试验
已开展了几种临床前体外研究和动物研究，对不同化合物进行评估，在抗寄生虫药物效果方面，研究已取得较为满意的结果。被检测的化合物包括呋喃二脒、克鲁斯氏锥体虫半胱氨酸蛋白酶抑制剂 K777、2,3-二苯基-1,4-萘醌、法呢基焦磷酸合酶、葡萄糖-6-磷酸脱氢酶、甘油醛 3-磷酸脱氢酶、硫利达嗪（一种锥虫胱甘肽还原酶抑制剂）、VFV（一种 CYP51 结构衍生药）和 N'-[（5-硝基呋喃-2-yl）亚甲基] 替代性酰肼。[262]Pardo Andreu GL, Inada NM, Pellon RF, et al. In vitro effect of a new cinnamic acid derivative against the epimastigote form of Trypanosoma cruzi. Arzneimittelforschung. 2009;59:207-211.http://www.ncbi.nlm.nih.gov/pubmed/19517898?tool=bestpractice.com[263]Ramos EI, Garza KM, Krauth-Siegel RL, et al. 2,3-diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi. J Parasitol. 2009;95:461-466.http://www.ncbi.nlm.nih.gov/pubmed/18788881?tool=bestpractice.com[264]Rivera G, Bocanegra-Garcia V, Ordaz-Pichardo C, et al. New therapeutic targets for drug design against Trypanosoma cruzi, advances and perspectives. Curr Med Chem. 2009;16:3286-3293.http://www.ncbi.nlm.nih.gov/pubmed/19548870?tool=bestpractice.com[265]Vieites M, Smircich P, Guggeri L, et al. Synthesis and characterization of a pyridine-2-thiol N-oxide gold(I) complex with potent antiproliferative effect against Trypanosoma cruzi and Leishmania sp. insight into its mechanism of action. J Inorg Biochem. 2009;103:1300-1306.http://www.ncbi.nlm.nih.gov/pubmed/19361864?tool=bestpractice.com[266]McKerrow JH, Doyle PS, Engel JC, et al. Two approaches to discovering and developing new drugs for Chagas disease. Mem Inst Oswaldo Cruz. 2009;104(suppl 1):263-269.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900034&lng=en&nrm=iso&tlng=enhttp://www.ncbi.nlm.nih.gov/pubmed/19753483?tool=bestpractice.com[267]Soeiro Mde N, Dantas AP, Daliry A, et al. Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies. Mem Inst Oswaldo Cruz. 2009;104(suppl 1):301-310.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900040&lng=en&nrm=iso&tlng=enhttp://www.ncbi.nlm.nih.gov/pubmed/19753489?tool=bestpractice.com[268]Palace-Berl F, Pasqualoto KF, Jorge SD, et al. Designing and exploring active N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against three Trypanosoma cruzi strains more prevalent in Chagas disease patients. Eur J Med Chem. 2015;96:330-339.http://www.ncbi.nlm.nih.gov/pubmed/25899337?tool=bestpractice.com[269]Lepesheva GI, Hargrove TY, Rachakonda G, et al. VFV as a new effective CYP51 structure-derived drug candidate for Chagas disease and visceral leishmaniasis. J Infect Dis. 2015;212:1439-1448.http://www.ncbi.nlm.nih.gov/pubmed/25883390?tool=bestpractice.com[270]Lo Presti MS, Bazán PC, Strauss M, et al. Trypanothione reductase inhibitors: overview of the action of thioridazine in different stages of Chagas disease. Acta Trop. 2015;145:79-87.http://www.ncbi.nlm.nih.gov/pubmed/25733492?tool=bestpractice.com[271]Britta EA, Scariot DB, Falzirolli H, et al. 4-Nitrobenzaldehyde thiosemicarbazone: a new compound derived from S-(-)-limonene that induces mitochondrial alterations in epimastigotes and trypomastigotes of Trypanosoma cruzi. Parasitology. 2015;142:978-988.http://www.ncbi.nlm.nih.gov/pubmed/25711881?tool=bestpractice.com然而，由于额外的临床试验需要花费一定的时间来获取结果，因此比苄硝唑或硝呋莫司更为有效的药物还不能在不久的将来获得。三唑类抗真菌药物，如泊沙康唑，已作为治疗的候选药物，但在治疗克氏锥虫感染方面，CHAGASAZOL 的研究未显示泊沙康唑作为单一疗法能取得满意的效果。[272]Molina I, Gómez i Prat J, Salvador F, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas' disease. N Engl J Med. 2014;370:1899-1908.http://www.nejm.org/doi/full/10.1056/NEJMoa1313122http://www.ncbi.nlm.nih.gov/pubmed/24827034?tool=bestpractice.com另一关于雷夫康唑治疗慢性非确定性恰加斯病的研究显示，雷夫康唑的治疗效果不如苄硝唑。[247]Urbina JA. Recent clinical trials for the etiological treatment of chronic Chagas disease: advances, challenges and perspectives. J Eukaryot Microbiol. 