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Antimicrobial Agents and Chemotherapy, March 1998, p. 654-658, Vol. 42, No. 3
Groupe de Recherche en Immunopathologie de la
Leishmaniose,
Received 28 July 1997/Returned for modification 21 October
1997/Accepted 24 December 1997
In the immunocompetent host, visceral leishmaniasis (VL) is a fatal
disease if untreated. In immunosuppressed patients, VL is an
opportunistic infection for which there is no effective treatment for
relapses. Here we report on the long-term activity of orally
administered hexadecylphosphocholine (HDPC) against established
Leishmania infantum infection in BALB/c mice. HDPC is a
synthetic phospholipid with antiproliferative properties that has been
extensively studied for its cancerostatic activity. Its short-term
leishmanicidal effects in mice recently infected with viscerotropic
Leishmania species have been previously reported. First, we
show that 5 days of oral therapy with HDPC (20 mg/kg of body
weight/day) led to amastigote suppression in the liver and the spleen
of 94 and 78%, respectively (versus 85 and 55% suppression by
meglumine antimonate in the liver and spleen, respectively), in mice
infected 6 weeks before treatment and examined 3 days after the end of
treatment. These results demonstrate the short-term efficacy of HDPC
against an established Leishmania infection. Next, the
long-term efficacy of HDPC was examined. In HDPC-treated mice both the
hepatic and splenic amastigote loads were significantly reduced (at
least 89%) 10, 31, and 52 days after the end of the treatment. In the
treated mice, the increase of the splenic load was significantly slower
than that in the untreated mice, demonstrating that the
HDPC-exerted inhibition of Leishmania growth persisted for
at least 7 to 8 weeks. Orally administered HDPC The viscerotropic
Leishmania species L. donovani and L. infantum (L. chagasi) may cause asymptomatic
infections, but clinically manifested human visceral leishmaniasis (VL)
is a fatal disease if untreated (33). Major epidemics of VL
have been reported in recent years in Brazil (24), Sudan
(56), and Bangladesh and India (1). An increasing
number of cases of VL are being diagnosed in human immunodeficiency
virus-positive patients, and VL has been designated an opportunistic
infection in the immunocompromised host (2).
Pentavalent antimonials remain, in most cases, an efficient
antileishmanial treatment, but they have to be administered
parenterally and may produce impairment of various vital functions,
although such impairment is usually reversible in immunocompetent
patients (3). In individuals coinfected with human
immunodeficiency virus the antimonial drugs are inefficient and toxic
(17, 30, 34, 53). Moreover, the emergence of
antimony-unresponsive strains has been registered in India (43,
44, 52), and increasing numbers of therapeutic failures have been
reported (5, 19). Amphotericin B has been shown to be
effective in immunocompetent individuals (5, 13-15, 43,
45), but some formulations resulted in serious side effects
(15, 16, 43). In immunosuppressed patients, a high-dose
liposomal amphotericin B regimen appeared to be safe and useful but was
ineffective in the treatment of relapses (27, 39). There is
no efficient therapy for leishmaniasis in dogs, the main reservoir of
L. infantum in Mediterranean areas. Therefore, in spite of
recent progress in chemotherapy for VL (22), the discovery
of new drug regimens is important. New formulations of old drugs
(10, 31) and potential new antileishmanial compounds (8, 25, 47) have been tested in experimental in vivo models and in in vitro studies.
In recent studies, orally administered
hexadecylphosphocholine (HDPC) (miltefosine) has shown promising
activity against viscerotropic Leishmania species in
BALB/c mice (12, 26). HDPC is a synthetic glycerol-free
phospholipid analog which has been widely studied for its
antiproliferative and cancerostatic properties. It is used as a topical
agent (11) and has been tested by the oral route in phase I
and II clinical antitumor trials (35, 46, 49), which have
provided valuable information on human tolerance for the drug. Clinical
trials of miltefosine in the treatment of VL in India are being planned
by the World Health Organization. In the present study we tested three
therapeutic schemes using the L. infantum-infected
BALB/c mouse model: i) short-term efficacy against a recent infection,
ii) short-term efficacy against an established infection, and iii)
long-term efficacy against an established infection. The experimental
protocols and the precise timing of the treatments are summarized in
Table 1. In all these conditions HDPC
proved to be nontoxic and highly efficient.
