<p>Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date</p>

Abstract

Sickle cell disease (SCD) is one of the most common inherited blood disorders globally. It is a grouping of autosomal recessive genetic disorders identified by a genetic mutation that replaces glutamic acid with valine at the sixth amino acid on the hemoglobin β-globin chain. Millions of people around the world live with a severe genotype of SCD that is often associated with occlusion of the microvasculature resulting in episodes of severe pain and multiple organ system dysfunction. These episodes, commonly categorized as vaso-occlusive crises (VOC), are a distinctive clinical presentation of SCD which represents the majority of SCD morbidity and associated hospitalizations. Though the complete process by which these crises occur is complex and not fully outlined, evidence reveals this process to be multifactorial and heterocellular. For nearly two decades, hydroxyurea was the only FDA-approved therapy for SCD. Evidence to date shows that hydroxyurea treatment significantly reduces the rate of VOC, hospitalizations, and mortality. Despite these benefits, adherence remains problematic due to a variety of adverse effects and interpatient variability connected with hydroxyurea therapy. Crizanlizumab, an adhesion inhibitor of sickled red blood cells, was recently granted breakthrough therapy designation. Results of a phase 2 study have reported a successful reduction in annual rates of vaso-occlusive crisis with a favorable safety profile. This paper reviews the available literature concerning crizanlizumab use in patients with SCD.

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

“… 33 The concentration-related interaction with hydroxyurea leading to a reduced effect at higher doses of crizanlizumab was erroneously thought to account for this phenomenon by some authors. 38 , 39 The trial was not powered to detect differences between subgroups, and the sample sizes were small in each subgroup. Patients with more severe disease are more likely to be put on hydroxyurea, potentially influencing the results.…”

Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle

“…Competitive inhibitors of P- and E-selectin and their binding partners, PSGL-1, CD44 and E-selectin ligand 1, have been investigated as antagonists to neutrophil and platelet-mediated vascular damage. Monoclonal antibody therapy to P- and E-selectin have shown promise in combating platelet and neutrophil-mediated injury [ 198 – 200 ], as is seen with the FDA approved P-selectin antibody crizanlizumab, designed to address vaso-occlusive crises in sickle cell anaemia [ 201 ]. However, clinical trials of Inclacumab, the monoclonal antibody designed to bind P-selectin, evidenced that a major limitation of antibody therapy is the need for high doses for therapeutic effects [ 90 , 202 ], leading to high production costs [ 203 , 204 ].…”

Shifting vantage, common musings: the politics of Wordsworthian excursus in the poetry of Peter Riley

“…40 The iambic monosyllables Ôpaint / What thenÕ and Ôdid not thenÕ, with their almost identical phrasing, lie at the heart of the echoic effect and the allusion. The plants on the tops of the mountains flower on our breath, the gentians and the tulips, when we breathe the language clear and benign 63 In ÔThe Glacial StairwayÕ Tesco functions as a verbal import that parallels the actual trade networks its presence implies, tainting the Ôvocabulary of pure poetryÕ and lowering the register. 64 Indeed, the question of register is formally central to RileyÕs mediation between the worldÕs Ôvulgar ordinanceÕ and the redemptive quality of the ordinary.…”