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Antimicrobial Agents and Chemotherapy, January 2000, p. 150-155, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Activities of the Triazole Derivative SCH 56592 (Posaconazole)
against Drug-Resistant Strains of the Protozoan Parasite
Trypanosoma (Schizotrypanum) cruzi in
Immunocompetent and Immunosuppressed Murine Hosts
Judith
Molina,1,2
Olindo
Martins-Filho,1
Zigman
Brener,1
Alvaro J.
Romanha,3
David
Loebenberg,4 and
Julio
A.
Urbina5,*
Laboratorio de Doença de
Chagas1 and Laboratorio de Parasitologia
Celular e Molecular,3 Centro de Pesquisas Rene
Rachou, Fundaçao Oswaldo Cruz, Belo Horizonte, Minas Gerais,
Brazil; Departmento de Parasitología, Instituto de
Zoología Tropical, Universidad Central de Venezuela, Caracas
1041,2 and Laboratorio de
Química Biológica, Centro de Biofísica y
Bioquímica, Instituto Venezolano de Investigaciones
Científicas, Caracas 1020A,5 Venezuela;
and Schering Plough Research Institute, Kenilworth, New
Jersey 07033-05394
Received 29 April 1999/Returned for modification 24 September
1999/Accepted 25 October 1999
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ABSTRACT |
We have studied the in vivo activity of the new experimental
triazole derivative SCH 56592 (posaconazole) against a variety of
strains of the protozoan parasite Trypanosoma
(Schizotrypanum) cruzi, the causative
agent of Chagas' disease, in both immunocompetent and
immunosuppressed murine hosts. The T. cruzi strains used in the study were previously characterized as susceptible (CL), partially resistant (Y), or highly resistant (Colombiana, SC-28, and
VL-10) to the drugs currently in clinical use, nifurtimox and
benznidazole. Furthermore, all strains are completely resistant
to conventional antifungal azoles, such as ketoconazole. In the first
study, acute infections with the CL, Y, and Colombiana strains in
both normal and cyclophosphamide-immunosuppressed mice were treated
orally, starting 4 days postinfection (p.i.), for 20 consecutive daily doses. The results indicated that in immunocompetent animals SCH 56592 at 20 mg/kg of body weight/day provided protection (80 to 90%)
against death caused by all strains, a level comparable or superior to
that provided by the optimal dose of benznidazole (100 mg/kg/day).
Evaluation of parasitological cure revealed that SCH 56592 was able to
cure 90 to 100% of the surviving animals infected with the CL and Y
strains and 50% of those which received the benznidazole- and
nifurtimox-resistant Colombiana strain. Immunosuppression markedly
reduced the mean survival time of untreated mice infected with any of
the strains, but this was not observed for the groups which received
SCH 56592 at 20 mg/kg/day or benznidazole at 100 mg/kg/day. However,
the overall cure rates were higher for animals treated with SCH 56592 than among those treated with benznidazole. The results were confirmed
in a second study, using the same model but a longer (43-dose)
treatment period. Finally, a model for the chronic disease in which
oral treatment was started 120 days p.i. and consisted of 20 daily
consecutive doses was investigated. The results showed that SCH 56592 at 20 mg/kg/day was able to induce a statistically significant increase
in survival of animals infected with all strains, while benznidazole at
100 mg/kg/day was able to increase survival only in animals infected with the Colombiana strain. Moreover, the triazole was able to induce
parasitological cures in 50 to 60% of surviving animals, irrespective
of the infecting strain, while no cures were obtained with
benznidazole. Taken together, the results demonstrate that SCH 56592 has in vivo trypanocidal activity, even against T. cruzi strains naturally resistant to nitrofurans, nitroimidazoles, and conventional antifungal azoles, and that this activity is retained to a
large extent in immunosuppressed hosts.