Drugs.
HDPC, as miltefosine, was a gift from Asta Medica
(Frankfurt, Germany); meglumine antimonate (MEGAN) (Glucantime; 85 mg
of antimony/ml) was purchased from Rhône-Poulenc-Rorer, Paris,
France.
Parasites and infection.
L. infantum MON1
(MHOM/FR/94/LPN101), isolated from a patient with VL, was
maintained by serial passages in Syrian hamsters. The promastigote form
was cultured under usual conditions (38, 42), and after
three in vitro passages, stationary-phase cells from 7-day-old cultures
were used at a concentration of 2.5 × 107
promastigotes/ml to infect BALB/c mice. For infection the parasites were washed twice by sedimentation at 2,500 × g at
4°C for 15 min each time, resuspended in 0.9% NaCl at 2 × 108 cells/ml, and injected into caudal vein at
108 promastigotes/mouse. Hereafter the day of infection
with L. infantum is termed day 0 (D0).
Mice and treatment.
Five-week-old female BALB/c mice,
purchased from Iffa Credo (Arbresle, France) and maintained in a
positive-pressure chamber (Flufrance) in our animal facility, were used
for experimentation at 6 weeks of age. After the injection of
Leishmania, the mice were randomly split into groups of 10 or 11 animals and were subsequently treated for 5 days, starting on D7,
D42, or D28 (Table 1), with either HDPC (20 mg/kg of body weight/day
administered orally through a soft feeding tube [Marquat; Genie
Biomedical] in 0.5 ml of H2O) or MEGAN (200 mg/kg of body
weight/day administered by subcutaneous injection in 0.5 ml of
H2O) or were left untreated (nontreated control [NTC]
group). Pursuant to the schedules of the experimental protocols
presented in Table 1, mice were anesthetized with sodium thiopental (50 µg/g of body weight) and sacrificed. Livers and spleens were taken
under sterile conditions and weighed. In the series of experiments
corresponding to protocol 3, mice maintained in the same cage were
randomly assigned to the HDPC and NTC groups to avoid any bias which
could arise from the caging.
Evaluation of Leishmania infection.
The
assessment of the amastigote burden was carried out by blinded
microscopic enumeration with Giemsa-stained liver and spleen touch
prints by two independent experienced parasitologists. The parasite
load was expressed in Leishman Donovan units (LDU, number of
amastigotes per 1,000 nucleated cells × organ weight [in grams] × 2 × 105), according to Stauber's formula
(40). The percent efficacy was calculated as [1 Statistics.
Due to the low number of animals per group (10 or 11 mice), statistical analyses were performed by using a
nonparametric test, i.e., the Kruskal-Wallis multiple comparison
z-value test. When two effects were analyzed, two-way
analysis of variance (ANOVA) was applied, followed by the Newman-Keuls
test.
Short-term efficacy against recent infection.
In a first
series of experiments we checked that the capacity of orally
administered HDPC to induce L. donovani (12, 26) and L. infantum (26) amastigote suppression in
BALB/c mice could be reproduced with the strain of L. infantum used in our laboratory. The treatment was initiated on D7
and was carried out for 5 consecutive days, and 3 days after the end of
the treatment (D14) mice were examined (Table 1). No adverse effects
were registered throughout the trial. No significant differences in the
body, liver, and spleen weights were detected between the groups. The
mean (± standard deviation [SD]) liver amastigote burden (expressed
in millions of LDU) on D14 was 158.9 ± 41.7 for the NTC group
(n = 10) compared to 0.52 ± 0.66 for the
MEGAN-treated group (n = 10) and 0.13 ± 0.24 for
the HDPC-treated group (n = 11). The amastigote
suppression efficacy of MEGAN was 99.7% and that of HDPC was 99.9%
(Kruskal-Wallis test, Short-term efficacy against established infection.
