title: Artificial oxygen carrier with pharmacologic actions of adenosine-5'-triphosphate, adenosine, and reduced glutathione formulated to treat an array of medical conditions.
abstract: Effective artificial oxygen carriers may offer a solution to tackling current transfusion medicine challenges such as blood shortages, red blood cell storage lesions, and transmission of emerging pathogens. These products, could provide additional therapeutic benefits besides oxygen delivery for an array of medical conditions. To meet these needs, we developed a hemoglobin (Hb)-based oxygen carrier, HemoTech, which utilizes the concept of pharmacologic cross-linking. It consists of purified bovine Hb cross-linked intramolecularly with open ring adenosine-5'-triphosphate (ATP) and intermolecularly with open ring adenosine, and conjugated with reduced glutathione (GSH). In this composition, ATP prevents Hb dimerization, and adenosine promotes formation of Hb polymers as well as counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine receptors. ATP also serves as a regulator of vascular tone through activation of purinergic receptors. GSH blocks Hb's extravasation and glomerular filtration by lowering the isoelectric point, as well as shields heme from nitric oxide and reactive oxygen species. HemoTech and its manufacturing technology have been broadly tested, including viral and prion clearance validation studies and various nonclinical pharmacology, toxicology, genotoxicity, and efficacy tests. The clinical proof-of-concept was carried out in sickle cell anemia subjects. The preclinical and clinical studies indicate that HemoTech works as a physiologic oxygen carrier and has efficacy in treating: (i) acute blood loss anemia by providing a temporary oxygen bridge while stimulating an endogenous erythropoietic response; (ii) sickle cell disease by counteracting vaso-occlusive/inflammatory episodes and anemia; and (iii) ischemic vascular diseases particularly thrombotic and restenotic events. The pharmacologic cross-linking of Hb with ATP, adenosine, and GSH showed usefulness in designing an artificial oxygen carrier for multiple therapeutic indications.
authors: Division of Artificial Oxygen Carriers, Texas HemoBioTherapeutics & BioInnovation Center (THBBC), Lubbock, TX, USA; School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Jan
authors: J
authors: Simoni
authors: Grace
authors: G
authors: Simoni
authors: John F
authors: JF
authors: Moeller
authors: Mario
authors: M
authors: Feola
authors: Donald E
authors: DE
authors: Wesson
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D000818:Animals; D001802:Blood Substitutes / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D006418:Heme / Q000627:therapeutic use*; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D010100:Oxygen / Q000378:metabolism*; D051381:Rats
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; C079129:hemoglobin polymer; D006418:Heme; D005978:Glutathione; D000241:Adenosine; D010100:Oxygen
keywords: Adenosine; Adenosine-5′-triphosphate; Anemia; Artificial oxygen carrier; Hemoglobin; Ischemia; Reduced glutathione