Post-exposure treatment with nasal atropine methyl bromide protects against microinstillation inhalation exposure to sarin in guinea pigs.
We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m(3) sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarin exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.
Che
Magnus M
MM
Department of Biochemical Pharmacology, Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.
Conti
Michele
M
Chanda
Soma
S
Boylan
Megan
M
Sabnekar
Praveena
P
Rezk
Peter
P
Amari
Ethery
E
Sciuto
Alfred M
AM
Gordon
Richard K
RK
Doctor
Bhupendra P
BP
Nambiar
Madhusoodana P
MP
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000281:Administration, Intranasal; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001286:Atropine Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D002452:Cell Count; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D019570:Inhalation Exposure / Q000009:adverse effects*; D007322:Instillation, Drug; D008168:Lung / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010276:Parasympatholytics / Q000008:administration & dosage / Q000627:therapeutic use*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control; D011663:Pulmonary Surfactants / Q000378:metabolism; D012524:Sarin / Q000633:toxicity*; D013997:Time Factors
D001286:Atropine Derivatives; D002619:Chemical Warfare Agents; D010276:Parasympatholytics; D011663:Pulmonary Surfactants; C006649:methylatropine; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000469:Alkaline Phosphatase; D010100:Oxygen