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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 104, Num. 4, 2009, pp. 549-554
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Memórias do Instituto Oswaldo Cruz, Vol. 104, No. 4, July, 2009, pp. 549-554
MINI-REVIEW
Present situation
and new strategies for Chagas disease chemotherapy - a proposal
José
Rodrigues Coura
Laboratório
de Doenças Parasitárias, Instituto Oswaldo Cruz-Fiocruz, Av. Brasil
4365, 21040-360 Rio de Janeiro, RJ, Brasil
Corresponding author:
coura@ioc.fiocruz.br
Received 7 January
2009
Accepted 22 April 2009
Code Number: oc09127
ABSTRACT
Treatments for
Chagas disease have been administered since the first attempts by Mayer &
Rocha Lima (1912, 1914) and up to the drugs currently in use (nifurtimox and
benznidazole), along with potential drugs such as allopurinol and first, second
and third-generation antifungal agents (imidazoles and triazoles), in separate
form. Several diseases such as tuberculosis, leprosy and AIDS only came under
control after they were treated with associations of drugs with different mechanisms
of action. This not only boosts the action of the different compounds, but also
may avoid the development of parasite resistance .To this end, over the short
term, we propose experimental studies on laboratory animals and clinical trials
with the following associations: (i) nifurtimox (8 mg/kg/day) + benznidazole
(5 mg/kg/day) x 60 consecutive days; (ii) nifurtimox (8 mg/kg/day) or benznidazole
(5 mg/kg/day) + allopurinol (8-10 mg/kg/day) x 60 days and (iii) nifurtimox
(8 mg/kg/day) or benznidazole (5 mg/kg/day) + ketoconazole, fluconazole or itraconazole
(5-6 mg/kg/day) x 60 consecutive days. The doses of the drugs and the treatment
schedules for the clinical trials must be adapted according to the side effects.
From these, other double or triple associations could be made, using drugs with
different mechanisms of action. This proposal does not exclude investigations
on new drugs over the median and long terms, targeting other aspects of the
metabolism of Trypanosoma cruzi. Until such time as the ideal drug for
specific treatment of Chagas disease might be discovered, we need to develop
new strategies for achieving greater efficacy with the old drugs in associations
and to develop rational experimentation with new drugs.
Key words:
Chagas disease - chemotherapy - present situation - new strategies - a proposal
Since 1912, just
three years after the discovery of Chagas disease, many attempts have been made
to treat the disease. Mayer and Rocha Lima (1912) experimentally tested atoxyl
(arsenic), fuchsine (rosaniline dye) and tartar emetic and soon afterwards (1914)
tried mercury chloride; all without favourable results. Carlos Chagas himself,
together with Evandro Chagas in their Manual on Tropical and Infectious Diseases
Volume I (1935), highlighted in just one paragraph of seven lines the ineffectiveness
of the attempts that had been made to treat the disease. In this passage, they
stated: "So far, no specific treatment for American trypanosomiasis exists.
Medications with trypanosomicidal action have been tried out experimentally
by many researchers without any success. Some clinical syndromes may experience
symptomatic therapeutic action, according to their manifestations and evolution."
A review conducted
by Coura and Silva (1961) showed that, up to that time, the following groups
of substances had been used clinically or experimentally: quinoline derivatives;
various other antimalarial agents; arsenobenzols and other arsenical compounds;
phenanthridines; gold, bismuth, copper and zinc salts; sodium iodide; gentian
violet; aminopterin; para-amino salicylic acid; hydrazides; antihistamines;
sulfonamides; adrenocorticotropic hormone and cortisone; stylomycin derivatives;
amphotericin B; more than 30 antibiotics and nitrofurans. Some nitrofurans had
shown promising results experimentally, according to Packanian (1952, 1957)
and Brenner (1961). Brenner (1968) highlighted that, among the 36 groups of
medications that had been used up to that time, the following had shown activity
against experimental Chagas disease: bis-quinaldine (Bayer 7602); phenanthridines;
amino-quinolines; trivalent arsenical compounds (Bayer 9736) and spirotrypan;
acromycin or stylomycin and stylomycin aminonucleoside; nitrofurans; 2-acetamide-5-nitrothiazole
and imidazole (Flagyl). However, Cançado (1968, 1973) criticised various
results considered "good" or "excellent" in treating human cases of Chagas disease
with these medications because they were contradictory to each other or because
the methodology was inadequate for cure verification. For example, Mazza et
al. (1937, 1942) and Pifano (1941) obtained "good" results using Bayer 7602
to treat acute cases of the disease, based on their observations of a reversal
of the clinical manifestations and a shift in smear drop results to negative;
however, these signs were also observed in untreated cases. The treated cases
with "good results" subsequently presented positive xenodiagnosis, which is
indicative of therapeutic failure.
