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Therapy with L-Glutamine reduces pain in patients with sickle cell disease
CSF Benioff Children’s Hospital Oakland clinical researchers, in conjunction with other sickle cell centers and scientists at Emmaus Life Sciences, Inc., have demonstrated that therapy with L-Glutamine reduced the frequency of pain episodes in both pediatric and adult patients with sickle cell disease (SCD). The results of the 48-week, phase 3 clinical trial are published in the July 19, 2018, issue of New England Journal of Medicine.
The paper, “A Phase 3 Trial of L-Glutamine in Sickle Cell Disease,” documented the effects of taking Endari™, a prescription-grade, pharmaceutical form of L-glutamine, as compared to placebo, for 230 patients aged 5 to 58 years of age with sickle cell disease. Endari™ was approved in July 2017 by the U.S. Food and Drug Administration based on the safety and efficacy data from this study. Glutamine is an amino acid that is involved in several biochemical reactions.
The study showed that whether administered alone or with hydroxyurea, L-glutamine reduced the frequency of sickle cell pain crises by 25 percent (a median of three events per patient in the L-glutamine group and four in the placebo group) and hospitalizations by 33 percent (a median of two hospitalizations in the L-glutamine group and three in the placebo group). Additional findings showed lower cumulative hospital days of 41 percent and a lower incidence of dangerous acute chest syndrome (ACS) by more than 60 percent.
“This study validated research on the safety of pharmaceutical grade L-glutamine which has antioxidant properties that improves the NAD redox potential in sickle cell patients. Safe neutraceuticals are of major importance to the sickle cell community,” said Elliott Vichinsky, MD, Director of Hematology/Oncology at the Northern California Sickle Center at UCSF Benioff Children’s Hospital Oakland. “Our clinical trial found that L-glutamine, which does not require any routine laboratory monitoring, decreases pain events in patients by itself or in combination with hydroxyurea. It is a major advance in therapy for sickle cell disease and offers families safe, new therapeutic options.”
Sickle cell disease is a genetic blood disorder that causes a distortion in the shape of red blood cells. This leads to the many symptoms and medical problems affecting children and adults with sickle cell disease, including pain, anemia, and bone, kidney, lung and neurologic problems.
“Endari, is the first approved treatment for sickle cell disease in pediatric patients 5 years of age and older and the first in nearly 20 years for adults,” said study co-author Yutaka Niihara, MD, CEO and founder of Emmaus, which produces the product. “Our hope in sharing the results of this data from the New England Journal of Medicine is to increase awareness of sickle cell disease, a lifelong hereditary blood disorder which commonly affects those of African descent, as well those from Central and South America and people of Middle Eastern, Asian, Indian and Mediterranean descent. It is important for patients to know that they have a treatment option for this debilitating disease.”
The double-blind trial evaluated the efficacy and safety of pharmaceutical-grade L-glutamine administered twice daily by mouth, as compared with placebo, in reducing the frequency of pain crises among patients with sickle cell anemia or sickle β0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period.
Patients were randomly assigned, in a 2:1 ratio, to receive L-glutamine (152 patients) or placebo (78 patients). Those in the L-glutamine group had significantly fewer pain crises than those in the placebo group (P = 0.005) and fewer hospitalizations (P = 0.005). Approximately 54 percent of the patients were female and 66 percent of the patients in both trial groups were already receiving hydroxyurea. The study found that low-grade nausea, non-cardiac chest pain, fatigue and musculoskeletal pain occurred more frequently in the L-glutamine group than in the placebo group.
Funding for this trial was provided by Emmaus Life Sciences, Inc.
