Return to search

Avalia??o do potencial analg?sico e anti-inflamat?rio do composto piraz?lico 1,5-difenil-3-hidrazinopirazol(a) - DHP

Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2016-08-24T15:39:27Z
No. of bitstreams: 1
2011 - Raphael Andrade de Castro.pdf: 917522 bytes, checksum: f65a225b9fc808c90016c649f5cb2be1 (MD5) / Made available in DSpace on 2016-08-24T15:39:27Z (GMT). No. of bitstreams: 1
2011 - Raphael Andrade de Castro.pdf: 917522 bytes, checksum: f65a225b9fc808c90016c649f5cb2be1 (MD5)
Previous issue date: 2011-02-18 / causing pain as a constant feature. The pyrazole compounds are the drugs of synthetic origin in their chemical structure consisting of a ring pirazol?nico, with which several studies show the effectiveness in controlling of pain, fever and inflammation. The need to develop new drugs with analgesic and anti-inflammatory, low cost and which have few adverse reactions, has stimulated the synthesis and study of pharmacological activities of pyrazole compounds. With this objective, we studied the antinociceptive and anti-inflammatory potential of compound 1.5-diphenyl-pyrazole-3-hidrazinopirazol(a) (DHP), administered orally in pharmacological models of the acetic acid writhing, tail-flick, formalin, ear edema induced by croton oil and carrageenan-induced peritonitis in mice, and mechanical allodynia (von Frey) and thermal hyperalgesia (Hargreaves) in rats. The administration of DHP (1, 3 and 10mg/kg) decreased in a dose-dependent (41.3, 62.7 and 76%) number of writhing (ID50 = 1.3mg/kg). In the tail-flick test, DHP (10mg/kg) was ineffective and the application of positive control fentanyl (200?g/kg, sc) increased the latency to thermal stimulation in up to 138%. Without changing the first phase of nociception (neurogenic pain) of the formalin test, DHP (10mg/kg) and the positive control indomethacin (10mg/kg, p.o.) inhibited the reactivity in the 2 phase (ndinflammatory pain) in 40.9 and 48.7% respectively. This same dose of DHP reduced by 54% the ear edema induced by croton oil, as well as the positive control, dexamethasone (2mg/kg, sc) at 55.3%. Also in a dose-dependent DHP (3, 10 and 30 mg / kg) inhibited by 11.8, 39 and 53.7%, respectively, leukocyte migration in peritonitis induced by carrageenan test (ID50 = 22.9mg/kg). In the assessment of mechanical allodynia incision group treated with DHP (GIDHP - 10mg/kg) showed a significant reversal of allodynia (RA) after one hour of administration, with maximum reading RA for 12 hours (28.2%) in the second stage of the experiment, remaining in the third stage with RA of 26.9, 43.4 and 60.4% in the 7th, 10th and 14th days of evaluations, when compared with the vehicle group incised (GIV). In thermal hyperalgesia GIDHP (10mg/kg) also significantly reversed the hyperalgesia (RH) after one hour of treatment, with RH maximum of three hours in reading (68.9%) in the second stage, obtaining in the third stage RA of 43.4, 32,1 and 64% in 7th, 10th and 14th days of evaluations, when compared to the GIV and obtaining similar values of the group not incised vehicle (GNIV) on 14 dayth. In the von Frey and Hargreaves GNIV showed similar readings in the three stages of the experiment. The DHP (10mg/kg) did not alter the motor activity of mice in rota-rod test. Whereas the compound DHP showed antinociceptive activity in writhing test, antiedematogenic in ear edema, inhibited the 2nd phase of nociception (inflammatory pain) in formalin test and leukocyte migration, promoting reversal of hypernociception in models of thermal hyperalgesia and allodynia mechanics, these results indicate that the effectiveness of DHP involves the participation of anti-inflammatory mechanisms and create favorable outlook for its future use with this therapeutic goal. / A inflama??o ? um processo fisiol?gico de resposta org?nica diante de les?o tissular ou infec??o, gerando a dor como caracter?stica constante. Os compostos piraz?licos s?o drogas de origem sint?tica com um anel pirazol?nico na sua estrutura qu?mica, com os quais diversos estudos demonstram a efic?cia no controle da dor, da febre e da inflama??o. A necessidade do desenvolvimento de novos f?rmacos com propriedades analg?sicas e anti-inflamat?rias, de baixo custo e que apresentem poucas rea??es adversas, tem estimulado a s?ntese e o estudo das atividades farmacol?gicas dos compostos piraz?licos. Com esse objetivo, foi estudado o potencial antinociceptivo e anti-inflamat?rio do composto piraz?lico 1,5-difenil-3-hidrazinopirazol(a) (DHP), administrado pela via oral, nos modelos farmacol?gicos das contor??es abdominais pelo ?cido ac?tico, tail-flick, formalina, edema de orelha induzido pelo ?leo de cr?ton e peritonite induzida pela carragenina em camundongos; e na alodinia mec?nica (von Frey) e hiperalgesia t?rmica (Hargreaves) em ratos. A administra??o do DHP (1, 3 e 10mg/kg) diminuiu de maneira dose-dependente (41,3, 62,7 e 76%) o numero de contor??es abdominais (ID50=1,3mg/kg). No teste de tail-flick, DHP (10mg/kg) n?o foi efetivo e a aplica??o do controle positivo fentanil (200?g/kg, s.c.) ampliou a lat?ncia ao est?mulo t?rmico em at? 138%. Sem alterarem a 1? fase de nocicep??o (dor neurog?nica) do teste da formalina, o DHP (10mg/kg) e o controle positivo indometacina (10mg/kg, p.o.) inibiram a reatividade na 2? fase (dor inflamat?ria) em 40,9 e 48,7% respectivamente. Essa mesma dose do DHP reduziu em 54% o edema de orelha induzido pelo ?leo de cr?ton, assim como o controle positivo dexametasona (2mg/kg, s.c.) em 55.3%. Tamb?m de forma dose-dependente o DHP (3, 10 e 30 mg/kg) inibiu em 11,8, 39 e 53,7% respectivamente, a migra??o de leuc?citos no teste da peritonite induzida pela carragenina (ID50=22,9mg/kg). Na avalia??o da alodinia mec?nica o grupo incisado tratado com o DHP (GIDHP - 10mg/kg) apresentou significativas revers?es da alodinia (RA) ap?s uma hora da administra??o, com RA m?xima na leitura de 12 horas (28,2%) na segunda etapa, mantendo-se na terceira etapa com RA de 26,9, 43,4 e 60,4% nos 7?, 10? e 14? dias de experimenta??o, comparados com o grupo incisado ve?culo (GIV). Na hiperalgesia t?rmica o GIDHP tamb?m produziu revers?o da hiperalgesia (RH) uma hora ap?s o tratamento, com RH m?ximo na leitura de 3 horas (68,9%) na segunda etapa, mantendo-se na terceira etapa com RH de 43,4, 32,1 e 64% nos 7?, 10? e 14? dias de experimenta??o, quando comparados ao GIV e obtendo valores semelhantes ao grupo n?o incisado ve?culo (GNIV) no 14? dia. No von Frey e no Hargreaves o GNIV apresentou leituras semelhantes nas tr?s etapas do experimento. O DHP (10mg/kg) n?o alterou a atividade motora de camundongos no teste do rota-rod. Considerando que o composto DHP apresentou atividade antinociceptiva no teste das contor??es, antiedematog?nica no edema de orelha, inibiu a 2? fase de nocicep??o (dor inflamat?ria) do teste da formalina e a migra??o leucocit?ria, promovendo ainda revers?o da hipernocicep??o nos modelos de hiperalgesia t?rmica e alodinia mec?nica; esses resultados indicam que a efetividade do DHP envolve a participa??o de mecanismos anti-inflamat?rios e criam perspectivas favor?veis para sua futura utiliza??o com esse objetivo terap?utico.

