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Developments on Treatment of Chagas Disease – from Discovery to Current Times European Review for Medical and Pharmacological Sciences 2019; 23: 2576-2586 Developments on treatment of Chagas disease – from discovery to current times T.O. CUSTODIO LEITE Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Programa de Pós-Graduação em Química, Rio de Janeiro, Brazil. Abstract. – OBJECTIVE: This work aims to The vector combat is the main prophylactic collect publications of available drugs for repo- strategy to control the disease, such as chemical sition and new substance development against treatment (pesticides) and the improvement of the Chagas disease, since they represent the be- housing conditions5, since the bug has the habit ginning of a path for new discoveries of viable al- ternatives to improve the prognosis of millions of living inside the houses, a characteristic of its of patients around the world. adaptation of life in the domestic environment. A PATIENTS AND METHODS: An extended re- better screening of blood bags used in blood do- search on English and Portuguese-language lit- nation is also involved6. erature in the Scientific Electronic Library Online It is also relevant to emphasize that, although – Scielo, SciFinder and PubMed – database was Chagas disease predominates in countries with made. The bibliography was screened using the keywords “Chagas Disease” and “Treatment”. low socioeconomic development, increased tou- RESULTS: Despite the low resources available rism and migrations have raised the importance for research and development of drugs against of greater investments directed to research and Chagas disease, the knowledge produced in this development of more effective treatments besides area is large but not directly proportional to the vaccines, to avoid its dissemination around the therapeutic advances. Two categories were ana- world7. lyzed, such as drug repositioning, and new sub- stances were researched. CONCLUSIONS: Even if great findings were Trypanosoma Cruzi: Transmission reported, more efforts are necessary to find new and Life Cycle therapies against Trypanosoma cruzi (T. cruzi). The parasite which causes Chagas disease can infect more than 100 mammal species and can be Key Words: transmitted by over 150 species of hematopha- Alternatives, Antichagasic, Chagas, Development, gous arthropod from the Triatominae family, Drug reposition. nifurtimox and benznidazole especially Triatoma, Panstrogylus, and Rhod- nius8,9. Their nocturnal habits make this period more propitious for disease transmission, since Introduction the infected insect, while sucking human’s blood, simultaneously defecates and eliminates the pro- The Chagas disease, also known as American tozoa. Because of the abrasion on the skin, caused Trypanosomiasis, was discovered by the Brazi- by individual itching, the protozoa is inoculated lian epidemiological physician Carlos Justiniano to human tissue, and quickly reaches the blood- Ribeiro Chagas in 1909 in Lassance, a municipa- stream10,11. The penetration can also be successful lity located in the state of Minas Gerais, Brazil1. through the intact mucosae, such as conjunctiva12. This pathology is caused by the flagellated pro- There are other forms of Chagas transmission tozoan Trypanosoma cruzi (T. cruzi) transmitted with major epidemiological relevance also report- by triatomine bugs, has infected 8 million people ed on literature, such as blood transfusion, breast- and is the cause of thousands of premature deaths feeding, congenital infection, organ donation or each year across the Americas, especially in Latin contaminated food – such as sugar cane juice and America, where it is endemic2,3. It is important to Brazilian fruit açaí3,1315. The exacerbation of oral mention that less than 1% of infected people have contamination with food ingestion was also relat- access to diagnosis and/or treatment4. ed to treatment with acetylsalicylic acid, because 2576 Corresponding Author: Talita Odriane, Custodio Leite, MD; e-mail: [email protected] Developments on Chagas disease pharmacotherapy of its gastric mucosal damage which facilitates T. tomine insect is infected by the blood ingestion cruzi infection16. of host’s blood containing a circulating parasite The life cycle of this parasite is very complex on trypomastigote form, which after achieving and involves two different types of hosts: (i) in- the vector’s medium intestine, differentiates into vertebrate host, represented by the triatomine bug epimastigote form. In this stage, after reaching and (ii) vertebrate host, represented especially by the posterior intestine, they are differentiated the human. Different developmental stages are re- into the infectious form, the metacyclic trypo- lated to this parasite as it migrates from one