Study authors for the Phase 3 Trial of l-Glutamine in Sickle Cell Disease include Yutaka Niihara, M.D., M.P.H., Emmaus Medical, Torrance and University of California at Los Angeles; Scott T. Miller, M.D., State University of New York-Downstate Medical Center; Julie Kanter, M.D., Medical University of South Carolina, Charleston; Sophie Lanzkron, M.D., M.H.S., Johns Hopkins Hospital, Baltimore; Wally R. Smith, M.D., Virginia Commonwealth University Healthcare Systems, Richmond; Lewis L. Hsu, M.D., Ph.D., Victor R. Gordeuk, M.D., University of Illinois at Chicago, Chicago; Kusum Viswanathan, M.D., Brookdale University Hospital and Medical Center; Sharada Sarnaik, M.D., Children’s Hospital of Michigan, Detroit; Ifeyinwa Osunkwo, M.D., Carolinas HealthCare System, Charlotte, NC; Edouard Guillaume, M.D., Interfaith Medical Center; Swayam Sadanandan, M.D., Brooklyn Hospital Center; Lance Sieger, M.D., Osbourne A. Blake, M.D., Los Angeles, Kaiser Permanente Medical Center, Inglewood; Joseph L. Lasky, M.D., Eduard H. Panosyan, M.D., Harbor–UCLA and Los Angeles BioMedical Research Institute; Tamara N. New, M.D., Children’s Healthcare of Atlanta, Emory University, Atlanta; Rita Bellevue, M.D., New York Presbyterian Brooklyn Methodist Hospital; Lan T. Tran, M.P.H., Rafael L. Razon, M.D., Charles W. Stark, Pharm.D., Emmaus Medical, Torrance; Lynne D. Neumayr, M.D., and Elliott P. Vichinsky, M.D., UCSF Benioff Children’s Hospital Oakland Research Center, Oakland.
Articles in the Medical Literature
J Pediatr Psychol. 2018 Jul 25. doi: 10.1093/jpepsy/jsy057. [Epub ahead of print]
Executive Functioning Mediates the Relationship Between Pain Coping and Quality of Life in Youth With Sickle Cell Disease.
Ludwig NN1, Sil S2,3, Khowaja MK1, Cohen LL1,3, Dampier C2,3.
Sickle cell disease (SCD) is a lifelong condition characterized by pain, which is associated with reduced health-related quality of life (HRQL). Data suggest that patients with SCD vary in how they cope and their neurocognitive abilities. This study aimed to characterize executive functioning and pain coping styles in children with SCD experiencing a range of pain frequency (i.e., chronic, episodic, and asymptomatic) and to examine whether executive functioning mediates the relationship between pain coping and HRQL.
Participants included 100 children and adolescents with SCD between the ages of 8 and 18 years (M = 13.53, SD = 2.8) and their parents who were recruited during outpatient SCD clinic visits in a children’s hospital. Children completed questionnaires related to pain experience and pain coping. Parents completed questionnaires about demographic information, their child’s executive functioning, and HRQL.
Pain intensity, executive dysfunction, and engagement in emotion-focused coping (i.e., internalizing/catastrophizing and externalizing) predicted poor HRQL. In addition, engagement in emotion-focused coping predicted executive dysfunction. Multivariate analysis of covariance revealed executive functioning did not differ based on pain frequency; however, executive functioning was a significant mediator that helped explain the relationships between distraction and emotion-focused coping techniques on HRQL.
Findings support that executive functioning is an important factor in understanding the relationship between pain coping and HRQL in youth with SCD. Future research is warranted to examine the potential impact of executive functioning on the utility of interventions targeting adaptive pain coping in youth with SCD.
J Pediatr Hematol Oncol. 2018 Jul 23. doi: 10.1097/MPH.0000000000001257. [Epub ahead of print]
Development of a Hydroxyurea Decision Aid for Parents of Children With Sickle Cell Anemia.
Crosby LE1,2,3, Walton A1,4, Shook LM2,5, Ware RE2,5, Treadwell M6, Saving KL7,8, Britto M2,3,8, Peugh J1,2, McTate E1,2, Oyeku S9, Nwankwo C1, Brinkman WB2,3,10.
National evidence-based guidelines recommend offering hydroxyurea to patients with sickle cell anemia 9 months of age and older using shared decision making, but offer no strategies to aid implementation. We developed a hydroxyurea multicomponent decision aid via a needs assessment, clinic observations, and iterative feedback to address parent decision needs and promote a discussion between clinicians and parents. A total of 75 parents and 28 clinicians participated across all phases. The decision aid was rated as useful. Hydroxyurea knowledge improved and decisional conflict decreased supporting the potential for use to facilitate shared decision making in pediatric sickle cell anemia.
J Pediatr Hematol Oncol. 2018 Jul 23. doi: 10.1097/MPH.0000000000001250. [Epub ahead of print]
Psychometric Properties of a Modified Version of the Faces Pain Scale-Revised (Modified FPS-R) to Evaluate Worst Pain in Children and Adolescents With Sickle Cell Anemia.
