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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Study of the Activity of 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one against Schistosomiasis Mansoni in Mice</title><author><name sortKey="Da Silva, Andrea Cristina Apolinario" sort="Da Silva, Andrea Cristina Apolinario" uniqKey="Da Silva A" first="Andréa Cristina Apolinário" last="Da Silva">Andréa Cristina Apolinário Da Silva</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Neves, Juliana Kelle De Andrade Lemoine" sort="Neves, Juliana Kelle De Andrade Lemoine" uniqKey="Neves J" first="Juliana Kelle De Andrade Lemoine" last="Neves">Juliana Kelle De Andrade Lemoine Neves</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Irmao, Joao Inacio" sort="Irmao, Joao Inacio" uniqKey="Irmao J" first="João Inácio" last="Irmão">João Inácio Irmão</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Costa, Vlaudia Maria Assis" sort="Costa, Vlaudia Maria Assis" uniqKey="Costa V" first="Vláudia Maria Assis" last="Costa">Vláudia Maria Assis Costa</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Souza, Valdenia Maria Oliveira" sort="Souza, Valdenia Maria Oliveira" uniqKey="Souza V" first="Valdênia Maria Oliveira" last="Souza">Valdênia Maria Oliveira Souza</name><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="De Medeiros, Paloma Lys" sort="De Medeiros, Paloma Lys" uniqKey="De Medeiros P" first="Paloma Lys" last="De Medeiros">Paloma Lys De Medeiros</name><affiliation><nlm:aff id="I4">Departamento de Histologia e Embriologia, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Da Silva, Eliete Cavalcanti" sort="Da Silva, Eliete Cavalcanti" uniqKey="Da Silva E" first="Eliete Cavalcanti" last="Da Silva">Eliete Cavalcanti Da Silva</name><affiliation><nlm:aff id="I4">Departamento de Histologia e Embriologia, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="De Lima, Maria Do Carmo Alves" sort="De Lima, Maria Do Carmo Alves" uniqKey="De Lima M" first="Maria Do Carmo Alves" last="De Lima">Maria Do Carmo Alves De Lima</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Pitta, Ivan Da Rocha" sort="Pitta, Ivan Da Rocha" uniqKey="Pitta I" first="Ivan Da Rocha" last="Pitta">Ivan Da Rocha Pitta</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Albuquerque, Monica Camelo Pessoa De Azevedo" sort="Albuquerque, Monica Camelo Pessoa De Azevedo" uniqKey="Albuquerque M" first="Mônica Camelo Pessoa De Azevedo" last="Albuquerque">Mônica Camelo Pessoa De Azevedo Albuquerque</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Galdino, Suely Lins" sort="Galdino, Suely Lins" uniqKey="Galdino S" first="Suely Lins" last="Galdino">Suely Lins Galdino</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22623908</idno><idno type="pmc">3353485</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353485</idno><idno type="RBID">PMC:3353485</idno><idno type="doi">10.1100/2012/520524</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002C66</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002C66</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Study of the Activity of 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one against Schistosomiasis Mansoni in Mice</title><author><name sortKey="Da Silva, Andrea Cristina Apolinario" sort="Da Silva, Andrea Cristina Apolinario" uniqKey="Da Silva A" first="Andréa Cristina Apolinário" last="Da Silva">Andréa Cristina Apolinário Da Silva</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Neves, Juliana Kelle De Andrade Lemoine" sort="Neves, Juliana Kelle De Andrade Lemoine" uniqKey="Neves J" first="Juliana Kelle De Andrade Lemoine" last="Neves">Juliana Kelle De Andrade Lemoine Neves</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Irmao, Joao Inacio" sort="Irmao, Joao Inacio" uniqKey="Irmao J" first="João Inácio" last="Irmão">João Inácio Irmão</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Costa, Vlaudia Maria Assis" sort="Costa, Vlaudia Maria Assis" uniqKey="Costa V" first="Vláudia Maria Assis" last="Costa">Vláudia Maria Assis Costa</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Souza, Valdenia Maria Oliveira" sort="Souza, Valdenia Maria Oliveira" uniqKey="Souza V" first="Valdênia Maria Oliveira" last="Souza">Valdênia Maria Oliveira Souza</name><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="De Medeiros, Paloma Lys" sort="De Medeiros, Paloma Lys" uniqKey="De Medeiros P" first="Paloma Lys" last="De Medeiros">Paloma Lys De Medeiros</name><affiliation><nlm:aff id="I4">Departamento de Histologia e Embriologia, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Da Silva, Eliete Cavalcanti" sort="Da Silva, Eliete Cavalcanti" uniqKey="Da Silva E" first="Eliete Cavalcanti" last="Da Silva">Eliete Cavalcanti Da Silva</name><affiliation><nlm:aff id="I4">Departamento de Histologia e Embriologia, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="De Lima, Maria Do Carmo Alves" sort="De Lima, Maria Do Carmo Alves" uniqKey="De Lima M" first="Maria Do Carmo Alves" last="De Lima">Maria Do Carmo Alves De Lima</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Pitta, Ivan Da Rocha" sort="Pitta, Ivan Da Rocha" uniqKey="Pitta I" first="Ivan Da Rocha" last="Pitta">Ivan Da Rocha Pitta</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Albuquerque, Monica Camelo Pessoa De Azevedo" sort="Albuquerque, Monica Camelo Pessoa De Azevedo" uniqKey="Albuquerque M" first="Mônica Camelo Pessoa De Azevedo" last="Albuquerque">Mônica Camelo Pessoa De Azevedo Albuquerque</name><affiliation><nlm:aff