title: Aerosolized delivery of oxime MMB-4 in combination with atropine sulfate protects against soman exposure in guinea pigs.
abstract: We evaluated the efficacy of aerosolized acetylcholinesterase (AChE) reactivator oxime MMB-4 in combination with the anticholinergic atropine sulfate for protection against respiratory toxicity and lung injury following microinstillation inhalation exposure to nerve agent soman (GD) in guinea pigs. Anesthetized animals were exposed to GD (841 mg/m(3), 1.2 LCt(50)) and treated with endotracheally aerosolized MMB-4 (50 µmol/kg) plus atropine sulfate (0.25 mg/kg) at 30 sec post-exposure. Treatment with MMB-4 plus atropine increased survival to 100% compared to 38% in animals exposed to GD. Decreases in the pulse rate and blood O(2) saturation following exposure to GD returned to normal levels in the treatment group. The body-weight loss and lung edema was significantly reduced in the treatment group. Similarly, bronchoalveolar cell death was significantly reduced in the treatment group while GD-induced increase in total cell count was decreased consistently but was not significant. GD-induced increase in bronchoalveolar protein was diminished after treatment with MMB-4 plus atropine. Bronchoalveolar lavage AChE and BChE activity were significantly increased in animals treated with MMB-4 plus atropine at 24 h. Lung and diaphragm tissue also showed a significant increase in AChE activity in the treatment group. Treatment with MMB-4 plus atropine sulfate normalized various respiratory dynamics parameters including respiratory frequency, tidal volume, peak inspiratory and expiratory flow, time of inspiration and expiration, enhanced pause and pause post-exposure to GD. Collectively, these results suggest that aerosolization of MMB-4 plus atropine increased survival, decreased respiratory toxicity and lung injury following GD inhalation exposure.
authors.affiliation: Medical/Analytical Toxicology, US Army Medical Research Institute of Chemical Defense, Silver Spring, MD, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Perkins
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pierre
authors.forename: Praveena
authors.initials: P
authors.lastname: Sabnekar
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
authors.forename: Jian
authors.initials: J
authors.lastname: Song
authors.forename: Iswarduth
authors.initials: I
authors.lastname: Soojhawon
authors.forename: Samuel
authors.initials: S
authors.lastname: Oguntayo
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001285:Atropine / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002091:Butyrylcholinesterase / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000008:administration & dosage*; D004338:Drug Combinations; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010091:Oximes / Q000008:administration & dosage*; D020011:Protective Agents / Q000008:administration & dosage*; D012999:Soman / Q000633:toxicity*
chemical_list: D000336:Aerosols; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D004338:Drug Combinations; D010091:Oximes; D020011:Protective Agents; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase