Chemotherapy Of Chagas' Disease: State Of The Art And Perspectives For The Development Of New Drugs [quimioterapia Da Doença De Chagas: Estado Da Arte E Perspectivas No Desenvolvimento De Novos Fármacos]

Neglected diseases are a major global cause of illness, long-term disability and death. Chagas' disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. The existing drug therapy suffers from a combination of drawbacks including poor efficacy, resistance and serious side effects. In 2009, we celebrate the 100th anniversary of the discovery of Chagas' disease, facing the challenges of developing new, safe and effective drugs for the treatment of this disease. This brief review attempts to highlight the state of the art, limitations and perspectives of Chagas' disease drug development.32924442457Ketter, H., Marjanovic, S., (2004) Nature Rev. Drug Discov., 3, p. 171Nwaka, S., Ridley, R.G., (2003) Nature Rev. Drug Discov., 2, p. 919Engels, D., Savioli, L., (2006) Trends Parasitol., 22, p. 363Gelb, M.H., Hol, W.G., (2002) Science, 297, p. 343Hoare, C.A., (1972) The Trypanosomes of Mammals, p. 20. , Blackwell Scientific Publications: OxfordHoare, C.A., Wallace, F.G., (1966) Nature, 212, p. 1385Boainain, E., Rassi, A., Arq. Bras. Cardiol., 32, pp. 1979-2395Dias, J.C., (1993) Cad. Saúde Pub. Minist. Saúde, 9, p. 201. , Fundação Oswaldo Cruz, Escola Nacional de Saúde PúblicaMarin-Neto, J.A., Simões, M.V., Maciel, B.C., Uptodate in Cardiovascular Medicine, , A CD-Rom Textbook, Section: CardiomyopathiesRose, B.D., Podrid, P.J., Gersh, B.J., (1998) Orgs., 6, p. 6. , 1st ed. Wellesley: Ma, USARossi, M.A., (1991) Int. J. Cardiol., 30, p. 335Kalil, J., Cunha-Neto, E., (1996) Parasitol. Today, 12, p. 396Bellotti, G., Bocchi, E.A., De Moraes, A.V., Higuchi, M.L., Barbero-Marcial, M., Sosa, E., (1996) Am. Heart J., 131, p. 301Levin, M.J., (1996) Parasitol. Today, 12, p. 415Hayes, R., Schofield, C.J., (1990) Volví. Oficial Sanit. Panam., 108, p. 308(1991) World Health Organization Tech. Rep. Ser., 811, p. 1. , WHODias, J.C., (1995) Parasitol. Today, 3, p. 336Brener, Z., Andrade, Z., (1979) Trypanosoma cruzi e Doença de Chagas, p. 362. , Guanabara Koogan: Rio de JaneiroBrener, Z., (1968) Terapêutica Experimental da Doença de Chagas, p. 510. , Cançado, J. R. ed. Imprensa Oficial de Minas Gerais: Belo HorizonteCoura, J.R., Castro, S.L., (2002) Mem. Inst. Oswaldo Cruz, 97, p. 3De Castro, S.L., (1993) Acta Tropical, 53, p. 83Brener, Z., (1961) Rev. Inst. Med. Trop., 3, p. 43. , São PauloCançado, J.R., Marra, U.D., Brener, Z., (1964) Rev. Inst. Med. Trop., 6, p. 12. , São PauloPackchanian, A., (1952) J. Parasitol., 38, p. 30Packchanian, A., (1957) Antib. Chemother., 7, p. 13Rassi, A., Ferreira, H.O., (1971) Rev. Inst. Med. Trop., 5, p. 235. , São PauloCoura, J.R., Ferreira, L.F., Silva, J.R., (1962) O Hospital, 62, p. 957Ferreira, H.O., (1961) Rev. Inst. Med. Trop., 3, p. 287. , São