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Specific treatment of infection by Trypanosoma cruzi has been performed up, until now, with the only available drugs: nifurtimox and benznidazole.1 Long follow-up is necessary, and both drugs are not devoid of side effects, nor are they effective in all treated cases. New drugs are welcome, but they may be not profitable for pharmaceutical companies. An alternative is to test the trypanocidal effect of well-known drugs used extensively for other diseases. A candidate with these characteristics was allopurinol, used for the treatment of gout, but not indicated in the treatment of T. cruzi infection. After preliminary reports of its trypanolytic activity in mice2 and cultured cells,3 some investigators started to use it in humans. The first reports4,5 were highly satisfactory, and a blind, placebo-controlled trial was proposed by the Tropical Diseases Research Center (TDR) of the World Health Organization (WHO; Genebra), which sponsored a study to be performed in three centers in three different countries: Argentina (coordinated by R. Gallerano), Bolivia (coordinated by A. Gi-anella), and Brazil (coordinated by A. Rassi). Protocols were designed and approved in 1991. We report the study performed in Brazil.
A double-blind, randomized, placebo-controlled clinical trial was conducted. The study was divided into three phases: selection of patients, administration of either allopurinol or placebo, and therapeutic evaluation.
The first phase was done by performing 572 xenodiagnosis examinations in 222 patients, all in the chronic phase of Cha-gas disease, with three positive serologic tests: indirect hem-agglutination,6 indirect immunofluorescence,7 and ELISA.8 Two, three, or four xenodiagnosis examinations were performed for each patient at monthly intervals. Briefly, for each xenodiagnosis, 40 first-instar nymphs of Dipetalogaster maxi-mus were applied in each patient, divided into 10 bugs per each of four boxes.9 Feces of 22,880 bugs were examined during the selection phase, 30 and 60 days after a blood meal. Only 39 of 222 (17.6%) patients were positive in at least one examination.
The following criteria were applied for inclusion: age between 15 and 65 years old; women without possibility of being or becoming pregnant during treatment; good nutritional status; normal kidney and liver function, absence of cardiopathy or presence of slight alterations; stable residence, outside endemic areas; absence of specific treatment of Chagas disease in the last year; no treatment of other infectious diseases or use of coumarin, thiazides drugs, aminophylline, or iron. Only 35 of 39 patients selected by positive xenodiagnosis fulfilled all these requirements and were included in the study (Table 1
). From them, 19 were women and 16 were men, with a mean age of 48.5 ± 11.7 years (age range: 18–64 years).
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Vials containing allopurinol or placebo were prepared by Wellcome (St. Albans, UK), labeled with a code number, and sent to Genebra (TDR, WHO), which retained the codes and sent the vials with sequential numbers to each center. Our center received vials numbered 41 to 60 and 101 to 120 (Table 1
) to be given in a sequential order. Tablets of allopurinol (300 mg) or placebo were administered orally three times a day for 60 days.
All patients were evaluated before, during (around Day 30), and immediately after the drug or placebo administration by the following laboratory tests: red and white cell blood count, uricemia, cholesterolemia, bilirubinemia, aspartate amino transferase (ASAT), alanino-amino-transferase (ALAT), alkaline phosphatase, urea, and creatinine blood levels, and urinalysis. Follow-up included clinical evaluation with attention to side effects.
Therapeutic evaluation was accomplished by monthly xe-nodiagnosis for each patient, during the first year, at the end of the study, and, after approval of the sponsor (TDR, WHO), extended to a longer period (2 years) because of the low sensitivity of this method in our region. Serologic tests were also performed every 3 months. After the end of the study, codes were received from the TDR, resulting in 23 patients under treatment and 12 under placebo. Seventeen patients of the intervention group and 10 of the placebo group completed the trial.
Side effects (Table 2) were observed in 11 patients in the intervention group and in 1 patient in the placebo group and appeared between Days 21 and 36 (mean of 27 days after starting treatment). The patient under placebo complained of vertigo, which was further studied and turned to be caused by a cerebellar tumor. None of the side effects left sequelae.
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Laboratory evaluation for hepatic and renal function and bone marrow involvement was normal for all patients, except for two that had slight leukopenia (from the intervention group) and recovered after the end of treatment.