Naegeli AN1, Heath L1, Zhou C1, Gupta N1, Dampier C2.
We evaluated psychometric properties (validity, reliability, and responsiveness) of a modified Faces Pain Scale-Revised (FPS-R) in 257 patients with sickle cell anemia (SCA) 7 to below 18 years old in a randomized, multinational clinical study. The modified FPS-R asks patients to report, by daily diary, their worst intraday SCA-related pain. Intraclass correlation coefficient assessed test-retest reliability between month 1 and month 2. Pearson correlations between monthly mean SCA-related pain intensity, activity interference score, analgesic use, and opioid use assessed convergent validity. Responsiveness was assessed with correlations of changes of monthly pain rate or intensity and changes in analgesic use or activity interference score from month 1 to month 9. Intraclass correlation coefficients for pain intensity and pain rate were 0.777 and 0.820, respectively, indicating agreement among stable patients. Moderate associations were shown between mean pain intensity and analgesic use (r=0.39) and opioid use (r=0.44), and between monthly pain rate and analgesic use (r=0.38). Moderate-to-large associations were observed between change in mean pain rate or intensity and changes in analgesic use (r=0.38 to 0.39, both P<0.001) and in activity interference scores (r=0.82 to 0.92, both P<0.001). These results support use of the modified FPS-R across cultures in children and adolescents aged 7 to below 18 years with SCA.
Emerg Med Clin North Am. 2018 Aug;36(3):567-576. doi: 10.1016/j.emc.2018.04.002.
Rapid Fire: Sickle Cell Disease.
1. Department of Emergency Medicine, Norman Regional Hospital, Norman, OK, USA. Electronic address: Michael.firstname.lastname@example.org.
Emergency providers are likely to encounter sickle cell disease-related emergencies. The pathophysiology of emergent complaints are usually related to either an acute anemia or a vasoocclusive crisis. Differentiating between the two is the first step in the workup. Anemic crises must then be differentiated by the source. Vasoocclusive crises must be appropriately treated with aggressive pain management, gentle hydration, and other appropriate adjuncts. Early recognition and treatment are key in providing excellent emergency care to those with sickle cell disease.
PMID: 30037443 [Indexed for MEDLINE]
Am J Hematol. 2018 Jul 23. doi: 10.1002/ajh.25168. [Epub ahead of print]
Predictors of acute care utilization and acute pain treatment outcomes in adults with sickle cell disease: The role of non-hematologic characteristics and baseline chronic opioid dose.
Carroll CP1, Cichowitz C2, Yu T3, Olagbaju YO4, Nelson JA5, Campbell T6, Lanzkron S4.
Despite its rarity in the United States, sickle cell disease accounts for a disproportionate amount of healthcare utilization and costs. The majority of this is due to acute care for painful crises. A small subpopulation of patients accounts for most these costs due to frequent visits to emergency departments and acute care facilities. Previous investigations have found that these high utilizing patients are distinguished by both a more severe disease course and certain non-hematologic characteristics, which may include higher socioeconomic status and some psychiatric and psychological characteristics. This prospective observational cohort study was undertaken to test the ability of these characteristics to prospectively predict acute pain care outcomes, including visit frequency, total opioid doses, and pain improvement at the Johns Hopkins Sickle Cell Infusion Center (SCIC). Seventy-three participants were followed for 12 months and SCIC utilization and treatment outcomes were tabulated for 378 visits. Participants who visited the SCIC most frequently had markedly worse pain improvement despite higher within-visit opioid doses. Higher utilization was associated with indicators of greater illness severity, more aggressive treatment for sickle cell disease, higher baseline opioid doses, higher socioeconomic status, greater pain-related anxiety, and a history of psychiatric treatment. Overall, poor acute pain treatment response was associated with higher utilization and higher baseline opioid doses. The pattern of association between high utilization, poor acute care outcomes, and higher baseline opioid doses is discussed in terms of prior research and future directions. This article is protected by copyright. All rights reserved.
Int J Hematol Res. 2017;3(1):171-179. doi: 10.17554/j.issn.2409-3548.2017.03.47. Epub 2017 Dec 12.
Assessment of Transition Readiness in Adolescents with Sickle Cell Disease and their Caretakers, A single institution experience.