host mastigote17. to another, and four steps of development are ne- eded to complete the parasite stages: (i) replica- Phases of the Disease and Diagnosis tive epimastigote; (ii) replicative amastigote; (iii) From the analysis of clinical and laboratory as- non-replicative trypomastigote, and (iv) blood pects of patients with this disease, three stages of trypomastigotes17. infection were determined18-20: (i) acute, occurring In general, as shown in Figure 1, a triatomi- in the first four months of the protozoan in the hu- ne vector insect infected with the parasite in its man body, with presence of an inflammatory le- metacyclic trypomastigote form bites the host to sion on the skin (inoculation chagoma or Romaña’s feed on blood and eliminates the trypomastigote sign, if parasitic inoculation occurred in the ocular forms of the parasite through its faeces, near the region), followed by degenerative and inflammato- site of the bite. Thus, trypomastigotes enter the ry tissue alterations, fever, malaise, subcutaneous host organism through the wound of the bite or oedema, lymph adenomegaly, splenomegaly and mucous membranes. Inside the host, the trypo- hepatomegaly, which may last for decades; (ii) an mastigote forms invade nucleated cells close to indeterminate phase, usually asymptomatic for a the inoculation site and differentiate into intra- period of 10 to 20 years; and (iii) chronic, with the cellular form the amastigote, which multiplies gradual disappearance of clinical manifestations, in the cellular cytoplasm. Such amastigote for- low parasitaemia (not detectable in direct parasito- ms differentiate again into trypomastigotes and logical clinical tests) and elevated immunoglobulin thus are released into the bloodstream, infecting G (IgG) antibodies presented under three clinical cells from various tissues, and again transfor- aspects, such as undetermined, cardiac (more se- med into intracellular amastigotes into new sites vere, with progressive myocardial damage) and of infection. Clinical manifestations may arise digestive (megaoesophagus and megacolon, with from this continuous infective cycle. The tria- destruction of the nervous cells of the enteric sys- Figure 1. Life cycle of T. cruzi. 2577 T.O. Custodio Leite Table I. Clinical and laboratory aspects of Chagas disease on acute and chronic phases. Disease Phases Clinical Aspects Laboratory Aspects Acute Depends on inoculation region. Skin chancre Parasite detection on blood and lymph nodes. or orbital unilateral oedema (Romaña’s sign), with local lymph adenomegaly and fever for weeks. Positive serological test for antibodies against Multiple lymph adenopathy, hepatosplenomegaly Trypanosoma cruzi. and myocarditis (chest pain, cardiac failure), meningoencephalopathy (not usual – seizure, paralysis). Asymptomatic patients. Examination in the faeces of uninfected triatomine fed with the patient’s blood. Chronic Long and latent period, with cardiac lesions Positive serological test for antibodies against (arrhythmia, cardiomyopathy, thromboembolism). Trypanosoma cruzi. Mostly asymptomatic. tem), as the parasite reaches and directly harms quired, such as xenodiagnoses, blood culture and vital organs, such as heart, oesophagus and colon, the use of molecular and serological strategies, respectively (Table I). such as enzyme-linked immunosorbent assay Infected patients usually exhibit normal life (ELISA), indirect immunofluorescence, or indi- for decades as the infection remains latent. The rect hemagglutination22,23. specific treatment can interfere with the disease evolution, preventing or obstructing its continu- Guidelines for Chagas Disease Treatment ity21. Thus, one of the major questionings in this Chagas disease is a well-known illness with field is related to the therapeutic involving distinct many published articles and permanent investiga- phases of the disease. tion of the life cycle and physiology of the para- The diagnosis of the disease is carried out di- site. After its discovery, some compounds, such rectly or indirectly. The direct form occurs in the as arsenic derivative, fuchsine, emetic tartar, and acute phase, which consists in the search of the mercury chloride (HgCl2) were used, but no good trypomastigote form of the parasite in the blood. clinical result was achieved24,25. This investigation is held through a blood drop Until now, only nifurtimox and benznidazole between glass blade and coverslip or taking thick are available to treat patients. The excessive cost drop colored with Giemsa or Leishman pigment. for research and development of new drugs asso- Therefore, an approach is very difficult due to an ciated with its major presence in emergent coun- irregular or low parasitemia. This is the reason tries makes the pharmaceutical industries still
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