Hydroxyurea in Sickle Cell Disease: Drug Review

Agrawal, Rohit; Patel, Rakesh Kantilal; Shah, Vaishal; Nainiwal, Lalit; Trivedi, Bhadra

doi:10.1007/s12288-013-0261-4

Cited by 169 publications

(169 citation statements)

References 21 publications

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“…20 HU improves RBC rheology, 21 has proven clinical efficacy, and reduces the frequency of VOCs by approximately 50%, but patients who receive this treatment still experience recurrent crises. 22,23 Furthermore, patient concerns regarding the HU safety profile and the monitoring that is required to determine a well-tolerated, effective dose have led to low prescription rates and poor patient adherence. 18,[23][24][25] A new therapeutic option is L-glutamine.…”

Section: Discussionmentioning

confidence: 99%

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

et al. 2018

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The cell adhesion molecule P‐selectin plays a key role in the pathogenesis of a vaso‐occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double‐blind, placebo‐controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2‐4/5‐10), SCD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event‐free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time‐to‐first VOC vs placebo in these subgroups. The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event‐free and delays time‐to‐first VOC.

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Section: Discussionmentioning

confidence: 99%

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

et al. 2018

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“…Nevertheless, the side effects of this drug include neutropenia, bone marrow suppression, elevation of hepatic enzymes, anorexia, nausea, vomiting and infertility. 10,11 Recently, on July 7, 2017, the U.S. FDA approved L-glutamine oral powder (Endari) as the rst new drug in 20 years for SCD, which acts by reducing acute complications in adults and children of 5 years and older. Although its mechanism of action is not fully understood, the drug is found to be involved in the oxidative stress phenomena of SCD.…”

Section: Introductionmentioning

confidence: 99%

Privileged substructures for anti-sickling activity via cheminformatic analysis

et al. 2018

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Sickle cell disease (SCD), an autosomal recessive genetic disorder, has been recognized by the World Health Organization (WHO) as a major public health problem as it affects 300 000 individuals worldwide.Complications arising from SCD include anemia, microvascular occlusion, severe pain, stokes, renal dysfunction and infections. A lucrative therapeutic strategy is to employ anti-sickling agents that can disrupt the formation of the HbS polymer. This study therefore employed cheminformatic approaches, encompassing classification structure-activity relationship (CSAR) modeling, to deduce the privileged substructures giving rise to the anti-sickling activity of an investigated set of 115 compounds, followed by substructure analysis. Briefly, the compiled compounds were described by fingerprint descriptors and used in the construction of CSAR models via several machine learning algorithms. The modelability of the data set, as exemplified by the MODI index, was determined to be in the range of 0.70-0.84. The predictive performance was deduced by the accuracy, sensitivity, specificity and Matthews correlation coefficient, which was found to be statistically robust, whereby the former three parameters afforded values in excess of 0.7 while the latter statistical parameter provided a value greater than 0.5. An analysis of the top 20 important substructure descriptors for anti-sickling activity revealed that 10 important features were significant in the differentiation of actives from inactives, as illustrated by aromaticity/ conjugation (e.g. SubFPC287, SubFPC171 and SubFPC5), carbonyl groups (e.g. SubFPC137, SubFPC139, SubFPC49 and SubFPC135) and miscellaneous groups (e.g. SubFPC303, SubFPC302 and SubFPC275).Furthermore, an analysis of the structure-activity relationship revealed that the length of alkyl chains, choice of functional moiety and position of substitution on the benzene ring may affect the anti-sickling activity of these compounds. Thus, this knowledge is anticipated to be useful for guiding the design of robust compounds against the gelling activity of HbS, as preliminarily demonstrated in the data-driven compound design presented herein.

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“…This has translated into clinical effects with chronic therapy with phosphodiesterase inhibitors for SCD-associated priapism prophylaxis (13). An additional effect of HU which may be beneficial in recurrent ischaemic priapism prophylaxis is its ability to increase HbF levels which reduces haemolysis (14). This effect potentiates NO homeostasis in SCD.…”

Section: Discussionmentioning

confidence: 99%

Effect of Hydroxyurea on Priapism in Men with Sickle Cell Disease

Morrison¹,

Hamilton²,

Reid³

2016

West Indian Med J

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Priapism is a devastating complication of sickle cell disease (SCD) with no uniformly accepted prophylaxis. Hydroxyurea (HU) has shown benefit in preventing chronic complications of SCD. We sought to determine the association between HU therapy and the prevention of priapism episodes in men with SCD. A retrospective case series study was conducted between July 1 and September 30, 2014, recruiting men treated at the Sickle Cell Unit, The University of the West Indies, Mona, Jamaica, who had a history of priapism and exposure to HU therapy. A questionnaire on priapism was administered, and changes in the characteristics of priapism episodes relative to HU therapy were recorded. Ten men with a mean age of 26.2 ± 10.7 years consented for the study. The most frequent indication for HU use was prevention of recurrent painful crises (50%). Three patients had baseline priapism episodes occurring daily or on alternate days. The baseline duration of the priapism episodes was greater than two hours in 50% of those interviewed, with 30% lasting over five hours. Five (50%) of the patients had cessation of episodes while on HU. Of the patients who continued to have priapism while on HU therapy, four had episodes lasting less than one hour, with one patient having episodes lasting beyond five hours. Chronic HU therapy appeared to be associated with an amelioration of recurrent priapism episodes in men with SCD.

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Hydroxyurea in Sickle Cell Disease: Drug Review

Cited by 169 publications

References 21 publications

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

Privileged substructures for anti-sickling activity via cheminformatic analysis

Effect of Hydroxyurea on Priapism in Men with Sickle Cell Disease

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