Palavras-chave
Vital Brazil
venenos e toxinas animais
inovação
bioprospecção
estratégia racional de desenvolvimento
venenos e toxinas animais
inovação
bioprospecção
estratégia racional de desenvolvimento
Como Citar
Tavassi, A. M. C., Picolo, G., Pasqualoto, K. F. M., & Cury, Y. (2014). Vital Brazil e o pioneirismo na utilização de venenos animais como agentes terapêuticos. Cadernos De História Da Ciência, 10(1), 13–32. https://doi.org/10.47692/cadhistcienc.2014.v10.33903
Resumo
O caráter investigativo e visionário fez do médico Vital Brazil um grande cientista, reconhecido nacional e internacionalmente. Vital Brazil sempre demonstrou visão inovadora sobre venenos e toxinas animais, sugerindo o potencial terapêutico e buscando a comprovação científica deste potencial por meio de estudos direcionados. Venenos, toxinas e secreções animais são considerados fontes naturais importantes à obtenção de compostos bioativos. Estes compostos têm sido utilizados como fonte para obtenção de novos compostos líderes e também como ferramentas para investigação de receptores, canais iônicos e enzimas. Contudo, apesar de diversos compostos obtidos de venenos animais terem sido descobertos e testados nas últimas décadas, raros chegaram, de fato, ao mercado. Processos de desenvolvimento de novos fármacos desta natureza requerem grandes investimentos de tempo e de dinheiro, sem garantia de sucesso. O surgimento de novas técnicas tanto de síntese química, como de triagem de atividade farmacológica, contribuiu sobremaneira para a preferência das indústrias farmacêuticas emde fontes naturais. Porém, as coleções de milhões de compostos, resultantes da era da abordagem combinatória, não corresponderam ao sucesso esperado. A evolução dos métodos de síntese de peptídeos permitiu que modificações na estrutura química de compostos de origem natural (animal) fossem planejadas a fim de melhorar a estabilidade e a biodisponibilidade oral de peptídeos. Assim, no novo milênio, a indústria farmacêutica retomou os investimentos em produtos de origem natural, tanto em candidatos a fármacos, como compostos líderes para serem otimizados no processo de desenvolvimento. O avanço das ciências “ômicas” também contribuiu, de forma significativa, no processo mais racional de descoberta de novos candidatos a fármacos e de novos protótipos, além da identificação de novos alvos moleculares. A estratégia de descoberta mais racional associada à biotecnologia tem permitido que compostos de origem natural (animal) tenham grande destaque tanto no processo de desenvolvimento de novas vacinas como de novos biofármacos.
Referências
Alvarez Flores MP, Zannin M, Chudzinski-Tavassi AM. New insight into the mechanism of Lonomia obliqua envenoming: toxin involvement and molecular approach. Pathophysiol Haemost Thromb. 2010; 37(1):1-16.
Alvarez-Flores MP, Furlin D, Ramos OH, Balan A, Konno K, Chudzinski-Tavassi AM. Losac, the first hemolin that exhibits procogulant activity through selective factor X proteolytic activation. J Biol Chem. 2011 Mar 4; 286(9):6918-28.
Barreiro EJ, Fraga CAM. A questão da inovação em fármacos no Brasil: proposta de criação do programa nacional de fármacos (PRONFAR). Quim. Nova 28:S56-S63, 2005.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E. The Protein Data Bank. Nuc. Acids Res. 28:235-242, 2000.
Brazil V. Do emprêgo da peçonha em terapêutica. Biologia Médica. 1934, 1: 7–21.
Brigatte P, Konno K, Gutierrez VP, Sampaio SC, Zambelli VO, Picolo G, Curi R, Cury Y. Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphinein a rat model of cancer pain. Pharmacol Biochem Behav. 2013; 109: 1-7.
Bryan J. From snake venom to ACE inhibitor: the discovery and rise of captopril. The Pharmaceutical Journal, Vol. 282, p455 , 2009.
Cohen, C. Guidebook on Molecular Modeling in Drug Design. First edition, Academic Press, 1996.