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INTRODUCTION |
Chemotherapy of Chagas' disease
(American trypanosomiasis), a parasitic disease caused by the
kinetoplastid protozoan Trypanosoma (Schizotrypanum) cruzi which afflicts 16 to 18 million people in Latin America, remains an enormous scientific
and social challenge, as the drugs currently available, nitrofurans
(nifurtimox; Bayer) and nitroimidazoles (benznidazole; Roche,
São Paulo, Brazil), have little or no activity in the prevalent
chronic form of the disease and can also produce serious toxic effects
in the host (7, 8, 24, 26). Like many fungi and yeasts,
T. cruzi has a strict requirement of specific endogenous
sterols for cell viability and growth and is extremely sensitive to
sterol biosynthesis inhibitors in vitro (13, 16, 29, 31-33, 35,
36). However, currently available sterol biosynthesis
inhibitors, which are highly successful in the treatment of fungal
diseases, are not powerful enough to eradicate T. cruzi from
experimentally infected animals or human patients (3, 18,
20). Recent work from our laboratories has shown that new azole
derivatives (inhibitors of fungal cytochrome P-450-dependent
C14 sterol demethylase), such as D0870 (Zeneca
Pharmaceuticals) and SCH 56592 (Schering-Plough Research Institute,
Kenilworth, N.J.), are capable of inducing parasitological cures
in murine models of both acute and chronic Chagas' disease
(13, 29, 30, 33, 34) and are the first compounds ever to
display such activity. It has been shown that this special
antiparasitic activity results from the potent and selective
anti-T. cruzi activity and special pharmacokinetic
properties of these compounds, particularly their long
terminal half-lives and large volumes of distribution
(13, 29, 30, 33, 34). Although the development of D0870 has
recently been discontinued, numerous studies have consistently shown
that SCH 56592 has a potent and broad-spectrum antifungal activity in
vivo and is well tolerated in a variety of animal models and in humans
(6, 12, 14, 15, 21-23, 28; R. Petraitiene, V. Petraitis, A. Groll, M. Candelario, A. Field-Ridley, T. Sien, R. L. Schaufele, J. Bacher, and T. J. Walsh, Abstr. 39th
Intersci. Conf. Antimicrob. Agents Chemother., p. 582, abstr. 2004, 1999; M. A. Pfaller, I. Zerva, S. A. Messer, and R. N. Jones, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. F87, 1996; D. Skiest, D. Ward, A. Northland, J. Reynes, and W. Greaves, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., p. 491, abstr. 1162, 1999). Our recent studies with
this compound (33) have shown that it is the most potent sterol biosynthesis and antiproliferative agent ever tested
against T. cruzi, making it an attractive
candidate for the treatment of human Chagas' disease.
It has been known for a number of years that T. cruzi
strains differ widely in terms of their biological properties as well as their susceptibility to nitrofurans and nitroimidazoles
(2). Filardi and Brener (10), in a study of
a large number of clinical and natural isolates from
different geographical areas, found three main groups characterized as
susceptible, partially drug resistant, and highly drug resistant.
Both nitrofuran/nitroimidazole-susceptible and -resistant
strains have recently been shown to be resistant in vivo to
conventional antifungal azoles, such as ketoconazole, also an inhibitor
of the parasite's C14 sterol demethylase (1). In this work, as in a previous study (10), a strain is
defined as resistant to a given drug if the drug is unable to induce a parasitological cure with an experimental protocol (inoculum, dose and
duration of treatment) which produces sterilization of animals infected
with reference (susceptible) strains.
Many studies have also been devoted to the characterization of the role
of the immune system in the resistance of vertebrate hosts,
including humans, to T. cruzi and its involvement in
the pathogenesis of Chagas' disease, particularly in its chronic
form (4, 25, 30). The crucial role of the immune system in
the maintenance of the host-parasite balance in the indeterminate phase
of Chagas' disease has been highlighted recently by reports of
dramatic reactivation phenomena observed in chronic chagasic patients
immunosuppressed due to AIDS or pharmacological intervention (9,
27). Finally, recent studies have demonstrated the participation of stimulatory cytokines such as gamma interferon or interleukin-12 (IL-12) in the antiparasitic activity of benznidazole in murine models
of acute Chagas' disease (19).
In the present study we investigated the in vivo activity of SCH
56592 against a series of T. cruzi strains selected from among those previously characterized by Filardi and Brener
(10) in a variety of murine models, including
immunosuppressed hosts.
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MATERIALS AND METHODS |
Parasites.
The CL, Y, Colombiana, SC-28, and VL-10 strains
were previously characterized (10); the original isolates
have been maintained as trypomastigotes in liquid nitrogen,
periodically transferred to mice, and refrozen, with full
retention of their biological and drug resistance
characteristics. Handling of live T. cruzi was
done according to established guidelines (11).
Models of acute infection.
The protocol developed by Filardi
and Brener (10) was followed for studies of acute
infections. Briefly, groups of 10 immunocompetent or immunosuppressed
(see below) outbred female Swiss albino mice, weighing 18 to 20 g,
were inoculated intraperitoneally (i.p.) with 104 blood
trypomastigotes of the different strains; oral treatment was initiated
4 days postinfection (p.i.) and given daily for a total of 20 doses.
Surviving animals were monitored for 60 days. In a second study, normal
(immunocompetent) animals were infected with the same inoculum
(104) and treatment was started at 4 days p.i. but given
daily for 28 days, followed by a 7-day rest and another 15 days of
treatment (16, 29, 32-35). Surviving animals were monitored
for up to 113 days p.i. SCH 56592 was suspended in aqueous 2%
methylcellulose plus 0.5% Tween 80, while benznidazole was dissolved
in water containing 1% arabic gum; both drugs were given by gavage.
Control (untreated) animals received the vehicle as a placebo, which
had no detectable toxic effects.
Model of chronic infection.
Outbred female Swiss albino mice
weighing 18 to 20 g were inoculated i.p. with 30 blood
trypomastigotes of the different strains to allow the development of a
chronic, latent infection. After 120 days, surviving animals with no
circulating parasites were randomly divided into different treatment
groups (12 animals per group) and subjected to oral treatment for 20 consecutive days, as described above. Surviving animals were monitored
for up to 191 days p.i.
Parasitological and serological tests.
Parasitemia was
measured in a hemacytometer with tail blood. Hemocultures were carried
out by inoculating 5 ml of liver infusion medium with 0.2 to 0.4 ml of
blood obtained from the orbital sinuses of experimental animals.
Cultures were incubated without agitation at 28°C and examined for
the presence of proliferative epimastigote forms at 30 and 60 days.
Xenodiagnosis was done with 10 second-stage Rodnius prolixus
and Triatoma infectans nymphs per mouse; 30 to 40 days after
feeding, the insect feces were analyzed for T. cruzi metacyclic forms. Antibodies against live T. cruzi were
evaluated by the procedure of Martins-Filho et al. (17),
with minor modifications. Briefly, 5 × 105 live
trypomastigotes were incubated at 37°C for 30 min in the presence of
different dilutions (1:1,500 to 1:3,000) of serum from experimental
animals. The parasites were then washed once with phosphate-buffered
saline (PBS) containing 10% fetal bovine serum (FBS) and incubated at
37°C for 30 min in the dark in the presence of fluorescein
isothiocyanate (FITC)-conjugated anti-mouse immunoglobulin G (IgG)
antibody solution (Sigma Immunochemical Reagents, St. Louis, Mo.),
diluted 200-fold with PBS containing 10% FBS. Each assay included a
control in which parasites were not exposed to mouse serum but were
incubated with FITC-conjugated anti-mouse IgG. FITC-labeled parasites
were washed once with PBS containing 10% FBS and fixed at 4°C with
FACS FIX solution (1% [wt/vol] paraformaldehyde, 0.01% sodium
azide, 1% sodium cacodylate [pH 7.2]). Labeled parasites were
analyzed by cytofluorometry in a Becton Dickinson FACScan interfaced to
a digital Micro HP 9153C as described before (17).
Statistical analysis.
The Kaplan-Meier nonparametric method
was used to estimate the survival functions of the different
experimental groups and rank tests (log-rank and Peto-Peto-Wilcoxon)
were used to compare them. The analyses were done with the Survival
Tools package for StatView 4.5 run on a Power Macintosh 6500/250 computer.
Immunosuppression.
Animals were immunosuppressed by
treatment with two doses of cyclophosphamide given i.p. at 50 mg/kg of
body weight/day 2 days and 1 day before infection.
Drugs.
SCH 56592 {posaconazole,
(
)-4-[4-[4-[4-[[(2R-cis)-5-(2,4-difluorophenyl)-tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]- 2,4-dihydro-2-[(S)-1-ethyl-2(S)-hydroxypropyl]-3H-1,2,4-triazol-3-one} (Fig. 1) was provided by Schering Plough
Research Institute. Benznidazole (Rochagan) was a product of Roche.
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RESULTS AND DISCUSSION |
Effects of SCH 56592 on acute experimental infections
caused by drug-resistant T. cruzi strains in
immunocompetent and immunosuppressed mice.
