. Author manuscript; available in PMC: 2019 Aug 1.

Published in final edited form as: Nat Rev Drug Discov. 2019 Feb;18(2):139–158. doi: 10.1038/s41573-018-0003-2

Table 4 |.

Agents that counteract free hemoglobin, heme and iron

Therapeutic agent	Properties	Comments
Nitric oxide	Vasodilates, anti-adhesive, replaces bioavailable NO	Inhaled NO did not improve SCD patients hospitalized with VOC²⁶⁶; NO helped priapism in SCD mice ²⁶⁷
Arginine	Substrate for NO synthesis	Efficacy in leg ulcers and pain in children¹¹⁴
Tetrahydrobiopterin	Co-factor for nitric oxide synthase	Improved endothelial dysfunction in several clinical settings²⁶⁸
Sildenafil	Blocksphosophodiesterase, increases cGMP	Increased hospitalizations in SCD patients²⁶⁹
Nitrite	Vasodilates, supplies NO	Enhanced healing of leg ulcers in SCD²⁷⁰
Hemeoxygenase inducers	Increases CO, biliverdin/bilirubin, ferritinand CO	Decreased VOC and inflammation in SCD mice⁴²
Dimethyl fumarate	Increases Nrf2	Increased HO1 and decreased VOC in SCD mice²⁷¹
Nrf2 inducers	Increases anti-oxidant, anti-inflammatory response	Decreased inflammation in SCD mice^272,273
Haptoglobin	Clears free hemoglobin via²⁷⁴ CD163	Decreased inflammation in SCD mice^44,275
Hemopexin	Clearshemevia CD91	Decreased TLR4 signaling in SCD mice^{43,44,118,276}
Iron chelators	Bind and clear excess iron, decrease oxidative stress	Decreased inflammation and VOC in SCD mice^44,241