Identiferoai:union.ndltd.org:IBICT/oai:localhost:jspui/1177
Date18 February 2011
CreatorsCastro, Raphael Andrade de
ContributorsVanderlinde, Frederico Argollo
PublisherUniversidade Federal Rural do Rio de Janeiro, Programa de P?s-Gradua??o em Medicina Veterin?ria (Patologia e Ci?ncias Cl?nicas), UFRRJ, Brasil, Instituto de Veterin?ria
Source SetsIBICT Brazilian ETDs
LanguagePortuguese
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis
Formatapplication/pdf
Sourcereponame:Biblioteca Digital de Teses e Dissertações da UFRRJ, instname:Universidade Federal Rural do Rio de Janeiro, instacron:UFRRJ
Rightsinfo:eu-repo/semantics/openAccess
Relation10 REFER?NCIAS BIBLIOGR?FICAS ALEY, K.O.; LEVINE, J.D. Role of protein kinase A in the maintenance of inflammatory pain. The Journal of Neuroscience, v.19, n.6, p.2181-2186, 1999. ALEY, K.O.; MESSING, R.O.; MONCHLY-ROSEN, D.; LEVINE, J.D. Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isoenzyme of protein kinase C. The Journal of Neuroscience, v.20, n.12, p.4680-4685, 2000. ARELLANO, R.; SACRISTAN, S.A. Metamizole: reassessment of its therapeutic role. European Journal of Clinical Pharmacology, v.38, p.617-619, 1990. BASBAUM, A.I.; JULIUS, D. Novos alvos contra a dor. Scientific American Brasil, v.50, p.76-83, 2006. BATTAGLIA, G.; RUSTIONI, A. Coexistence of glutamate and substance P in dorsal root ganglion neurons of the rat and monkey. The Journal of Comparative Neurology, v.277, n.2, p.302-312, 1988. BEAR, M.F.; CONNORS, B.W.; PARADISO, M.A. Neuroci?ncia ? Desvendando o Sistema Nervoso. Porto Alegre: Artmed, 2? ed., 2002. BERTOLINI, A.; OTTANI A.; SANDRINI, M. Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks. Current Medicinal Chemistry, v.9, n.10, p.1033-1043, 2002. BESTER, H.; CHAPMAN, V.; BESSON, J.M. Physiological properties of the lamina I spinoparabrachial neurons in the rat. Journal of Neurophysiology, v.83, p.2239-2259, 2000. BESSON, J.M.; CHAOUCH, A. Peripheral and spinal mechanisms of nociception. Physiological Reviews, v.67, n.1, p.67-186, 1987. BJ?RKMAN, R. Central antinociceptive affects of non-steroidal anti-inflamatory drugs and paracetamol. Acta Anaesthesiologia Scandinavica, v.39, n.103, p.1-44, 1995. 61 BRENNAN, F.; CARR, D. B.; COUSINS, M. Pain management: A fundamental human right. Anesthesia & Analgesia, v.105, p.205-221, 2007. BRENNAN, T.J.; VANDERMEULEN, E.; GEBHART, G.F. Characterization of a rat model of incisional pain. Pain, v.64, p.493-501, 1996. BONACORSO, H.G.; OLIVEIRA, M.R.; WENTZ, A.P.; WASTOWSKY, A.D.; OLIVEIRA, A.B.; H?ERNER, M.; ZAMATTA, N.; MARTINS, M.A.P. Haloacetylated enol ethers: 12 [18]. Region specific synthesis and structural determination of stable 5-=hidroxy-1H-pyrazolynes. Tetrahedron, v.55, p.345-352, 1999. BORNE, R.F. Nonsterioidal anti-inflammatory drugs. In: FOYE, W.O.; WILLIANS, D.A. Medicinal Chemistry. Baltimore: Willians & Wilkins, 1995. BOTTING, R.M. Cyclooxygenase: Past, present and future. A tribute to John R. Vane (1927?2004). Journal of Thermal Biology, v.31, p.208-219, 2006. BRICKS, L.F.; SILVA, C.A.A. Toxicidade dos anti-inflamat?rios n?o-hormonais. Pediatria, v.27, n.3, p.181-193, 2005. BROOKS, P.M.; DAY, R.O. Nonsteroidal anti-inflammatory drugs ? differences and similarities. The New England Journal of Medicine, v.324, p.1716-1725, 1991. BROOKS, P.M.; EMERY, E.; EVANS, F. Interpreting the clinical significance of the diferential inhibition of cyclooxygenase I and cyclooxygenase II. Rheumatology, v.38, p. 779-788, 1999. BURIAN, M.; GEISSLINGER, G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacology & Therapeutics, v.107, p.139-154, 2005. 62 CARVALHO, W.A.; CARVALHO, R.D.S.; RIOS-SANTOS, F. Analg?sicos inibidores espec?ficos da ciclooxigenase-2: avan?os terap?uticos. Revista Brasileira de Anestesiologia, v.54, p.448-464, 2004. CHAI, Z.; GATTI, S.; TONIATTI, C.; POLI, V.; BARTFAI, T. Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1?: a study on IL-6 deficient mice. The Journal of Experimental Medicine, v.183, p.311-316, 1996. CHICHORRO, J.G.; LORENZETTI, B.B.; ZAMPRONIO, A.R. Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. British Journal of Pharmacology, v.141, p.1175-1184, 2004. CLARK, T.P. The clinical pharmacology of cyclooxygenase-2-selective and dual inhibitors. Veterinary Clinics of North America: Small Animal Practice, v.36, p.1061-1085, 2006. CORR?A, C.R.; CALIXTO, J. B. Evidence for participation of B1 and B2 kinin receptors in formalin-induced nociceptive response in the mouse. British Journal of Pharmacology, v.110, p.93-98, 1993. COTRAN, R.S.; KUMAR, V.; COLLINS, T. Patologia Estrutural e Funcional. 7? ed. Rio de Janeiro: Editora Guanabara Koogan, 2006. COWAN, A.; PORRECA, F.; WHEELER, H. Use of the formalin test in evaluation analgesics. NIDA Research Monograph, v.95, p.116-122, 1989. CUNHA, F.Q.; LORENZETTI, B.B.; POOLE, S.; FERREIRA, S.H. Interleukin-8 as a mediator of sympathetic pain. British Journal of Pharmacology, v.104, n.3, p.765-767, 1991. CUNHA, F.Q.; POOLE, S.; LORENZETTI, B.B.; FERREIRA, S.H. The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. British Journal of Pharmacology, v.107, n.3, p.660-664, 1992. 63 DAMAS, J.; BOURDON, V.; REMACLE-VOLON, G.; ADAM, A. Kinins and peritoneal exudates induced by carrageenin and zymosan in rats. British Journal of Pharmacology, v.101, p.418-422, 1990. D?AMOUR, F.E.; SMITH, J. A method for determining loss of pain sensation. Journal of Pharmacology and Experimental Therapeutics, v.72, p.74-79, 1941. D?MELLO, R.; DICKENSON, A.H. Spinal cord mechanisms of pain. British Journal of Anasthesia, v.101, p.8-16, 2008. DEVOR, M. Unexplained peculiarities of the dorsal root ganglion, Pain, v.6, p.27-35, 1999. DICKENSON, A.H.; SULLIVAN, A.F. Peripheral origins and central modulation of subcutaneous formalin?induced activity of rat dorsal horn neurones. Neuroscience Letters v.83, p.207-211, 1987 DICKENSON, A.H. Central acute pain mechanisms. Annals of Medicine, v.27, p.223-227, 1995. DINARELO, C.A. Interleukin 1 as mediator of the acute-phase response. Survey of Immunologic Research, v.3, n.1, p.29-33, 1984. DINARELLO, C.A. Interleukin-1, interleukin-1 receptors and interleukin-1 antagonist. International Reviews of Immunology, v.16, p.457-499, 1998. DI ROSA, M.; GIROUD, J.P.; WILLOUGHBY, D.A. Studies of the mediators of the acute inflammatory response induced in rats in different sites by carrageenin and turpentine. Journal of Pathology, v.104, p.15-29, 1971. DOUGLASS, D.K.; CARSTENS, E. Responses of rat sacral spinal neurons to mechanical and noxious thermal stimulation of the tail. Journal of Neurophysiology, v.77, p.611?620, 1997. 64 DUBINSKY, B.; GEBREMARIAM, S.; CAPETOLA, R.J.; ROSENTHALE, M.E. The antialgesic drugs: human therapeutic correlates of their potency in laboratory animal models of hyperalgesia. Agents and Actions, v.20, n.1/2, p.50-60, 1987. DUBNER, R.; BENNETT, G.J. Spinal and trigeminal mechanisms of nociception. Annual Review of Neuroscience, v.6, p.381-418, 1983. DUBUISSON, D.; DENNIS, S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, v.4, p.161-174, 1977. DUHAM, N.W.; MIYA, T.S. A note on a simple apparatus for detecting neurological deficit in rats and mice. Journal of the American Pharmaceutical Association, v.46, p.208-209, 1957. ENGELHARDT, G.; B?GEL, R.; SCHNOTZLER, C.; UTZMANN, R. Meloxican: Influence on Arachidonic Acid Metabolism ? Part II ? In vivo findings. Biochemical Pharmacology, v.51, p.29-38, 1996. FERR?NDIZ, M.L.; ALCARAZ, M.J. Antiinflammatory activity and inhibition of arachidonic acid metabolism by flavonoids: Agents and Actions, v.32, n.3-4, p.283-288, 1991. FERREIRA, K.A.S.L. Dor e qualidade de vida relacionada a sa?de de pacientes com c?ncer: influ?ncia das citocinas pro-inflamat?ria TNF-?, IL-6, IL-8 e IL1-?. Tese de doutorado apresentada ? Escola de Enfermagem da Universidade de S?o Paulo, 2008. FERREIRA, S.H.; LORENZETTI, B.B.; CORREA, F.M. Central and peripheral analgesic action of aspirin-like drugs. European Journal of Pharmacology, v. 53, p.39-48, 1978. FERREIRA, S.H.; NAKAMURA, M.I. Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins, v.18, n.2, p.179-190, 1979. 65 FERREIRA, S.H.; LORENZETTI, B.B.; BRISTOW, A.F.; POOLE, S. Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature, v.334, n.6184, p.698-700, 1988. FERREIRA, S.H. The role of interleukins and nitric oxide in the mediation of inflamamatory pain and its control by peripheral analgesics. Drugs, v.46, n.1, p.1-9, 1993. FERREIRA, S.H.; LORENZETTI, B.B.; POOLE, S. Bradykinin initiates cytoline-mediated inflammatory hyperalgesia. British Journal of Pharmacology, v.110, n.3, p.1227-1231, 1993. FERREIRA, S.H. Hiperalgesia inflamat?rial, ?xido n?trico y control perif?rico del dolor. Revista Latino Americana de Dolor, v.12, p. 6-17, 1995. FERREIRA, S.H.; FERRARI, L.F.; CUNHA, T.M.; NASCIMENTO, P.G.B.D.; VERRI, W.A.; CUNHA, F.Q. Dor Inflamat?ria. Dispon?vel em: <http://www.dol. inf.br/Html/DorInflamatoria.html>, Acessado em: outubro/2010. FILHO, M.M.M.; RAHAL, S.C. O uso de antiinflamat?rios inibidores COX II seletivos na osteoartrite canina. Veterin?ria e Zootecnia, v.15, n.3. p.407-415, 2008. FISCHER, L.G.; SANTOS, D.; SERAFIN, C.; MALHEIROS, A.; DELLE MONACHE, F.; DELLE MONACHE, G.; CECHINEL, V.F.; SOUZA, M.M. Further antinociceptive properties of extracts and phenolic compounds from Plinia glomerata (Myrtaceae) leaves. Biological & Pharmaceutical Bulletin, v.32, p.235-239, 2008. FRANCO, G.C.N.; MORETTI, D.; CAVALCANTE, P.F.C.; LOPES, L.C. Uma an?lise cr?tica sobre viabilidade do uso dos inibidores seletivos de COX II em odontologia. Revista de Odontologia da Universidade Cidade de S?o Paulo, v.18, n.1, p.75-81, 2006. GILMAN, A.G.; GOODMAN, L.S.; RALL, T.W.; MURAD, F. Goodman & Gilman's the pharmacological basis of terapeutics. 11a ed. Rio de Janeiro: Grow-Hill, 2006. 66 GODOY, M.C.M.; FIGHERA, M.R.; SOUZA, F.R.; FLORES, A.E.; RUBIN, M.A.; OLIVEIRA, M.R.; ZAMATTA, N.; MARTINS, M.A.P.; BONACORSO, H.G.; MELLO, C.F. ?2-adrenorecptors and 5-HT receptors mediate the antinociceptive effects of new pyrazolines, but not of dipyrone. European Journal of Pharmacology, v.496, p.93-97, 2004. GOEL, A.; MADAN, A.K. Structure-activity study on anti-inflammatory pyrazole carboxylic acid hydrazide analogs using molecular connectivity indices. Journal of Chemical Information and Computer Sciences, v.35, n.3, p.510-524, 1995. GOMES, K.S. Express?o da Prote?na Fos na Investiga??o do Substrato Neural da Antinocicep??o Induzida pelo Medo. Disserta??o de Mestrado apresentada ? Faculdade de Filosofia, Ci?ncias e Letras de Ribeir?o Preto da Universidade de S?o Paulo, 2005. GON?ALVES, J.C.; OLIVEIRA, F.S.; BENEDITO, R.B.; SOUSA, D.P.; ALMEIDA, R.N.; ARA?JO, D.A. Antinociceptive activity of (-) Carvone: Evidence of association decrease peripheral nerve excitability. Biological & Pharmaceutical Bulletin, v.31, p.1017-1020, 2008. GOODMAN, L.; TORRES, B.; PUNKE, J.; REYNOLDS, L.; SPEAS, A.; ELLIS, A.; BUDSBERG, S. Effects of firocoxib and tepoxalin on healing in a canine gastric mucosal injury model. Journal of Veterinary Internal Medicine, v.23, p.56-62, 2009. G?RSOY, A.; DEMIRAYAK, S.; CAPAN, G.; EROL, K.; VURAL, K. Synthesis and preliminary evaluation of new 5-pyrazolinone derivatives as analgesic agents. European Journal of Medicinal Chemistry, v.35, p.359-364, 2000. GOUDET, C.; CHAPUY, E.; ALLOUI, A.; ACHER, F.; PIN, J. P.; ESCHALIER, A. Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain. Pain, v.137, p.112-24, 2008. GREVES, P.L.; NYBERG, F.; TERENIUS, L.; H?KFELT, T. Calcitonin gene related peptide is a potent inhibitor of substance P degradation. European Journal Pharmacology, v.115, p.309-311, 1985. 67 HARDY, J.D.; WOLFF, H.G.; GOODELL, H. Experimental evidence on the nature of cutaneous hyperalgesia. The Journal Clinical Investigation, v.29, n.1, p.115-140, 1950. HARGREAVES, K.; DUBNER, R.; BROWN, F.; FLORES, C.; JORIS, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain, v.32, n.1, p.77-88, 1988. HAZEWINKEL, H.A.W.; VAN DEN BROM, W.E.; THEYSE, L.F.H.; POLLMEIER, M.; HANSON, P.D. Comparison of the effects of firocoxib, carprofen and vedaprofen in a sodium urte crystal induced synovitis model of arthritis in dogs. Research in Veterinary Science, v.84, p.74-79, 2008. HEADLEY, PM., GRILLNER S. Excitatory amino - acids and synaptic transmission: the evidence for a physiological function. Trends in Pharmacological Sciences, v.11, p.205-211, 1990. HERNANDEZ, N.; VANEGAS, H. Antinociception induced by PAG-microinjected dipyrone (metamizol) in rats: involvement of spinal endogenous opioids. Brain Research, v.896, p.175-178, 2001. HIGGS, G.A.; EAKINS, K.E.; MUGRIDGE, K.G.; MONCADA, S.; VANE, J.R. The effects on non-steroid anti-inflammatory drugs on leukocyte migration in carrageenin-induced inflammation. European Journal Pharmacology, v.66, p.81-86, 1980. HIL?RIO, M.O.E.; TERRERI, M.T.; LEN, C.A. Antiinflamat?rios n?o-hormonais: inibidores da ciclooxigenase 2. Journal of Pediatrics, v.82, n.5, 2006. HILL, R.G. Molecular basis for the perception of pain. The Neuroscience, v.7, p.282-292, 2001. HOLDEN, J.E.; PIZZI, J. A. The Challenge of chronic pain. Advanced Drug Delivery Reviews, v.55, p. 935-948, 2003. 