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Nitric Oxide, Phosphodiesterase Inhibitors and Soluble Guanylate Cyclase Stimulators as Candidate Treatments for Sickle Cell Disease
source: Journal of Sickle Cell Disease and Hemoglobinopathies
year: 2016
authors: Deva Sharma, Karin P. Potoka, Gregory J. Kato
summary/abstract:Despite being described in the medical literature over a hundred years ago, sickle cell disease continues to be associated with significant morbidity and mortality secondary to end-organ damage resulting from ischemia, chronic inflammation, iron overload and endothelial dysfunction. Unfortunately, current therapies for sickle cell disease remain limited, and the only current curative treatment is allogeneic bone marrow transplant, which is associated with significant risks. Impaired nitric oxide bioavailability has been documented in patients with sickle cell disease and has been implicated in the pathophysiology of pulmonary vascular complications and other vasomotor defects, suggesting that therapies aimed at restoring nitric oxide balance may be promising in this patient population.
Therapeutic strategies to restore nitric oxide balance in prior clinical trials have included direct inhalation of nitric oxide gas and its donors, amplification of nitric oxide effects through inhibition of cyclic guanosine monophosphate hydrolysis, and oral supplementation with substrates of nitric oxide synthesis. While preclinical trials of nitric oxide-based therapies for the treatment of pulmonary vascular complications in sickle cell disease have been promising, early clinical trials in this patient population have been limited, largely due to the increased risk of painful vasoocclusive crises, which might be attributable to the known dual nociceptive effects of nitric oxide. Further preclinical and clinical trials are warranted to investigate the therapeutic benefits of nitric oxide-based therapies in the treatment of specific complications of sickle cell disease, including pulmonary and systemic hypertension and chronic kidney disease.
organization: University of Pittsburgh, USADOI: 10.14223/JSCDH-D-16-00097
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