title: Pyridostigmine bromide modulates topical irritant-induced cytokine release from human epidermal keratinocytes and isolated perfused porcine skin.
abstract: Gulf War personnel were given pyridostigmine bromide (PB) as a prophylactic treatment against organophosphate nerve agent exposure, and were exposed to the insecticide permethrin and the insect repellent N,N-diethyl-m-toluamide (DEET). The purpose of this study was to assess the effects of PB to modulate release of inflammatory biomarkers after topical chemical exposure to chemical mixtures containing permethrin and DEET applied in ethanol or water vehicles. Treatments were topically applied to isolated perfused porcine skin flaps (IPPSFs). Concentrations of interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) were assayed in perfusate to probe for potential inflammatory effects after complex mixture application. IPPSFs (n=4/treatment) were topically dosed with mixtures of permethrin, DEET, and permethrin/DEET, in ethanol. Each treatment was repeated with perfusate spiked with 50 ng/ml of PB. Perfusate was also spiked with 30 ng/ml diisopropylfluorophosphate to simulate low level organophosphate nerve agent exposure. Timed IPPSF venous effluent samples (0.5,1,2,4, and 8 h) were assayed by ELISA for IL-8 and TNF-alpha and by EIA for PGE(2). Overall, PB infusion caused a decrease or IL-8 and PGE(2) release. Effects on TNF-alpha were vehicle dependent. To probe the potential mechanism of this PB effect, human epidermal keratinocyte HEK cell cultures were exposed to permethrin DEET permethrin/DEET, with and without PB in DMSO. IL-8 was assayed at 1, 2, 4, 8, 12 and 24 h. PB suppressed IL-8 in permethrin and ethanol treatment from 4 to 24 h confirming the IPPSF results. In conclusion, these studies suggest that systemic exposure to PB suppressed IL-8 release at multiple time points in two skin model systems. This interaction merits further study.
authors.affiliation: Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA. nancy_monteiro@ncsu.edu
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Monteiro-Riviere
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Baynes
authors.forename: Jim E
authors.initials: JE
authors.lastname: Riviere
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D003671:DEET / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015232:Dinoprostone / Q000096:biosynthesis; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007302:Insect Repellents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007306:Insecticides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D016209:Interleukin-8 / Q000096:biosynthesis; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D026023:Permethrin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D018923:Persian Gulf Syndrome / Q000139:chemically induced*; D011729:Pyridostigmine Bromide / Q000493:pharmacokinetics / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D002800:Cholinesterase Inhibitors; D016207:Cytokines; D007302:Insect Repellents; D007306:Insecticides; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D003671:DEET; D026023:Permethrin; D015232:Dinoprostone; D011729:Pyridostigmine Bromide