Cushman DW, Cheung HS, Sabo EF, Ondetti MA. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry, 1977, 16:5485-5491.
Chudzinski-Tavassi AM, Carrijo-Carvalho LC, Waismam K, Farsky SH, Ramos OH, Reis CV. A lipocalin sequence signature modulates cell survival. FEBS Lett. 2010b Jul 2; 584(13):2896-900.
Chudzinski-Tavassi AM, Alvarez Flores MP. Exploring new molecules and activities from Lonomia obliqua caterpillars.Pathophysiol Haemost Thromb. 2005; 34(4-5):228-33.
Review. Erratum in: Pathophysiol Haemost Thromb. 2006; 35(5):410.
Cura JE, Blanzaco DP, Brisson C, Cura MA, Cabrol R, Larrateguy L, Mendez C, Sechi JC, Silveira JS, Theiller E, de Roodt AR, Vidal JC. Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer. Clin Cancer Res. 2002; 8(4):1033-41.
Cury Y, Picolo G. Animal toxins as analgesics--an overview. Drug News Perspect. 2006; 19(7):381-92.
Chudzinski-Tavassi AM, De-Sá-Júnior PL, Simons SM, Maria DA, de Souza Ventura J, Batista IF, Faria F, Durães E, Reis EM, Demasi M. A new tick Kunitz type inhibitor, Amblyomin-X, induces tumor cell death by modulating genes related to the cell cycle and targeting the ubiquitin-proteasome system. Toxicon. 2010a Dec 15; 56(7):1145-54.
Cury Y, Picolo G. Are animal toxins good models for analgesics? In: de Lima ME, de Castro Pimenta AM, Martin-Eauclaire MF, Zingali RB, Rochat H. (Org.). Animal Toxins: State of the Art Perspectives in Health And Biotechnology. 1ed.Minas Gerais: Editora UFMG, v. 1, p. 661-678, 2009.
Da Silva SL, Rowan EG, Albericio F, Stábeli RG, Calderon LA, Soares AM. Animal toxins and their advantages in biotechnology and pharmacology. Biomed Res Int. 2014;2014:951561.
Faure G., Xu H., Saul, F.A. Crystal structure of crotoxin reveals key residues involved in the stability and toxicity of this potent heterodimeric ß-neurotoxin. J. Mol. Biol. 412: 176-191, 2011. FDA-2013 Novel New Drugs Summary. (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM381803.pdf)
Ferreira, LO. Introdução: José Francisco Xavier Sigaud e a tradução local do higienismo. In: Siguad, J.F.X. Do clima e das doenças do Brasil ou estatística médica deste império. Trad. de Renato Aguiar. Rio de Janeiro: Editora Fiocruz, 2009. P. 17-26.
Ferreira SH. A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca. Brit J Pharmacol Chemother, 24: 163-169, 1965.
Ferreira SH, Greene LJ, Alabaster VA, BakhleYS, Vane JR. Nature 225:379-380, 1970 Ferro ES. Biotecnologia translacional: hemopressina e outros peptídeos intracelulares. Estud. Av. 24:109-121, 2010.
Gentilucci L, De Marco R, Cerisoli L. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Cur Phama Design 2010, 16:3185-3203.
Gibson, DG. et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science, v.329, n.5987, p.52-6, July 2010.
Gilchrist J, Bosmans F. Animal toxins can alter the function of Nav1.8 and Nav1.9. Toxins (Basel). 2012, 4(8):620-32.
Giorgi R, Bernardi MM, Cury Y. Analgesic effect evoked by low molecular weight substances extracted from Crotalus durissus terrificus venom. Toxicon. 1993 Oct;31(10):1257-65.
Gutierrez VP, Konno K, Chacur M, Sampaio SC, Picolo G, Brigatte P, Zambelli VO, Cury Y. Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors. Eur J Pharmacol. 2008; 594(1-3):84-92.
Gutierrez VP, Zambelli VO, Picolo G, Chacur M, Sampaio SC, Brigatte P, Konno K, Cury Y. The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K+ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats. Behav Pharmacol. 2012; 23(1):14-24.
Konno K, Picolo G, Gutierrez VP, Brigatte P, Zambelli VO, Camargo AC, Cury Y. Crotalphine, a novel potent analgesic peptide from the venom of the
South American rattlesnake Crotalus durissus terrificus. Peptides. 2008; 29(8):1293-304 Hannon HE, Atchison WD. Omega-conotoxins as experimental tools and therapeutics in pain management. Mar. Drugs 2013, 11:680-699.
Harvey AL. Toxins and drug discovery. Toxicon 92 (2014) 193e200.
Kohno T, Kim JI, Kobayashi K, Kodera Y, Maeda T, Sato K. Three-dimensional structure in solution of the calcium channel blocker omegaconotoxin MVIIA. Biochemistry. 1995 Aug 15;34(32):10256-65.
Lam KS. New aspects of natural products in drug discovery TRENDS in Microbiology Vol.15 No.6, 2007.
Leach, A.R. Molecular Modelling: Principles and Applications. 2 ed. England: Pearson Education, 2001.
Machado FC, Zambelli VO, Fernandes AC, Heimann AS, Cury Y, Picolo G. Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine. Br J Pharmacol. 2014; 171(4):961-72.
McGivern JG. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007 Feb;3(1):69-85 Morgon, NH, Coutinho, K. Métodos de Química Teórica e Modelagem Molecular. São Paulo: Editora Livraria da Física, 2007.
Nasiripourdori A, Taly V, Grutter T, Taly A. From toxins targeting ligand gated ion channels to therapeutic molecules. Toxins (Basel). 2011 3(3):260-93.
Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR. Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24.
Nogueira-Neto F de S, Amorim RL, Brigatte P, Picolo G, Ferreira WA Jr, Gutierrez VP, Conceição IM, Della-Casa MS, Takahira RK, Nicoletti JL, Cury Y. The analgesic effect of crotoxin on neuropathic pain is mediated by central muscarinic receptors and 5-lipoxygenase-derivedmediators. Pharmacol Biochem Behav. 2008; 91(2):252-60.
Oliveira DG, Alvarez-Flores MP, Lopes AR, Chudzinski-Tavassi AM. Functional characterisation of vizottin, the first factor Xa inhibitor purified from the leech Haementeria vizottoi. Thromb Haemost. 2012 Sep; 108(3):570-8.
Pasqualoto KFM, Carrijo-Carvalho LC, ChudzinskiTavassi AM. Rational development of novel leads from animal secretion based on coagulation and cell targets: 1. In silico analysis to explore a peptide derivative as lipocalins’ signature. Toxicon. 2013 Jul; 69:200-10.
Pasqualoto KF, Balan A, Barreto SA, Simons SM, Chudzinski-Tavassi AM. Structural findings and molecular modeling approach of a TFPIlike inhibitor. Protein Pept Lett. 2014 May; 21(5):452-7.
Patrick, GL. An Introduction to Medicinal Chemistry, fourth edition, Oxford, 2010.
Picolo G, Giorgi R, Cury Y. delta-opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom. Eur J Pharmacol. 2000; 391(1-2):55-62.
Picolo G, Cassola AC, Cury Y. Activation of peripheral ATP-sensitive K+ channels mediates the antinociceptive effect of Crotalus durissus terrificus snake venom. Eur J Pharmacol. 2003; 469(1-3):57-64.
Picolo G, Cury Y. Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a delta- and kappa-opioid receptor agonist. Life Sci. 2004; 75(5):559-73.
Smith CG, Vane JR. The Discovery of Captopril. The FASEB Journal, vol. 17 no. 8 788-789, 2003.
Sigaud JFX. – Dicionário Histórico-Biográfico das Ciências da Saúde no Brasil (1832-1930) – Casa de Oswaldo Cruz/ Fiocruz, p.1-7 (http://www.dichistoriasaude.coc.fiocruz.br).
Snutch TP. 2004. N-type channels, small organic molecules and pain. Spring Pain Research Conference, Grand Cayman, BWI.
