Monday, December 23, 2019

Therapeutics in Sickle Cell Anemia

Apart from Hydroxyurea, Analgesics and vasodilators like phosphodiesterase inhibitors, certain tantalizing novel drugs have been approved for Sickle cell anemia.... Let's take a closer look at them.

(1) Voxelotor (HbS polymerization inhibitor) binds covalently to N-terminal valine of alpha chain of HbS (around 30% of HbS in individual cell) stabilizing it's oxygenated form and causing left ward shift of dissociation curve without impairing oxygen delivery to tissues.

Consistently reduces hemolysis and viscosity with in 2 weeks of administration... FIRST EVER therapy targeting core defect.


It's ability to bind only around 30% of Hb in individual cells is crucial to maintain delicate balance between shifting the dissociation curve just enough to increase the affinity for oxygen so as to preclude vaso-occlusive crisis, while simultaneously ensuring that the oxygen delivery to tissues is not compromised because of excessive shift.

(2) Crizanlizumab (Antibody against P-Selectin) blocks interaction between P-Selectin and PSGL1, resulting in reduced adhesion of erythrocytes to endothelium, and also preventing aggregation and migration of leukocytes to vascular bed, approved for reducing the frequency of vaso-occlusive crisis in sickle cell disease.

(3) Glutamine is an amino acid oral powder for acute complications associated with SCD. Sickle RBCs are more susceptible to oxidative damage than normal RBCs, which may contribute to chronic hemolysis and vaso-occlusive events associated with SCD. Pyridine nucleotides, NAD+ and its reduced form NADH, regulates and prevents oxidative damage in RBCs. Glutamine is believed to improve the NAD redox potential in sickle RBCs by increasing reduced glutathione’s availability.

What the future holds?

Sevuparin - Lies along the spectrum of crizanlizumab, and has possible interactions with thrombospondin, fibronectin, vWF, P-Selectin and L- Selectin.

Antibodies against iNKT (invariant Natural Killer T cells) - Oxygenation- Reoxygenation stress results in release of Adenosine, which acts on iNKT cells serving to fuel the NF-kappa beta pathway and subsequent Vasculopathy due to release of inflammatory mediators.

Others - L-Arginine, PUFA, Endothelin antagonists, PAR antagonists...

Submitted by Kirtan Patolia

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