2015;62:149-156.http://onlinelibrary.wiley.com/doi/10.1111/jeu.12184/fullhttp://www.ncbi.nlm.nih.gov/pubmed/25284065?tool=bestpractice.com在未来的试验中，应优先考虑对新药和最佳治疗方案（包括联合疗法）的研究。[233]Dias JC, Coura JR, Yasuda MA. The present situation, challenges, and perspectives regarding the production and utilization of effective drugs against human Chagas disease. Rev Soc Bras Med Trop. 2014;47:123-125.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0037-86822014000100123&lng=en&nrm=iso&tlng=enhttp://www.ncbi.nlm.nih.gov/pubmed/24603750?tool=bestpractice.com[273]Keenan M, Chaplin JH. A new era for Chagas disease drug discovery? Prog Med Chem. 2015;54:185-230.http://www.ncbi.nlm.nih.gov/pubmed/25727705?tool=bestpractice.com[274]Morilla MJ, Romero EL. Nanomedicines against Chagas disease: an update on therapeutics, prophylaxis and diagnosis. Nanomedicine (Lond). 2015;10:465-481.http://www.ncbi.nlm.nih.gov/pubmed/25707979?tool=bestpractice.com被忽略疾病药物研发组织 (Drugs for Neglected Diseases Initiative, DNDi) 是一个为恰加斯病和其他全球传染病开发新的治疗方法的非营利组织。Drugs for Neglected Diseases Initiative (DNDi): Chagas在确定该病新的治疗方案的同时，也需要确定对治疗和治愈患者的反应进行有效监测的生物标志物。[247]Urbina JA. Recent clinical trials for the etiological treatment of chronic Chagas disease: advances, challenges and perspectives. J Eukaryot Microbiol. 2015;62:149-156.http://onlinelibrary.wiley.com/doi/10.1111/jeu.12184/fullhttp://www.ncbi.nlm.nih.gov/pubmed/25284065?tool=bestpractice.com
干细胞治疗
用骨髓干细胞进行的细胞移植已被认为是治疗慢性恰加斯心肌病的一种替代性疗法。[275]Campos de Carvalho AC, Goldenberg RC, Jelicks LA, et al. Cell therapy in Chagas disease. Interdiscip Perspect Infect Dis. 2009;2009:484358.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696023/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/19547703?tool=bestpractice.com[276]Soares MB, dos Santos RR. Current status and perspectives of cell therapy in Chagas disease. Mem Inst Oswaldo Cruz. 2009;104(suppl 1):325-332.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900043&lng=en&nrm=iso&tlng=enhttp://www.ncbi.nlm.nih.gov/pubmed/19753492?tool=bestpractice.com[277]Zhang Y, Mi JY, Rui YJ, et al. Stem cell therapy for the treatment of parasitic infections: is it far away? Parasitol Res. 2014;113:607-612.http://www.ncbi.nlm.nih.gov/pubmed/24276645?tool=bestpractice.com[278]de Carvalho KA, Abdelwahid E, Ferreira RJ, et al. Preclinical stem cell therapy in Chagas Disease: perspectives for future research. World J Transplant. 2013;3:119-126.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879521/http://www.ncbi.nlm.nih.gov/pubmed/24392316?tool=bestpractice.com此种疗法的目的不是杀死锥虫，而是改善慢性心脏病的病情。[279]Silva DN, de Freitas Souza BS, Azevedo CM, et al. Intramyocardial transplantation of cardiac mesenchymal stem cells reduces myocarditis in a model of chronic Chagas disease cardiomyopathy. Stem Cell Res Ther. 2014;5:81.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229984/http://www.ncbi.nlm.nih.gov/pubmed/24984860?tool=bestpractice.com事实上，对于有慢性恰加斯病感染的小鼠，来自正常捐赠者的骨髓单核细胞可减少心脏炎症和纤维变性，并可预防右心室扩大。[280]Soares MB, Lima RS, Rocha LL, et al. Transplanted bone marrow cells repair heart tissue and reduce myocarditis in chronic Chagasic mice. Am J Pathol. 2004;164:441-447.http://www.ncbi.nlm.nih.gov/pubmed/14742250?tool=bestpractice.com[281]Goldenberg RC, Jelicks LA, Fortes FS, et al. Bone marrow cell therapy ameliorates and reverses Chagasic cardiomyopathy in a mouse model. J Infect Dis. 2008;197:544-547.http://www.ncbi.nlm.nih.gov/pubmed/18237267?tool=bestpractice.com关于自体骨髓细胞移植后 6 个月病情改善的证据还较为有限，[282]Vilas-Boas F, Feitosa GS, Soares MB, et al. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease [in Portuguese]. Arq Bras Cardiol. 2006;87:159-166.http://www.ncbi.nlm.nih.gov/pubmed/16951834?tool=bestpractice.com尽管已有其他研究显示此治疗并无上述治疗方法的好处。[283]Ribeiro Dos Santos R, Rassi S, Feitosa G, et al; Chagas Arm of the MiHeart Study Investigators. Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicenter randomized trial. Circulation. 2012;125:2454-2461.http://circ.ahajournals.org/content/125/20/2454.fullhttp://www.ncbi.nlm.nih.gov/pubmed/22523306?tool=bestpractice.com