68 HUCHO, T.; LEVINE, J. D. Signaling pathways in sensitization: Toward a nociceptor cell biology. Neuron, v.55, p.365-376, 2007. HUNSKAAR, S.; FASMER, O.B.; HOLE, K. Formalin test in mice, a useful technique for evaluating mild analgesia. Journal Neuroscience Methods, v.14, p.69-76, 1985. HUNSKAAR, S.; BERGER, O.G.; HOLE, K. Dissociation between antinociceptive and antiinflammatory effects of acetylsalicylic acid and indomethacin in the formalin test. Pain, v.25, p.125-132, 1986. HUNSKAAR, S.; HOLE, K. The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain, v.30, p.103-114, 1987. INSEL, P.A. Analgesic ? antipyretic and anti-iflammatory agents and drugs employed in the treatment of gout. In: HARDMAN, J.G.; LINBIRD, L.E.; MALINOFF, P.B.; RUDDON, R.W.; GOODMAN GILMAN, A. Pharmacological, 1996. ISHII, K.; MOTOYOSHI, S.; KAWATA, J.; NAKAGAWA, H.; TAKEYAMA, K. A useful method for differential evaluation of anti-inflammatory effects due to cyclooxygenase and 5-lipoxygenase inhibitors in mice. The Japanese Journal of Pharmacology, v.65, p.297-303, 1994. JONES, S.L. Anatomy of pain. In SINATRA, R.S.; HORD, A.H; GINSBERG, B; PREBLE, L. Acute pain: Mecanisms & Management. St. Louis: Mosby-YearBook, 1992. JU, G.; HOKFELT, T.; BRODIN, E.; FAHRENKRUG, J.; FISCHER, J.A.; FREY, P.; ELDE, R.P.; BROWN, J.C. Primary sensory neurons of the rat showing calcitonin gene-related peptide immunoreactivity and their relation to substance P-, somatostatin-, galanin-, vasoactive intestinal polypeptide- and cholecystokinin-imunoreactive ganglion cells. Cell and Tissue Research, v.247, n.2, p.417-431, 1987. JULIUS, D; BASBAUM, A. I. Molecular mechanisms of nociception. Nature, v.413, p.203-210, 2001. 69 KANDEL, E. R.; SCHWARTZ, J. H.; JESSEL, T. M. Principles of Neuronal Science. New York: McGraw-Hill, 2000. p. 472-491. KATZUNG, B.G. Farmacologia b?sica e cl?nica. 9? ed. Rio de Janeiro: Guanabara Koogan, 2006. KHASABOV, S.G.; ROGERS, S.D.; GHILARDI, J.R.; PETERS, C.M.; MANTYH, P.W.; SIMONE, D.A. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. The Journal of Neuroscience, v.22 p.9086-9098, 2002. KING, J.N.; DAWSON, J.; ESSER, R.E.; FUJIMOTO, R.; KIMBLE, E.F.; MANIARA, W.; MARSHALL, P.J.; O?BYRNE, L.; QUADROS, E.; TOUTAIN, P.L.; LEE, P. Preclinical pharmacology of rofecoxib: a novel selective inhibitor of cyclooxygenase-2. Journal of Veterinary Pharmacology Therapeutics, v.32, p.1-17, 2009. KOSTER, R.; ANDERSON, M.; DE BEER, E.J. Acetic acid for analgesic screening. Federation Proceedings, v.18, p.412, 1959. KUMMER, C.L.; COELHO, T.C.R.B. Anti-inflamat?rios n?o ester?ides inibidores da ciclooxigenase II (COX II): aspectos atuais. Revista Brasileira de Anestesiologia, v.5, n.4, 2002. KVATERNICK, V.; POLLMEIER, M.; FISCHER, J.; HANSON, P.D. Pharmacokinetics and metabolism of orally administered firocoxib, a novel second generation coxib, in horses. Journal of Veterinary Pharmacology Therapeutics, v.30, p.208-217, 2007. LAMONT, L.A.; TRANQUILLI, W.J.; KURT, A.G. Physiology of pain. Veterinary Clinics of North America Small Animal Practice, v. 30, n. 4, p.703-728, 2000. LE BARS, D.; GOZARIU, M.; CADDEN, S.W. Animal models of nociception. Pharmacological Reviews, v.53, p.597-652, 2001. LECANNELIER, S. Antiinflamatorios no esteroideos. In: Marcondes, J. Farmacolog?a. Buenos Aires: Interm?dica, 1976. 70 LEES, P. Pharmacology of drugs used to treat osteoarthritis in veterinary practice. Inflammopharmacology, v.11, p.385-399, 2003. LEES, P.; LANDONI, M.F.; GIRAUDEL, J.; TOUTAIN, P.L. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Veterinary of Pharmacology and Therapeutics, v.27, p.479-490, 2004. LIU, H.; WANG, H.; SHENG, M.; JAN, L.Y.; JAN, Y.N.; BASBAUM, A.I. Evidence for presynaptic Nmethyl-D-aspartate autoreceptores in the spinal cord dorsal horn. Proceedings of the National Academy of Sciences of United States of America, v.91, p.8383-8387, 1994. LIU, H; MANTYH, PW; BASBAUM, A.I. NMDA-receptor regulation of substance P release form primary afferent nociceptors. Nature, v.386, p.721-724, 1997. LOESER, J. D.; MELZACK, R. Pain: An Overview. Lancet, v.353, p.1607-1609, 1999. MAI, C.M.G. Avalia??o do potencial antinociceptivo de novos 3-metil-1h-1-pirazol metil esteres 5-substitu?dos em camundongos. Disserta??o de Mestrado apresentada ao Programa de P?s-gradua??o em Bioqu?mica Toxicol?gica da Universidade Federal de Santa Maria, 2007. MARNETT, L.J. The COXIB experience: A look in the rear-view mirror. Annual Review of Pharmacology and Toxicology, v.49, p.265-290, 2009. MATHEWS, K.A.; DOHERTY, T.; DYSON, D.H.; WILCOCK, B.; VALLIANT, A. Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. The Canadian Veterinary Journal, v.31, p.766-771, 1990. MATHEUS, M.E.; OLIVEIRA, L.F.; FREITAS, A.C.C.; CARVALHO, A.M.S.P.; BARREIRO, E.J. Antinociceptive property of new 4-acyl-arilhidrazone pyrazole compounds. Brazilian Journal of Medical and Biological Research, v.24, p.1219-1222, 1991. 