In the 17 patients that completed treatment with allopuri-nol, all had a positive xenodiagnosis afterward (Table 3), as well as the 10 patients that completed the placebo schedule (Table 4). In a single case (no. 32), xenodiagnosis was negative after placebo administration, but complete follow-up was not possible because of skin hypersensitivity to the bugs applied on the third xenodiagnosis (Table 4).
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Compliance of patients to the trial was excellent. However, in one case, the patient (placebo group) discontinued the follow up; nevertheless, this case was included in the analysis, because dropping out was after the first positive post-treatment xenodiagnosis. For ethical reasons, at the end of the study, all the patients were offered treatment with benz-nidazole.
Our results showed, by the persistence of circulating parasites, detected by xenodiagnosis, that allopurinol at the dose schedule used was ineffective in all 17 patients that received this drug. Results of uricemia were below the normal values in all patients using allopurinol and returned to normal values 1 month after treatment, a further test to prove compliance of the participants. It should be emphasized that the dose used was three times higher than the usual dose used for gout, which may explain the side effects observed in 11 of 23 patients in the drug group. In 6 of 23, these side effects caused interruption of treatment because of the intensity of the side effects.
Our data are similar to another study on chronic phase patients,10 in parallel to our study, and also to a study on acute phase patients,11 but differs from those referred by oth-ers.4,5,12 The drug schedule and doses were similar or even higher than those used by these investigators. These discrepant results may be explained by geographical reasons, because of the different susceptibility of different strains of the parasite to the drugs, as shown by Andrade and Figueira,13 Andrade and others,14 and Filardi and Brener.15 Some reports did show differences for another drug, nifurtimox, which has had good performance in Argentina, Chile, and south of Brazil (bordering Argentina) but poor results in central Brazil.16 Another reason for this discrepancy may be the low number of xenodiagnosis examinations, a mean of two or three xenodiagnoses after treatment, in the study reported by Gallerano and others5 and seven in the study of Apt and others.12 It is well known that the sensitivity of xenodiagnosis is low, and the only way to augment it is by increasing the number of examinations. We also emphasized the need for a long parasitologic follow-up before any conclusion about the trypanolitic effect of a drug for T. cruzi infection is taken. As stated by Galvão and others17 and Rassi and Luquetti,18 the absolute value of parasitologic tests consists in their positivity. Negative results have no value to ascertain the absence of parasites. Furthermore, Urbina19 stated that "the reasons for the lack of in vivo trypanocidal activity of allopurinol include low incorporation of the drug in the vertebrate stages of many T. cruzi strains and probably inadequate pharmacokinetic properties."
We conclude that to further test candidate drugs on their trypanocidal efficacy in T. cruzi infection, it is recommended to perform a significant number of xenodiagnosis examinations during several years or while serological tests remain positive. The other obvious conclusion is that allopurinol, at the doses used, at least in central Brazil, is not effective.
Received March 11, 2006. Accepted for publication August 31, 2006.
Acknowledgments: We acknowledge Dr Álvaro Moncayo, TDR, for support in this project and Dr Daniela V. Luquetti for the English review of the manuscript.
Financial support: This work was financed by UNDP/WORLD BANK/WHO SPECIAL PROGRAMME, TDR Project 900415 and was monitored by Dr Lorrin Pang, WHO, to whom we are indebted.
* Address correspondence to Laboratório de Pesquisa da Doença de Chagas, Faculdade de Medicina, Universidade Federal de Goiás, Caixa Postal 1.031, 74001-970 Goiânia, Brazil. E-mail: aluquetti{at}hotmail.com 
Authors’ addresses: Anis Rassi, Anis Rassi Jr, Gustavo Gabriel Rassi, Sergio Gabriel Rassi, and Alexandre Gabriel Rassi, Anis Rassi Hospital, Avenida José Alves Nr. 453, Setor Oeste, CEP 74110-020 Goiânia, Brazil. Alejandro O. Luquetti, Laboratório de Pesquisa da Doença de Chagas, Faculdade de Medicina, Universidade Federal de Goiás, Caixa Postal 1.031, 74001-970 Goiânia, Brazil. Ionizete Garcia da Silva, Departamento de Microbiologia, Imunologia, Parasitologia e Patologia, Instituto de Patologia Tropical e Saúde Pública, Univer-sidade Federal de Goiás, Goiânia, Brazil, Telephone: 55-62-9973-2315, Fax: 55-62-3521-1835, E-mail: aluquetti{at}hotmail.com or anisrassi{at}arh.com.br.
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