ABSTRACT
Identifying sources of infection and establishing source control is an essential component of the workup and treatment of sepsis. Investigation with history, physical examination, laboratory tests, and imaging can in identifying sources of infection. All organ systems have the potential to develop sources of infection. However, there are inherent difficulties presented by some that require additional diligence, namely, urinalysis, chest radiographs, and intraabdominal infections. Interventions include administration of antibiotics and may require surgical or other specialist intervention. This is highlighted by the Surviving Sepsis Campaign with specific recommendations for time to antibiotics and expeditious time to surgical source control.
Subject(s)
Sepsis/etiology , Anti-Bacterial Agents/therapeutic use , Emergency Service, Hospital , Humans , Intraabdominal Infections/diagnosis , Intraabdominal Infections/etiology , Intraabdominal Infections/microbiology , Intraabdominal Infections/therapy , Physical Examination , Sepsis/diagnosis , Sepsis/microbiology , Sepsis/therapyABSTRACT
Human paraoxonase-1 (HuPON1) has been proposed as a catalytic bioscavenger of organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poisoning using two different paradigms. First, recombinant HuPON1 purified from cabbage loopers (iPON1; Trichoplusia ni) was administered to guinea pigs, followed by exposure to at least 2 times the median lethal dose (LD(50)) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic metabolite of the OP pesticide chlorpyrifos. In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then exposed to sequential doses of GD, VX, or (as reported previously) diazoxon, the toxic metabolite of the OP pesticide diazinon. In both animal models, the exogenously added HuPON1 protected animals against otherwise lethal doses of the OP pesticides but not against the nerve agents. Together, the results support prior modeling and in vitro activity data which suggest that wild-type HuPON1 does not have sufficient catalytic activity to provide in vivo protection against nerve agents.
Subject(s)
Aryldialkylphosphatase/administration & dosage , Chemical Warfare Agents/toxicity , Organophosphorus Compounds/toxicity , Pesticides/toxicity , Animals , Antidotes/administration & dosage , Antidotes/pharmacokinetics , Aryldialkylphosphatase/genetics , Aryldialkylphosphatase/isolation & purification , Aryldialkylphosphatase/pharmacokinetics , Chlorpyrifos/analogs & derivatives , Chlorpyrifos/toxicity , Guinea Pigs , Humans , Male , Mice , Moths , Organophosphates/toxicity , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/pharmacokinetics , Sarin/toxicity , Soman/toxicityABSTRACT
The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.