Snutch TP, Feng ZP, Belardetti F, et al. 2003. Novel N-type calcium channel blockers efficacious en animal models of chronic pain. 226th American Chemical Society National Meeting, New York, NY.
Wermuth, C.G. The Practice of Medicinal Chemistry, third edition, Academic Press, 2008.
Wolz-Richter S, Esser KH, Hess A. Antinociceptive activity of crotoxin in the central nervous system: a functional Magnetic Resonance Imaging study. Toxicon. 2013; 74:44-55.
Zambelli VO, Fernandes AC, Gutierrez VP, Ferreira JC, Parada CA, Mochly-Rosen D, Cury Y. Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats. PLoS One. 2014; 9(3):e90576.
Zhang HL, Han R, Chen ZX, Chen BW, Gu ZL, Reid PF, Raymond LN, Qin ZH. Opiate and acetylcholine-independent analgesic actions of crotoxin isolated from crotalus durissus terrificus venom. Toxicon. 2006; 48(2):175-82.
Zhu Q, Wu DC, Zhou XP, Gong S, Cheng BC, Qin ZH, Reid PF, Yin QZ, Jiang XH. Inhibitory effect of crotoxin on the pain-evoked discharge of neurons in thalamic parafascicular nucleus in rats. Toxicon. 2008; 51(1):102-11.
Alvarez-Flores MP, Furlin D, Ramos OH, Balan A, Konno K, Chudzinski-Tavassi AM. Losac, the first hemolin that exhibits procogulant activity through selective factor X proteolytic activation. J Biol Chem. 2011 Mar 4; 286(9):6918-28.
Barreiro EJ, Fraga CAM. A questão da inovação em fármacos no Brasil: proposta de criação do programa nacional de fármacos (PRONFAR). Quim. Nova 28:S56-S63, 2005.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E. The Protein Data Bank. Nuc. Acids Res. 28:235-242, 2000.
Brazil V. Do emprêgo da peçonha em terapêutica. Biologia Médica. 1934, 1: 7–21.
Brigatte P, Konno K, Gutierrez VP, Sampaio SC, Zambelli VO, Picolo G, Curi R, Cury Y. Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphinein a rat model of cancer pain. Pharmacol Biochem Behav. 2013; 109: 1-7.
Bryan J. From snake venom to ACE inhibitor: the discovery and rise of captopril. The Pharmaceutical Journal, Vol. 282, p455 , 2009.
Cohen, C. Guidebook on Molecular Modeling in Drug Design. First edition, Academic Press, 1996.
Cushman DW, Cheung HS, Sabo EF, Ondetti MA. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry, 1977, 16:5485-5491.
Chudzinski-Tavassi AM, Carrijo-Carvalho LC, Waismam K, Farsky SH, Ramos OH, Reis CV. A lipocalin sequence signature modulates cell survival. FEBS Lett. 2010b Jul 2; 584(13):2896-900.
Chudzinski-Tavassi AM, Alvarez Flores MP. Exploring new molecules and activities from Lonomia obliqua caterpillars.Pathophysiol Haemost Thromb. 2005; 34(4-5):228-33.
Review. Erratum in: Pathophysiol Haemost Thromb. 2006; 35(5):410.
Cura JE, Blanzaco DP, Brisson C, Cura MA, Cabrol R, Larrateguy L, Mendez C, Sechi JC, Silveira JS, Theiller E, de Roodt AR, Vidal JC. Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer. Clin Cancer Res. 2002; 8(4):1033-41.
Cury Y, Picolo G. Animal toxins as analgesics--an overview. Drug News Perspect. 2006; 19(7):381-92.
Chudzinski-Tavassi AM, De-Sá-Júnior PL, Simons SM, Maria DA, de Souza Ventura J, Batista IF, Faria F, Durães E, Reis EM, Demasi M. A new tick Kunitz type inhibitor, Amblyomin-X, induces tumor cell death by modulating genes related to the cell cycle and targeting the ubiquitin-proteasome system. Toxicon. 2010a Dec 15; 56(7):1145-54.
