DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Optimized Liposomal Dexamethasone Therapy Improves Functional Outcome of Post-Traumatic Skeletal Muscle and Neuromuscular Junction

Posted June 25, 2019

Yu-Long Li, M.D., Ph.D., Department of Emergency Medicine, University of Nebraska Medical Center


Dr. Yu-Long Li

Tourniquets are critical to successful first-line treatment of hemorrhaging extremity injuries on the battlefield. During Operation Iraqi Freedom, pre-hospital tourniquet use may have prevented 57% of deaths caused by major limb trauma.1 While tourniquets are important in the treatment of extremity traumas in the battlefield, there are significant adverse effects associated with their long-term use; namely, acute ischemia-reperfusion (IR) injury. IR injuries can result in skeletal muscle cell death, necrosis, and disruption of motor nerve function in a limb treated with a tourniquet. Furthermore, acute IR injuries can result in long-term limb dysfunction, permanent neurological deficits, or complete limb paralysis. Because of the risks associated with IR injuries, tourniquet use remains controversial among treatment providers.

Previous work has demonstrated that IR injuries cause the release of inflammatory cytokines and reactive oxygen species that can damage neural and muscle tissue in the injured limb. In a preliminary study, Dr. Yu-Long Li from the University of Nebraska Medical Center found that treatment of a tourniquet-induced IR injury in mice with dexamethasone (Dex), an anti-inflammatory drug, during the first week after injury significantly improved function of IR injured muscles when compared to untreated mice. While Dex can be used to treat the symptoms of IR injury, it must be taken daily and its use causes severe side effects when given systemically, including increased blood glucose levels and osteoporosis. In Fiscal Year 2016 (FY16), Dr. Li was awarded a Defense Medical Research and Development Program Broad Agency Announcement award to investigate a novel drug delivery system that packages Dex within liposomes. This unique system allows Dex to be released slowly at target sites and avoids the complications associated with its use. Dr. Li will use this delivery system in mice to determine whether it can be used as an effective therapeutic for tourniquet-induced IR injuries.

Preliminary results from Dr. Li’s award demonstrate that Dex delivered as liposomal dexamethasone (lipo-Dex) is retained within IR-injured skeletal muscles up to 1 week after treatment. Treatment with Dex or lipo-Dex in tourniquet-induced IR injured mice showed marked improvement in muscle contraction at 1, 2, 4, and 6 weeks post-injury when compared to untreated mice. Additionally, Dex or lipo-Dex significantly inhibited inflammatory cytokines that are typically overexpressed in IR injured skeletal muscles. Based on these findings, Dr. Li concluded that treatment with Dex or lipo-Dex after tourniquet-induced IR injury reduces inflammation and promotes the recovery of damaged muscle structure and function.

The lipo-Dex delivery system could prove to be a critical treatment for the management of combat casualties treated with a tourniquet. Importantly, lipo-Dex may be used on the battlefield as a stop-gap for soldiers with severe limb trauma who will have delayed access to a hospital capable of treating their injuries. The findings from Dr. Li’s study have the potential to make a significant impact by providing evidence that a novel drug delivery system is capable of reducing the adverse effects associated with tourniquet use without causing significant risks to the patient’s limb structure and function.

Reference:

1 Beekley AC, Sebesta JA, Blackbourne LH, et al.  2008.  Prehospital tourniquet use in Operation Iraqi Freedom:  Effect on hemorrhage control and outcomes.  J Trauma 64(2):S28-S37.

Link:

Public and Technical Abstracts:  Optimized Liposomal Dexamethasone Therapy Improves Functional Outcome of Post-Traumatic Skeletal Muscle and Neuromuscular Junction

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Last updated Thursday, June 27, 2019