In our initial studies,
a murine model of acute Chagas' disease previously designed to
characterize drug resistance among different T. cruzi
strains (10) was used. In this protocol mice were infected
with 104 bloodstream trypomastigotes of different T. cruzi strains; oral treatment was started 4 days p.i. and given
daily for 20 consecutive days. As can be seen in Fig.
2, with this protocol SCH 56592 at 20 mg/kg/day provided a high level of protection (80 to 90%) against death, which was comparable (CL and Y strains) or superior (Colombiana strain) to that observed with benznidazole at 100 mg/kg/day, which is
the optimal dose of this drug (10). Highly significant
statistical differences in survival were obtained between control
(untreated) and both drug-treated groups (P values in
log-rank and Peto-Peto-Wilcoxon tests were 
0.0001 and 0.0002
for SCH 56592 and 0.01 and 0.03 for benznidazole,
respectively). Parasitological cures in surviving animals were verified
by three independent criteria: hemoculture, xenodiagnosis, and
the presence of anti-live T. cruzi antibodies, detected by flow cytometry (17). Results are presented in
Table 1. Against the CL strain, which
is susceptible to nifurtimox and benznidazole (10) but
resistant to ketoconazole at doses as high as 120 mg/kg/day
(1), SCH 56592 at 20 mg/kg/day was able to cure 100% of the
surviving animals; this high cure rate was, as expected, comparable to
that obtained with benznidazole at 100 mg/kg/day. For the Y strain,
previously characterized as partially resistant to nitrofurans and
nitroimidazoles but completely resistant to ketoconazole (1,
10), benznidazole at 100 mg/kg/day was able to cure less
than 50% of the surviving animals while the cure rate for
animals which received SCH 56592 at 20 mg/kg/day approached 90%. For
the Colombiana strain, benznidazole at 100 mg/kg/day was unable to
induce parasitological cures, in agreement with previous results
(10), but 50% of the surviving animals which received
SCH 56592 at 20 mg/kg/day were cured. This is the first report of such
a high level of parasitological cure in experimental infections with
drug-resistant T. cruzi strains. These results show
that the mechanisms of resistance against benznidazole, nifurtimox, and conventional azoles in T. cruzi are much less effective
against recently developed triazoles, which are inhibitors of
C14 sterol demethylase; this fact could be explained
by a higher affinity of the latter to their biochemical target
(D. Sanglard, F. Ischer, J. Bille, Abstr. 37th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. C-11, 1997) and/or the
differential interaction of the drugs with the cell's detoxifying
systems.
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FIG. 2.
Effects of SCH 56592 and benznidazole treatment on
survival of immunocompetent and immunosuppressed hosts in a murine
model of acute Chagas' disease. Immunocompetent (A to C) and
immunosuppressed (D to F) female albino Swiss mice were each challenged
with 104 blood trypomastigotes of the CL (A and D), Y (B
and E), or Colombiana (C and F) strain, and oral treatment was
initiated 4 days p.i. for a total of 20 daily consecutive doses. Each
experimental group contained 10 animals. Symbols:  , control
(untreated) animals;  , animals which received SCH 56592 at 20 mg/kg/day;  , animals which received benznidazole at 100 mg/kg/day.
Statistical analyses of the survival plots were carried out using both
the log-rank (Mantel-Cox) and Peto-Peto-Wilcoxon tests. For details,
see the text.
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TABLE 1.
Effects of SCH 56592 and benznidazole in immunocompetent
and immunosuppressed murine models of acute Chagas' disease with
different strains of T. cruzi
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|
To evaluate the role of the immune system in the antiparasitic activity
of benznidazole and SCH 56592, mice were immunosuppressed
by treatment
with 50 mg of cyclophosphamide per kg during two
consecutive days
previous to infection; animals were then infected
and given
antiparasitic treatment as described above for normal
(immunocompetent)
animals. Figure
2 shows survival plots for the
different
experimental groups. It was found that immunosuppression
led to a
significant (
P 0.04 [log-rank test] in all cases)
reduction
in the mean survival time for all strains (mean survival
times
for control and immunosuppressed animals were 26.9 and 18.9 days,
25.2 and 14.8 days, and 29.1 and 22.3 days for the CL, Y, and
Colombiana strains, respectively). Nevertheless, as in
immunocompetent
animals, there were very significant differences
in survival between
control and drug-treated groups (
P
values in log-rank and Peto-Peto-Wilcoxon
tests of
0.0001 and
0.0002 for SCH 56592 and 0.001 and 0.003
for benznidazole,
respectively), while there were no significant
differences in
survival between immunocompetent and immunosuppressed
animals which
received either drug treatment. For all strains,
survival levels for
immunosuppressed animals which received SCH
56592 at 20 mg/kg/day were
higher than those for mice receiving
benznidazole at 100 mg/kg/day, but
there was no statistically
significant difference between data for the
two drugs. These results
clearly show that both drugs can protect
from a lethal parasitic
infection, even in the presence of a severe
immunosuppression.
