Treatment Of Sickle Cell Disease Research Articles

Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial

BackgroundDespite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.MethodsSTArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE.DiscussionBuilding on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children.Trial registrationThe STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).

Impact of vitamin B12 on the reproductive health of women with sickle cell disease: a narrative review.

Sickle cell disease (SCD) poses an increased risk of infertility, pregnancy complications and maternal and perinatal mortality among women of reproductive age. This risk is particularly higher for women in sub-Saharan Africa, where the disease burden is highest and access to comprehensive health care is limited, as well as in other countries with a high SCD prevalence due to migration. Disease modifying treatments for SCD could directly and indirectly harm the ovaries, potentially compromising quality and quantity of existing oocytes. Therefore, it is essential to explore alternative interventions, such as nutritional modifications that are less harmful and cost-effective in order to improve reproductive outcomes, and enhance the overall well-being of both mother and child in this population. Maintaining optimal levels of B12 may possibly provide benefits to the ovaries and pregnancy by decreasing homocysteine levels, increasing nitric oxide (NO) bioavailability, and promoting antioxidant and anti-inflammatory activities. Individuals living with SCD are more susceptible to vitamin B12 (B12) deficiency. However, there is a lack of clinical data investigating the relationship between systemic levels of B12, its supplementation, and reproductive outcome measures in SCD women. Therefore, this review aims to examine the current evidence regarding the impact of SCD on female reproductive health and the role of B12 in the reproductive biology of women living with SCD.

The Role of Antiplatelet in the Management of Sickle Cell Disease Patients.

Sickle cell disease (SCD) is a genetic disorder characterized by abnormal hemoglobin, leading to red blood cell deformities and subsequent vaso-occlusive events. Platelet activation and adhesion play a significant role in the pathophysiology of SCD, contributing to the development of complications such as vaso-occlusive events, stroke, acute chest syndrome, and other manifestations. Antiplatelet therapy has emerged as a potential strategy to mitigate these complications by modulating the platelet function and reducing thrombotic events. This review article provides an overview of antiplatelet therapy's role in managing SCD patients. It discusses the pathophysiological abnormalities in the platelet function in SCD, the rationale for antiplatelet therapy, and the evidence supporting its use in various clinical scenarios. The article explores aspirin as the primary antiplatelet agent in SCD, including its mechanism of action, dosing considerations, and efficacy and safety data. Additionally, it highlights other antiplatelet agents, such as clopidogrel, prasugrel, ticagrelor, and emerging therapies under investigation. Clinical applications of antiplatelet therapy in primary and secondary prevention and the management of acute chest syndrome and other SCD complications are also discussed. Safety considerations are emphasized, including bleeding risk assessment, monitoring, and patient selection for antiplatelet therapy. Finally, the review highlights future research and clinical practice directions, including the development of novel antiplatelet agents, combination therapies, and the integration of antiplatelet therapy with other SCD treatments. Overall, this review provides a comprehensive understanding of the current role of antiplatelet therapy in SCD management, the challenges faced, and future directions for improving patient outcomes.

Cost-Effectiveness of Hydroxyurea for Sickle Cell Anemia in a Low-Income African Setting: A Model-Based Evaluation of Two Dosing Regimens.

The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efficacy suitable for SSA; however, no one has quantified the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-effectiveness of hydroxyurea as a fixed-dose regimen or maximumtolerated dose (MTD) regimen, versus SCA care without hydroxyurea. We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450mL units), for patients between 9months and 18years of age. We calculated cost-effectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3% annually. To test the robustness of our findings, and the impact of uncertainty, we conducted probabilistic and one-way sensitivity analyses, scenario analysis, and price threshold analyses. Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fixed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1-11.4) units of blood per patient, compared with 9.1 (95% CI 9.0-9.2) units of blood per patient at the fixed-dose alternative. Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fixed dose regimen, treatment dosing at MTD is likely to be a cost-effective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of life.

Access to essential therapy for sickle cell disease in Africa: Experience from a national program in Ghana

Novartis, a global medicines company, and the Sickle Cell Foundation of Ghana (SCFG), an advocacy organization, have endeavored to support the implementation of global best practices in the care of people living with sickle cell disease (SCD) in Africa, and to address unmet needs relating to this condition on the continent. Beginning in 2019, a multifaceted SCD program was implemented in Ghana through a public-private partnership involving the government of Ghana, the SCFG, Novartis, and other partners. A key component of the program involved expanding the reach of hydroxyurea (HU), the only approved disease-modifying generic treatment for SCD, in ways that would promote sustainable access. The program helped to raise the profile of SCD in Ghana and, in 2022, the government adopted HU into its National Health Insurance Scheme. Features of the effort in Ghana are now being expanded to other countries in Africa through cocreated programs with in-country partners. This article reviews the program's history, progress, challenges, and lessons learned.