Kwarteng-Siaw M1, Paintsil V2, Toboh CK2, Owusu-Ansah A3, Green NS1.
Sickle Cell Disease (SCD) is associated with high child mortality and birth incidence in sub-Saharan Africa. Improved SCD medical services in Ghana aims to enhance survival into adulthood, creating emerging need for transition from pediatric to adult care. Anticipating transition for adolescents with SCD, we sought to understand patient and caretaker perspectives on transition to adult care within Ghana.
MATERIALS AND METHODS:
Structured interviews were conducted with a sample of patients ages 12-15 years and accompanying adults at Ghana’s Komfo Anokye Teaching Hospital Sickle Cell Clinic (KATH SCC) covering four areas: SCD medical knowledge, symptom self-management, psychosocial impact, and transition preparation.
In total, 46 children (mean age 13 years) paired with 46 adults were interviewed. Most children and caretakers had some knowledge about SCD and disease management. At least one-third lacked knowledge about SCD as an inherited condition. Youth were significantly more concerned about family burden and social stigmatization than adults. Most were unaware that patients are expected to switch care to adult medical providers by age 15 years, but were willing to transfer if needed.
Our clinic-based assessment at KATH SCC identified needs of adolescents and caretakers for education and counseling about disease, self-management, transition, family burden, and stigmatization. These findings provide insights into perspectives and educational gaps of families treated for SCD. Results suggest consideration of transition planning for adolescents with SCD and their caretakers in Ghana. Generalizability of our findings and practical methods to address needs for transition within Africa remain to be tested.
PMCID: PMC6054488 Free PMC Article
Conflict of interest statement
Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.
Transfus Med Rev. 2018 Jun 18. pii: S0887-7963(18)30015-4. doi: 10.1016/j.tmrv.2018.06.001. [Epub ahead of print]
Current Evidence for the Use of Prophylactic Transfusion to Treat Sickle Cell Disease During Pregnancy.
Jackson B1, Fasano R2, Roback J2.
1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA. Electronic address: email@example.com.
2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
The role of prophylactic transfusion therapy for the treatment of sickle cell disease during pregnancy is unclear. An analysis of the existing literature shows a limited number of publications that address this issue and specifically compare clinical outcomes in this population based on a treatment strategy of prophylactic transfusion versus transfusion only for clinical indications (on-demand transfusion). The existing studies show a wide variation in study design and outcomes measured. The results of this analysis suggest that there are insufficient data to support a clinically significant difference in morbidity and mortality outcomes based on transfusion strategy. Additional prospective clinical studies need to be performed to adequately address the risks and benefits of prophylactic transfusion and guide clinical decision making.
Br J Haematol. 2018 Jul 19. doi: 10.1111/bjh.15462. [Epub ahead of print]
Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil.
Carneiro-Proietti ABF1, Kelly S2,3, Miranda Teixeira C1, Sabino EC4, Alencar CS4, Capuani L5, Salomon Silva TP1, Araujo A6, Loureiro P6, Máximo C7, Lobo C7, Flor-Park MV8, Rodrigues DOW1, Mota RA1, Gonçalez TT2, Hoppe C3, Ferreira JE4, Ozahata M4, Page GP9, Guo Y9, Preiss LR9, Brambilla D9, Busch MP2, Custer B2; International Component of the NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS-III).
Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sβ0 (3·0%) and Sβ+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.
Science. 2018 Jul 20;361(6399):285-290. doi: 10.1126/science.aao0932.
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
Grevet JD1,2, Lan X1, Hamagami N1, Edwards CR1, Sankaranarayanan L1, Ji X2, Bhardwaj SK1, Face CJ1, Posocco DF1, Abdulmalik O1, Keller CA3, Giardine B3, Sidoli S4, Garcia BA4, Chou ST1, Liebhaber SA2, Hardison RC3, Shi J5, Blobel GA6,2.
Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of β-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain-focused CRISPR-Cas9-based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
Blood. 2018 Jul 19. pii: blood-2018-05-851360. doi: 10.1182/blood-2018-05-851360. [Epub ahead of print]
RH genotype matching for transfusion support in sickle cell disease.
Chou ST1, Evans P2, Vege S3, Coleman SL4, Friedman DF5, Keller M6, Westhoff CM3.