The first experimental
results that showed real effectiveness were observed with the use of nitrofurans,
in a line of research initiated by Pakchanian (1952, 1957). These results led
to the introduction of nitrofurazone (5-nitro-2-furaldehyde-semicarbazone),
which was put on the market in Brazil by the Eaton laboratory as Furacin ointment
for topical use. Subsequently, this drug was used by Brener (1961) at a dose
of 100 mg/kg/day orally for prolonged periods (53 days) in mice infected with
Trypanosoma cruzi and it was observed that 95.4% of the animals treated
achieved parasitological cure (62/65). Ferreira (1961, 1962) and Ferreira et
al. (1963) observed "good results" in the first acute cases of human disease
in children, with few side effects. During this same period, Coura et al. (1961,
1962) treated 14 chronic cases of Chagas disease with nitrofurazone at progressive
doses from 10-30 mg/kg/day over prolonged periods and observed significant side
effects (particularly polyneuropathy), which made it necessary to halt the treatment
in most cases. By reducing the dose to 10 mg/kg/day, they were able to treat
10 patients for 60 days. Three of the patients experienced parasitological cure.
Of the three treated patients, one had the early form of the disease, acquired
in Goiás 18 months earlier when he made a journey to that state as a
truck driver and the other two were in the late chronic phase.
A review by Brener
(1984) on recent advances in the knowledge of Chagas disease, published in a
special issue of the Memórias do Instituto Oswaldo Cruz to mark the 50th
anniversary of the death of Carlos Chagas (1889-1934), highlighted several new
drugs for treating this disease, along with their mechanisms. Among these drugs
were fexinidazole (HOE239), MK-436, ketoconazole, megazole (CL 64'855) and allopurinol.
More recently, Coura and De Castro (2002) published an extensive "Critical Review
on Chagas Disease Chemotherapy", in which they analysed the experimental and
clinical studies carried out since 1970, including the rules and recommendations
for clinical treatment, the prospects of new drugs in clinical trials and promising
new targets. The experimental studies of Andrade et al. (1977, 1991, 2000) on
the resistance of T. cruzi strains to treatment and the persistence of
the parasite's antigen, which delays the change to negative serological reactions
for cure verification, were highlighted.
The objectives
of the present paper are to review the present situation regarding specific
treatments for Chagas disease and to propose new treatment strategies using
existing drugs of different mechanisms of action in combination, as is done
in the treatment for tuberculosis, leprosy and AIDS, among other infectious
diseases, with the aims of avoiding resistance and increasing treatment efficacy.
Present situation
regarding specific treatments for Chagas disease - At present, there are
only two effective drugs for the treatment of Chagas disease, particularly in
the acute and chronic, early phase of the infection: nifurtimox and benznidazole.
However, neither of these therapeutics meets the precepts for a good drug in
accordance with the criteria of the World Health Organisation: (i) parasitological
cure of acute and chronic cases of the infection; (ii) effective in a single
dose or with few doses; (iii) accessible to patients, i.e., low cost and easy
to obtain; (iv) no side effects or teratogenic effects; (v) no need for hospitalisation
for treatment and (vi) no resistance shown or induced in the etiological agent.
Both of these drugs cure around 80% of acute cases and 20% of chronic cases.
Patients require 60 days of treatment, with 2-3 doses per day. The drugs are
not accessible for patients; at least not in Brazil, where nifurtimox is unavailable
and the distribution of benznidazole is restricted to specialised clinics that
require medical monitoring during the course of treatment. Both drugs induce
significant side effects and some strains of T. cruzi are resistant to
treatment.
Nifurtimox -
Nifurtimox is 5-nitrofuran [3-methyl-4-(5'-nitrofurfuridene-amine) tetrahydro-4H-1,4-thiazine
1,1-dioxide (Bayer 2502). The mechanism of action of nifurtimox involves the
production of nitro-anion radicals, which, in the presence of oxygen, leave
T. cruzi incapable of detoxifying free radicals (Do Campo & Moreno
1986). Nifurtimox was put on the market in Brazil under the name of Lampit and
was subsequently withdrawn from the market in Brazil, Argentina, Chile and Uruguay.
Today, this medication is produced and used predominantly in Central America.
Nifurtimox is the most active of the 5-nitrofurfuridenes tested experimentally
by Bock et al. in 1969 and clinically by several other researchers (Bocca-Tourres
1969, Cançado et al. 1969, 1975, 1976, Rubio & Donoso 1969, Schenone
et al. 1969, 1972, 1981, Rassi & Ferreira 1971, Prata et al. 1975, Ferreira
1990, Rassi & Luquetti 1992, Coura 1996, Coura et al. 1997). All research
shows the best results are obtained when treatment is started during the acute
phase; results are highly variable for patients in the chronic phase. It is
important to note that some strains of T. cruzi present natural resistance
to treatment with nifurtimox, which has also been proven experimentally (Andrade
et al. 1977).
The nifurtimox
treatment regimen from which the best results have been obtained and which continues
to be recommended, is 8-10 mg/kg/day, divided into 2-3 doses per day, for 60
days. The side effects most frequently observed have been anorexia, weight loss,
psychological changes, excitability, muscle tremors, somnolence, hallucinations
and digestive manifestations such as nausea, vomiting and, occasionally, abdominal
pain and diarrhoea. In rare cases, localised convulsions have been observed.
These side effects can be controlled with diazepam, cimetidine, metoclopramide,
antihistamines and other medications.
Benznidazole
- Benznidazole is 2-nitroimidazole (N-benzyl-2-nitroimidazole-acetamide
(RO-1051). The action of benznidazole is related to the nitroreduction of components
of the parasite and the binding of metabolites to the nuclear DNA and k-DNA
of T. cruzi and the lipids and proteins of the parasite (Polack &
Richle 1978, Diaz de Taranzo et al. 1988). Benznidazole was put on the market
in Brazil by Roche (which recently transferred the patent to LAFEPE, the Pharmaceutical
Laboratory of the state of Pernambuco) under the name Rochagan and in Argentina
as Rodanil. Experimentally, benznidazole shows high levels of in vitro and in
vivo activity against T. cruzi (Richle 1973). Clinically, benznidazole
has been tested on both the acute and the chronic phase of Chagas disease by
many researchers, particularly in Argentina, Brazil and Chile (Schenone et al.
1975, 1981, Ferreira 1976, Coura et al. 1978, 1997, Cançado & Brenner
1979, Rassi & Luquetti 1992, Viotti et al. 1994, Andrade et al. 1996, Coura
1996, Cançado 1997, Sosa-Stani et al. 1998, Rassi et al. 1999). Coura
et al. (1978) analysed 309 cases treated with benznidazole (54 acute and 255
chronic cases) by 10 groups of Brazilian researchers with therapeutic regimens
of 5-8 mg/kg/day for 30 or 60 days and observed that the degree of suppression
of parasitaemia (as assessed by xenodiagnosis) and the side effects were identical
after 30 or 60 days of treatment. Further, there was no treatment advantage
with doses greater than 5 mg/kg/day. Subsequently, Coura et al. (1997) found
from a randomised, controlled field study treating groups of patients with nifurtimox,
benznidazole and placebo, that benznidazole was better at suppressing parasitaemia
in chronic cases of Chagas disease.
The best regimen
for treating Chagas disease with benznidazole is 5 mg/kg/day, divided into 2-3
daily doses, for 60 days. The main side effects observed have been (i) hypersensitivity
(dermatitis, generalised oedema, ganglionic infarction and joint and muscle
pains; (ii) bone marrow depletion (neutropaenia, thrombocytopaenic purpura and
agranulocytosis) and (iii) peripheral polyneuropathy. These side effects can
be controlled with antihistamines, corticosteroids and, in severe cases of agranulocytosis,
thrombocytopaenic purpura or Stevens-Johnson syndrome, suspension of the treatment.
Other drugs
used in experimental and clinical trials for the treatment of Chagas disease
- Other drugs such as allopurinol, a hypoxanthine analogue that inhibits
xanthine oxidase and is used as an antihyperuricaemic agent for treating gout
and antifungal agents such as ketoconazole (a derivative of imidazole), fluconazole
and itraconazole (derivatives of triazole) and, more recently, posaconazole
(also an azole derivative) have been shown to be active in vitro against T.
cruzi. Nonetheless, the experimental and clinical results have been controversial.
Allopurinol
- Allopurinol acts as an alternative substrate for the hypoxanthine-guanidine
phosphoryl transferase system; it is incorporated into the RNA and leads to
the formation of a non-physiological nucleotide that blocks de novo synthesis
of purines. According to Marr et al. (1978, 1984) and Marr (1991), allopurinol
could act as a therapeutic agent against leishmaniasis and American trypanosomiasis.