Evaluation of the parasitological cure (Table
1) revealed that, while
immunosuppression did not affect significantly the
level of cures
induced by SCH 56592 in animals infected with the
susceptible CL or
drug-resistant Colombiana strain, it had a significant
effect in
animals infected with the partially drug-resistant Y
strain (Table
1).
However, even in immunosuppressed animals,
the overall cure rates for
animals infected with the Y or Colombiana
strain and treated with the
triazole remained higher than values
for those treated with
benznidazole. These results indicate that
the potent anti-
T.
cruzi effects of SCH 56592 against the Y strain
in normal hosts
are partially dependent on cooperation from the
immune system but also
that its trypanocidal activity is higher
than that of benznidazole even
in immunosuppressed animals. Recent
studies have demonstrated that
early activation of the immune
system by cytokines such as IL-12 may be
involved in the trypanocidal
activity of benznidazole in acute
murine infections with
T. cruzi (
19). The results
described above suggest that the anti-
T. cruzi effects of
SCH 56592 may be further enhanced when it is used in
combination with
IL-12 and related
cytokines.
In a second set of experiments the same acute model was used but with a
longer treatment course, starting 4 days p.i. and
given daily for 28 consecutive days followed by a 7-day rest and
another 15 days of
treatment, for a total of 43 doses. This course
of treatment was used
in our previous studies that first demonstrated
the in vivo
trypanocidal effects of both D0870 and SCH 56592 (
13,
16,
32-35). In addition, other
T. cruzi strains (SC-28
and VL-10,
both nifurtimox and benznidazole resistant
[
10]) were included
in the study. As shown in Table
2, with this protocol SCH 56592
given at
10 mg/kg/day was able to induce very high (90 to 100%)
survival
levels for all strains, comparable or superior to those
obtained with
benznidazole at 100 mg/kg/day. It can be seen in
Table
3 that SCH 56592 at just 5 mg/kg/day
produced levels of
parasitological cures which were comparable to those
obtained
with benznidazole at 100 mg/kg/day, but when the triazole was
given at 20 mg/kg/day, cure rates reached 80 to 100% in survivors
infected with the susceptible and partially drug-resistant strains
and
55 to 100% in those infected with the drug-resistant strains.
The
results confirmed those of the initial study and demonstrated
that SCH
56592 can eliminate both susceptible and drug-resistant
parasite
populations from murine hosts.
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TABLE 2.
Effects of SCH 56592 and benznidazole in a murine model
of acute Chagas' disease with different strains of
T. cruzi
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TABLE 3.
Effects of SCH 56592 and benznidazole in a murine model
of acute Chagas' disease with different strains of
T. cruzi
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In vivo activity of SCH 56592 and benznidazole in a murine
model of chronic Chagas' disease with different T. cruzi strains.
In a third model of infection, mice
were infected with a small inoculum of blood trypomastigotes (30 per
animal) of the CL, Y, or Colombiana strain, which led to a more
controlled infection and higher survival levels. Animals that survived
after 120 days and had developed a chronic, latent infection with
no circulating parasites were treated orally with the short
(20 consecutive daily doses) protocol described above. As shown
in Fig. 3, for all strains, animals which
received SCH 56592 at 20 mg/kg/day had survival curves with highly
significant statistical differences from curves for untreated controls
(P values for both log-rank and Peto-Peto-Wilcoxon tests of
0.0035) while for those receiving benznidazole at 100 mg/kg/day,
statistically significant differences were only observed with the
Colombiana strain (P values for both log-rank and
Peto-Peto-Wilcoxon tests of 0.03). Table
4 shows that SCH 56592 at 20 mg/kg/day was able to cure 50 to 60% of the surviving animals,
independently of the infecting strain, while no cures were
observed with benznidazole at 100 mg/kg/day. The levels of cure
observed in this chronic model were lower than those obtained in a
previous study with the Bertoldo strain (33), a fact which
could be explained by intrinsic differences between the strains and/or
by the longer treatment (total of 43 doses) used in that study.