Rh alloimmunization remains a challenge for patients with sickle cell disease despite transfusion of serologic Rh C, E and K antigen-matched red cells. Inheritance of altered RH alleles contributes to the prevalence of Rh antibodies following blood transfusion in patients with SCD and explains approximately one-third of cases. The remainder appear to be stimulated by altered Rh proteins on African-American donor red cells. Matching of patients with donors based on RH genotype may mitigate Rh alloimmunization, but the feasibility and resources required are not known. We compared RH allele frequencies between patients with SCD (n=857) and African-American donors (n=587) and show that RH allele frequencies are similar. Overall, 29% of RHD and 53% of RHCE alleles are altered in patients and African-American donors. We modeled RH genotype matching compared to serologic Rh D, C, and E, along with K antigen-matching, and found that approximately twice the number of African-American donors would be required for RH genotype versus Rh serologic matching at our institution. We demonstrate that African-American donor recruitment is necessary to maintain an adequate supply of C, E, and K negative donor units to avoid depleting the Rh negative (RhD-) blood supply. Our results suggest that prophylactic RH genetic matching for patients with SCD is feasible with a donor pool comprised primarily of African-Americans and would optimize utilization of our existing minority donor inventory. The current cost of RH genotyping all minority donors and management of the data remain limiting factors.
J Med Internet Res. 2018 Jul 19;20(7):e10940. doi: 10.2196/10940.
Patient-Centered eHealth Interventions for Children, Adolescents, and Adults With Sickle Cell Disease: Systematic Review.
Badawy SM#1,2,3, Cronin RM#4,5, Hankins J6, Crosby L7,8, DeBaun M9, Thompson AA1,2, Shah N10.
Sickle cell disease is an inherited blood disorder that affects over 100,000 Americans. Sickle cell disease-related complications lead to significant morbidity and early death. Evidence supporting the feasibility, acceptability, and efficacy of self-management electronic health (eHealth) interventions in chronic diseases is growing; however, the evidence is unclear in sickle cell disease.
We systematically evaluated the most recent evidence in the literature to (1) review the different types of technological tools used for self-management of sickle cell disease, (2) discover and describe what self-management activities these tools were used for, and (3) assess the efficacy of these technologies in self-management.
We reviewed literature published between 1995 and 2016 with no language limits. We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and other sources. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened titles and abstracts, assessed full-text articles, and extracted data from articles that met inclusion criteria. Eligible studies were original research articles that included texting, mobile phone-based apps, or other eHealth interventions designed to improve self-management in pediatric and adult patients with sickle cell disease.
Of 1680 citations, 16 articles met all predefined criteria with a total of 747 study participants. Interventions were text messaging (4/16, 25%), native mobile apps (3/16, 19%), Web-based apps (5/16, 31%), mobile directly observed therapy (2/16, 13%), internet-delivered cognitive behavioral therapy (2/16, 13%), electronic pill bottle (1/16, 6%), or interactive gamification (2/16, 13%). Interventions targeted monitoring or improvement of medication adherence (5/16, 31%); self-management, pain reporting, and symptom reporting (7/16, 44%); stress, coping, sleep, and daily activities reporting (4/16, 25%); cognitive training for memory (1/16, 6%); sickle cell disease and reproductive health knowledge (5/16, 31%); cognitive behavioral therapy (2/16, 13%); and guided relaxation interventions (1/16, 6%). Most studies (11/16, 69%) included older children or adolescents (mean or median age 10-17 years; 11/16, 69%) and 5 included young adults (≥18 years old) (5/16, 31%). Sample size ranged from 11 to 236, with a median of 21 per study: <20 in 6 (38%), ≥20 to <50 in 6 (38%), and >50 participants in 4 studies (25%). Most reported improvement in self-management-related outcomes (15/16, 94%), as well as high satisfaction and acceptability of different study interventions (10/16, 63%).
Our systematic review identified eHealth interventions measuring a variety of outcomes, which showed improvement in multiple components of self-management of sickle cell disease. Despite the promising feasibility and acceptability of eHealth interventions in improving self-management of sickle cell disease, the evidence overall is modest. Future eHealth intervention studies are needed to evaluate their efficacy, effectiveness, and cost effectiveness in promoting self-management in patients with sickle cell disease using rigorous methods and theoretical frameworks with clearly defined clinical outcomes.