71 McNAMARA, C.R.; MANDEL-BREHM, J.; BAUTISTA, D.M.; SIEMENS, J.; DERANIAN, K.L.; ZHAO, M.; HAYWARD, N.J.; CHONG, J.A.; JULIUS, D.; MORAN, M.M.; FANGER, C.M. TRPA1 mediates formalin-induced pain. Proceedings of the National Academy of Sciences of the United States of America, v.104, n.33, 2007. MENEZES, G.B.; REIS, W.G.; SANTOS, J.M.; DUARTE, I.D. FRANCISCHI, J.N. Inhibition of prostaglandin F (2alpha) by selective cyclooxygenase 2 inhibitors accounts for reduced rat leukocyte migration. Inflammation, v.29, p.163-169, 2005. MIKAMI, T.; MIYASAKA, K. Effects of several anti?inflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin?induced pleurisy. European Journal of Pharmacology, v.95, p.1-12, 1983. MILANO, J. Avalia??o do Potencial Antinociceptivo de 5-trialometil-4,5-diidro-1h- pirazol metil ?steres In?ditos em Camundongos. Tese de doutorado apresentada ao Programa de P?s-Gradua??o em Ci?ncias Biol?gicas da Universidade Federal de Santa Maria, 2008. MILANO, J.; ROSSATO, M.F.; OLIVEIRA, S.M.; DREWES, C.; MACHADO, P.; BECK, P.; ZANATTA, N.; MARTINS, M.A.P.; MELLO, C.F.; RUBIN, M.A.; FERREIRA, J.; BONACORSO, H.G. Antinociceptive action of 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester in models of inflammatory pain in mice. Life Sciences, v.83, p.739-746, 2008. MILLAN, M.J. The induction of pain: an integrative review. Progress in Neurobiology, v.57, p.1-164, 1999. MOLLER, K.A.; JOHANSSON, B.; BERGE, O.G. Assessing mechanical allodynia in the rat paw with a new electronic algometer. Journal of Neuroscience Methods, v.84, p.41-47, 1998. MULLER, W.A. Leukocyte-endothelial cell interactions in the inflammatory response. Laboratory Investigation, v.82, p.521-533, 2002. 72 NESTLER, E.J.; HYMAN, S.E.; MALENKA, R.C. Molecular neuropharmacology: a foundation for clinical neuroscience. New York: Macgraw-Hill, 2001. NODINE, J.H.; SIEGLER, P.E. Animal and Clinical Pharmacologic Techniques in Drug Evaluation. EUA, Year Book Medical Publishers Inc. 1964, 660p. OCHI, T.; GOTO, T. The spinal antinociceptive effect of FR140423 in mice. Involvement of the descending noradrenergic and serotoninergic systems. Life Science, v.69, p.2256-2264, 2001. OCHI, T.; FUJII, T.; MOTOYANA, Y.; GOTO, T. Antinociceptive properties of FR140423 mediated through spinal ?- but not M-and ?-, opioid receptors. European Journal of Pharmacology, v.380, p.73-79, 1999b. OCHI, T.; FUJII, T.; MOTOYANA, Y.; GOTO, T. The profile of FR140423, a novel anti-inflammatory compound, in yeast-induced rat hyperalgesia. Jananase Journal of Pharmacology, v.81, n.1, p.94-98, 1999a. OCHI, T.; JOBO-MAGARI, K.; YONEZAWA, A.; MATSUMORI, K.; FUJJI, T. Anti-inflammatory and analgesic effects of a novel pyrazole derivative, FR140423. European Journal of Pharmacology, v.365, p.259-266, 1999c. OKUSE, K. Pain signalling pathways: from cytokines to ion channels. The International Journal of Biochemistry & Cell Biology, v.39, n.3, p.490-496, 2007. OLIVEIRA, F.S.; SOUSA, D.P.; ALMEIDA, R.N. Antinociceptive effect of hydroxydihydrocarvone. Biological & Pharmaceutical Bulletin, v.31, p.588-591, 2008. OLIVEIRA, C.M.B.; ISSY, A.M.; SAKATA, R.K. Fisiopatologia da dor p?s operat?ria. Revista Brasileira de Medicina, v.11, n.67, p.415-418, 2010. OMOTE, K.; KAWAMATA, T.; NAMIKI, A. Formalin-induced release of excitatory amino acids in the skin of the rat hindpaw. Brain Research, v.787, p.161-164, 1998. 73 ORTIZ, M.I.; CASTA?EDA-HERN?NDEZ, G.; GRANADOS-SOTO, V. Pharmacological evidence for the activation of Ca2+-activated K+ channels by meloxicam in the formalin test. Pharmacology, Biochemistry and Behavior, v.81, p.725?731, 2005. OSHIMA, Y.; AKIMOTO, T.; TSUCADA, W.; YAMASAKI, T.; IAMAGUCI, K.; KOJIMA, H. Studies on pyrimidinylpyrazoles, IV. Pharmacological actives of 1(4-metoxy-6-methyl-2-pyrimidinyl)-3-methyl-5-metoxypyrazol and its related compounds. Chemical & Pharmaceutical bulletin, v.17, n.7, p.1492-1497, 1969. OTERO, P.E. Manejo da dor e a medicina veterin?ria. In OTERO, P.E. Dor: avalia??o e tratamento em pequenos animais. S?o Paulo: Interbook, 2005, p.02-05. OTTEN, U.; GOEDERT, M.; MAYER, N.; LEMBECK, F. Requirement of nerve growth factor for development of substance P-containing sensory neurones. Nature, v.287, p.158-159, 1980. PAPICH, M.G. An update on nonsteroidal anti-inflammatory drugs (NSAIDs) in Small Animals. Veterinary Clinics of North America: Small Animal Practice, v.38, p.1243-1266, 2008. PARADA, S.A.; TAMBELI, C.H.; CUNHA, F.Q.; FERREIRA, S.H. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience, v.4, p.937-944, 2001. PARADA, S.A.; VIVANCOS, G.G.; TAMBELI, C.H.; CUNHA, F.Q.; FERREIRA, S.H. Activation of presynaptic NMDA receptors coupled to NaV1.8-resistant sodium channel C-fiber causes retrograde mechanical nociceptor sesitilization. Proceedings of the National Academy of Sciences of the United States of America, v.100, n.5, p.2923-2928, 2003. PARVEEN, Z.; DENG, Y.; SAEED, M.K.; DAI, R.; AHAMAD, W.; YU, Y.H. Antiinflammatory and analgesic activities of Thesium chinese Turcz extracts and its major flavonoids, kaampferol and kaempferol-3-O-glucoside. Yakugaku Zasshi, v.127, p.1275-1279, 2007. 74 PELLEGRINO, F. Organiza??o funcional das vias da dor. In OTERO, P.E. Dor: avalia??o e tratamento em pequenos animais. S?o Paulo: Interbook, 2005. p.06-28. PERL, E.R. Ideas about pain, a historical view. Nature Reviews Neuroscience, v.8, p.71-80, 2007. PIRES, P.A. Potencial analg?sico, anti-edematog?nico, antipir?tico e atividade ulcerog?nica de f?rmacos anti-inflamat?rios, em roedores. Disserta??o de Mestrado apresentada ao Programa de P?s-gradua??o em Medicina Veterin?ria da Universidade Federal Rural do Rio de Janeiro, 2009. PONG, S.F.; DEMUTH, S.M.; KINNEY, C.M.; DEEGAN, P. Prediction of human analgesic dosages of nonsteroidal anti?inflammatory drugs (NSAIDs) from analgesic ED50 values in mice. Archives Internationales de Pharmacodynamie et de Therapie, v.273, p.212-220, 1985. PORTER, D.G. Ethical scores for animal experiments. Nature, v.356, n.6365, p.101-102, 1992. PROKOPP, C.R. 2-[5-triclorometil-5-hidr?xi-3-fenil-4,5-dihidro-1H-pirazol-1-il]-4-(4-bromofenil)-5-metiltiazol (B50) provoca antinocicep??o em camundongos. Disserta??o de Mestrado apresentada ao Programa de P?s-gradua??o em Bioqu?mica Toxicol?gica da Universidade Federal de Santa Maria, 2004. RANG, H.P.; BEVAN, S.; DRAY, A. Chemical activation of nociceptive peripheral neurons. British Medical Bulletin, v.47, n.3, p.534-548, 1991. RANG, H.P.; DALE, M.M.; RITTER, J.M.; MOORE. P.K. Farmacologia. 6? Ed. Editora Elsevier, 2007. RATES, S.M.K.; BARROS, H.M.T. Modelos animais para a avalia??o da dor: m?todos para triagem de novos analg?sicos. Revista Brasileira de Farmacologia, v.75, n.2, p.31?34, 1994. 75 RIBEIRO, R.A.; VALE, M.L.; THOMAZZI, S.M.; PASCHOALATO, A.B.; POOLE, S.; FERREIRA, S.H.; CUNHA, F.Q. Involvement of resident macrophages and mast cells in the writhing nociceptive response induced by zymosan and acetic acid in mice. European Journal of Pharmacology, v.387, n.1, p.111-118, 2000. ROTH, J.; RUMMEL, C.; BARTH, S.W.; GERSTBERGER, R.; H?BSCHLE, T. Molecular aspects of fever and hyperthermia. Immunology And Allergy Clinics of North America, v.29, p.229-245, 2009. SANTOS, A.R.S.; CALIXTO, J.B. Further evidence for the involvement of tachykinin receptor subtypes in formalin and capsaicin models of pain in mice. Neuropeptides, v.31, p.381-389, 1997. SANTOS, A.R.S.; VEDANA, E.M.A.; FREITAS, G.A.G. Antinociceptive effects of meloxicam, in neurogenic and inflammatory nociceptive models in mice. Inflammation Research, v.47, p.302-307, 1998. SAUZEM, P.D. Derivados piraz?licos in?ditos causam antinocicep??o em camundongos no teste da formalina. Disserta??o de Mestrado apresentada ao Programa de P?s-gradua??o em Bioqu?mica Toxicol?gica da Universidade Federal de Santa Maria, 2004. SAUZEM, P.D.; MACHADO, P.; RUBIN, M.A.; SANT?ANNA, G.S.; FABER, H.B.; SOUZA, A.H.; MELLO, C.F.; BECK, P.; BURROW, R.A.; BONACORSO, H.G.; ZANATTA, N.; MARTINS, M.A.P. Design and microwave-assisted synthesis of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles: Novel agents with analgesic and anti-inflammatory properties. European Journal of Medicinal Chemistry, v.43, p.1237-1247, 2008. SCHOLZ, J.; WOOLF, C.J. Can we conquer pain? Nature Neurosci, v.5, p.1062-1067, 2002. SHIBATA, M.; OHKUBO, T.; TAKAHASHI, H.; INOKI, R. Modified formalin test: characteristic biphasic pain response. Pain, v.38, p.347-52, 1989. 76 SHIN, J.W.; HWANG, K.S.; KIM, Y.K.; LEEM, J.G.; LEE, C. Nonsteroidal anti-inflammatory drugs suppress pain-related behaviors, but not referred hiperalgesia of visceral pain in mice. Anesthesia & Analgesia, v.102, p.195-200, 2006. SIEGMUND, E.; CADMUS, R.; LU, G. Method for evaluating both non?narcotic and narcotic analgesics. Proceedings of the Society for Experimental Biology and Medicine, v.95, p.729, 1957. SHIBATA, M.; OHKUBO, T.; TAKAHASHI, H.; INOKI, R. Modified formalin test: characteristic biphasic pain response. Pain, v.38, p.347-352, 1989. SMITH, C.H.; BARKER, J.N.; MORRIS, R.W.; MACDONALD, D.M.; LEE, T.H. