title: Subacute arsenic exposure through drinking water reduces the pharmacodynamic effects of ketoprofen in male rats.
abstract: We evaluated the modulatory role of the groundwater contaminant arsenic on the pharmacodynamic responses of the nonsteroidal analgesic-antipyretic drug ketoprofen and the major pro-inflammatory mediators linked to the mechanism of ketoprofen's therapeutic effects. Rats were pre-exposed to sodium arsenite (0.4, 4 and 40 ppm) through drinking water for 28 days. The pharmacological effects of orally administered ketoprofen (5 mg/kg) were evaluated the following day. Pain, inflammation and pyretic responses were, respectively, assessed through formalin-induced nociception, carrageenan-induced inflammation and lipopolysaccharide-induced pyrexia. Arsenic inhibited ketoprofen's analgesic, anti-inflammatory and antipyretic effects. Further, arsenic enhanced cyclooxygenase-1 and cyclooxygenase-2 activities and tumor necrosis factor-α, interleukin-1β and prostaglandin-E(2) production in hind paw muscle. These results suggest a functional antagonism of ketoprofen by arsenic. This may relate to arsenic-mediated local release of tumor necrosis factor-α and interleukin-1β, which causes cyclooxygenase induction and consequent prostaglandin-E(2) release. In conclusion, subacute exposure to environmentally relevant concentrations of arsenic through drinking water may aggravate pain, inflammation and pyrexia and thereby, may reduce the therapeutic efficacy of ketoprofen.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar 243 122, Bareilly, Uttar Pradesh, India.
authors.forename: Wasif
authors.initials: W
authors.lastname: Ahmad
authors.forename: Shahid
authors.initials: S
authors.lastname: Prawez
authors.forename: H H
authors.initials: HH
authors.lastname: Chanderashekara
authors.forename: Surendra Kumar
authors.initials: SK
authors.lastname: Tandan
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Sankar
authors.forename: Souvendra Nath
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water / Q000737:chemistry*; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D005557:Formaldehyde; D006614:Hindlimb; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018053:Arsenites; D060766:Drinking Water; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D017670:Sodium Compounds; D014409:Tumor Necrosis Factor-alpha; D014874:Water Pollutants, Chemical; D005557:Formaldehyde; C017947:sodium arsenite; D002351:Carrageenan; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D015232:Dinoprostone