A case report study on long term follow up treatment of T-AYU-HM Premium in Sickle cell anaemia Patient

Sickle cell anaemia is a haemoglobin condition for which the Indian government has set up particular support provisions within the ministry of tribal affairs. Despite epidemiological and recent advances in the treatment of sickle cell anaemia over the past few years, it remains a global concern for everyone. To demonstrate the impact of T-AYU-HM Premium, the long-term treatment outcomes of a patient with sickle cell trait are detailed in this case study. A 35-year-old female patient with a family history of sickle cell anaemia was unable to finish her studies because she had blood transfusions every other month and experienced excruciating pain. Her reported painful crises, treatment compliance, the number of blood transfusions she received, and the number of hospitalizations she needed were all reviewed in this case study. Her past medication and medical history were assessed in 2008 following which the T-AYU-HM Premium treatment was started once she approached the clinic with these complaints. It was noted that the patient followed the prescribed line of treatment, had symptomatic relief from episodic pain, and was able to perform day-to-day tasks. It was noted that the patient only required one blood transfusion and one hospital stay throughout the course of the 15 years of follow-up. This case study would further the understanding and practical application of complementary medicine in the treatment of sickle cell anaemia. The potential for long-term treatment using alternative medical systems may well be established.

An Online Educational Module to Improve General Internal Medicine Trainees’ Knowledge and Comfort in Managing Acute Complications of Sickle Cell Disease

BACKGROUND: Sickle cell disease (SCD) is a genetic disorder characterized by hemolytic anemia and vaso-occlusive episodes. Many adults with SCD require hospitalization for the management of acute manifestations. There appears to be a gap in the level of knowledge that general internal medicine (GIM) trainees possess regarding the treatment and management of SCD. METHODS: We created an online module that helps medical residents improve their knowledge about SCD. Participants were exposed to different scenarios related to SCD. A pre-and posttests were administered to detect improvement in knowledge and comfort when managing SCD and its acute complications. RESULTS: Thirty consecutive GIM residents participated. Of these, 20 completed the demographic survey, 17 completed the pretest, and 10 completed the posttest and usability survey. The median time to complete the module was 68 min. Fifty percent of participants were 1st-year postgraduation from medical school. Forty-five percent stated that they were uncomfortable managing patients with SCD 80% had cared for at least 1–5 patients with SCD. All reported having no SCD lectures in residency. The median pretest score was 12/20 (range, 8–15) and posttest score was 20.5/25 (range, 13–24). CONCLUSIONS: Residents agreed that the module was useful, helps understanding about SCD and its complication, and aids with clinical duties. This module demonstrated to be an effective educational tool that can support resident education during their internal medicine. Further strategies will be needed to improve the delivery of online modules to keep residents engaged with the module and attaint full benefit from these activities.

In-vitro Antisickling Activity of Pergularia daemia, Canna indica and Petiveria alliacea Plants used in the Treatment of Sickle Cell Anaemia in Edo State, Nigeria

Sickle cell disease is a genetic blood disorder that affects the shape and transportation of the red blood cells (RBCs) in blood vessels, leading to various clinical complications. Available medicines for treating the disease are insufficiently effective, toxic or expensive. Therefore, there has been a pressing need for effective and inexpensive therapeutic agents from indigenous medicinal plants. Petiveria alliacea, Canna indica and Pergularia daemia, respectively were evaluated for their cationic constituents as a measure for their antisickling activity in sickle cell anaemia disorder. The three medicinal plants were extracted separately with methanol solvent using maceration method for 72 hours. The extracts were concentrated using a rotary evaporator (Model RE, 200, USA). Phytochemical screenings were conducted using standard method, while other portions of the extract were subjected to dry ash digestion for determination of mineral elements by emission flame photometry (EFP) and atomic absorption spectrophotometry (AAS). Evaluation of the antisickling activity of the extracts was done using the sodium metabisulphite (SMBS) test. Eugenol, terpenoids and alkaloids were present in the three plant extracts, while K+ values recorded for Petiveria alliacea, Canna indica and Pergularia daemia were 54.30 mg kg–1, 180.10 mg kg–1 and 28.30 mg kg–1, respectively. Other mineral elements detected in the three plants were Cu2+, Zn2+, Fe2+ and Mg2+. The leaves extract of Canna indica and Pergularia daemia at high dose of 300 µg/mL caused significant reductions of sickle red blood cells from 15% to 6% and 15% to 1%, respectively at 90 minutes of the antisickling test. The research confirmed that extracts of both Canna indica and Pergularia daemia used in this study have significant antisickling properties in invitro studies than Petiveria alliacea.
 Keywords: Antisickling activity, Petiveria alliacea, Canna indica, Pergularia daemia, sickle cell, phytochemicals, minerals