id="I2">Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation><affiliation><nlm:aff id="I3">Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author><author><name sortKey="Galdino, Suely Lins" sort="Galdino, Suely Lins" uniqKey="Galdino S" first="Suely Lins" last="Galdino">Suely Lins Galdino</name><affiliation><nlm:aff id="I1">Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</nlm:aff></affiliation></author></analytic><series><title level="j">The Scientific World Journal</title><idno type="ISSN">2356-6140</idno><idno type="eISSN">1537-744X</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Previous studies conducted with the imidazolidinic derivative 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one (LPSF-PT05) show outstanding activity against adult <italic>Schistosoma mansoni</italic> worms <italic>in vitro</italic>. In the first phase of this study, <italic>S. mansoni</italic>-infected mice were treated, orally, with 100 mg/Kg of the LPSF-PT05 in three formulations: Tween 80 and saline solution, oil/water (70 : 30) emulsion, and solid dispersion with polyethylene glycol (PEG). In the second phase, three other doses of the LPSF-PT05 in PEG were tested: 3, 10, 30 mg/kg. These treatment regimens significantly reduced the number of recovered worms due to increases in the solubility of the compound in this formulation; the greatest reduction (70.5%) was observed at the dose of 100 mg/kg. There was no changes in the pattern of mature egg compared to immature eggs; however there was a significant increase in the number of dead eggs. Histopathological analysis of liver tissue showed changes in morphological aspects of the hepatic parenchyma with decrease exudative-productive hepatic granuloma stages, although we found no significant differences in IFN-<italic><italic>γ</italic></italic>, IL-4, IL-10, or NO production in response to the specific antigen SEA. The results show the derivative LPSF-PT05 to be a potential candidate in the etiological treatment of schistosomiasis with a possible dampening effect of the granulomatous process.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Steinmann, P" uniqKey="Steinmann P">P Steinmann</name></author><author><name sortKey="Keiser, J" uniqKey="Keiser J">J Keiser</name></author><author><name sortKey="Bos, R" uniqKey="Bos R">R Bos</name></author><author><name sortKey="Tanner, M" uniqKey="Tanner M">M Tanner</name></author><author><name sortKey="Utzinger, J" uniqKey="Utzinger J">J Utzinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blanchard, Tj" uniqKey="Blanchard T">TJ Blanchard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fenwick, A" uniqKey="Fenwick A">A Fenwick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Utzinger, J" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">ScientificWorldJournal</journal-id><journal-id journal-id-type="iso-abbrev">ScientificWorldJournal</journal-id><journal-id journal-id-type="publisher-id">TSWJ</journal-id><journal-title-group><journal-title>The Scientific World Journal</journal-title></journal-title-group><issn pub-type="ppub">2356-6140</issn><issn pub-type="epub">1537-744X</issn><publisher><publisher-name>The Scientific World Journal</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22623908</article-id><article-id pub-id-type="pmc">3353485</article-id><article-id pub-id-type="doi">10.1100/2012/520524</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Study of the Activity of 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one against Schistosomiasis Mansoni in Mice</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>da Silva</surname><given-names>Andréa Cristina Apolinário</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neves</surname><given-names>Juliana Kelle de Andrade Lemoine</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Irmão</surname><given-names>João Inácio</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Costa</surname><given-names>Vláudia Maria Assis</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref><xref ref-type="aff" rid="I3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Souza</surname><given-names>Valdênia Maria Oliveira</given-names></name><xref ref-type="aff" rid="I3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Medeiros</surname><given-names>Paloma Lys</given-names></name><xref ref-type="aff" rid="I4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>da Silva</surname><given-names>Eliete Cavalcanti</given-names></name><xref ref-type="aff" rid="I4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Lima</surname><given-names>Maria do Carmo Alves</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pitta</surname><given-names>Ivan da Rocha</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Albuquerque</surname><given-names>Mônica Camelo Pessoa de Azevedo</given-names></name><xref ref-type="aff" rid="I2"><sup>2</sup></xref><xref ref-type="aff" rid="I3"><sup>3</sup></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Galdino</surname><given-names>Suely Lins</given-names></name><xref ref-type="aff" rid="I1"><sup>1</sup></xref></contrib></contrib-group><aff id="I1"><sup>1</sup>Laboratório de Planejamento e Síntese de Fármacos (LPSF), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</aff><aff id="I2"><sup>2</sup>Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</aff><aff id="I3"><sup>3</sup>Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</aff><aff id="I4"><sup>4</sup>Departamento de Histologia e Embriologia, Universidade Federal de Pernambuco, Avenida Profssors Moraes Rego 1265, Cidade Universitária, 50670-901 Recife, PE, Brazil</aff><author-notes><corresp id="cor1">*Mônica Camelo Pessoa de Azevedo Albuquerque: <email>jcmonica@globo.com</email></corresp><fn fn-type="other"><p>Academic Editor: Issa Nebie</p></fn></author-notes><pub-date pub-type="collection"><year>2012</year></pub-date><pub-date pub-type="epub"><day>1</day><month>5</month><year>2012</year></pub-date><volume>2012</volume><elocation-id>520524</elocation-id><history><date date-type="received"><day>31</day><month>10</month><year>2011</year></date><date date-type="accepted"><day>29</day><month>12</month><year>2011</year></date></history><permissions><copyright-statement>Copyright © 2012 Andréa Cristina Apolinário da Silva et al.</copyright-statement><copyright-year>2012</copyright-year><license xlink:href="https://creativecommons.org/licenses/by/3.0/"><license-p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Previous studies conducted with the imidazolidinic derivative 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin-2-one (LPSF-PT05) show outstanding activity against adult <italic>Schistosoma mansoni</italic> worms <italic>in vitro</italic>. In the first phase of this study, <italic>S. mansoni</italic>-infected mice were treated, orally, with 100 mg/Kg of the LPSF-PT05 in three formulations: Tween 80 and saline solution, oil/water (70 : 30) emulsion, and solid dispersion with polyethylene glycol (PEG). In the second phase, three other doses of the LPSF-PT05 in PEG were tested: 3, 10, 30 mg/kg. These treatment regimens significantly reduced the number of recovered worms due to increases in the solubility of the compound in this formulation; the greatest reduction (70.5%) was observed at the dose of 100 mg/kg. There was no changes in the pattern of mature egg compared to immature eggs; however there was a significant increase in the number of dead eggs. Histopathological analysis of liver tissue showed changes in morphological aspects of the hepatic parenchyma with decrease exudative-productive hepatic granuloma stages, although we found no significant differences in IFN-<italic><italic>γ</italic></italic>, IL-4, IL-10, or NO production in response to the specific antigen SEA. The results show the derivative LPSF-PT05 to be a potential candidate in the etiological treatment of schistosomiasis with a possible dampening effect of the granulomatous process.</p></abstract></article-meta></front><body><sec id="sec1"><title>1. Introduction</title><p>Schistosomiasis is the second most significant parasitic disease in the world after malaria in terms of socioeconomic and public health importance. It is estimated that 207 million people are infected in 74 countries throughout Latin America, Africa, and Asia and more than 779 million people are at risk of infection, with mortality estimated at up to 280,000 deaths annually in sub-Saharan Africa alone [<xref rid="B1" ref-type="bibr">1</xref>–<xref rid="B3" ref-type="bibr">3</xref>]. Estimates of the global burden of schistosomiasis range from 1.7 to 4.5 million disability-adjusted life years (DALYs) lost [<xref rid="B4" ref-type="bibr">4</xref>–<xref rid="B6" ref-type="bibr">6</xref>] or even higher [<xref rid="B7" ref-type="bibr">7</xref>].</p><p>Chemotherapy is currently the main strategy in use for schistosomiasis control. Praziquantel (2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexa-hydro-4H-pyrazino{2,1-a}isoquinoline-4-one) is the drug of choice for the treatment of schistosomiasis because of its efficacy against all schistosome species [<xref rid="B8" ref-type="bibr">8</xref>, <xref rid="B9" ref-type="bibr">9</xref>]. The control of Asian schistosomiasis has relied on large-scale chemotherapy using the praziquantel [<xref rid="B10" ref-type="bibr">10</xref>]. However, mass treatment does not prevent reinfection [<xref rid="B11" ref-type="bibr">11</xref>]. Data assembled over the past five years suggest that schistosomiasis is reemerging in parts of China [<xref rid="B12" ref-type="bibr">12</xref>]. Furthermore, despite the fact that there is not yet clear-cut evidence for the existence of praziquantel-resistant schistosome strains, decreased susceptibility to the drug has been reported in several countries [<xref rid="B11" ref-type="bibr">11</xref>]. The reliance on one single antischistosomal drug is alarming and the scientific community has called for research and development of novel and inexpensive drugs against schistosomiasis [<xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B14" ref-type="bibr">14</xref>].</p><p>The imidazolidines are a broad class of bioactive pentagonal heterocyclic compounds with diverse biological activity [<xref rid="B15" ref-type="bibr">15</xref>]. The imidazolidine system has antifungal and antimicrobial properties [<xref rid="B16" ref-type="bibr">16</xref>], hypnotic [<xref rid="B17" ref-type="bibr">17</xref>], and hypoglycemic [<xref rid="B18" ref-type="bibr">18</xref>, <xref rid="B19" ref-type="bibr">19</xref>] effects.</p><p>Niridazole, 1-(5-nitro-thiazol-2-yl)-imidazolidin-2-one, has been used over the past century for its schistosomicidal properties. The drug received considerable attention, probably because it was one of the early treatment options to be administered orally [<xref rid="B20" ref-type="bibr">20</xref>].</p><p>The schistosomicidal properties of imidazolidine derivatives have been demonstrated by <italic>in vitro</italic> studies with adult <italic>S. mansoni</italic> worms [<xref rid="B21" ref-type="bibr">21</xref>–<xref rid="B25" ref-type="bibr">25</xref>]. The 3-benzyl-5-(4-chloro-arylazo)-4thioxo-imidazolidin-2-one, also known as LPSF-PT05 (CAS Registry Number 197504-87-3) [<xref rid="B26" ref-type="bibr">26</xref>], used in this work was synthesized by the Laboratório de Planejamento e Síntese de Fármacos (LPSF) (UFPE) using diazonium ions formed from a phenylamine that acts as an electrophilic reagent and engages with the active hydrogen in position 5 of 3-benzyl-4thioxo-imidazolidine-2-one, yielding the arylazo imidazolidine [<xref rid="B27" ref-type="bibr">27</xref>].</p><p>Recently, Neves and collaborators [<xref rid="B28" ref-type="bibr">28</xref>] demonstrated the schistosomicidal activity <italic>in vitro</italic> of LPSF-PT05 with significant ultrastructural changes induced in worms and less cytotoxic effect on splenocytes than praziquantel. Based on this, the purpose of this study was to investigate the effects of LPSF-PT05, <italic>in vivo</italic>, against adult worms of <italic>S. mansoni.</italic> and also the immunomodulating and histopathological effects of the granulomatous inflammation.</p></sec><sec id="sec2"><title>2. Materials and Methods</title><sec sec-type="subsection" id="sec2.1"><title>2.1. Parasites and Hosts</title><p>The BH (BH—Belo Horizonte, MG, Brazil) strain of <italic>S. mansoni</italic> that has been maintained in the laboratory was used throughout this study. The strain was kept after it had passed through <italic>Biomphalaria glabrata</italic> molluscs provided by the Department of Tropical Medicine (Universidade Federal de Pernambuco) and Swiss mice (Mus musculus).</p></sec><sec sec-type="subsection" id="sec2.2"><title>2.2. Animals</title><p>Swiss Webster mice females were used, average weight 20 ± 2 g and 5 weeks of age, and were bred and maintained at the Laboratório de Imunopatologia Keizo Asami (LIKA) of the Universidade Federal de Pernambuco, Recife, Brazil. Animals were housed in a controlled temperature and light environment and were given water and standard diet a<italic>d libitum</italic>. The experiments were approved by the Federal University of Pernambuco's Animal Experiments Ethics Committee, Process no. 009645/2006-23, in accordance with Law 9605 Article 32 Decree 3179. Art 17.</p><p>Mice were infected by exposure to a cercarian suspension of <italic>S. mansoni</italic> with approximately 100 ± 10 cercariae, using the tail immersion technique [<xref rid="B29" ref-type="bibr">29</xref>].</p></sec><sec sec-type="subsection" id="sec2.3"><title>2.3. Experimental Treatment</title><p>Animals previously selected and properly weighed were submitted to a common diet with free access to water before the administration of formulations containing LPSF-PT05. In the first formulation, 1% Tween 80 was used to solubilize LPSF-PT05 in a saline solution (LPSF-PT05-Tween). The second formulation was prepared in an oil/water (70 : 30) emulsion (LPSF-PT05-Emulsion). The third formulation was a solid dispersion containing 10% LPSF-PT05 in the hydrophilic polymer polyethylene glycol (PEG) solubilized in water (LPSF-PT05-PEG).</p><p>The administration of the three formulations was done orally, after 49 days of the infection, at a dose of 100 mg/Kg for 5 consecutive days. The solid dispersion containing 10% LPSF PEG-PT05 in three other doses (3, 10, and 30 mg/kg) was administered. The controls groups, free of LPSF-PT05, were submitted to the same testing conditions. At 15 days posttreatment, the animals were euthanized by cervical displacement.</p></sec><sec sec-type="subsection" id="sec2.4"><title>2.4. Assessment of Parasitological Criteria</title><p>Worms were recovered from the hepatic portal system and mesenteric vessels using the perfusion technique described by Smithers and Terry [<xref rid="B30" ref-type="bibr">30</xref>]. The percent of reduction in worm number after treatment was calculated by the method of Tendler and collaborators [<xref rid="B31" ref-type="bibr">31</xref>] as follows: % reduction = <italic>C</italic> − <italic>V</italic>/<italic>C</italic> × 100, where <italic>C</italic> is the mean number of parasites recovered from infected untreated animals and <italic>V</italic> is the mean number of parasites recovered from treated animals.</p><p>Percentages at each egg developmental stage (oogram pattern), the proportion of eggs at various stages of maturity for the quantitative oogram test, were estimated following the experimental method described by Pellegrino and collaborators [<xref rid="B32" ref-type="bibr">32</xref>]. One hundred eggs per oogram were randomly chosen, evaluated by microscopic examination, and classified as dead, immature, or mature for all infected untreated and treated groups.</p></sec><sec sec-type="subsection" id="sec2.5"><title>2.5. Culture of Spleen Cells</title><p>Spleen cell suspensions were prepared from albino Swiss mice infected with <italic>S. mansoni</italic> and treated with 3, 10, 30, or 100 mg/kg of LPSF-PT05-PEG. The suspensions were depleted of erythrocytes by hypotonic lysis with distilled water and resuspended in RPMI 1640 complete medium containing 5% FCS, 10 mM L-glutamine, penicillin (100 U/mL), and streptomycin (100 <italic>μ</italic>g/mL) (Sigma Chemical, St. Louis, MO, USA). Spleen cells were cultured in 48-well flat-bottom plates (Corning Costar 3548) at 5 × 10<sup>6</sup> cells per well and incubated at 37°C and 5% CO<sub>2</sub> for 24 and 72 hours, under stimulation with 20 <italic>μ</italic>g/mL SEA (<italic>Schistosoma mansoni</italic> soluble egg antigen). Supernatants from the cultures were harvested for assessment of cytokine and NO levels. For each experiment, the spleen cells of five mice were pooled.