Studies conducted by Lauria-Pires et al. (1998) showed that allopurinol was
ineffective during the acute phase of Chagas disease. Gallerano et al. (1990)
treated two groups of patients with 600 and 900 mg/day of allopurinol for 60
days and compared these patients to two other groups treated with nifurtimox
and benznidazole. They found that the xenodiagnosis became negative (ranging
from 75-92%) in all four groups, with the lowest toxicity exhibited in the group
treated with allopurinol. Apt et al. (1998) treated 104 chronic patients with
allopurinol (8.5 mg/kg/day for 60 days), monitoring the patients by clinical
examination, serology, xenodiagnosis, haemoculture and electrocardiogram. Parasitological
cure was achieved in 44% of the allopurinol-treated patients. However, this
study needs to be better evaluated prospectively. Allopurinol has also been
indicated in heart transplantation cases with reactivation of infection due
to post-surgical immunosuppression. Erythematous lesions on superior and inferior
members were observed in one patient, but the lesions disappeared within three
weeks (Tomimori-Yamashita et al. 1997).
Ketoconazole
- Ketoconazole is an antifungal agent and acts by altering the permeability
of the cytoplasmic membrane, thereby inhibiting sterol synthesis by the membrane
and the formation of ergosterol, with degradation of the fatty acids and endogenous
steroids of the cells. Brener et al. (1993) demonstrated that ketoconazole was
incapable of eradicating parasitaemia from six of the eight Chagas patients
treated with doses of 3.1-8.7 mg/kg/day during 51-96 days by oral route and
followed up for 60 months. Ketoconazole was the first imidazole to show in vitro
activity against T. cruzi in the acute phase of experimental infection,
but it was shown to be ineffective against the chronic phase (De Castro 1993).
Fluconazole,
itraconazole and other triazoles - The triazoles fluconazole and itraconazole
present significant action against filamentous fungi and yeasts, acting in the
same way as other azoles, i.e., by inhibiting the cytochrome P450 enzyme, which
is responsible for synthesising ergosterol in the cytoplasmic membrane, thereby
leading to increased permeability and rupturing of the membrane. Second-generation
triazoles, including terconazole, saperconazole (R 66905), electrazole (BAY
R-3783), genaconazole (SCH 39304) and D0870, along with third-generation triazoles
such as variconazole (UK109-496), posaconazole (SCH 56592), ravuconazole (ER
30346) and TAK-187, are drugs that show potential for the treatment of Chagas
disease. Some of these drugs have already been shown to have in vitro action
against T. cruzi (Urbina et al. 1996, 1999, 2000, Molina et al. 2000,
2001, Do Campo 2001). Posaconazole is currently the greatest hope for the treatment
of Chagas disease and is already in its initial phase of experimentation in
human subjects.
Indications
and contraindications for treating Chagas disease - Over the last 10-12
years, several meetings on developing treatments for Chagas disease have been
held in Brazil and abroad. Two of these meetings had a prominent role in defining
the position of specialists on this subject. The first such meeting was held
in Brazil by the Brazilian Ministry of Health, with the participation of 13
specialists and was very well summarised by Luqueti (1997). The second was held
at the Oswaldo Cruz Institute (Fiocruz) by OPS/OMS, from April 23-April 25 1998;
at this meeting, the rules for Chagas disease treatment using the drugs that
are still in use today were established. At the latter meeting, the indications
for treatment in the acute phase of the disease, the congenital form, laboratory
accidents, chronic phase, recent cases, late chronic phase, organ transplantation
cases and acute reactivation of the chronic phase were defined, as described
in the critical review by Coura and De Castro (2002). The indications for treating
Chagas disease are summarised: (i) acute cases of any nature; (ii) acute reactivations
due to immunosuppression; (iii) recent cases: cases among children up to 12
years of age or among adults infected recently and (iv) indeterminate or benign
chronic form, at the discretion of the attending physician. Patients in the
severe acute phase and symptomatic congenital patients should be hospitalised
for treatment. Asymptomatic or oligosymptomatic acute cases and chronic cases
can be treated at the outpatient level, with follow-up by an experienced physician.
The contraindications for specific treatment are: pregnancy, liver failure,
kidney failure, neurological diseases unrelated to Chagas disease, advanced
Chagas disease with grade III or IV cardiopathy (OPS/OMS) and other diseases
that might be worsened by this treatment.
Cure verification
for Chagas disease - To verify that cure has been achieved, parasitological
cure needs to be considered, with evaluation by means of serological tests,
polymerase chain reaction (PCR), blood culturing and xenodiagnosis (Coura &
De Castro 2002) as well as by observation of the clinical evolution of the disease
using conventional electrocardiography, dynamic electrocardiography (Holter),
echocardiography, myocardial scintigraphy, ergonometry, assessment of the autonomic
system and radiological and manometric evaluations of the digestive system (Rezende-Filho
et al. 2005, Rocha et al. 2005). Verification of parasitological cure in the
acute phase is relatively easy and fast and is achieved by observing no parasites
in direct blood tests, blood cultures, xenodiagnosis, PCR and serological tests.
