Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure.

Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This work demonstrates that an enzyme-cleavable polymeric prodrug of tafenoquine addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low cost of goods sold (COGS) at less than $1.50 per dose. Liver targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced glucose 6-phosphate dehydrogenase-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for P. vivax eradication campaigns.

Damage-control resuscitation increases successful nonoperative management rates and survival after severe blunt liver injury.

BACKGROUND: Nonoperative multidisciplinary management for severe (American Association for the Surgery of Trauma Grades IV and V) liver injury has been used for two decades. We have previously shown that Damage Control Resuscitation (DCR) using low-volume, balanced resuscitation improves survival of severely injured trauma patients; however, little attention has been paid to organ-specific outcomes. We wanted to determine if implementation of DCR has improved survival and successful nonoperative management after severe blunt liver injury. METHODS: A retrospective study was performed on all adult trauma patients with severe blunt liver injury who were admitted from 2005 to 2011. Patients were divided into pre-DCR (2005-2008) and DCR (2009-2011) groups. Patients who died before leaving the emergency department (ED) were excluded. Outcomes (resuscitation products used, survival, and length of stay) were then compared by univariate and multivariate analyses. RESULTS: Between 2005 and 2011, 29,801 adult trauma patients were admitted, and 1,412 (4.7%) experienced blunt liver injury. Of these, 244 (17%) sustained Grade IV and V injuries, with 206 patients surviving to leave the ED. The pre-DCR group (2005-2008) was composed of 108 patients, and the DCR group (2009-2011) had 98 patients. The groups were not different in demographics as well as prehospital and ED vital signs or Injury Severity Score (ISS). No change in operative or interventional radiology techniques occurred in this time frame. The DCR cohort had an increase in successful nonoperative management (from 54% to 74%, p < 0.01) as well as a reduction in initial 24-hour packed red blood cell (median, from 13 U to 6.5 U; p < 0.01), plasma (median, from 13 U to 8 U; p < 0.01), and crystalloid (median, from 5,800 mL to 4,100 mL; p < 0.01) administration. The DCR treatment was associated with improved survival, from 73% to 94% (p < 0.01). CONCLUSION: In patients with severe blunt liver injury, DCR was associated with less crystalloid and blood product use, a higher successful nonoperative management rate, and improved survival. Resuscitation technique may improve outcomes after severe liver injury. LEVEL OF EVIDENCE: Therapeutic/care management, level III.

A clinical series of resuscitative endovascular balloon occlusion of the aorta for hemorrhage control and resuscitation.

BACKGROUND: A requirement for improved methods of hemorrhage control and resuscitation along with the translation of endovascular specialty skills has resulted in reappraisal of resuscitative endovascular balloon occlusion of the aorta (REBOA) for end-stage shock. The objective of this report was to describe implementation of REBOA in civilian trauma centers. METHODS: Descriptive case series of REBOA (December 2012 to March 2013) used in scenarios of end-stage hemorrhagic shock at the University of Maryland, R. Adams Cowley Shock Trauma Center, Baltimore, Maryland, and Herman Memorial Hospital, The Texas Trauma Institute, Houston, Texas. RESULTS: REBOA was performed by trauma and acute care surgeons for blunt (n = 4) and penetrating (n = 2) mechanisms. Three cases were REBOA in the descending thoracic aorta (Zone I) and three in the infrarenal aorta (Zone III). Mean (SD) systolic blood pressure at the time of REBOA was 59 (27) mm Hg, and mean (SD) base deficit was 13 (5). Arterial access was accomplished using both direct cutdown (n = 3) and percutaneous (n = 3) access to the common femoral artery. REBOA resulted in a mean (SD) increase in blood pressure of 55 (20) mm Hg, and the mean (SD) aortic occlusion time was 18 (34) minutes. There were no REBOA-related complications, and there was no hemorrhage-related mortality. CONCLUSION: REBOA is a feasible and effective means of proactive aortic control for patients in end-stage shock from blunt and penetrating mechanisms. With available technology, this method of resuscitation can be performed by trauma and acute care surgeons who have benefited from instruction on a limited endovascular skill set. Future work should be aimed at devices that allow easy, fluoroscopy-free access and studies to define patients most likely to benefit from this procedure. LEVEL OF EVIDENCE: Therapeutic study, level V.