</p></sec><sec sec-type="subsection" id="sec2.6"><title>2.6. Measurement of Nitrite Production and Detection of Cytokines</title><p>Nitrite (NO<sub>2</sub><sup>−</sup>) accumulation in 72 h supernatants of cultured cells was used as an indicator of NO production and was determined by the Griess reaction with sodium nitrite as a standard, as previously described (detection limit: 1.56 <italic>μ</italic>M) [<xref rid="B33" ref-type="bibr">33</xref>]. Fifty microliters of supernatant were incubated for 10 min, in the dark, at room temperature, with 50 <italic>μ</italic>L of a freshly mixed solution of N-[1-naphthyl]-ethylenediamine (1 mg/mL), sulfanilamide (10 mg/mL), and 5% phosphoric acid in distilled water. The absorbance was measured at 540 nm. Production of IFN-<italic>γ</italic>, IL-10, and IL-4 was measured in supernatants of spleen cell cultures harvested after 24 or 72 hours, using a two-site sandwich enzyme-linked immunosorbent assay (ELISA). Levels of IL-4, IL-10, and IFN-<italic>γ</italic> in culture supernatants were determined using antibody pairs and recombinant cytokines from PharMingen, following the manufacturer's instructions, followed by treatment with streptavidin-peroxidase (Sigma). The reaction was developed using ABTS [(2,2′-azinobis (3-ethylbenzthiazoline-6-sulfonic acid)] (Sigma Chemical, St. Louis, MO, USA) as a peroxidase substrate and read at 405 nm.</p></sec><sec sec-type="subsection" id="sec2.7"><title>2.7. Histopathological Evaluation</title><p>Tissue samples of livers were removed, fixed immediately in 10% neutral-buffered formalin, embedded in paraffin, and 5 <italic>μ</italic>m sections were stained with Mayer's hematoxylin and eosin [<xref rid="B34" ref-type="bibr">34</xref>]. The analysis was performed using a video microscope system (LEICA DMIL microscope, LEICA DFC 280 video-camera). Only transverse sections of tissue samples showing granulomas with visible eggs in the center were analyzed. The granulomas were classified according to Costa-Silva et al. [<xref rid="B35" ref-type="bibr">35</xref>]; they were discriminated in two granulomatous stages: exudative-proliferative and involutional. Liver egg granulomas of five mice were counted in five successive low power fields (10x) per each group according to different treatment. </p></sec><sec sec-type="subsection" id="sec2.8"><title>2.8. Statistical Analysis</title><p>Results were expressed as mean ± SEM. Data were statistically analyzed by one-way analysis of variance, followed by the Mann-Whitney test for parasitological and immunological studies and Student's <italic>t</italic>-test for histopathological study. Measurements with <italic>P</italic> values ≤ 0.05 were considered significantly different.</p></sec></sec><sec id="sec3"><title>3. Results</title><p>Initially, oral doses of 100 mg/kg of the three formulations of LPSF-PT05 was used to treat mice infected with <italic>Schistosoma mansoni</italic>. The average worm burden was significantly lower than in the control group (<italic>P</italic> < 0.05) when treatment was done with LPSF-PT05-PEG with a mean reduction of worm burden ranging from 19.8% to 70.5%. In groups treated with LPSF-PT05-Tween and LPSF-PT05-emulsion, a reduction rate was of 21% and 40%, respectively (<xref ref-type="table" rid="tab1">Table 1</xref>).</p><p>The egg count test, although the absence of any one stage of immature eggs was not seen by 15 days after the end of treatment, we observed that the number of immature eggs was lower in all formulations, with a significant reduction (at <italic>P</italic> < 0.05 compared to its control) with the formulation LPSF-PT05-PEG at a dose of 100 mg/kg. This was inversely proportional to the number of dead eggs, which increased in all formulations and was also significant (<italic>P</italic> < 0.001) in the treatment with the formulation LPSF-PT05-PEG at doses of 10, 30, and 100 mg/kg (<xref ref-type="table" rid="tab1">Table 1</xref>).</p><p>To investigate the immunomodulating effects of LPSF-PT05-PEG, IFN-<italic>γ</italic>, IL-4, and IL-10 were quantified in supernatants of spleen cell cultures using sandwich ELISA. The NO production was determined by the Griess reaction. </p><p>As shown in <xref ref-type="fig" rid="fig1">Figure 1(a)</xref>, treatment significantly affect IFN-<italic>γ</italic> production in cultures stimulated with the egg antigen in mice treated with 3 mg/Kg and 30 mg/Kg of the drug. IL-4 in SEA-stimulated cultures was higher in cultures from treated animals, but the levels of production of this cytokine were not significant (<xref ref-type="fig" rid="fig1">Figure 1(b)</xref>). </p><p>At this stage of infection, nitric oxide production was not affected by the treatment of infected animals. Control and treated mice showed no significant difference in their production of NO. However, the cultures stimulated with SEA showed higher production of nitric oxide for mice treated with doses of 10, 30, and 100 mg/kg, but the difference was not statistically significant (<xref ref-type="fig" rid="fig1">Figure 1(c)</xref>). Regarding IL-10 production, this cytokine was below detection level in spleen cell cultures for both control and treated mice. </p><p>Histopathological evaluation of effect of LPSF-PT05-PEG on granulomatous inflammation was measured in H&E stained liver of mice