title: Synergistic antinociceptive effect and gastric safety of the combination of docosahexaenoic acid and indomethacin in rats.
abstract: The use of analgesics is limited by the presence of significant adverse side effects. Thus, combinations of non-steroidal anti-inflammatory drugs (NSAIDs) with other antinociceptive agents are frequently used to decrease these adverse reactions. The aims of this work were to evaluate the antinociceptive interaction of the systemic administration of the combination of DHA and indomethacin through an isobolographic analysis of the theoretical and experimental antinociceptive effect and to demonstrate the gastric safety of the mixture compared with indomethacin alone. Female Wistar rats were orally administered indomethacin (1-10 mg/kg), DHA (100-300 mg/kg), or the DHA-indomethacin mixture at a fixed-ratio combination (1:1, 1:3, 3:1), and the antinociceptive effects of these treatments were evaluated through the formalin (1%) test. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and indomethacin. The degree of gastric injury in all of the rats was determined 1 h after the formalin test. The theoretical ED₃₀ values (Zadd) for the 1:1, 1:3, and 3:1 combinations were 73.48 ± 8.96, 37.75 ± 4.50, and 109.2 ± 13.43 mg/kg, p.o., respectively, and the experimental ED30 values (Zexp) were 43.63 ± 5.18, 13.13 ± 1.61, and 54.20 ± 6.53, respectively. The isobolographic analysis showed that the three fixed-ratio combinations studied exhibited a synergistic interaction. Furthermore, the gastric damage induced by indomethacin was abolished when this drug was combined with DHA. These data suggest that the systemic administration of the DHA-indomethacin combination induces a synergistic and gastric safety effect.
authors.affiliation: Laboratorio de Farmacología, Programa Institucional en Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, México, D.F., Mexico.
authors.forename: Arlette Guadalupe
authors.initials: AG
authors.lastname: Arroyo-Lira
authors.affiliation: Departamento de Ciencias Naturales, DCNI, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, México, D.F., Mexico.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Ramos
authors.affiliation: Laboratorio de Farmacología, Programa Institucional en Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, México, D.F., Mexico; Doctorado en Biotecnología en Red, Escuela Nacional de Medicina y Homeopatía del Instituto Politécnico Nacional, México, D.F., Mexico. Electronic address: achavezp@ipn.mx.
authors.forename: Aracely Evangelina
authors.initials: AE
authors.lastname: Chávez-Piña
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D007213:Indomethacin / Q000008:administration & dosage* / Q000009:adverse effects; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004281:Docosahexaenoic Acids; D007213:Indomethacin
keywords: Analgesic; Antinociceptive; Docosahexaenoic acid; Gastric injury; Indomethacin; Interaction