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One more attempt

Treatment with existing drugs could be the new weapon against the Trypanosoma cruzi

Revista Memórias do Instituto Oswaldo Cruz journal (August 1909)On the 100th anniversary of the discovery of Chagas Disease, it seems, at first glance, that this disease is no longer a problem inBrazil. In 2006, the Ministry of Health was granted a certification from the Pan-American Health Organization/PAHO in recognition of the fact that the disease was no longer being transmitted by the “barbeiro” (Triatoma infestans) insect. As the consensus is that the best way to eradicate the disease is to eliminate the transmitter, it stands to reason that the chosen measures are correct. However,Brazilhas approximately 3 million people infected with the disease and the Trypanosoma cruzi parasite is far from being eradicated. Research studies to understand how this parasite acts in the human body have been progressing very slowly and the possibility that a new drug for this disease will appear in the forthcoming years is remote. Nonetheless, a proposal based on treatments that were successful in treating other diseases might help change this situation. Instead of chasing after molecules and new compounds that will probably never be invested in by pharmaceutical industries for commercial purposes, why not combine the few existing drugs and use them together? The idea is to repeat the concept of a medical drug cocktail, which has already proved to be efficient in the cases of Aids, tuberculosis and leprosy.

The proposal has two aspects: one of them theoretical and the other one applied. The theory is expounded in an article written by José Rodrigues Coura, researcher and former director of the Instituto Oswaldo Cruz institute. The paper was published in July in the Memórias journal published by Instituto Oswaldo Cruz. “The intention is to use the only two drugs that have ever been developed for this disease – Benznidazole and Nifurtimox – and combine them with Allopurinol, a well-known, low-toxicity drug used in the case of gout, and some antifungal drugs of the triazole class, such as ketoconazole, fluconazole, and intraconazole,” he says. The objective is to attack the T. cruzi parasite with the entire arsenal available to see whether it is eliminated from the human body during the chronic phase of the disease. “Of course it will be necessary to perform experimental and clinical essays before using this therapy,” he states.

Application – In the 1990s, Venezuelan biologist Julio Urbina, from the Universidade Central da Venezuela, tested a combination of antifungal compounds that inhibit the multiplication of the T. cruzi. The problem is that these substances, called first-generation ergosterol biosynthesis inhibitors, were not able to eradicate the parasite entirely, even though they had a deleterious effect on it, as attested to by tests on animals and human beings. Professor Coura´s proposal is to go beyond and combine all the possible drugs that have already been approved by the regulatory authorities.

The application aspect of the proposal is on course at the Federal University of Ouro Preto/Ufop, following the same line of reasoning as that of Coura, and continuing the work begun by Urbina. The research study, headed by biochemist Maria Terezinha Bahia, is coordinated by an international organization called Drugs for Neglected Diseases initiative/DNDi. The DNDi is an offshoot of the humanitarian organization Médecins sans Frontiéres – winner of the Nobel Peace Prize in 1999 – whose objective is to enter into partnerships to research, develop and make available new treatments for so-called neglected diseases, which get little or no attention from private and public laboratories. This list comprises such diseases as Chagas Disease, visceral leishmaniasis, malaria, and human
African trypanosomiasis (sleeping sickness).

At Ufop, the partnership with DNDi for the combination of the drugs began approximately one year ago. “The drugs currently being used provoke many side effects, such as allergies and peripheral neuropathies; their efficacy is low and patient compliance is poor,” says Isabela Ribeiro, the DNDi´s Director of Projects forLatin America. “This is why it is important to reduce the dosage and the treatment period, which nowadays lasts for up to 60 days, and expand tolerability to the therapy. By combining the drugs in lower doses with shorter periods of time, we will be able to maximize their effects and improve the patient´s response.”

Isabela, who is an infectologist, says that the results from Ouro Preto are promising and are going through the second phase of tests. “If the positive data is confirmed in this phase, next year we should be able to start the clinical tests on human beings,” she says. One of her prerogatives at the DNDi is to give it a more practical direction, focusing on scientific research for those who really need it. “Many years – from 10 to 15 – elapse from the time a new molecule is discovered to the finding of an available solution. Patients who need these drugs cannot afford to wait.”