In the chronic phase, verification that parasitological cure has been achieved
becomes much more complicated and much slower, considering the low levels of
parasitaemia (with treatment) and the long time required for serological tests
to become negative (10, 15, 20 or more years), because of the sensitisation
of dendritic cells by the antigens of T. cruzi (Andrade et al. 1991).
Serological tests continue to be positive for many years, even though there
is a gradual decline in the titres of anti-T. cruzi antibodies. On the
other hand, evaluation of the clinical evolution of Chagas disease or of its
regression is extremely complex and there is no unanimity on this in studies
conducted so far. This is partially due to the small number of cases evaluated
and the different evaluation methods used by different authors. A project currently
in progress, called BENEFIT (supported by TDR/WHO and several other institutions)
is evaluating 1,500 patients treated with benznidazole in three countries (Argentina,
Brazil and Colombia) and the respective controls, to define the benefits of
treatment on the evolution of Chagas cardiopathy.
Proposal for
a new strategy for treating Chagas disease - Several diseases such
as tuberculosis, leprosy and AIDS only came under control after they were treated
with combinations of drugs with different mechanisms of action. Combinatorial
treatments can not only boost the action of the different therapeutic compounds,
but may also aid in avoiding the development of parasite chemotherapeutic resistance.
To this end, over
the short term, we propose experimental studies on laboratory animals and clinical
trials with the following associations: (i) nifurtimox (8 mg/kg/day) + benznidazole
(5 mg/kg/day) x 60 consecutive days; (ii) nifurtimox (8 mg/kg/day) or benznidazole
(5 mg/kg/day) + allopurinol (8-10 mg/kg/day) x 60 consecutive days; (iii) nifurtimox
(8 mg/kg/day) or benznidazole (5 mg/kg/day) + ketoconazole, fluconazole or itraconazole
(5-6 mg/kg/day) x 60 consecutive days.
The dosage of the
drugs and the treatment schedules for the clinical trials must be adapted according
to the observation of any side effects.
Based on data obtained
from these studies, other double or triple associations could be designed, using
drugs with different mechanisms of action. This proposal does not exclude investigations
of new drugs over the medium and long terms, targeting other aspects of the
metabolism of T. cruzi. Until the ideal drug for the specific treatment
of Chagas disease is discovered, we need to develop new strategies for achieving
greater efficacy with the old drugs by using combinatorial treatments and develop
rational experimentation courses for novel drugs.
REFERENCES
- Andrade AL, Zicker
F, Oliveira RM, Silva SA, Luquetti A, Travassos LR, Almeida IC, Andrade SS,
Andrade JG 1996. Randomised trial of efficacy of benznidazole in the treatment
of early Trypanosoma cruzi infection. Lancet 318: 1407-1413.
- Andrade SG, Andrade
ZA, Figueira RM 1977. Estudo experimental sobre a resistência de uma cepa
ao Bay 2502. Rev Inst Med Trop Sao Paulo 19: 124-129.
- Andrade SG, Freitas
LAR, Peyrol S, Pimentel AR, Sadigursky M 1991. Experimental chemotherapy of Trypanosoma cruzi infection persistence on parasite antigens and positive
sorology in parasitologically cured mice. Bull WHO 69: 191-199.
- Andrade SG, Pimentel
AR, Souza MM, Andrade ZA 2000. Interstitial dendritics cells of the heart harbor Trypanosoma cruzi antigens in experimentally infected dogs: importance
for the pathogenesis of Changes myocarditis. Am J Trop Med 63: 64-70.
- Apt W, Aguilera
X, Arribada A, Perez C, Miranda C, Sandez G, Zulantay I, Cortes P, Rodrigues
J, Iuri D 1998. Treatment of chronic Chagas disease with itraconazole and allopurinol. Am J Trop Med Hyg 59: 133-138.
- Bocca-Tourres LC
1969. La enfermedad de Chagas en período agudo y su tratamiento con el
Bay 2502. Bol Chil Parasitol 24: 24-27.
- Bock M, Gonert
R, Hberkom A 1969. Studies with Bay 25-02 on animals. Bol Chile Parasitol
24: 13-19.
- Brener Z 1961.
Atividade tereapêutica do 5 - nitrofuraldeido - semicarbazona (nitrofurazona)
em esquemas de duração prolongada na infecção experimental
pelo Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo 3: 43-49.