In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters

NDec is a novel combination of oral decitabine and tetrahydrouridine that is currently under clinical development for the treatment of sickle cell disease (SCD). Here, we investigate the potential for the tetrahydrouridine component of NDec to act as an inhibitor or substrate of key concentrative nucleoside transporters (CNT1–3) and equilibrative nucleoside transporters (ENT1–2). Nucleoside transporter inhibition and tetrahydrouridine accumulation assays were performed using Madin-Darby canine kidney strain II (MDCKII) cells overexpressing human CNT1, CNT2, CNT3, ENT1, and ENT2 transporters. Results showed that tetrahydrouridine did not influence CNT- or ENT-mediated uridine/adenosine accumulation in MDCKII cells at the concentrations tested (25 and 250 µM). Accumulation of tetrahydrouridine in MDCKII cells was initially shown to be mediated by CNT3 and ENT2. However, while time- and concentration-dependence experiments showed active accumulation of tetrahydrouridine in CNT3-expressing cells, allowing for estimation of Km (3,140 µM) and Vmax (1,600 pmol/mg protein/min), accumulation of tetrahydrouridine was not observed in ENT2-expressing cells. Potent CNT3 inhibitors are a class of drugs not generally prescribed to patients with SCD, except in certain specific circumstances. These data suggest that NDec can be administered safely with drugs that act as substrates and inhibitors of the nucleoside transporters included in this study.

Structure-based computational design of novel covalent binders for the treatment of sickle cell disease

The quest in finding an everlasting panacea to the pernicious impact of sickle cell disease (SCD) in the society hit a turn of success since the recent discovery of a small molecule reversible covalent inhibitor, Voxelotor. A drug that primarily promotes the stability of oxygenated hemoglobin and inhibit the polymerization of HbS by enhancing hemoglobin's affinity for oxygen has opened a new frontier in drug discovery and development. Despite eminent efforts made to reproduce small molecules with better therapeutic targets, none has been successful. To this end, we employed the use of structure-based computational techniques with emphasis on the electrophilic warhead group of Voxelotor to harness novel covalent binders that could elicit better therapeutic response against HbS. The PubChem database and DataWarrior software were used to design random molecules using Voxelotor's electrophilic functionality. Following the compilation of these chemical entities, a high-throughput covalent docking-based virtual screening campaign was conducted which revealed three (Compound_166, Compound_2301, and Compound_2335) putative druglike candidates with higher baseline energy value compared to the standard drug. Subsequently, in silico ADMET profiling was carried out to evaluate their pharmacokinetics and pharmacodynamics properties, and their stability was evaluated for 1 μs (1 μs) using molecular dynamics simulation. Finally, to prioritize these compounds for further development in drug discovery, MM/PBSA calculations was employed to evaluate their molecular interactions and solvation energy within the HbS protein. Despite the admirable druglike and stability properties of these compounds, further experimental validations are required to establish their preclinical relevance for drug development.

Knowledge of fertility and perception of fertility treatment among adults with sickle cell disease (KNOW FERTILITY).

This study assessed fertility knowledge in adults with sickle cell disease using the Cardiff Fertility Knowledge Scale and Fertility Treatment Perception Survey and compared knowledge scores in respondents with sickle cell disease to previously reported unaffected cohorts. This cross-sectional study surveyed adults over age 18 with sickle cell disease at an adult sickle cell disease center using a 35-question survey addressing infertility risk factor knowledge and perceptions of fertility treatment. Analyses included summary statistics for continuous and categorical variables, univariate linear regression, and Mann-Whitney U tests for group comparisons of Fertility Knowledge Scale scores. Fertility Treatment Perception Survey scores were measured by medians of the two positive statements and four negative statements to generate separate positive and negative treatment belief scores. Statistical significance was set at p < 0.05 for all analyses. Ninety-two respondents (71 female, 21 male) with median age of 32 years (IQR: 25.0, 42.5) completed the survey between October 2020-May 2021. Sixty-five percent of respondents reported taking sickle cell disease treatment and 18% reported refusing at least one sickle cell disease treatment due to fertility concerns. The mean Fertility Knowledge Score was 49% (SD: 5.2), lower than reported in an international cohort (57% vs. 49%, p = 0.001), and higher than in a cohort of reproductive-aged Black women in the USA (49% vs. 38%, p = 0.001). Less than 50% of respondents correctly identified common infertility risk factors including sexually transmitted infections, advanced age, and obesity. Mean positive fertility perception score was 3 (IQR 3, 4), and negative fertility perception score was 3.5 (IQR 3, 4). Factors associated with agreement with negative fertility perception statements included: trying to conceive, refusing sickle cell disease treatment, and undergoing fertility treatment. Opportunities exist to improve knowledge of infertility risk factors among adults with sickle cell disease. This study raises the possibility that nearly one in five adults with sickle cell disease refuse SCD treatment or cure due to infertility concerns. Education about common infertility risks factors needs to be addressed alongside disease- and treatment- associated fertility risks.