©Sherif M Badawy, Robert M Cronin, Jane Hankins, Lori Crosby, Michael DeBaun, Alexis A Thompson, Nirmish Shah. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 19.07.2018.
N Engl J Med. 2018 Jul 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.
A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.
Niihara Y1, Miller ST1, Kanter J1, Lanzkron S1, Smith WR1, Hsu LL1, Gordeuk VR1, Viswanathan K1, Sarnaik S1, Osunkwo I1, Guillaume E1, Sadanandan S1, Sieger L1, Lasky JL1, Panosyan EH1, Blake OA1, New TN1, Bellevue R1, Tran LT1, Razon RL1, Stark CW1, Neumayr LD1, Vichinsky EP1; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease.
O’Neal P, Haynes J, Labotka R, Sharon B, McMahon L, Kruse-Jarres R, Kerr J, Moulton T, Hassell K, Dunbar L, Hussein A, Woods G, Osarogiagbon R, Goyal-Khemka M, Ferber A, Iyer R, Smith M, Majumdar S, Raj A, Puthenveetil G, Bryant P, Abdul Rashid N, Ikeda A.
- l-Glutamine and the Dawn of Combination Therapy for Sickle Cell Disease. [N Engl J Med. 2018]
Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain.
In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period.
A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group.
Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).
Cannabis Cannabinoid Res. 2018 Jul 1;3(1):162-165. doi: 10.1089/can.2018.0001. eCollection 2018.
Marijuana Use in Adults Living with Sickle Cell Disease.
Roberts JD1, Spodick J2, Cole J3, Bozzo J4, Curtis S1, Forray A5.
Introduction: Legal access to marijuana, most frequently as “medical marijuana,” is becoming more common in the United States, but most states do not specify sickle cell disease as a qualifying condition. We were aware that some of our patients living with sickle cell disease used illicit marijuana, and we sought more information about this. Materials and Methods: We practice at an urban, academic medical center and provide primary, secondary, and tertiary care for ∼130 adults living with sickle cell disease. We surveyed our patients with a brief, anonymous, paper-and-pen instrument. We reviewed institutional records for clinically driven urine drug testing. We tracked patient requests for certification for medical marijuana. Results: Among 58 patients surveyed, 42% reported marijuana use within the past 2 years. Among users, most endorsed five medicinal indications; a minority reported recreational use. Among 57 patients who had at least one urine drug test, 18% tested positive for cannabinoids only, 12% tested positive for cocaine and/or phencyclidine only, and 5% tested positive for both cannabinoids and cocaine/phencyclidine. Subsequent to these studies, sickle cell disease became a qualifying condition for medical marijuana in our state. In the interval ∼1.5 years, 44 patients have requested certification. Conclusion: Our findings and those of others create a rationale for research into the possible therapeutic effects of marijuana or cannabinoids, the presumed active constituents of marijuana, in sickle cell disease. Explicit inclusion of sickle cell disease as a qualifying condition for medical marijuana might reduce illicit marijuana use and related risks and costs to both persons living with sickle cell disease and society.
PMCID: PMC6044416 Free PMC Article
Conflict of interest statement
No competing financial interests exist.
P T. 2018 Jul;43(7):417-437.
Review of Medication Therapy for the Prevention of Sickle Cell Crisis.
Riley TR, Boss A, McClain D, Riley TT.
This article reviews the clinical data concerning the uses of hydroxyurea, L-glutamine, and crizanlizumab in treating pain crises associated with sickle cell disease.
PMCID: PMC6027858 [Available on 2018-08-01]
Am J Emerg Med. 2018 Jul 3. pii: S0735-6757(18)30562-X. doi: 10.1016/j.ajem.2018.07.006. [Epub ahead of print]
Use of bedside ultrasound as a predictive tool for acute chest syndrome in sickle cell patients: A prospective exploratory study.
Colla JS1, Kotini-Shah P1, Soppet S2, Chen YF3, Molokie R4, Prajapati P5, Prendergast HM1.
Acute chest syndrome (ACS) is the leading cause of death for patients with sickle cell disease (SCD). Early recognition of ACS improves prognosis.
Investigate the use of bedside lung ultrasound (BLU) in identification of early pulmonary findings associated with ACS in SCD patients.
Prospective, observational study of a convenience sample of SCD patients presenting to the Emergency Department (ED) for a pain crisis. BLU interpretations were made by an emergency physician blinded to the diagnosis of ACS, and were validated by a second reviewer. The electronic medical record was reviewed at discharge and at 30 days.