PauloCoura, J.R., Castro, S.L., (2002) Mem. Inst., 97, p. 3. , Oswaldo CruzRubio, M., Donoso, F., (1969) Bol. Chil. Parasitol., 24, p. 43Schenone, H., Concha, L., Aranda, R., Rojas, A., Alfaro, E., Knierin, E., Rojo, M., (1975) Bol. Chil. Parasitol., 30, p. 91Schenone, H., Concha, L., Aranda, R., Rojas, A., Knierim, F., Rojo, M., (1972) Bol. Chil. Parasitol., 27, p. 11Maya, J.D., Bollo, S., Nuñez-Vergara, L.J., Squella, J.A., Repetto, Y., Morello, A., Périé, J., Chauvière, G., (2003) Biochem. Pharmacol., 65, p. 999Maya, J.D., Cassels, B.K., Iturriaga-Ásquez V, P., Ferreira, J., Faúdez, M., Galanti, N., Ferreira, A., Morello, A., (2007) Comp. Bio-chem. Physiol. A Mol. Integr. Physiol., 146, p. 601Moreno, S.N., Docampo, R., Mason, R.P., León, W., Stoppani, A.O., (1982) Archiv. Biochem Biophys., 218, p. 585Mason, R.P., Holtzman, J.L., (1975) Biochem. Biophys. Res. Commun., 67, p. 1267Temperton, N.J., Wilkinson, S.R., Meyer, D.J., Kelly, J.M., (1998) Mol. Biochem. Parasitol., 96, p. 167Docampo, R., Moreno, S.N., (1984) Rev. Infec. Diseases, 6, p. 223Docampo, R., Moreno, S.N., Stoppani, A.O., León, W., Cruz, F.S., Villalta, F., Muñiz, R.F., (1981) Biochem. Pharmacol., 30, p. 1947Díaz De Toranzo, E.G., Castro, J.A., Franke De Cazzulo, B.M., Cazzulo, J.J., (1988) Experientia, 44, p. 880Romanha, A.J., Alves, R.O., Murta, S.M., Silva, J.S., Ropert, C., Gazzinelli, R.T., (2002) J. Infec. Diseases, 186, p. 823Turrens, J.F., Watts Jr., B.P., Zhong, L., Docampo, R., (1996) Mol. Biochem. Parasitol., 82, p. 125Castro, J.A., Meca, M.M., Bartel, L.C., (2006) Hum. Exp. Toxicol., 25, p. 471Nwaka, S., Hudson, A., (2006) Nature Rev., 5, p. 941Kola, I., (2008) Mol. Therapy, 83, p. 227Duschak, V.G., Couto, A.S., (2007) Recent Pat. Anti-Infec Drug Discov., 2, p. 19McKerrow, J.H., Rosenthal, P.J., Swenerton, R., Doyle, P., (2008) Cur. Opin. Infc. Dis., 21, p. 668Andricopulo, A.D., Yunes, R.A., Nunes, R.J., Savi, A.O.S., Cruz, A.B., Cechinel, V., (1998) Quim. Nova, 21, p. 573Sealey-Cardona, M., Cammerer, S., Jones, S., Ruiz-Perez, L.M., Brun, R., Gilbert, I.H., Urbina, J.A., Gonzalez-Pacanowska, D., (2007) Antimicrob. Agents Chemother., 51, p. 2123Jr., W.F.A., Soares, M.B.P., (2009) Cur. Drug Targets, 10, p. 193Moreira, D.R.M., Leite, A.C.L., Dos Santos, R.R., Soares, M.B.P., (2009) Cur. Drug Targets, 10, p. 212Soeiro, M.N.C., Castro, S.L., (2009) Expert. Opinion, 13, p. 105Sajid, M., McKerrow, J.H., (2002) Mol. Biochem. Parasitol., 120, p. 1Brak, K., Doyle, P.S., McKerrow, J.H., Ellman, J.A., (2008) J. Am. Chem. Soc., 130, p. 6404Zanatta, N., Amaral, S.S., Dos Santos, J.M., De Mello, D.L., Fernandes, L.S., Bonacorso, H.G., Martins, M.A.P., Borchhardt, D.M., (2008) Biorg. Med. Chem., 16, p. 10236Fricker, S.P., Mosi, R.M., Cameron, B.R., Baird, I., Zhu, Y., Anastassov, V., Cox, J., McKerrow, J.H., (2008) J. Inorg. Biochem., 102, p. 