Voxelotor does not inhibit sickle hemoglobin fiber formation upon complete deoxygenation

The drug voxelotor (commercially known as Oxbryta) has been approved by the US Food and Drug Administration for the treatment of sickle cell disease. It is known to reduce disease-causing sickling by inhibiting the transformation of the non-polymerizing, high-oxygen-affinity R quaternary structure of sickle hemoglobin into its polymerizing, low-affinity T quaternary structure. It has not been established whether the binding of the drug has anti-sickling effects beyond restricting the change of quaternary structure. By using a laser photolysis method that employs microscope optics, we have determined that fully deoxygenated sickle hemoglobin will assume the T structure. We show that the nucleation rates essential to generate the sickle fibers are not significantly affected by voxelotor. The method employed here should be useful for determining the mechanism of sickling inhibition for proposed drugs.

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings.

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment. Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at -80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449nm detector and 5 micron C18 column; and 2) portable PolyLC with 415nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania. Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%-20% of the actual values. Both HPLC systems measured hydroxyurea with <10% variance from the prepared concentrations, and paired analysis of samples on both machines documented <15% variance. Serial measurements of 300 and 100μM concentrations using the PolyLC system were precise with 2.5% coefficient of variance. After transport to Tanzania with setup and training, the modified PolyLC HPLC system produced similar calibration curves with R2 > 0.99. Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses.

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

EPH247 Pain and Arthralgia Adverse Events Associated with Crizanlizumab and Voxelotor: Disproportionality Analysis of US FDA Adverse Events Reporting System (FAERS)

Sickle cell disease (SCD) is a genetic erythrocyte disorder with limited treatment options. In the past few years, the FDA has approved a monoclonal antibody, crizanlizumab (Nov 15, 2019), and a HbS polymerization inhibitor, voxelotor (Nov 25, 2019), for the treatment of SCD. As newly approved medications become more widely used in real-world clinical practice, it is important to monitor their safety. This study aimed to assess adverse event reports for arthralgia and pain associated with crizanlizumab and voxelotor.

X-ray crystallography and sickle cell disease drug discovery-a tribute to Donald Abraham.

X-ray crystallography and structure-based drug discovery have played a major role in the discovery of antisickling agents that target hemoglobin (Hb) for the treatment of sickle cell disease (SCD). Sickle cell disease, the most common inherited hematologic disorder, occurs as a result of a single point mutation of βGlu6 in normal human adult hemoglobin (HbA) to βVal6 in sickle hemoglobin (HbS). The disease is characterized by polymerization of HbS and sickling of red blood cells (RBCs), leading to several secondary pathophysiologies, including but not limited to vaso-occlusion, hemolytic anemia, oxidative stress, inflammation, stroke, pain crisis, and organ damage. Despite the fact that SCD was the first disease to have its molecular basis established, the development of therapies was for a very long time a challenge and took several decades to find therapeutic agents. The determination of the crystal structure of Hb by Max Perutz in the early 60s, and the pioneering X-ray crystallography research by Donald J. Abraham in the early 80s, which resulted in the first structures of Hb in complex with small molecule allosteric effectors of Hb, gave much hope that structure-based drug discovery (SBDD) could be used to accelerate development of antisickling drugs that target the primary pathophysiology of hypoxia-induced HbS polymerization to treat SCD. This article, which is dedicated to Donald J. Abraham, briefly reviews structural biology, X-ray crystallography and structure-based drug discovery from the perspective of Hb. The review also presents the impact of X-ray crystallography in SCD drug development using Hb as a target, emphasizing the major and important contributions by Don Abraham in this field.