Twenty SCD patients were enrolled. Median age was 31 years, median hemoglobin was 7.7 g/dL. Six patients developed ACS. Five patients in the ACS group had lung consolidations on BLU (83%) compared to 3 patients in the non-ACS group (21%), p = 0.0181, (OR = 12.05, 95% CI 1.24 to 116.73). The ACS group was also more likely to have a pleural effusion and B-lines on BLU than the non-ACS group, p = 0.0175; 0.1657, respectively. In the ACS group, peripheral and frank consolidations on BLU was 83% and 50% sensitive, 79% and 100% specific for ACS, respectively; whereas an infiltrate on initial chest X-ray (CXR) was only 17% sensitive. BLU identified lung abnormalities sooner than CXR (median 3.6 vs. 31.8 h).
Pulmonary abnormalities on BLU of an adult SCD patient presenting to the ED for a painful crisis appear before CXR, and highly suggest ACS. BLU is a promising predictive tool for ACS.
Copyright © 2018. Published by Elsevier Inc.
Hematology. 2018 Jul 16:1-9. doi: 10.1080/10245332.2018.1498441. [Epub ahead of print]
Oxidative stress, antioxidant capacity, biomolecule damage, and inflammation symptoms of sickle cell disease in children.
Biswal S1, Rizwan H2, Pal S2, Sabnam S2, Parida P3, Pal A4.
The phenotypic expression of sickle cell disease (SCD) is a complex pathophysiologic condition. However, sickle erythrocytes might be the cause for multiple sources of pro-oxidant processes with consequent linked to chronic and systemic oxidative stress. Herein, we explored the SCD phenomena could be the result in formation of oxidative stress as well as inflammation in children.
MATERIAL AND METHODS:
Blood samples of 147 SCD subjects were evaluated. A control group was formed of 156 individuals without SCD. Different oxidative stress markers and inflammatory mediators were measured by using various biochemical techniques. Plasma samples were collected from blood for the measurement of antioxidants and reactive oxygen species (ROS).
The levels of plasma hydroxyl radical (HO•), and nitric oxide (NO) production were higher in SCD children in compared to control groups. The plasma antioxidants capacities such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and protein thiol levels were significantly reduced in SCD children. The plasma lipid peroxidation, protein carbonylation, DNA damage markers were significantly altered in different age groups of SCD children. Further, our results showed that SCD children have chronic inflammatory disease due to persistent alteration of haemoglobin content, reticulocyte, total bilirubin, platelet, creatinine, leukocytes, and altered expression of inflammatory mediators in compared to control groups.
SCD children have high oxidative stress, and conversely, decreased antioxidant activity. Decrease in antioxidant activity might explained the reduction in lipid peroxidation, protein carbonylation and increased inflammation, which in turn intensify the symptoms of SCD in children.
Transfusion. 2018 Jul 8. doi: 10.1111/trf.14767. [Epub ahead of print]
Improvement of maternal and fetal outcomes in women with sickle cell disease treated with early prophylactic erythrocytapheresis.
Vianello A1, Vencato E1, Cantini M2, Zanconato G3, Manfrin E4, Zamo A4, Zorzi F1, Mazzi F1, Martinelli N1, Cavaliere E3, Monari F5, Venturelli D6, Ferrara F7, Olivieri O1, De Franceschi L1.
The desire for pregnancy in sickle cell disease (SCD) women has become a true challenge for hematologists, requiring a multidisciplinary approach. Erythrocytapheresis (ECP) is an important therapeutic tool in SCD, but only limited data on starting time and the effects of ECP during pregnancy are available.
STUDY DESIGN AND METHODS:
This is a double-center retrospective cross-sectional study on a total of 46 single pregnancies in SCD women from January 2008 to June 2017. ECP was started at 10.7 ± 5.2 weeks of gestation, and prophylactic enoxaparin (4,000 U daily) was introduced due to the reported high prevalence of thromboembolic events in pregnant SCD women.
