title: Isobolographic Analyses of Proglumide-Celecoxib Interaction in Rats with Painful Diabetic Neuropathy.
abstract: Preclinical Research The aim of the present study was to analyze the antihyperalgesic and antiallodynic interaction between the non-selective cholecystokinin (CCK) antagonist receptor, proglumide, and the selective cyclooxygenase-2 inhibitor, celecoxib in streptozotocin (STZ)-induced diabetic rats. Hyperalgesia was evaluated in the formalin test and tactile allodynia using von Frey filaments. Isobolographic analyses were employed to define the nature of the compound interactions, using a fixed dose ratio (0.5:0.5). Proglumide (20-160 mg/kg) and celecoxib (0.3-30 mg/kg) in these fixed dose ratio combinations induced dose-dependent antihyperalgesia and an antiallodynic effect in diabetic rats. ED40values were calculated for the treatments and an isobologram was constructed. Theoretical ED40values for combination proglumide-celecoxib estimated from the isobolograms for antihyperalgesic and antiallodynic activity (30.50 ± 1.90 mg/kg and 45.81 ± 4.55 mg/kg, respectively) were obtained, while experimental ED40values for this antihyperalgesic and antiallodynic combined effect (13.83 ± 0.65 mg/kg and 17.74 ± 3.57 mg/kg; respectively) were significantly different. Coadministration of proglumide-celecoxib showed an interaction index value of 0.45 ± 0.03 for the antihyperalgesic effect and 0.39 ± 0.08 for the antiallodynic activity, indicating a synergistic interaction. These data suggest that proglumide and celecoxib can interact synergistically to reduce hyperalgesic and allodynic behaviors in diabetic neuropathy. This combination could be useful to treat neuropathic pain in diabetic patients. Drug Dev Res 78 : 116-123, 2017. ©2017 Wiley Periodicals, Inc.
authors.affiliation: Division Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, México.
authors.forename: Samuel
authors.initials: S
authors.lastname: Suarez-Mendez
authors.affiliation: Division Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Tabasco, México.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Tovilla-Zarate
authors.affiliation: Escuela de Enfermería y Salud Pública, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, México.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Ortega-Varela
authors.affiliation: Division Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Tabasco, México.
authors.forename: Deysi Y
authors.initials: DY
authors.lastname: Bermudez-Ocaña
authors.affiliation: Division Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, México.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Blé-Castillo
authors.affiliation: Division Académica Multidisciplinaria de Jalpa de Méndez, Universidad Juárez Autónoma de Tabasco, Tabasco, México.
authors.forename: Thelma B
authors.initials: TB
authors.lastname: González-Castro
authors.affiliation: Division Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, México.
authors.forename: Alma M
authors.initials: AM
authors.lastname: Zetina-Esquivel
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, UNAM, Ciudad de México, México.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Diaz-Zagoya
authors.affiliation: Division Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, México.
authors.forename: Isela
authors.identifier: 0000-0003-3760-7394
authors.initials: I
authors.lastname: Esther Juárez-Rojop
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000008:administration & dosage* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D011377:Proglumide / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D013311:Streptozocin; D011377:Proglumide; D000068579:Celecoxib
keywords: celecoxib; diabetic neuropathy; isobolographic analysis; proglumide