infected by <italic>Schistosoma mansoni</italic>. </p><p>The analysis showed that treatment with LPSF-PT05-PEG at doses of 10, 30, or 100 mg/kg per day had a positive effect in reducing the liver damage caused by <italic>S. mansoni</italic> infection, as shown by the reduced number of worms and the downmodulation of granulomatous response (<xref ref-type="fig" rid="fig2">Figure 2</xref>), thereby avoiding the development of host pathology. </p><p>Regarding general pathology, the effects of periovular schistosomal granulomas are dynamically similar to those of wound healing, with production of granulation tissue that becomes less vascularized over time, while the fibrous cicatricial tissue becomes more compact and mature. We observed a decrease of the exudative-productive stages in the livers at all concentrations of LPSF-PT05-PEG with a considerably significant decrease at doses of 10 and 100 mg/kg (<xref ref-type="fig" rid="fig2">Figure 2</xref> and <xref ref-type="table" rid="tab2">Table 2</xref>). </p></sec><sec id="sec4"><title>4. Discussion</title><p>Chemotherapy is the mainstay of schistosomiasis control and is carried out largely through the use of praziquantel. The efficacy of this compound against adult worms of all schistosome species that infect humans has led to its widespread use [<xref rid="B8" ref-type="bibr">8</xref>, <xref rid="B9" ref-type="bibr">9</xref>]. The nearly complete reliance on praziquantel for schistosomiasis control may hasten the selection of drug-resistant parasites. The potential for development of resistance to the conventional schistosomicidal drugs has justified the search for new compounds. Several compounds have shown promise for schistosomiasis therapy, for example, artemether, protease inhibitors, 2-(alkylamino)-1-phenyl-1-ethanethiosulfuric acids, and oxadiazoles with emphasis on the 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide [<xref rid="B36" ref-type="bibr">36</xref>–<xref rid="B39" ref-type="bibr">39</xref>]. </p><p>The schistosomicidal effect of imidazolidine derivatives was first reported in 1954 by Luttermoser and Bond [<xref rid="B40" ref-type="bibr">40</xref>], who described the activity of 5,5-diphenylhydantoin and 5-(4-chlorophenyl)-5-methylhydantoin against <italic>Schistosoma mansoni</italic> infections in mice. Other studies confirmed modest activity at toxic doses of 5,5-diphenylhydantoin, and 5-(2,4,5-trichlorophenyl) hydantoin showed a potent schistosomicidal effect [<xref rid="B41" ref-type="bibr">41</xref>]. </p><p>More recently, evaluation of the schistosomicidal properties of the derivative 3-benzyl-5-(4-chloro-arylazo)-4thioxo-imidazolidin-2-one, or LPSF-PT05, showed higher activity <italic>in vitro</italic> against adult male worms, with 100% mortality after 24 hours of contact at all the concentrations tested. Maximal efficacy against adult female worms was observed after 72 hours. The relationship between the concentration and the effect obtained in a 24-hour period shows a dose-dependent relationship. Electron microscopic observation of the derivative LPSF/PT05 revealed alterations in the integument surface of the worms with the formation of bubbles and peeling, indicating damage to cells; the magnitude of effect was directly related to the duration of exposure [<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B28" ref-type="bibr">28</xref>]. </p><p>This <italic>in vitro</italic> study of LPSF-PT05 confirmed the promising <italic>in vivo</italic> results. However, imidazolidinic compounds present a limitation in their use due to their poor solubility in water. One strategy used to overcome this inconvenience was to create a complex of LPSF-PT05 with the hydrophilic polymer PEG, which was then solubilized in water. This formulation produced a reduction in worm burden of 70.5% compared to a 50% and 30% reduction in worm burden in relation to formulations LPSF-PT05-Tween and LPSF-PT05-emulsion, respectively. The reduced burden of residual worm was also seen in the pattern of egg count, when assessed 15 days after the end of treatment. This showed an increase in the number of dead eggs and decrease in the number of immature eggs which leads us to believe that LPSF-PT05-PEG could have interfered with egg laying by female worms; yet the time of observation adopted in this experiment did not allow us to confirm this suspicion. </p><p>The effect achieved with the formulation of LPSF-PT05-PEG nearly achieved the criterion established by the World Health Organization to identify potential leaders in the development of schistosomicidal compounds, which is defined as a highly active compound that produces a reduction greater than 80% in worm burden after intraperitoneal administration of 100 mg/kg repeated five times in formulations with 10% DMSO [<xref rid="B42" ref-type="bibr">42</xref>]. Taking into account the barriers in the process of absorption from oral administration, the LPSF-PT05-PEG, undoubtedly, has potential as a schistosomicide. We believe that adjustments in dosing schedule or even complexion with other adjuvants that promote higher solubility can ensure the schistosomicidal character of this imidazolidic compound. </p><p>Cellular immune response to <italic>S. mansoni</italic> has been intensively studied because of the granulomatous response and fibrosis that occur during pathogenesis. Granulomas play a protective role by sequestering hepatotoxins secreted by eggs [<xref rid="B43" ref-type="bibr">43</xref>]; however, they also cause a cell-mediated