Route Optimization of the Noncovalent Modulator of Hemoglobin PF-07059013 for Treatment of Sickle Cell Disease through a Palladium-Mediated C–O Coupling, Part II: Pilot Plant Scale Manufacture

Herein, we report the optimization of the first process chemistry route for pilot-plant-scale manufacture of PF-07059013 (1), a noncovalent modulator of hemoglobin for the treatment of sickle cell disease. Five areas of improvement are discussed in detail, namely, an alternative synthetic sequence to install the pyridone functionality before benzylic ether formation, a shorter and safer route to quinoline fragment 9, a tosyl-swap strategy to avoid isolation of a thermally unstable tosylate intermediate, Pd-catalyzed C–O coupling with low catalyst loading and efficient Pd removal, and improved final isolation of the API freebase. The new route was executed in our pilot plant facility to deliver 76 kg of API.

Antisickling Studies of the Aqueous Leaf Extract of Detarium microcarpum (Tallow Tree)

Detarium microcarpum (DM) is shrub that grows wildly in Nigeria. Few studies have been conducted on the leaf extract. The plant forms part of some recipes used in the treatment of sickle cell disease. This study aims to determine the phytochemical composition and antisickling property of various concentrations of Detarium microcarpum aqueous leaf extract. Quantitative and qualitative phytochemical screenings were conducted using established protocols while the antisickling prevention and reversal studies were evaluated using Emmel’s test. There was no significant difference between the antisickling prevention (p&gt;0.05) and reversal (p&gt;0.05) property of the aqueous extract compared to positive control (p-hydroxybenzoic acid). Phytochemical screening revealed high abundance of flavonoids and very little presence of terpenoids among the classes of phytochemicals screened. There was also no significant variation in the antisickling activity of the various doses (0.1 mg/ml, 1 mg/ml and 10 mg/ml) of the extract tested. The LD50 conducted showed that it is completely safe in mice. The findings from this study suggest that Detarium microcarpum aqueous extract at various concentrations possesses both sickling prevention and reversal effect which may be exploited for the management of sickle cell disease.

A Critical Review of Sickle Cell Disease Burden and Challenges in Sub-Saharan Africa.

Sickle cell disease is caused by an abnormality of the β-globin gene and is characterised by sickling of the red blood cells. Globally, sub-Saharan African countries share the highest burden of the disease. This study aimed at critically reviewing studies focusing on challenges of sickle cell anaemia in sub-Saharan Africa. A literature search was carried out in five major databases. Articles that met the inclusion criteria were included in the bibliometric review and critical analysis. A majority of the studies were undertaken in the West African region (85.5%), followed by Central Africa (9.1%). Very few studies had been undertaken in East Africa (3.6%), whilst the Southern African region had the fewest studies (1.8%). Distribution in relation to country revealed that three quarters of the studies were carried out in Nigeria (74.5%), followed by the Democratic Republic of the Congo (9.1%). According to healthcare settings, a strong majority of the studies were undertaken in tertiary health care facilities (92.7%). Major themes that emerged from the review include interventions, cost of treatment, and knowledge about sickle cell disease. Public health awareness and promotion as well as improving the quality of sickle cell centers for prompt management of patients with sickle cell disorder was identified as a critical strategy towards reducing the burden of the disease in sub-Saharan Africa. To achieve this, governments in countries located in this region need to adopt a proactive strategy in addressing gaps that have been identified in this study, as well as instituting other relevant measures, such as continuous media engagement and public health interventions relating to genetic counselling. Reforms in other areas that can help reduce the disease burden, include training of practitioners and equipping sickle cell disease treatment centers according to World Health Organization specifications.

Simultaneous adjunctive treatment of malaria and its coevolved genetic disorder sickle cell anemia

AbstractEffective treatments for genetic disorders that coevolved with pathogens require simultaneous betterment of both conditions. Hydroxyurea (HU) offers safe and efficacious treatment for sickle cell anemia (SCA) by reducing clinical complications, transfusions, and death rates. Despite concerns that the HU treatment for SCA would increase infection risk by the human malaria Plasmodium falciparum, (the genetic driver of the sickle mutation), HU instead reduced clinical malaria. We used physiologically relevant drug exposures that mimic in vivo pharmacokinetics in humans. Under these conditions, we showed that HU and other ribonucleotide reductase (RNR) inhibitors have significant, intrinsic killing activity in vitro against schizont stages of P falciparum in both normal and sickle red blood cells. Long-term in vitro selection with HU increased the expression of Pfrnr genes but showed a low risk of eliciting stably resistant parasites or compromising the potency of current antimalarial drugs. Additive activity devoid of antagonism by HU was observed with a wide spectrum of commonly used antimalarial treatments. These data endorse broad, safe, and long-term use of HU for SCA in malaria-endemic countries and provide a novel biological model for the treatment of a genetic disorder with simultaneous, adjunct therapy of a life-threatening infection needed in a global health setting.