1839Ascenzi, P., Salvati, L., Bolognesi, M., Colasanti, M., Polticelli, F., Venturini, G., (2001) Curr. Prot. Pept. Sci., 2, p. 137Silva, J.J.N., Osakabe, A.L., Pavanelli, W.R., Silva, J.S., Franco, D.W., (2007) Br. J. Pharmacol., 152, p. 112Doyle, P., Zhou, Y.M., Engel, J.C., McKerrow, J.H., (2007) Antimicrob. Agents Chemother., 51, p. 3932Apt, W., Aguilera, X., Arribada, A., Perez, C., Miranda, C., Sanchez, G., Zulantay, I., Júri, D., (1998) Am. J. Trop. Med. Hyg., 59, p. 133Hucke, O., Gelb, M.H., Verlinde, C.L., Buckner, F.S., (2005) J. Med. Chem., 48, p. 5415Kraus, J.M., Verlinde, C.L., Karimi, M., Lepesheva, G.I., Gelb, M.H., Buckner, F.S., (2009) J. Med. Chem., 52, p. 1639Verline, C.L.M.J., Hannaert, V., Blonski, C., Willson, M., Périé, J.J., Fathergill-Gilmore, L.A., Opperdoes, F.R., Michels, P.A.M., (2001) Antimicrob. Anticancer Chemother., 4, p. 1Souza, D.H.F., Garratt, R.C., Araújo, A.P.U., Guimarães, B.G., Jesus, W.D.P., Michels, P.A.M., Hannaert, V., Oliva, G., (1998) FEBS Lett., 424, p. 131Urbina, J.A., Crespo, A., (1984) Mol. Biochem. Parasitol., 11, p. 225Freitas, R.F., Prokopczyk, I.M., Zottis, A., Oliva, G., Andricopulo, A.D., Trevisan, M.T.S., Villegas, W., Montanari, C.A., (2009) Bioorg. Med. Chem., 17, p. 2476Pereira, J.M., Severino, R.P., Vieira, P.C., Fernandes, J.B., Silva, M.F.G.F., Zottis, A., Andricopulo, A.D., Correa, A.G., (2008) Bioorg. Med. Chem., 16, p. 8889Mohr, S., Stamler, J.S., Brüne, B., (1994) FEBS Lett., 348, p. 223Lopez, B.E., Wink, D.A., Fukuto, J.M., (2007) Arch. Biochem. Biophys., 465, p. 430Silva, J.J.N., Guedes, P.M.M., Zottis, A., Balliano, T.L., Da Silva, F.O.N., Lopes, L.G.F., Ellena, J., Franco, D.W., (2009) Br. J. Pharmacol., , in pressWilkinson, S.R., Kelly, J.M., (2003) Molecular Mechanisms in the Pathogenesis of Chagas' Disease, p. 56. , Kelly, J. M. ed. Landes Bioscience: LondonSilva, J.J.N., Pavanelli, W.R., Gutierrez, F.R.S., Lima, F.C.A., Silva, A.B.F., Silva, J.S., Franco, D.W., (2008) J. Med. Chem., 51, p. 4104Gutteridge, J.M., Halliwell, B., (2000) Ann. New York Acad. Sci., 899, p. 136Lopez, J.A., Carvalho, T.U., De Souza, W., Flohe, L., Guerrero, S.A., Montemartini, M., Kalisz, H.M., Colli, W., (2000) Free Radic. Biol. Med., 28, p. 767Frasch, A.C.C., Leguizamon, M.S., Campetella, O., Russomando, G., (1994) J. Infect. Dis., 170, p. 1570Tse-Dinh, Y.C., (2007) Infect. Disord. Drug Targets, 7, p. 3Guido, R.V.C., Oliva, G., Andricopulo, A.D., (2008) Cur. Med. Chem., 15, p. 37Andricopulo, A.D., Montanari, C.A., (2005) Mini-Rev. Med. Chem., 5, p. 585Andricopulo, A.D., Akoachere, M.B., Krogh, R., Nickel, C., Mcleish, M.J., Kenyon, G.L., Arscott, L.D., Becker, K., (2006) Bioorg. Med. Chem. Lett., 16, p. 2283Chung, M.C., Guido, R.V.C., Martinelli, T.F., Goncalves, M.F., Polli, M.C., Botelho, K.C.A., Varanda, E.A., Ferreira, E.I., (2003) Bioorg. Med. Chem., 11, p. 4779Cerecetto, H., Di Maio, R., González, M., Risso, M., Saenz, P., Seoane, G., Denicola, A., Olea-Azar, C., (1999) J. Med. Chem., 