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FIG. 3.
Effects of SCH 56592 and benznidazole
treatment on survival of immunocompetent hosts in a murine model of
chronic Chagas' disease. Normal female albino Swiss mice were each
challenged with 30 blood trypomastigotes of the CL (A), Y (B), or
Colombiana (C) strain, and oral treatment was initiated 120 days p.i.
for a total of 20 daily consecutive doses. Each experimental group
contained 12 animals. Symbols: , control (untreated) animals; ,
animals which received SCH 56592 at 20 mg/kg/day; , animals which
received benznidazole at 100 mg/kg/day. Statistical analyses of the
survival plots were carried out with both the log-rank
(Mantel-Cox) and Peto-Peto-Wilcoxon tests. For details, see the text.
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TABLE 4.
Effects of SCH 56592 and benznidazole in a murine model
of chronic Chagas' disease with different strains of
T. cruzi
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A recent report demonstrated the possibility of inducing azole
resistance in
T. cruzi by exposing mammalian stages of the
parasite to increasing concentrations of fluconazole in vitro
(
5). Cross-resistance was demonstrated with other azoles,
such
as ketoconazole, both in vitro and in vivo. However, there was
a
significant reduction in the virulence of the azole-resistant
parasites, a fact that could indicate a possible relationship
between
the mechanism of drug resistance and loss of viability
of the parasite
in its mammalian host (
5). In the present work
we found that
naturally ketoconazole-resistant strains are highly
susceptible to the
triazole derivative SCH 56592. Our results
agree with those obtained by
Oakley et al. (
21) and Lozano-Chiu
et al. (
14),
who demonstrated that SCH 56592 was active, both
in vitro and in vivo,
against
Aspergillus and
Fusarium
populations
completely resistant to the currently available azoles
(fluconazole
and itraconazole). It has been argued before
(
33) that the superior
intrinsic antifungal and
antiprotozoal activity of SCH 56592 could
probably be associated with
the higher affinity of this triazole
derivative to its biochemical
target, cytochrome P-450-dependent
C
14 sterol
demethylase (Sanglard et al., 37th
ICAAC).
In conclusion, our results indicated that SCH 56592 has trypanocidal
activity against a variety of
T. cruzi strains, including
benznidazole-, nifurtimox-, and ketoconazole-resistant organisms,
in
murine models of both acute and chronic Chagas' disease and
that this
activity is retained to a large extent even if the host
is
immunosuppressed. Such results have been obtained before only
with the bis-triazole D0870 (J. Molina, M. S. S. Araujo, M. E.
S. Pereira, Z. Brener, and J. A. Urbina,
Abstr. 37th Intersci.
Conf. Antimicrob. Agents Chemother., abstr.
B-41b, 1997; Molina
et al., unpublished data) but are consistent
with recent reports
on the efficacy of SCH 56592 in the treatment and
prevention of
invasive pulmonary aspergillosis in persistently
neutropenic rabbits
(Petraitiene et al., 39th ICAAC) as well as in the
treatment of
azole-refractory candidiasis in human immunodeficiency
virus-infected
patients with advanced AIDS (Skiest et al., 39th ICAAC).
Taken
together, these results support the proposal that SCH 56592 be
considered for clinical trials in human Chagas'
disease.
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ACKNOWLEDGMENTS |
This work received financial support from Programa de Apoio a
Nucleos de Excelencia do MCT (PRONEX # 2704), Brazil, and the UNDP/World Bank/World Health Organization Programme for Research and
Training in Tropical Diseases (grant 970297).
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FOOTNOTES |
*
Corresponding author. Mailing address: Laboratorio de
Química Biológica, Centro de Biofísica y
Bioquímica, Instituto Venezolano de Investigaciones
Científicas, Apartado 21827, Caracas 1020A, Venezuela. Phone:
58-2-5041479. Fax: 58-2-5041093. E-mail:
jaurbina{at}cbb.ivic.ve.
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Antimicrobial Agents and Chemotherapy, January 2000, p. 150-155, Vol. 44, No. 1
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