inflammatory response that results in the pathology of periportal fibrosis [<xref rid="B44" ref-type="bibr">44</xref>, <xref rid="B45" ref-type="bibr">45</xref>]. The immune response in <italic>S. mansoni</italic> infection has been shown to be a T-cell-dependent mechanism, where the host initially has a Th1 response against the early stages of the parasite [<xref rid="B46" ref-type="bibr">46</xref>]. After deposition of the eggs, the Th2 response increases with IL-4 and IL-5 production [<xref rid="B47" ref-type="bibr">47</xref>]. The balance of Th1 and Th2 cytokines is a determining factor in the regulation of pathology and the formation of granulomas and hepatic fibrosis. </p><p>It has been reported that PZQ chemotherapy could modulate humoral and cellular immune responses in individuals infected by <italic>S. mansoni</italic>, probably due to destruction of parasites and releasing of inflammatory stimulating factors such as SEA [<xref rid="B48" ref-type="bibr">48</xref>]. In our previous results we observed that praziquantel downregulated the IL-4, modulates IFN-<italic>γ</italic> production, and increased IL-10 production in spleen cells with 120 days of infection (data not shown). </p><p>We expected that LPSF-PT05 could also modulate cytokine production after infect mice treatment. The present study describes the effects of treatment with LPSF-PT05-PEG on the production of cytokines in response to SEA and we found no significant differences in IL-4, IL-10, and nitric oxide production in response to the specific antigen SEA. However, IFN-<italic>γ</italic> production in cultures stimulated with the egg antigen in mice treated with 3 mg/Kg and 30 mg/Kg of the drug was significantly higher in comparison with control group. In spite of these results we did not believe that this IFN-<italic>γ</italic> higher production could affect the evolution of inflammatory response. </p><p>In the histopathological study of <italic>Schistosoma mansoni</italic> infection, the eggs swept into the liver elicit T-cell-dependent responses, which lead to macrophage activation and granuloma formation around the eggs [<xref rid="B49" ref-type="bibr">49</xref>]. The severity of the disease is determined by the number of eggs deposited in the tissues and the extent of granuloma formation around them. An important feature of murine schistosomiasis caused by <italic>S. mansoni</italic> is granuloma immunomodulation, that is, the spontaneous downregulation of the response to newly deposited eggs with increased duration of infection [<xref rid="B50" ref-type="bibr">50</xref>, <xref rid="B51" ref-type="bibr">51</xref>]. Immunomodulation has been linked to a decrease in T-cell responses to egg antigens and is beneficial to the host in that it limits tissue injury and morbidity [<xref rid="B52" ref-type="bibr">52</xref>]. Although we did not detect changes in the profile of IFN-<italic>γ</italic> and IL-4 against the egg antigen, the treated animals sacrificed at 60 days following infection showed changes on morphological aspects of the hepatic parenchyma of mice infected and treated with LPSF-PT05-PEG, at a dose of 100 mg/kg. At this dosage, the involutional granuloma stages limit tissue injury. The decrease in exudative-productive hepatic granuloma stages was observed at all doses, but more so at 100 mg/kg. </p><p>These results together suggest LPSF-PT05-PEG at a dose of 100 mg/Kg as a potential candidate for use in schistosomiasis treatment. At this dose, we found a toxic effect to the worms and an attenuation of granuloma possibly via immunomodulatory properties. Our next concern is to prepare new formulations that can ensure greater solubility of the compound at even lower doses, which would be ideal, since it would minimize the occurrence of side effects and also evaluate the activity of PSF-PEG-PT05 on granulomatous reaction in the chronic phase of schistosomiasis.</p></sec></body><back><ack><title>Acknowledgments</title><p>This work was supported by grants from the Financiadora de Estudos e Projetos (FINEP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).</p></ack><ref-list><ref id="B1"><label>1</label><element-citation publication-type="journal"><person-group 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(a) Infected control exhibiting exudative-productive stage granulomas (arrows) with a mature, viable egg in the center of the fibrocellular granulomas. (b) LPSF-PT05-PEG (3 mg/kg per day); micrographs show well-circumscribed small fibrocellular granulomas and marked ovum degeneration (asterisks). (c) LPSF-PT05-PEG (10 mg/kg per day); productive (arrow) and involutional (asterisk) granulomas stage. (d) LPSF-PT05-PEG (30 mg/kg per day). (e) LPSF-PT05-PEG (100 mg/kg per day) involutional stage granulomas (asterisks). H&E, micrographs are at 100x magnification.</p></caption><graphic xlink:href="TSWJ2012-520524.002"></graphic></fig><table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Effect of different formulations of LPSF-PT05 on worm burdens and oogram patterns in experimentally infected mice harbouring adult <italic>S. mansoni</italic> (BH strain).