title: Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning.
abstract: Certain organophosphorus (OP) nerve agents (e.g. soman) induce neuroinflammatory processes during acute poisoning. An increased level of typical inflammation markers was also observed in poisoning by alkylating agents such as sulfur mustard (HD). The therapeutic potential of new bifunctional compounds was investigated, eliciting activity of non-steroidal anti-inflammatory drug (NSAID) and anti-cholinesterase (anti-ChE) activity, as an antidotal treatment for both soman and HD poisoning in mice. Three bifunctional compounds were used that include the ChE inhibitor pyridostigmine (PYR) coupled to either ibuprofen (IBU) or diclofenac (DICLO) through an eight (octyl) or ten (decyl) hydrocarbon chain spacer: IBU-PO, IBU-PD and DICLO-PD. These compounds are 15-25 fold less toxic than PYR in mice and exert peripheral and central anti-inflammatory and anti-ChE activity in vivo. IBU-PO (4 mg kg(-1), i.p.), IBU-PD (4 mg kg(-1), i.p.) and PYR (0.13 mg kg(-1), i.p.) reduced to control levels the brain edema in soman-poisoned mice (1.1 LD50, s.c.). Pre-treatment with IBU-PO, IBU-PD and DICLO-PD 4-5 h before soman challenge (2.2-2.3 LD50, s.c.) combined with antidotal treatment (atropine, 11 mg kg(-1), 2-PAM-Cl, 25 mg kg(-1), i.m.) afforded a longer 24 h survival rate (SR) than with PYR pre-treatment. DICLO-PD exhibited the largest protection efficacy (SR = 70% vs 17% with PYR). These results indicate a longer duration of action of bifunctional compounds compared with PYR. DICLO-PD (5% in propyleneglycol) reduced significantly the HD-induced edema in mouse ear-skin (51% increase in biopsy weight compared with 100% without treatment). Quantitative evaluation of ear-skin sections showed that only following DICLO-PD treatment was there a marked decrease in edema. DICLO-PD also elicited a significant decrease in HD-induced vesication as displayed by the reduced sub-epidermal blister level. The data indicate possible use of NSAID-ChEI bifunctional compounds for the medical treatment of both nerve and alkylating chemical agents.
authors.affiliation: Division of Medicinal Chemistry, Israel Institute for Biological Research, PO Box 19, Ness Ziona 74100, Israel. amitai@iibr.gov.il
authors.forename: Gabi
authors.initials: G
authors.lastname: Amitai
authors.forename: Rachel
authors.initials: R
authors.lastname: Adani
authors.forename: Eliezer
authors.initials: E
authors.lastname: Fishbein
authors.forename: Haim
authors.initials: H
authors.lastname: Meshulam
authors.forename: Ido
authors.initials: I
authors.lastname: Laish
authors.forename: Shlomit
authors.initials: S
authors.lastname: Dachir
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001768:Blister / Q000139:chemically induced / Q000188:drug therapy; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002619:Chemical Warfare Agents / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007052:Ibuprofen / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009151:Mustard Gas / Q000506:poisoning*; D011729:Pyridostigmine Bromide / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012999:Soman / Q000506:poisoning*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D004008:Diclofenac; D012999:Soman; D011729:Pyridostigmine Bromide; D009151:Mustard Gas; D007052:Ibuprofen