Nirmani Yasara1, Anuja Premawardhena2,3, Sachith Mettananda4,5. 1. Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka. 2. Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka. 3. Colombo North Teaching Hospital, Ragama, Sri Lanka. 4. Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, 11010, Sri Lanka. sachith.mettananda@kln.ac.lk. 5. Colombo North Teaching Hospital, Ragama, Sri Lanka. sachith.mettananda@kln.ac.lk.
Abstract
BACKGROUND: Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. MAIN BODY: Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. CONCLUSION: Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.
BACKGROUND:Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include β-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in β-thalassaemia major and haemoglobin E β-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with β-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in β-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. MAIN BODY: Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with β-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent β-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent β-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. CONCLUSION:Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with β-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent β-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent β-thalassaemia which should be confirmed by randomised clinical trials.
Authors: Idowu Akinsheye; Abdulrahman Alsultan; Nadia Solovieff; Duyen Ngo; Clinton T Baldwin; Paola Sebastiani; David H K Chui; Martin H Steinberg Journal: Blood Date: 2011-04-13 Impact factor: 22.113
Authors: Matthew C Canver; Elenoe C Smith; Falak Sher; Luca Pinello; Neville E Sanjana; Ophir Shalem; Diane D Chen; Patrick G Schupp; Divya S Vinjamur; Sara P Garcia; Sidinh Luc; Ryo Kurita; Yukio Nakamura; Yuko Fujiwara; Takahiro Maeda; Guo-Cheng Yuan; Feng Zhang; Stuart H Orkin; Daniel E Bauer Journal: Nature Date: 2015-09-16 Impact factor: 49.962
Authors: Khuthala Mnika; Gaston K Mazandu; Mario Jonas; Gift D Pule; Emile R Chimusa; Neil A Hanchard; Ambroise Wonkam Journal: Front Genet Date: 2019-05-28 Impact factor: 4.599
Authors: Rayan Bou-Fakhredin; Lucia De Franceschi; Irene Motta; Maria Domenica Cappellini; Ali T Taher Journal: Pharmaceuticals (Basel) Date: 2022-06-16