Revista Memórias do Instituto Oswaldo Cruz journal (August 1909)Forms of the T. cruzi, in a drawing by Castro SilvaRevista Memórias do Instituto Oswaldo Cruz journal (August 1909)

In the opinion of João Carlos Pinto Dias, a researcher at the Centro de Pesquisas René Rachou,ResearchCenter, (Fiocruz Minas), in the city ofBelo Horizonte, Coura´s proposal and the attempts being made at Ouro Preto might be successful. “I don´t know why we haven’t seriously tested this therapy yet,” he says. Dias has always worked on the forefront of the prophylaxis involving the “ barbeiro” in the hinterland ofBrazil; he is one of the people responsible for the current successful control of the infection. In addition, he heads the Posto Avançado de Estudos Emmanuel Dias, Advanced Studies Center of Fiocruz, in the town ofBambuí, State ofMinas Gerais. “Nowadays, in addition to the lack of efficient drugs, our major problem is that we do not have a cure marker, that is, a test that allows us to know whether the patient is truly free of the T. cruzi.” In the acute phase of the disease, serological tests can take from one to two years to provide an accurate result. During the chronic phase, this period can take up to 25 years, because of the existence of immunological memory, remains of the DNA of the trypanosoma, and antigens that do not inform whether the patient is truly rid of the parasite. When a cure marker is developed, it will be possible to immediately identify if the patient is cured and what kind of drug is efficacious within a short period of time.

During the acute phase, which lasts from six to eight weeks, it is still possible to eliminate the T. cruzi from the patient´s blood stream by medicating the patient with benzidazole; however, this medication is successful in only 70% of the cases. “The drug is less efficient if the parasite load is very high or if the patient´s immunity levels are low,” explains biochemist Walter Colli, from the Chemistry Institute of the University of São Paulo, who has done research work on this disease for 40 years. Treatment of the chronic phase is much difficult for lesser known reasons. It can take various decades for the symptoms to appear, generally in the gastrointestinal tract or in the heart. When this occurs, the organ is already undergoing inflammation process and muscle fibers or connective tissues have been destroyed, which affect the quality of life and can lead to death. It is difficult to find the parasite in this phase because it hides in the tissues. “Once the parasite is inside the body, it is very complicated to find any solution. All the research studies that I seen so far to find a new drug or control the trypanosoma have been unsuccessful,” he says.

No vaccine
There are many research projects inBrazilthat investigate the physiology and biochemistry of the T. cruzi, as well as experiments with a wide range of chemical-therapeutic compounds to eradicate the parasite. Most trials are promising when tested in controlled environments. Coura comments that “in vitro, nearly everything kills the parasite, even water.” However, when the experiments are tested on animals and then on human beings, this proportion is inverted. Moreover, even if a compound proves to have potential, it is difficult to find pharmaceutical companies interested in working on the development of the compound to come up with a drug.

Dias thinks that a drug or a vaccine to cure the disease will never materialize. “The industry is not interested in investing from US$ 10 to US$ 20 million on a pharmaceutical drug for this kind of disease,” he says. This discouraging scenario does not release researchers from looking for other solutions. “The WHO, the DNDi and funding agencies should continue encouraging and financing basic research because we need to gain more knowledge about this disease.”

Because it is familiar with this reality, the DNDi entered into an agreement with the Laboratório Farmacêutico do Estado de Pernambuco/Lafepe, State Pharmaceutical Lab, to develop infant benznidazole by 2010. Nowadays, the benznidazole pill has to be broken into multiple pieces or crushed and mixed with water when it is given to children; there is a great risk of giving the wrong dose. Nifurtimox, the other drug used for Chagas Disease, has been off the market for many years. This is why Chagas Disease is on the top of the list of neglected diseases and kills approximately 14 thousand people a year in the Americas, even though it is roughly estimated that the percentage of chronic patients with symptoms ranges from 20% to 60%, depending on the region and age group – according to Paho, this percentage is higher than the percentage for malaria.

060-063_memoria2_163-01In Brazil nowadays, the leading form of contamination is oral; contamination occurs when a person eats food contaminated with the feces of the barbeiro. According to the Ministry of Health, there were 57 reported cases of the orally transmitted disease in the period from 2000 to 2004. This number went up to254 inthe period from 2005 to 2007. Most of the cases come from the Amazon Region. Because of immigration, the disease also affects countries that do not have the disease-transmitting insect, such asCanada,JapanandAustralia. In theUnited States, where there are approximately 300 thousand cases, there has been talk about applying tests to detect the disease. One of the problems related to the disease is the lack of reliable records. The estimate of the number of infected people in theAmericasranges from 8 million to 18 million, depending on the source.

Such inconsistent figures reinforce the need for attention, In Lassance, where everything was discovered 100 years ago, there are 31 infected people at the moment. The youngest is 60 years old, which means that the infection occurred a long time ago and transmission of the disease was controlled. “ But if the health authorities discontinue or do not perform their surveillance accordingly, this situation might invert and gradually go back to alarming outbreaks,” Dias warns. Given the lack of perspectives in obtaining a cure, the researcher believes that it is better to continue staying alert.

Scientific article
COURA, J.R. Present situation and new strategies for Chagas disease chemotherapy – a proposal. Memórias do Instituto Oswaldo Cruz. v.104 (4) July 2009.