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.