- Brener Z 1968.
Terapêutica experimental da doença de Chagas. In JR Cançado, Doença de Chagas, Imprensa Oficial de Minas Gerais, Belo Horizonte,
p. 510-516.
- Brener Z 1984.
Recent advances in the chemotherapy of Chagas disease. Mem Inst Oswaldo Cruz
79 (Suppl.): 149-155.
- Brener Z, Cançado
JR, Galvão LM, Da Luz ZM, Filardi LS, Pereira ME, Santos LM, Cançado
CB 1993. An experimental and clinical assay with ketoconazole in the treatment
of Chagas disease. Mem Inst Oswaldo Cruz 88: 149-143.
- Cançado
JR 1968. Tratamento da doença de Chagas. In JR Cançado, Doença
de Chagas, Imprensa Oficial de Minas Gerais, Belo Horizonte, p. 517-540.
- Cançado
JR 1997. Terapêutica específica. In JCP Dias, JR Coura (eds.), Clínica e terapêutica da doença de Chagas, Editora
Fiocruz, Rio de Janeiro, p. 323-351.
- Cançado
JR, Brener Z 1979. Terapêutica, In Z Brener, ZA Andrade, Trypanosoma cruzi e Doença de Chagas, Guanabara Koogan, Rio de Janeiro, p. 362-424.
- Cançado
JR, Duval Marra U, Mourão OG, Alvares JM, Oliveira JRM, Machado JR, Salgado
AA 1973. Bases para a avaliação do tratamento específico
da doença de Chagas humana. Rev Soc Bras Med Trop 7: 155-166.
- Cançado
JR, Marra UD, Lopes M, Mourão O, Faria CAF, Álvares JM, Salgado
AA 1969. Toxicidade y valor terapêutico del Bay 2502 em la enfermedad
de Chagas em três esquemas posológicos. Bol Chil Parasitol 24:
28-32.
- Cançado
JR, Salgado AA, Batista SM, Chiari C 1976. Segundo ensaio terapêutico
com o nifurtimox na doença de Chagas. Rev Goiana Med 22: 203-233.
- Cançado
JR, Salgado AA, Marra UD, Alvares JM, Machado JR 1975. Clinical therapeutic
trial in chronic Chagas disease using nifurtimox in 3 schedules of long duration. Rev Inst Med Trop Sao Paulo 17: 111-127.
- Chagas C, Chagas
E 1935. Manual de doenças tropicais e infectuosas, Vol. I, Livraria
Editora Freitas Bastos, Rio de Janeiro, 189 pp.
- Coura JR 1996.
Perspectivas actuales del tratamiento especifico de la enfermedad de Chagas. Bol Chil Parasitol 51: 69-75.
- Coura JR, Abreu
LL, Willcox HP, Petana W 1997. Comparative controlled study on the use of benznidazole,
nifurtimox and placebo, in the chronic form of Chagas disease, in a field area
with interrupted transmission. I. Preliminary evaluation. Rev Soc Bras Med
Trop 30: 139-144.
- Coura JR, Brindeiro
PJ, Ferreira I 1978. Benznidazole in the treatment of Chagas disease. Current
chemotherapy. Proc 10th Int Cong Chemotherapy 1: 161-162.
- Coura JR, De Castro
SL 2002. A critical review on Chagas disease chemotherapy 2002. Mem Inst
Oswaldo Cruz 97: 3-24.
- Coura JR, Ferreira
LF, Saad EA, Mortel RE, Silva JR 1961. Tentativa terapêutica com a nitrofurazona
(Furacin) na forma crônica da doença de Chagas. O Hospital 60:
425-429.
- Coura JR, Ferreira
LF, Silva JR 1962. Experiências com nitrofurazona na fase crônica
da doença de Chagas. O Hospital 62: 957-964.
- Coura JR, Silva
JR 1961. Aspectos atuais do tratamento da doença de Chagas. Rev Bras
Med 51: 283-290.
- De Castro SL 1993.
The challenge of Chagas disease chemotherapy: an update of drugs assayed against Trypanosoma cruzi. Acta Tropica 53: 83-98.
- Diaz de Toranzo
EG, Castro JA, Franke de Cazzulo BM, Cazzulo JJ 1988. Interaction of benznidazole
reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids
from Trypanosoma cruzi. Experientia 44: 880-881.
- Do Campo R 2001.
Recent developments in the chemotherapy of Chagas disease. Curr Pharm Design
7: 1157-1164.
- DoCampo R, Moreno
SNJ 1986. Free radical metabolism of antiparasitic agents. Fed Proceed 45:
2471-2476.
- Ferreira H 1976.
Ensaio terapêutico-clínico com benznidazol na doença de
Chagas. Rev Inst Med Trop Sao Paulo 18: 357-364.
- Ferreira H 1990.
Tratamento da forma indeterminada da doença de Chagas com nifurtimox
e benznidazol. Rev Soc Bras Med Trop 23: 209-211.
- Ferreira HO 1961.
Forma aguda da doença de Chagas tratada pela nitrofurazona. Rev Inst
Med Trop Sao Paulo 3: 287-289.
- Ferreira HO 1962.
Fase aguda da doença de Chagas. O Hospital 61: 307-311.
- Ferreira HO, Prata
A, Rassi A 1963. Administração prolongada de nitrofurazona no
tratamento da doença de Chagas aguda. O Hospital 63: 139-139.
- Gallerano RH, Mar
JJ, Sosa RR 1990. Therapeutic efficacy of allupurinol in patients with chronic
Chagas disease. Am J Trop Med Hyg 43: 159-166.
- Lauria-Pires L,
Castro CN, Emanuel A, Prata A 1998. Ineficácia do allopurinol em pacientes
na fase aguda da doença de Chagas. Rev Soc Med Trop 21: 79.
- Luquetti AO 1997.
Etiological treatment for Chagas disease. Parasit Today 13: 127-128.
- Marr JJ 1991. Purine
analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis. J Lab Clin Med 118: 111-119.
- Marr JJ, Berens
RL, Cohn NK, Nelson DJ 1978. Anti-trypanosomal effects of allopurinol: conversion in vitro to aminopyrazolopymidine nucleotides by Trypanosoma cruzi. Science 201: 1018-1020.
- Marr JJ, Berens
RL, Cohn NK, Nelson DJ, Klein RS 1984. Biological action of inosine analogs
in Leishmania and Trypanosoma spp. Antimicrob Agents Chemoter
25: 292-295.
- Mayer M, Rocha
Lima H 1912. Zur Entwicklung von Schizotrypanum cruzi in Saengetieren. Archff Schisffs u Tropen Hyg 16: 90-94.
- Mayer M, Rocha
Lima H 1914. Zum verhalten von Schizotrypanum cruzi in Warmbluetern un
Arthropoden. Arch Schiffs u Tropen Hyg 5: 101-136.
- Mazza S, Basso
G, Basso R 1942. Ensayos terapêuticos del producto 9736 (As) Bayer y de
su acción comparada con el 7602 (Ac) Bayer en la enfermedad de Chagas. Mis Est Patol Reg Argentina Publ 70 (Univ Buenos Aires) (MEPRA) 61: 3-81.
- Mazza S, Cossio
R, Zucardi E 1937. Primer caso agudo de enfermedad de Chagas, comprovado em
Tucuman y su tratamiento com Bayer 7602. Mis Estudios Patolog Reg Argentina
Publ 70 (Univ Buenos Aires) (MEPRA) 32: 3-18.
- Molina J, Martins-Filho
O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA 2000. Activities of the triazole
derivative SCH 56592 (pozoconazole) against drug-resistant strains of the protozoan
parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent
and immunosuppressed murine hosts. Antimicrob Agents Chemother 44: 150-155.
- Molina J, Urbina
J, Gref R, Brener Z, Rodrigues Junior JM 2001. Cure of experimental Chagas disease
by the bis-triazole DO870 incorporated into "stealth" polyethyleneglycolpolylactide
menospheres. J Antimicrob Chemother 47: 101-104.
- OPS/OMS 1998. Tratamiento
etiológico de la enfermedad de Chagas. Conclusiones de una consulta técnica. Rev Pat Trop 28: 247-279.
- Packchanian A 1952.
Chemotherapy of experimental Chagas disease with nitrofuran compounds. J
Parasitol 38: 30-40.
- Packchanian A 1957.
Chemotherapy of experimental Chagas disease with nitrofuran compounds. Antibiot
Chemother 7: 13-23.
- Pifano FC 1941.
La enfermedad de Chagas en el Estado Jaracuy, Venezuela. Caracas Medico 8:
1103-1166.
- Polak A, Richle
R 1978. Mode of action of 2-nitroimidazole derivative benznidazole. Ann Trop
Med Parasitol 72: 228-232.
- Prata A, Macedo
V, Porto G, Santos I, Cerisola JA, Silva NN 1975. Tratamento da doença
de Chagas pelo nifurtimox (Bayer 2502). Rev Soc Bras Med Trop 9: 297-307.
