebo-controlled, double-blind trial of NAC at 600 mg twice daily for 6 months did not decrease the rate of SCD-related pain days per patient year, vaso-occlusive crises, hospital admission days, number of admissions, or days with home analgesic use compared with placebo 92 . The safety and efficacy of NAC, administered at a higher dose during pain crisis, is being explored in a phase I/II study (NCT01800526) ( Table 2 ).…”

Section: Drug Therapies For Sickle Cell Diseasementioning

confidence: 86%

Drug Therapies for the Management of Sickle Cell Disease

Rai

Ataga

2020

F1000Res

View full text Add to dashboard Cite

Sickle cell disease (SCD) afflicts millions of people worldwide but is referred to as an orphan disease in the United States. Over the past several decades, there has been an increasing understanding of the pathophysiology of SCD and its complications. While most individuals with SCD in resource-rich countries survive into adulthood, the life expectancy of patients with SCD remains substantially shorter than for the general African-American population. SCD can be cured using hematopoietic stem cell transplantation and possibly gene therapy, but these treatment approaches are not available to most patients, the majority of whom reside in low- and middle-income countries. Until relatively recently, only one drug, hydroxyurea, was approved by the US Food and Drug Administration to ameliorate disease severity. Multiple other drugs (L-glutamine, crizanlizumab, and voxelotor) have recently been approved for the treatment of SCD, with several others at various stages of clinical testing. The availability of multiple agents to treat SCD raises questions related to the choice of appropriate drug therapy, combination of multiple agents, and affordability of recently approved products. The enthusiasm for new drug development provides opportunities to involve patients in low- and middle-income nations in the testing of potentially disease-modifying therapies and has the potential to contribute to capacity building in these environments. Demonstration that these agents, alone or in combination, can prevent or decrease end-organ damage would provide additional evidence for the role of drug therapies in improving outcomes in SCD.

show abstract

“…No patients experienced painful crises or other significant SCD-or NAC-related complications during the trial. In a randomized, placebo-controlled, double-blind trial, treatment with NAC at a dose of 600 mg twice daily for 6 months did not decrease the rate of SCD-related pain days per patient year compared with placebo [96]. In addition, there were no differences in the days with vaso-occlusive crises, admission days, number of admissions or days with home analgesic use.…”

Section: Anti-oxidant Agentsmentioning

confidence: 99%

Advances in new drug therapies for the management of sickle cell disease

Ataga

Desai

2018

Expert Opinion on Orphan Drugs

View full text Add to dashboard Cite

Introduction: Sickle cell disease (SCD) is an orphan disease in the United States, but is highly prevalent worldwide. Only two drugs, hydroxyurea and L-glutamine, are approved for this disease. With an improved understanding of the pathophysiology of SCD as well as the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of drugs for SCD. Areas covered: This review summarizes published studies of drug therapies and ongoing trials of novel agents. Expert opinion: The development of drugs with different mechanisms of action offers opportunities for combination and individualized therapy in SCD. In addition to acute pain crisis, the evaluation of other SCD-related complications, exercise capacity, patient reported outcomes and validated surrogate endpoints are necessary to advance drug development. It is important to involve sites in sub-Saharan Africa and India, which have the highest burden of SCD, in trials of novel therapies.

show abstract

Effect of N‐acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial

Cited by 27 publications

References 9 publications

Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia

Drug Therapies for the Management of Sickle Cell Disease

Advances in new drug therapies for the management of sickle cell disease

Contact Info

Product

Resources

About