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="2" colspan="1">Group</th><th align="center" rowspan="2" colspan="1">Dosing protocols (mg/Kg × day) </th><th align="center" colspan="2" rowspan="1">Worm reductions</th><th align="center" colspan="3" rowspan="1">% egg developmental stages</th></tr><tr><th align="center" rowspan="1" colspan="1">Total worms</th><th align="center" rowspan="1" colspan="1">Total worms reduction%</th><th align="center" rowspan="1" colspan="1">Total Immature</th><th align="center" rowspan="1" colspan="1">Mature</th><th align="center" rowspan="1" colspan="1">Dead</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Control (7)</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">24.60 ± 16.29</td><td align="center" rowspan="1" colspan="1">—</td><td align="center" rowspan="1" colspan="1">58.88 ± 14.19</td><td align="center" rowspan="1" colspan="1">27.80 ± 10.18</td><td align="center" rowspan="1" colspan="1">13.33 ± 4.40</td></tr><tr><td align="left" rowspan="1" colspan="1">LPSF-PT05-Tween (7)</td><td align="center" rowspan="1" colspan="1">100 × 5</td><td align="center" rowspan="1" colspan="1">19.43 ± 7.87</td><td align="center" rowspan="1" colspan="1">21.0</td><td align="center" rowspan="1" colspan="1">47.50 ± 7.37</td><td align="center" rowspan="1" colspan="1">27.93 ± 5.49</td><td align="center" rowspan="1" colspan="1">24.58 ± 7.97</td></tr><tr><td align="left" colspan="7" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1">Control (5)</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">30.43 ± 12.20</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">50.72 ± 6.14</td><td align="center" rowspan="1" colspan="1">29.52 ± 4.16</td><td align="center" rowspan="1" colspan="1">19.71 ± 5.51</td></tr><tr><td align="left" rowspan="1" colspan="1">LPSF-PT05-Emulsion (5)</td><td align="center" rowspan="1" colspan="1">100 × 5</td><td align="center" rowspan="1" colspan="1">18.25 ± 2.87</td><td align="center" rowspan="1" colspan="1">40.0</td><td align="center" rowspan="1" colspan="1">36.10 ± 12.68</td><td align="center" rowspan="1" colspan="1">31.67 ± 4.35</td><td align="center" rowspan="1" colspan="1">32.23 ± 14.57</td></tr><tr><td align="left" colspan="7" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1">Control (5)</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">26.50 ± 12.34</td><td align="center" rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">57.51 ± 1.17</td><td align="center" rowspan="1" colspan="1">34.16 ± 3.53</td><td align="center" rowspan="1" colspan="1">8.330 ± 2.36</td></tr><tr><td align="left" rowspan="4" colspan="1">LPSF-PT05-PEG (5)</td><td align="center" rowspan="1" colspan="1">100 × 5</td><td align="center" rowspan="1" colspan="1">7.80 ± 3.27</td><td align="center" rowspan="1" colspan="1">70.5<sup>#</sup></td><td align="center" rowspan="1" colspan="1">35.34 ± 7.05*</td><td align="center" rowspan="1" colspan="1">41.41 ± 3.48</td><td align="center" rowspan="1" colspan="1">23.25 ± 5.01<sup>#</sup></td></tr><tr><td align="center" rowspan="1" colspan="1">30 × 5</td><td align="center" rowspan="1" colspan="1">14.00 ± 2.08</td><td align="center" rowspan="1" colspan="1">47.1<sup>#</sup></td><td align="center" rowspan="1" colspan="1">49.17 ± 6.06</td><td align="center" rowspan="1" colspan="1">24.38 ± 4.87</td><td align="center" rowspan="1" colspan="1">26.46 ± 4.66<sup>#</sup></td></tr><tr><td align="center" rowspan="1" colspan="1">10 × 5</td><td align="center" rowspan="1" colspan="1">13.80 ± 4.43</td><td align="center" rowspan="1" colspan="1">47.9<sup>#</sup></td><td align="center" rowspan="1" colspan="1">40.59 ± 15.46</td><td align="center" rowspan="1" colspan="1">33.33 ± 12.02</td><td align="center" rowspan="1" colspan="1">26.10 ± 3.48<sup>#</sup></td></tr><tr><td align="center" rowspan="1" colspan="1">3 × 5</td><td align="center" rowspan="1" colspan="1">21.25 ± 3.40</td><td align="center" rowspan="1" colspan="1">19.8</td><td align="center" rowspan="1" colspan="1">53.76 ± 5.99</td><td align="center" rowspan="1" colspan="1">28.33 ± 3.60</td><td align="center" rowspan="1" colspan="1">16.66 ± 2.35</td></tr></tbody></table><table-wrap-foot><fn><p>The values are expressed in means ± SD. *<italic>P</italic> ≤ 0.05, <sup>#</sup><italic>P</italic> ≤ 0.01 in comparison to control.</p></fn><fn><p>Numbers in brackets represent the numbers of mice.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>Hepatic granulomas of mice infected by <italic>S.mansoni</italic> and treated with LPSF/PT05-PEG.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Granuloma stages</th><th align="center" rowspan="1" colspan="1">Control</th><th align="center" rowspan="1" colspan="1">3 mg/Kg</th><th align="center" rowspan="1" colspan="1">10 mg/Kg</th><th align="center" rowspan="1" colspan="1">30 mg/Kg</th><th align="center" rowspan="1" colspan="1">100 mg/Kg</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Exudative-productive</td><td align="center" rowspan="1" colspan="1">22.33 ± 4.16</td><td align="center" rowspan="1" colspan="1">15.66 ± 8.50</td><td align="center" rowspan="1" colspan="1">8.00 ± 1.70*</td><td align="center" rowspan="1" colspan="1">20.66 ± 5.80</td><td align="center" rowspan="1" colspan="1">11.00 ± 1.00*</td></tr><tr><td align="left" rowspan="1" colspan="1">Involutional</td><td align="center" rowspan="1" colspan="1">32.33 ± 12.50</td><td align="center" rowspan="1" colspan="1">43.33 ± 16.20</td><td align="center" rowspan="1" colspan="1">20.66 ± 7.76</td><td align="center" rowspan="1" colspan="1">44.00 ± 11.35</td><td align="center" rowspan="1" colspan="1">29.66 ± 9.29</td></tr></tbody></table><table-wrap-foot><fn><p>Animals per groups (<italic>n</italic> = 5). The values are expressed in means ± SD. Comparisons were made by Student's <italic>t</italic>-test (*<italic>P</italic> ≤ 0.05).</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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