- Rassi A, Amato
Neto V, De Siqueira AF, Ferriolli Filho F, Amato VS, Rassi Jr 1999. Protective
effect of benznidazole against parasite reactivation in patients chronically
infected with Trypanosoma cruzi and treated with corticoids for associated
diseases. Rev Soc Bras Med Trop 32: 475-482.
- Rassi A, Ferreira
H 1971. Tentativa de tratamento específico na fase aguda da doença
de Chagas com nifurtimox em esquemas de duração prolongada. Rev
Soc Bras Med Trop 5: 235-262.
- Rassi A, Luquetti
AO 1992. Therapy of Chagas disease. In S Wendel, Z Brener, ME Camargo, A Rassi
(eds), Chagas disease (American trypanosomiasis): its impact on transfusion
and clinical medicine, ISBT, São Paulo, p. 237-247.
- Rezende-Filho JR,
Moreira Junior H, Rezende JM 2005. Métodos radiológico e manométrico
para o diganóstico da esofagopatia e da colopatia chagásicas.
In JR Coura, Dinâmica das doenças infecciosas e parasitárias, Editora Guanabara Koogan, Rio de Janeiro, p. 653-666.
- Richle R 1973.
Chemotherapy of experimental acute Chagas disease in mice: beneficial effect
of Ro-71051 on parasitemia and tissue parasitsm. Le Progres Medical 101:
282.
- Rocha MOC, Barros
MVL, Tostes VTV, Junqueira LJ, Ribeiro ALP 2005. Métodos de avaliação
funcional não-invasivos da cardiopatia chagásica e outras cardiopatias
infecciosas. In JR Coura, Dinâmica das doenças infecciosas e
parasitárias, Editora Guanabara Koogan, Rio de Janeiro, p. 639-652.
- Rubio M, Donoso
F 1969. Enfermedad de Chagas en niños y tratamiento com Bay 2502. Bol
Chil Parasitol 24: 43-48.
- Schenone H, Concha
L, Aranda R, Rojas A, Alfaro E 1969. Experiência terapêutica com
Bay 2502 en la infección chagásica crônica del adulto. Importância
del uso adequado del xenodiagnóstico. Bol Chil Parasitol 24: 66-69.
- Schenone H, Concha
L, Aranda R, Rojas A, Alfaro E, Knierim F 1975. Actividad quimioterápica
de um derivado de la nitroimidazolacetamida em la infección chagásica
crônica. Bol Chil Parasitol 30: 91-93.
- Schenone H, Concha
L, Aranda R, Rojas A, Knierim F, Rojo M 1972. Tratamiento de la infección
chagásica crónica com "Lampit". Bol Chil Parasitol 27:
11-14.
- Schenone H, Rojas
A, Alfaro E, Concha L, Aranda R 1981. Estudio longitudinal de la persistencia
de la acción terapêutica del nifurtimox y del benznidazol em pacientes
con infección chagásica crônica. Bol Chil Parasitol 36:
59-62.
- Sosa Estani S,
Segura EL, Ruiz AM, Porcel BM, Yampotis C 1998. Efficacy of chemotherapy with
benznidazole in children in the indeterminate phase of Chagas desease. Am
J Trop Med Hyg 59: 526-529.
- Tomimori-Yamashita
J, Deps PD, Almeida DR, Enokihara MM, De Seixas MT, Freymuller E 1997. Cutaneous
manifestation of Chagas disease after heart transplantation: successful treatment
with allopurinol. Br J Dermatol 37: 626-630.
- Urbina JA, Lira
R, Visbal G, Bartroli J 2000. In vitro antiprolifetative effects and
mechanism of action of the new triazole derivative UR-9825 against the protozoan
parasite Trypanosoma (Shizotrypanum) cruzi. Antimicrob
Agents Chemother 44: 2498-2502.
- Urbina JA, Moreno
B, Vierkotter S, Oldfield E, Payares G, Sanoja C, Bailey BN, Yan W, Scott DA,
Moreno SN, DoCampo R 1999. Trypanosoma cruzi contains major pyrophosphate
stores and its growth in vitro and in vivo is blocked by pyrophosphate
analogs. J Biol Chem 274: 33609-33615.
- Urbina JA, Payares
G, Molina J, Sanoja C, Liendo A, Lizardi, Piras MM, Piras R, Perez N, Wincker
P, Riley JF 1996. Cure of short and long-term experimental Chagas disease using
D0870. Science 273: 969-971.
- Viotti R, Vigliano
C, Armenti H, Segura E 1994. Treatment of chronic Chagas disease with benznidazole:
clinical and serologic evolution with long-term follow-up. Am Heart J 27:
151-162.
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