Cury Y, Picolo G. Are animal toxins good models for analgesics? In: de Lima ME, de Castro Pimenta AM, Martin-Eauclaire MF, Zingali RB, Rochat H. (Org.). Animal Toxins: State of the Art Perspectives in Health And Biotechnology. 1ed.Minas Gerais: Editora UFMG, v. 1, p. 661-678, 2009.
Da Silva SL, Rowan EG, Albericio F, Stábeli RG, Calderon LA, Soares AM. Animal toxins and their advantages in biotechnology and pharmacology. Biomed Res Int. 2014;2014:951561.
Faure G., Xu H., Saul, F.A. Crystal structure of crotoxin reveals key residues involved in the stability and toxicity of this potent heterodimeric ß-neurotoxin. J. Mol. Biol. 412: 176-191, 2011. FDA-2013 Novel New Drugs Summary. (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM381803.pdf)
Ferreira, LO. Introdução: José Francisco Xavier Sigaud e a tradução local do higienismo. In: Siguad, J.F.X. Do clima e das doenças do Brasil ou estatística médica deste império. Trad. de Renato Aguiar. Rio de Janeiro: Editora Fiocruz, 2009. P. 17-26.
Ferreira SH. A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca. Brit J Pharmacol Chemother, 24: 163-169, 1965.
Ferreira SH, Greene LJ, Alabaster VA, BakhleYS, Vane JR. Nature 225:379-380, 1970 Ferro ES. Biotecnologia translacional: hemopressina e outros peptídeos intracelulares. Estud. Av. 24:109-121, 2010.
Gentilucci L, De Marco R, Cerisoli L. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Cur Phama Design 2010, 16:3185-3203.
Gibson, DG. et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science, v.329, n.5987, p.52-6, July 2010.
Gilchrist J, Bosmans F. Animal toxins can alter the function of Nav1.8 and Nav1.9. Toxins (Basel). 2012, 4(8):620-32.
Giorgi R, Bernardi MM, Cury Y. Analgesic effect evoked by low molecular weight substances extracted from Crotalus durissus terrificus venom. Toxicon. 1993 Oct;31(10):1257-65.
Gutierrez VP, Konno K, Chacur M, Sampaio SC, Picolo G, Brigatte P, Zambelli VO, Cury Y. Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors. Eur J Pharmacol. 2008; 594(1-3):84-92.
Gutierrez VP, Zambelli VO, Picolo G, Chacur M, Sampaio SC, Brigatte P, Konno K, Cury Y. The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K+ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats. Behav Pharmacol. 2012; 23(1):14-24.
Konno K, Picolo G, Gutierrez VP, Brigatte P, Zambelli VO, Camargo AC, Cury Y. Crotalphine, a novel potent analgesic peptide from the venom of the
South American rattlesnake Crotalus durissus terrificus. Peptides. 2008; 29(8):1293-304 Hannon HE, Atchison WD. Omega-conotoxins as experimental tools and therapeutics in pain management. Mar. Drugs 2013, 11:680-699.
Harvey AL. Toxins and drug discovery. Toxicon 92 (2014) 193e200.
Kohno T, Kim JI, Kobayashi K, Kodera Y, Maeda T, Sato K. Three-dimensional structure in solution of the calcium channel blocker omegaconotoxin MVIIA. Biochemistry. 1995 Aug 15;34(32):10256-65.
Lam KS. New aspects of natural products in drug discovery TRENDS in Microbiology Vol.15 No.6, 2007.
Leach, A.R. Molecular Modelling: Principles and Applications. 2 ed. England: Pearson Education, 2001.
Machado FC, Zambelli VO, Fernandes AC, Heimann AS, Cury Y, Picolo G. Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine. Br J Pharmacol. 2014; 171(4):961-72.
McGivern JG. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007 Feb;3(1):69-85 Morgon, NH, Coutinho, K. Métodos de Química Teórica e Modelagem Molecular. São Paulo: Editora Livraria da Física, 2007.