42, p. 1941Aguirre, G., Cerecetto, H., Di Maio, R., González, M., Porcal, W., Seoane, G., Denicola, A., Monge-Vega, A., (2002) Arch. Pharm., 335, p. 15Olea-Azar, C., Rigol, C., Opazo, L., Morello, A., Maya, J.D., Repetto, Y., Aguirre, G., Porcal, W., (2003) J. Chil. Chem. Soc., 48, p. 77Olea-Azar, C., Rigol, C., Mendizábal, F., Briones, R., Cerecetto, H., Di Maio, R., González, M., Risso, M., (2003) Spectrochim. Acta Part A, 59, p. 69Olea-Azar, C., Rigol, C., Mendizábal, F., Cerecetto, H., Di Maio, R., González, M., Porcal, W., Maya, J.D., (2005) Lett. Drug Des. Discov., 2, p. 294Aguirre, G., Boiani, L., Boiani, M., Cerecetto, H., Di Maio, R., González, M., Porcal, W., Barreiro, E.J., (2005) Bioorg. Med. Chem., 13, p. 6336Aguirre, G., Boiani, L., Cerecetto, H., Di Maio, R., González, M., Porcal, W., Thomson, L., Moller, M., (2005) Bioorg. Med. Chem., 13, p. 6324Aguirre, G., Boiani, M., Cerecetto, H., Gerpe, A., González, M., Fernández, S., Denicola, A., Escario, J.A., (2004) Arch. Pharm., 337, p. 259Boiani, M., González, M., (2005) Mini-Rev. Med. Chem., 5, p. 235Fielden, R., Meth-Cohn, O., Price, D., Suschitzky, H., (1973) J. Chem. Soc., Perkin Trans., 1, p. 696Baliani, A., Bueno, G.J., Stewart, M.L., Yardley, V., Brun, R., Barrett, M.P., Gilbert, I.H., (2005) J. Med. Chem., 48, p. 5570Carter, N.S., Fairlamb, A.H., (1993) Nature, 361, p. 173Stewart, M.L., Bueno, G.J., Baliani, A., Klenke, B., Brun, R., Brock, J.M., Gilbert, I.H., Barrett, M.P., (2004) Antimicrob. Agents Chemother., 48, p. 1733Tye, C.-K., Kasinathan, G., Barrett, M.P., Brun, R., Doyle, V.E., Fairlamb, A.H., Weaver, R., Gilbert, I.H., (1998) Bioorg. Med. Chem., 8, p. 811Barrett, M.P., Fairlamb, A.H., (1999) Parasitol. Today, 15, p. 136Sanchez-Delgado, R.A., Anzellotti, A., (2004) Mini.-Rev. Med. Chem., 4, p. 23Otero, L., Vieites, M., Bioani, L., Denicola, A., Rigol, C., Opazo, L., Olea-Azar, C., Cerecetto, H., (2006) J. Med. Chem., 49, p. 3322Sanchez-Delgado, R.A., Navarro, M., Lazardi, K., Atencio, R., Capparelli, M., Vargas, F., Urbina, J.A., Mais, D., (1998) Inorg. Chim. Acta, 276, p. 528Buckner, F.S., Verlinde, C.L.M.J., La Flamme, A.C., Van Voorhis, W.C., (1996) Antimicrob. Agents Chemother., 40, p. 2592Bruce, R.D., (1985) Fund. Appl. Toxicol., 5, p. 151Brener, Z., (1962) Rev. Inst. Med. Trop., 4, p. 389http://apps.who.int/tdr/svc/research/lead-discovery-drugs, acessada em Maio 2009http://apps.who.int/tdr/svc/research/lead-discovery-drugs/ partnerships-networks, acessada em Maio 2009Chirac, P., Torreele, R., (2006) Lancet, 12, p. 1560http://www.dndi.org, acessada em Maio 2009http://www.dndi.org.br/Portugues/sobre_dndi.aspx, acessada em Maio 200

Levels of mRNA for bone morphogenetic proteins, their receptors and SMADs in goat ovarian follicles grown in vivo and in vitro

