Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.
Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. Electronic address: meprice1@dstl.gov.uk.
Matthew E
ME
Price
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Cerys J
CJ
Docx
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Helen
H
Rice
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Sarah J
SJ
Fairhall
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Sarah J C
SJC
Poole
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Michael
M
Bird
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Luke
L
Whiley
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Daniel P
DP
Flint
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
A Christopher
AC
Green
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
Christopher M
CM
Timperley
Chemical, Biological and Radiological Division, Defence Science and Technology Laboratory (DSTL), Porton Down, Salisbury, Wiltshire SP4 0JQ, UK.
John E H
JEH
Tattersall
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D001285:Atropine / Q000008:administration & dosage; D004151:Dipeptides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D000067397:Nerve Agents; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011041:Poisoning / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D012999:Soman
D000927:Anticonvulsants; D000931:Antidotes; D004151:Dipeptides; C571852:MB327; D018727:Muscarinic Antagonists; D000067397:Nerve Agents; D018733:Nicotinic Antagonists; D011726:Pyridinium Compounds; C065249:pro-diazepam; D001285:Atropine; D012999:Soman
Antinicotinic; Bispyridinium compounds; Guinea-pig; MB327; Nerve agent poisoning; Nicotinic acetylcholine receptor antagonists; Organophosphorus anticholinesterase; Oximes; Soman