I was approached by a healthcare student-“what is this buzz about hydroxyurea and its use in the management of sickle cell disease (SCD)”. In responding to this enquiry, I turned to a review article published by Agrawal et al titled “Hydroxyurea in Sickle Cell Disease: Drug Review”.Indian Journal of Haematology and Blood Transfusion (Apr-June 2014) 30(2):91–96.

Patients with sickle cell disease experience both chronic and episodic pain and have a reduced quality of life. Painful crisis is the most common reason for emergency department use by patients with sickle cell disease.

Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. There is substantial evidence regarding its safety and efficacy for patients with SCA.The phase 3 National Heart, Lung and Blood Institute (U.S.A)—sponsored multicenter study of hydroxyurea trialproved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events. Recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage.

In spite of the abundant evidence for its efficacy,  hydroxyurea has not yet translated into effective therapy for SCA. Many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears.

Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment. In the discussion of harms of hydroxyurea treatment, the panel of National Institutes of Health Consensus Conference (U.S.A.) wrote, ‘‘the risks of hydroxyurea are acceptable compared with the risks of untreated sickle cell disease’’. Current evidence suggests that several potential mechanisms of action by hydroxyurea may be relevant for patients with SCA, which together lead not only to HbF (foetal haemoglobin) induction but also to additional benefits. The efficacy of hydroxyurea in the treatment of SCDis attributed to its ability to boost the levels of fetal hemoglobin (Hb F). This lowers the concentration of Hb S (haemoglobin S) within a cell resulting in less polymerization of the abnormal hemoglobin.

Beyond HbF induction, the cytotoxic effects of hydroxyurea also reduce marrow production of neutrophils, reticulocytes and also reduce the number ofplatelets, which is an important mediator of inflammation. Because an elevated white blood cell (WBC) has been associated with both morbidity and mortality of SCA, lowering the WBC count in SCA is itself potentially therapeutic.

Both neutrophils and reticulocytes promote vaso-occlusion through vascular adhesion. Hydroxyurea lowers their absolute numbers and reduces surface expression of adhesion receptors.

Additional benefits of hydroxyurea treatment include salutary effects on the circulating erythrocytes. Peripheral erythrocytes undergo numerous morphologic and physiologic changes during hydroxyurea dose escalation to maximum tolerated dose (MTD), including macrocytosis, increased mean corpuscular hemoglobin, better hydration, more targeting, less hemolysis, and fewer sickled forms. Overall blood flow is improved, with a higher haemoglobin concentration and lower  lactate dehydrogenase (LDH) and bilirubin levels.

The hydroxyurea molecule contains an nitric oxide (NO) moiety that can be released directly through unknown metabolic processes. NO has beneficial effects on vascular endothelium, including local vasodilatation, and could help offset proposed hemolysis-related NO consumption. This effect may help explain the clinical improvement some patients feel soon after initiating hydroxyurea treatment, before reaching MTD with maximal HbF induction.

Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1–4 h after an oral dose.

Hydroxyurea has become an accepted therapeutic option for many patients with SCA. For SCA, an ideal therapeutic intervention would require the following characteristics: (1) General features: single-agent, inexpensive, orally administered and once-daily dosing.  (2) Laboratory efficacy, increases HbF and total Hb, reduction in WBC and reticulocytes, and lowers LDH.  (3) Clinical efficacy: ameliorates anemia, less vaso occlusive events and hospitalizations, and decreased hemolysis. (4) Treatment goals: works in all age groups, prevents acute events and chronic organ dysfunction. (5) Sustainability: benefits continue over time without medication resistance or tolerance.  (6) Side effects: few short-term toxicities that might limit adherence, and a wide therapeutic index.  (7) Safety: no major short-term toxicities, plus no known long-term sequelae or complications of therapy.

Based on currently available data, hydroxyurea treatment fulfills these criteria for SCA and should be offered much more frequently, especially to young patients before the development of chronic complications and end-organ damage

Among published predictors of clinical severity, the amount of foetal haemoglobin (percentage HbF) is the most critical laboratory parameter. HbF is protective against clinical severity. Low-percentage HbF is associated with a higher risk of developing vaso-occlusive complications, organ damage, and early death. Accordingly, pharmacologic induction of HbF is a logical treatment goal in SCA.

An increased WBC count has also been associated with poor clinical outcomes, and more recently, elevated serum lactate dehydrogenase (LDH, reflecting intravascular hemolysis) has been associated with morbidity and mortality in SCA.

Hydroxyurea has emerged as an exciting therapeutic agent because of its ease of oral administration, modest toxicity profile, predictable laboratory efficacy for increasing percentage HbF and reducing hemolysis, and proven clinical efficacy for preventing acute vaso-occlusive events.

Hydroxyurea reduces the number of painful events along with hospitalisations in adults and children. There is preservation of splenic function in infants receiving hydroxyurea.  Hydroxyurea has clinical efficacy for children with variable sickle-related organ damage, including proteinuria, spleen dysfunction, hypoxaemia, pulmonary hypertension, glomerular hyperfiltration, neurocognitive delay, silent brain infarcts, primarystroke prevention, and secondary stroke prevention.

Standard indications for hydroxyurea include frequent pain crises, acute chest syndrome, and severe or symptomatic anaemia.

Contraindications to hydroxyurea include pregnancy or sexually active and unwillingness to use contraception, active liver disease (HBV or HCV infection), and history of severe hydroxyurea toxicity or hypersensitivity.

Recent studies suggest that patients with sickle cell disease suffer from decreased nitric oxide (NO) reserves. Blood plasma levels of L-arginine (the precursor to NO) are depressed in patients with sickle cell disease, particularly during vaso-occlusive crisis and the acute chest syndrome, and these levels vary inversely with pain symptoms. It is a clear case for increased cocoa consumption in persons with sickle cell disease.

By Dr Edward O. Ampofo

The writer is the Chief Pharmacist, Cocoa Clinic

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