Nasiripourdori A, Taly V, Grutter T, Taly A. From toxins targeting ligand gated ion channels to therapeutic molecules. Toxins (Basel). 2011 3(3):260-93.
Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR. Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24.
Nogueira-Neto F de S, Amorim RL, Brigatte P, Picolo G, Ferreira WA Jr, Gutierrez VP, Conceição IM, Della-Casa MS, Takahira RK, Nicoletti JL, Cury Y. The analgesic effect of crotoxin on neuropathic pain is mediated by central muscarinic receptors and 5-lipoxygenase-derivedmediators. Pharmacol Biochem Behav. 2008; 91(2):252-60.
Oliveira DG, Alvarez-Flores MP, Lopes AR, Chudzinski-Tavassi AM. Functional characterisation of vizottin, the first factor Xa inhibitor purified from the leech Haementeria vizottoi. Thromb Haemost. 2012 Sep; 108(3):570-8.
Pasqualoto KFM, Carrijo-Carvalho LC, ChudzinskiTavassi AM. Rational development of novel leads from animal secretion based on coagulation and cell targets: 1. In silico analysis to explore a peptide derivative as lipocalins’ signature. Toxicon. 2013 Jul; 69:200-10.
Pasqualoto KF, Balan A, Barreto SA, Simons SM, Chudzinski-Tavassi AM. Structural findings and molecular modeling approach of a TFPIlike inhibitor. Protein Pept Lett. 2014 May; 21(5):452-7.
Patrick, GL. An Introduction to Medicinal Chemistry, fourth edition, Oxford, 2010.
Picolo G, Giorgi R, Cury Y. delta-opioid receptors and nitric oxide mediate the analgesic effect of Crotalus durissus terrificus snake venom. Eur J Pharmacol. 2000; 391(1-2):55-62.
Picolo G, Cassola AC, Cury Y. Activation of peripheral ATP-sensitive K+ channels mediates the antinociceptive effect of Crotalus durissus terrificus snake venom. Eur J Pharmacol. 2003; 469(1-3):57-64.
Picolo G, Cury Y. Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a delta- and kappa-opioid receptor agonist. Life Sci. 2004; 75(5):559-73.
Smith CG, Vane JR. The Discovery of Captopril. The FASEB Journal, vol. 17 no. 8 788-789, 2003.
Sigaud JFX. – Dicionário Histórico-Biográfico das Ciências da Saúde no Brasil (1832-1930) – Casa de Oswaldo Cruz/ Fiocruz, p.1-7 (http://www.dichistoriasaude.coc.fiocruz.br).
Snutch TP. 2004. N-type channels, small organic molecules and pain. Spring Pain Research Conference, Grand Cayman, BWI.
Snutch TP, Feng ZP, Belardetti F, et al. 2003. Novel N-type calcium channel blockers efficacious en animal models of chronic pain. 226th American Chemical Society National Meeting, New York, NY.
Wermuth, C.G. The Practice of Medicinal Chemistry, third edition, Academic Press, 2008.
Wolz-Richter S, Esser KH, Hess A. Antinociceptive activity of crotoxin in the central nervous system: a functional Magnetic Resonance Imaging study. Toxicon. 2013; 74:44-55.
Zambelli VO, Fernandes AC, Gutierrez VP, Ferreira JC, Parada CA, Mochly-Rosen D, Cury Y. Peripheral sensitization increases opioid receptor expression and activation by crotalphine in rats. PLoS One. 2014; 9(3):e90576.
Zhang HL, Han R, Chen ZX, Chen BW, Gu ZL, Reid PF, Raymond LN, Qin ZH. Opiate and acetylcholine-independent analgesic actions of crotoxin isolated from crotalus durissus terrificus venom. Toxicon. 2006; 48(2):175-82.
Zhu Q, Wu DC, Zhou XP, Gong S, Cheng BC, Qin ZH, Reid PF, Yin QZ, Jiang XH. Inhibitory effect of crotoxin on the pain-evoked discharge of neurons in thalamic parafascicular nucleus in rats. Toxicon. 2008; 51(1):102-11.
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