Severe hemorrhage is the leading cause of death among trauma victims, and is responsible for approximately 3 million deaths worldwide. Much of the mortality may be prevented by the timely availability of a safe and uni- versal resuscitation fluid. While whole blood or red blood cells (RBCs) remain the preferred transfusion fluids, inadequate availability of safe blood remains a problem. Despite the optimism in combating transfusion-related infections and ensuring an educated donor population, the limited shelf-life of blood and the need to cross- match frequently cause blood inventory shortages. These issues have stimulated a search for safe, immune- tolerant, shelf-stable and efficacious oxygen carrier for both civilian emergency and military applications. He- moglobin based oxygen carriers increase both oxygen-carriage and cardiac preload. We are developing liposome-encapsulated hemoglobin or LEH as a substitute oxygen carrier closely mimick- ing the RBCs. Encapsulated hemoglobin is believed to have better control over hemodynamics as compared to other chemically-modified, but free hemoglobin products. Using a novel formulation and advanced processing technologies, we have overcome the barriers of low encapsulation, oxidative instability, expense and scale-up. The product (called NeoLEH) circulates in blood for a prolonged time, and improves cerebral metabolism. Pre- liminary data demonstrate that the smaller size of LEH (275 nm) as compared to the RBCs (7.5 5m) results in more efficient oxygen delivery to the brain, which in turn improves cerebral oxygen and energy metabolism. In the proposed work, we will test our overall hypothesis that NeoLEH improves survival and cerebral metabol- ism, and serves as a long-circulating and non-toxic oxygen carrier in hemorrhagic shock.
The specific aims are to assess: 1) Survival and cerebral metabolism in a rat model of 40% hemorrhage, 2) Pharmacokinetics and biodistribution of NeoLEH, and the effect of reinjection, 3) Acute toxic effects of NeoLEH in the animal model of 40% hemorrhage, and 4) NeoLEH resuscitation and ischemia-reperfusion (I/R) injury. We propose a 4-y project for testing efficacy and safety of NeoLEH. We will study 24 h survival of rats receiv- ing NeoLEH resuscitation after 40% blood loss. Ringer's lactate, shed blood and Hextend will be used as con- trol fluids. Improvement in cerebral oxygen, glucose and energy metabolism will be evaluated by positron emission tomography and magnetic resonance imaging. Circulation persistence and biodistribution of NeoLEH will be assessed by monitoring the blood and organ levels of radiolabeled 99mTc-NeoLEH. In order to test the safety of NeoLEH, acute effects of NeoLEH infusion on phagocytic capacity of liver and complement-mediated platelet activation will be studied. Lastly, we will assess if NeoLEH infusion has any salutary effects in ische- mia-reperfusion phenomenon by monitoring intestinal integrity, neutrophil sequestration, etc. The results of the proposed investigations will be critical for the clinical development of NeoLEH. Targeted towards resuscitation in acute blood loss due to surgery or trauma, NeoLEH will serve civilian as well as military needs alike.

Public Health Relevance

Transfusion practices in hemorrhagic shock would benefit from adequate and safe availability of a universal substitute for red blood cells. This research pertains to the development of a novel liposome-encapsulated hemoglobin preparation as an oxygen carrier. The product, called NeoLEH, will be evaluated in a rat model of hemorrhagic shock.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL104286-03
Application #
8460860
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Mitchell, Phyllis
Project Start
2011-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$352,240
Indirect Cost
$114,240
Name
University of Oklahoma Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Yadav, Vivek R; Rao, Geeta; Houson, Hailey et al. (2016) Nanovesicular liposome-encapsulated hemoglobin (LEH) prevents multi-organ injuries in a rat model of hemorrhagic shock. Eur J Pharm Sci 93:97-106
Yadav, Vivek R; Hussain, Alamdar; Xie, Jun et al. (2015) The salutary effects of diphenyldifluoroketone EF24 in liver of a rat hemorrhagic shock model. Scand J Trauma Resusc Emerg Med 23:8
Rao, Geeta; Hedrick, Andria F; Yadav, Vivek R et al. (2015) The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock. J Cereb Blood Flow Metab 35:1528-36
Nag, Okhil K; Yadav, Vivek R; Croft, Brandon et al. (2015) Liposomes modified with superhydrophilic polymer linked to a nonphospholipid anchor exhibit reduced complement activation and enhanced circulation. J Pharm Sci 104:114-23
Rao, Geeta; Xie, Jun; Hedrick, Andria et al. (2015) Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model. Neuropharmacology 99:318-27
Yadav, Vivek R; Vilekar, Prachi; Awasthi, Shanjana et al. (2014) Hemorrhage-induced interleukin-1 receptor pathway in lung is suppressed by 3,5-bis(2-fluorobenzylidene)-4-piperidone in a rat model of hypovolemic shock. Artif Organs 38:675-83
Yadav, Vivek R; Hussain, Alamdar; Sahoo, Kaustuv et al. (2014) Remediation of hemorrhagic shock-induced intestinal barrier dysfunction by treatment with diphenyldihaloketones EF24 and CLEFMA. J Pharmacol Exp Ther 351:413-22
Yadav, Vivek R; Nag, Okhil; Awasthi, Vibhudutta (2014) Biological evaluation of liposome-encapsulated hemoglobin surface-modified with a novel PEGylated nonphospholipid amphiphile. Artif Organs 38:625-33
Nag, Okhil K; Yadav, Vivek R; Hedrick, Andria et al. (2013) Post-modification of preformed liposomes with novel non-phospholipid poly(ethylene glycol)-conjugated hexadecylcarbamoylmethyl hexadecanoic acid for enhanced circulation persistence in vivo. Int J Pharm 446:119-29
Yadav, Vivek R; Sahoo, Kaustuv; Roberts, Pamela R et al. (2013) Pharmacologic suppression of inflammation by a diphenyldifluoroketone, EF24, in a rat model of fixed-volume hemorrhage improves survival. J Pharmacol Exp Ther 347:346-56

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