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic infiltration in human skin. The Journal of Immunology, v.151, n.6, p.3274-3282, 1993. SOKAL, R.R.; ROHLF, F.J. Biometry: The principles an Practice of Statistics. New York: W. H. Freemann, 1981. SORKIN, L. S.; WALLACE, M. S. Acute pain mechanisms. Surgical Clinics of North America, v.79, p.213-229, 1999. SOUCCAR, C.; LAPA, A.J. Analgesic and anti?inflammatory screening of two Brazilian medicinal plants: A positive and a false?positive result. Ci?ncia e Cultura Journal of the Brazilian Association for the Advancement of Science, v.49, n.5/6, p.417-421, 1997. SOUZA, F.R.; FIGHERA, M.R.; LIMA, T.T.F.; BASTIANI, J.; BARCELLOS,I.B.; ALMEIDA, C.E.; OLIVEIRA, M.R.; BONACORSO, H.G.; FLORES, A.E.; MELLO, C.F. 3-metil-5-hidr?xi-5-triclorometil-4,5-diidro-1H-1-piraxolcarboxiamide induces antinociception. Pharmacology, Biochemistry and Behavior, v.68, p.525-530, 2001. SOUZA, F.R.; SOUZA, V.T.; RATZLAFF, V.; BORGES, L.P.; OLIVEIRA, M.R.; BONACORSO, H.G.; ZAMATTA, N.; MARTINS, M.A.P.; MELLO, C.F. Hypothermic and antipyretic effects of 3-metyl and 3-phenyl-5-hidr?xi-5-triclorometil-4,5-diidro-1H-1- 77 piraxolcarboxiamide induces antinociception. Pharmacology, Biochemistry and Behavior, v.451, p.141-147, 2002. SPINOSA, H.S.; G?RNIAK, S.L.; BERNARDI, M.M. Farmacologia aplicada a Medicina Veterin?ria. 4? ed. Rio de Janeiro: Guanabara Koogan, 2006. STEAGALL, P.V.M.; MOUTINHO, F.Q.; MATOVANI,F.B.; PASSARELLI, D.; THOMASSIAN, A. Evaluation of the adverse effects of subcutaneous carprofen over six days in healthy cats. Research in Veterinary Science, v.86, p.115-120, 2009. TABARELLI, Z.; RUBIN, M.A.; BERLESE, D.B.; SAUZEN, P.D.; MISSIO, T.P.; TEIXEIRA, M.V.; SINHORIN, A.P.; MARTINS, M.A.P.; ZAMATTA, N.; BONACORSO, H.G.; MELLO, C.F. Antinociceptive, effects of model pyrazolines en mice. Brazilian Journal of Medical and Biological Research, v.37, in press, 2004. TAIWO, Y.O.; LEVINE, J.D. Characterization of the arachidonic acid metabolites mediating bradikinin and noradrenaline hiperalgesia. Brain Research, v.458, p.402-406, 1988. TAIWO, Y.O.; BJERKNES, L.K.; GOETZL, E.J.; LEVINE, J.D. Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience, v.32, n.3, p.577-580, 1989. TASSORELLI, C.; GRECO, R.; WANG, D.; SANDRINI, G.; NAPPI, G. Prostaglandins, glutamate and nitric oxide synthase mediate nitroglycerin-induced hyperalgesia in the formalin test. Eurpean Journal Pharmacology, v.534 p.103-107, 2006. TEIXEIRA, F.M. Avalia??o comparativa do efeito de f?rmacos anti-inflamat?rios com a acupuntura no modelo de dor p?s-incisional em ratos Disserta??o de Mestrado apresentada ao Programa de P?s-gradua??o em Medicina Veterin?ria da Universidade Federal Rural do Rio de Janeiro, 2010. TIZARD, I.R. Imunologia veterin?ria: uma introdu??o. 6? ed. S?o Paulo: Editora Roca, 2002. 78 TJOLSEN, A.; BERGE, O.; HUNSKAAR, S.; ROSLAND, J. H.; HOLE, K. The formalin test: an evaluation of the method. Pain, v.51, p.5-17, 1992. TJOLSEN, A.; HOLE, K. Animal models of analgesia. In: DICKENSON, A.; BESSON, J.M (eds). The Pharmacology of Pain, Germany: Springer, Berlin, 1997, p.1-20. TORTORICI, V.; VASQUES, E.; VANEGAS, H. Naloxone partial reversal of the antinociception produced by dipyrone microinjected into the periaqueductal grey of rats: possible involvement of medulary off- and on cells. Brain Research, v.726, p.106-111, 1996. TRACEY, D.J.; DE BIASI, S.; PHEND, K.; Rustioni, A. Aspartate-like immunoreactivity in primary afferent neurons. Neuroscience, v.40, n.3, p.673-686, 1991. TSUJI, K.; KONISHI, N.; SPEARS, G.W.; OGINO, T.; NAKAMURA, K.; TOJO, T.; OCHI, T.; SHIMOJO, F.; SENOH, H.; MATSUO, M. Studies on anti-inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluormetil)-1-(4-metoxifenil)-5-[4-(metilsulfinil)fenil] pyrazole and relates compounds. Chemical & Pharmaceutical Bulletin, v.45, p.1475-1481, 1997. TUBARO, A.; DRI, P.; MELATO, M.; MULAS, G.; BIANCHI, P.; DEL NEGRO, P.; DELLA LOGGIA, R. In the croton oil ear test the effects of non steroidal anti-inflammatory drug (NSAIDs) are dependent on the dose of the irritant. Agents & Actions, v.19, p.371?373, 1986. VACHER, P.J.; DUCH?NE-MARULLAZ, P.; BARBOT, P. A propos de quelques produits usuels ? comparaison de deux m?thodes d??tude des analg?siques. Medicina Experimentalis, v.11, p.51-58, 1964. VALE, M.

Page generated in 0.02 seconds