This study investigated the stability of housekeeping genes (glyceraldehyde-3-phosphate dehydrogenase, β-tubulin, β-actin, phosphoglycerate kinase (PGK), 18S rRNA, ubiquitin and ribosomal protein 19) and the levels of mRNA for bone morphogenetic protein-2 (BMP-2), -4 (BMP-4), -6 (BMP-6), -7 (BMP-7) and -15 (BMP-15), their receptors (BMPR-IA, -IB and -II) and Similar to Mothers Against Decapentaplegic (SMADs) (-1, -5 and -8) in goat follicles of 0.2, 0.5 and 1.0 mm, as well as in secondary follicles before and after culture for 18 days. β-tubulin and PGK were the most stable housekeeping genes and the levels of mRNA for BMP-2 in follicles of 0.2 mm were higher than in follicles of 0.5 and 1.0 mm. For BMP-4, -6 and -7, the highest levels of mRNA were found in follicles of 1.0 mm. The expression of BMPR-IB was higher in follicles of 0.2 mm, whereas the levels of BMPR-II were higher in follicles of 0.5 mm. The levels of mRNA for SMAD-5 were higher in follicles of 0.2 mm, whereas SMAD-8 had higher levels in 0.5-mm follicles. After culture, follicles showed increased levels of mRNA for BMP-2 and reduced mRNA for BMP-4, BMP-7, BMPR-IA and SMAD-5. In conclusion, β-tubulin and PGK are the most stable reference genes, and BMPs, their receptors and SMADs have variable levels of mRNA in the follicular size classes analysed.</jats:p

Phytohemagglutinin improves the development and ultrastructure of in vitro-cultured goat (Capra hircus) preantral follicles

The objective this study was to determine the effect of phytohemagglutinin (PHA) on survival, growth and gene expression in caprine secondary follicles cultured in vitro. Secondary follicles (&#8764;0.2&#8197;mm) were isolated from the cortex of caprine ovaries and cultured individually for 6 days in &#945;-MEM+ supplemented with PHA (0, 1, 10, 50, 100, or 200&#8197;&#181;g/mL). After 6 days of culture, follicle diameter and survival, antrum formation, ultrastructure and expression of mRNA for FSH receptors (FSH-R), proliferating cell nuclear antigen (PCNA), and neuronal nitric oxide synthase were determined. All treatments maintained follicular survival [&#945;-MEM+ (94.59%); 1&#8197;&#181;g/mL PHA (96.43%); 10&#8197;&#181;g/mL PHA (84.85%); 50&#8197;&#181;g/mL PHA (85.29%); 100&#8197;&#181;g/mL PHA (88.57%), and 200&#8197;&#181;g/mL PHA (87.50)], but the presence of 10&#8197;&#181;g/mL PHA in the culture medium increased the antrum formation rate (21.21%) when compared with control (5.41%, P < 0.05) and ensured the maintenance of oocyte and granulosa cell ultrastructures after 6 days of culture. The expression of mRNA for FSH-R (2.7 &#177; 0.1) and PCNA (4.4 &#177; 0.2) was also significantly increased in follicles cultured with 10&#8197;&#181;g/mL PHA in relation to those cultured in &#945;-MEM+ (1.0 &#177; 0.1). In conclusion, supplementation of culture medium with 10&#8197;&#181;g/mL PHA maintains the follicular viability and ultrastructure, and promotes the formation of antral cavity after 6 days of culture in vitro