疫苗接种
数十年来，为了研究恰加斯病疫苗已进行了许多尝试，但从总体上看，研究结果并不理想。在不久的将来，对有效疫苗的研发看似也不太可能。[284]Camargo EP. Perspectives of vaccination in Chagas disease revisited. Mem Inst Oswaldo Cruz. 2009;104(suppl 1):275-280.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762009000900036&lng=en&nrm=iso&tlng=enhttp://www.ncbi.nlm.nih.gov/pubmed/19753485?tool=bestpractice.com[285]Cazorla SI, Frank FM, Malchiodi EL. Vaccination approaches against Trypanosoma cruzi infection. Expert Rev Vaccines. 2009;8:921-935.http://www.ncbi.nlm.nih.gov/pubmed/19538117?tool=bestpractice.com然而，目前存在几种克氏锥虫的候选蛋白，近来已被考虑应用于疫苗的研发（例如：锥虫蛋白酶、反式唾液酸酶、无鞭毛体表面蛋白）。[285]Cazorla SI, Frank FM, Malchiodi EL. Vaccination approaches against Trypanosoma cruzi infection. Expert Rev Vaccines. 2009;8:921-935.http://www.ncbi.nlm.nih.gov/pubmed/19538117?tool=bestpractice.com[286]Duschak VG, Couto AS. Cruzipain, the major cysteine protease of Trypanosoma cruzi: a sulfated glycoprotein antigen as relevant candidate for vaccine development and drug target. A review. Curr Med Chem. 2009;16:3174-3202.http://www.ncbi.nlm.nih.gov/pubmed/19689291?tool=bestpractice.com[287]Schnapp AR, Eickhoff CS, Sizemore D, et al. Cruzipain induces both mucosal and systemic protection against Trypanosoma cruzi in mice. Infect Immun. 2002;70:5065-5074.http://iai.asm.org/cgi/content/full/70/9/5065?view=long&pmid=12183554http://www.ncbi.nlm.nih.gov/pubmed/12183554?tool=bestpractice.com[288]Bontempi IA, Vicco MH, Cabrera G, et al. Efficacy of a trans-sialidase-ISCOMATRIX subunit vaccine candidate to protect against experimental Chagas disease. Vaccine. 2015;33:1274-1283.http://www.ncbi.nlm.nih.gov/pubmed/25625671?tool=bestpractice.com[289]Serna C, Lara JA, Rodrigues SP, et al. A synthetic peptide from Trypanosoma cruzi mucin-like associated surface protein as candidate for a vaccine against Chagas disease. Vaccine. 2014;32:3525-3532.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058865/http://www.ncbi.nlm.nih.gov/pubmed/24793944?tool=bestpractice.com研究已经确定了超过 30 种可作为未来免疫靶向的基因片段。[290]Tekiel V, Alba-Soto CD, Gonzalez Cappa SM, et al. Identification of novel vaccine candidates for Chagas' disease by immunization with sequential fractions of a trypomastigote cDNA expression library. Vaccine. 2009;27:1323-1332.http://www.ncbi.nlm.nih.gov/pubmed/19162108?tool=bestpractice.com[291]Gupta S, Wan X, Zago MP, et al. Antigenicity and diagnostic potential of vaccine candidates in human Chagas disease. PLoS Negl Trop Dis. 2013;7:e2018.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547861/http://www.ncbi.nlm.nih.gov/pubmed/23350012?tool=bestpractice.com[292]Basso B. Modulation of immune response in experimental Chagas disease. World J Exp Med. 2013;3:1-10.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905588/http://www.ncbi.nlm.nih.gov/pubmed/24520540?tool=bestpractice.com[293]Balouz V, Cámara Mde L, Cánepa GE, et al. Mapping antigenic motifs in the trypomastigote small surface antigen from Trypanosoma cruzi. Clin Vaccine Immunol. 2015;22:304-312.http://www.ncbi.nlm.nih.gov/pubmed/25589551?tool=bestpractice.com