The alloimmunization ratio was 2.1 per 1,000 and the alloimmunization rate was 5.6%. In early ECP-treated SCD women, no severe vaso-occlusive crisis, sepsis or severe infection, or preeclampsia or eclampsia were observed. We found normal umbilical arterial impedance during pregnancy, suggesting an optimal uteroplacental function in early ECP-treated SCD women. This was also supported by the improvement in newborn birthweights compared to previous studies. In our cohort, three SCD women were started later on ECP (20-25 weeks), and gestation ended with late fetal loss. Placenta pathology documented SCD-related damage and erythroblasts in placental vessels, indicating fetal hypoxia.
Collectively, our data generate a rationale to support a larger clinical trial of early ECP program in SCD pregnancy.
© 2018 AABB.
Am J Hematol. 2018 Jul 7. doi: 10.1002/ajh.25202. [Epub ahead of print]
Clustering of end-organ disease and earlier mortality in adults with sickle cell disease: A prospective cohort study.
Chaturvedi S1, Ghafuri DL2, Jordan N2,3, Kassim A2,3, Rodeghier M4, DeBaun MR2,5.
Chronic end-organ complications result in morbidity and mortality in adults with sickle cell disease (SCD). In a prospective cohort of 150 adults with SCD who received standard care screening for pulmonary function abnormalities, cardiac disease, and renal assessment from January 2003 to January 2016, we tested the hypothesis that clustering of end-organ disease is common and multiple organ impairment predicts mortality. Any end-organ disease occurred in 59.3% of individuals, and 24.0% developed multiple organ (>1) end-organ disease. The number of end-organs affected was associated with mortality (P=<0.001); 8.2% of individuals with no affected end-organ, 9.4% of those with one affected organ, 20.7% of those with two affected end-organs, and 85.7% with three affected end-organs died over a median follow up period of 8.7 (interquartile range 3.5, 11.4) years. Of the 22 individuals who died, 59.3% had evidence of SCD-related end-organ impairment, and this was the primary or secondary cause of death in 45.0%. SCD-related chronic impairment in multiple organs, and its association with mortality, highlights the need to understand the common mechanisms underlying chronic end-organ damage in SCD, and the urgent need to develop interventions to prevent irreversible end-organ complications in SCD. This article is protected by copyright. All rights reserved.
Sickle Cell Conferences and Events
2018 Sickle Cell in Focus October 22-23, 2018 National Institutes of Health Natcher Conference Center Bethesda, MD 20892
Click here for event details and to register!
To view the agenda click here.
46TH ANNUAL NATIONAL CONVENTION THEME ANNOUNCED
This year’s theme for the conference is Celebrating the Diversity Within the Sickle Cell Community: Commitment, Innovation, and Practice
With over 600 researchers, physicians, nurses, social workers, individuals living with SCD & SCT in attendance, last year’s year’s convention was a major success and our largest to date. We are excited to unite again with you at the 46th Annual National Convention in Baltimore, MD on October 10-13, 2018! https://www.sicklecelldisease.org/2017/03/07/46th-annual-national-convention/
The 4th Annual Sickle Cell Disease Symposium for Carolinas Healthcare System – Atrium Health
will be held on Saturday, October 27, 2018 at the Speedway Club in Charlotte, NC. The theme this year is: “4th Annual SCD Symposium: Racing to Improve the Access to Care & Outcomes for SCD”.
2018 (Re) imagining Health: Sickle Cell Anemia & Thalassaemia: An International Biomedical-Sociocultural Conference November 16 – 17, 2018
Edmonton Clinic Health Academy, University of Alberta Edmonton, Alberta, Canada
This event will join our community of physicians, surgeons, researchers, medical practitioners and patients with a deep understanding and commitment to finding the cure for Sickle Cell Anemia.
We aim to bring together multiple voices to support and build inclusive and equitable teaching and learning environments, while increasing knowledge of the continued effects of the Sickle Cell Anemia trait. The Sickle Cell Foundation of Alberta is proud to announce the following expert speakers
Dr. Lakiea Bailey, of Georgia, USA
Dr. Carl James, of Toronto, ON
Dr. Emily Meier of Indiana, USA
Dr. Greg Guilcher of Calgary, AB
Dr. Santosh Saraf of Illinois, USA
Dr. Courtney Fitzhugh of Maryland, USA
REGISTRATION – Conference registration is now open. A variety of registration categories are available for the conference. Please see the fee details below or register online here. https://ourscfa.org/conference/
More information can be found on the conference website
www.ourscfa.org/conference Contact us at SCFA@buksa.com