Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning.
Studies cited by Cowan et al. [J. Appl. Toxicol. 23, 177 (2003)] indicate existence of inflammatory and cholinergic pathways in both nerve agents and sulfur mustard (HD) injury. Increase in AChE synthesis and neurite extension was noted after exposure to HD [K.W. Lanks et al., Exp. Cell Res. 355 (1975)]. Moreover, anti-inflammatory drugs reduce the dermal, respiratory and ocular damage caused by exposure to HD. On the other hand, recent studies have noted the involvement of neuro-inflammatory processes during exposure to the nerve agents sarin or soman [Cowan et al., 2003]. The use of various anti-inflammatory drugs in addition to the classical antidotal drugs (e.g. atropine and oximes) caused decrease in certain toxic symptoms and inflammation-induced brain damage. Our new bifunctional drugs (Scheme 1) are based on CNS-permeable molecular combination of pseudo-reversible AChE inhibitor (pyridostigmine, PYR) coupled via a hydrophobic spacer (octyl or decyl hydrocarbon chain) to a non-steroidal anti-inflammatory drug (NSAID) such as Ibuprofen or Diclofenac (Scheme 1). This study evaluates the efficacy of certain bifunctional compounds against HD and soman poisoning in mice in vivo.
Amitai
Gabi
G
Division of Medicinal Chemistry, Israel Institute for Biological Research, Ness Ziona 74100, Israel.
Adani
Rachel
R
Fishbein
Eliezer
E
Meshulam
Haim
H
Laish
Ido
I
Dachir
Schlomit
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D001768:Blister / Q000139:chemically induced* / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D002802:Cholinesterases / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D012999:Soman / Q000633:toxicity; D015996:Survival Rate
D000893:Anti-Inflammatory Agents; D002800:Cholinesterase Inhibitors; D012999:Soman; D002802:Cholinesterases