In the next
series of experiments we examined the capacity of HDPC to suppress
L. infantum amastigotes in an established infection. Figure
1 shows a typical time course of VL in
BALB/c mice (9, 32, 38, 51). At 6 weeks after
promastigote inoculation, i.e., at the end of the acute phase of
the disease, the parasite load in the liver is decreasing but still
high and in the spleen it is well detectable and increasing. The
treatments (HDPC and MEGAN) were thus started on D42, and mice were
examined 3 days after the end of the 5-day treatment. Table
2 shows the average body weights, the
relative liver and spleen weights, and the average hepatic and splenic
amastigote burdens for the treated and untreated mice on D49. The
parasite load in the liver was significantly higher in the NTC group
than in the HDPC-treated (z value = 4.291) or the
MEGAN-treated (z value = 3.039) mice, whereas in the
spleen only HDPC was significantly effective (z value = 3.283) (the z value for the MEGAN-treated group was 1.494).
No wasting was detected during the course of the disease in L. infantum-infected BALB/c mice, and as previously reported for VL
in mice due to L. infantum infection (38),
hepatomegaly was not detected either, in contrast to L. infantum infection in humans, dogs, and hamsters. The degree of
splenomegaly was notable, i.e., 3.3-fold normal spleen weight (which is
on average 100 [± 10] mg), and there was no significant difference
between the experimental groups (
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Short- and Long-Term Efficacy of
Hexadecylphosphocholine against Established Leishmania
infantum Infection in BALB/c Mice
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
the safe doses and
side effects of which are at least partially knownappears to be a
promising candidate for the treatment of VL.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
TABLE 1.
Assessment of HDPC efficacy against L. infantum infection in BALB/c mice:
experimental protocolsa
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
(mean amastigote load in treated mice/mean amastigote load in NTC)] × 100.
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
< 0.001) in these experimental conditions.
= 0.6), indicating that 3 days
after the end of HDPC uptake, inflammation was still present in spite
of the suppression of amastigotes.
View larger version (15K):
[in a new window]
FIG. 1.
Course of L. infantum infection in BALB/c
mice. Mice were inoculated with 108 stationary-phase
promastigotes/mouse via the caudal vein, and parasite loads were
evaluated on liver and spleen touch prints at the indicated time points
after injection. Visceral proliferation of amastigotes was quantified
in LDU (defined in Materials and Methods). Results are from a
representative infection experiment, and the values are means ± SD for three mice at each time point. Patterns were similar in seven
experiments.
TABLE 2.
Short-term efficacy of HDPC against established L. infantum infection in BALB/c micea
Long-term efficacy against established infection.
Our next aim
was to determine for how long after the end of the treatment HDPC
remained effective against the amastigote burden. Mice infected as
described above were left untreated or were treated orally with HDPC
for 5 consecutive days starting on D28 and were then examined after
prolonged time periods. Figure 2 shows
liver (Fig. 2A) and spleen (Fig. 2B) amastigote loads on D42, D63, and D84 for NTC and HDPC-treated mice (corresponding, respectively, to 10, 31, and 52 days after the end of the treatment). Between D42 and D84,
the parasite burden of L. infantum-infected untreated mice decreased in the liver and increased steadily in the
spleen (Fig. 1). In HDPC-treated mice the hepatic and splenic
amastigote loads (Fig. 2 and Table 3)
were suppressed by 98.8% on D42 and remained significantly lower
(around 90% suppression) than in the untreated controls throughout the
duration of the experiment. Two-factor (time and treatment group
effect, < 0.001) ANOVA indicated that even if the splenic parasite
loads increased in both the HDPC-treated and untreated mice (time
effect, < 0.001), the increase was less important on D84 in
HDPC-treated mice than in the control group (time-treatment interaction
effect, = 0.02). The data concerning body and organ weights were
analyzed by two-way ANOVA and Newman-Keuls test and are summarized in
Table 3. A moderate hepatomegaly was found which was slightly but
significantly higher at each time point for the NTC mice (treatment
effect, < 0.001) than for the HDPC-treated mice. Splenomegaly was
apparent and much more patent in the NTC group at all times ( < 0.001); moreover, a time-treatment interaction ( < 0.001) was evident, indicating that the increase of spleen weights was
much less important in HDPC-treated mice than in the NTC mice.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In this paper we report on a remarkable long-term in vivo activity of orally administered HDPC against established L. infantum infection in BALB/c mice.
The data from previous studies (12, 26) showed some dependence of the optimal dose of HDPC on the particular species of Leishmania and, within a species, on the particular isolate. Therefore, we first demonstrated that HDPC at 20 mg/kg of body weight/day showed a high short-term efficacy against recent infection with the strain of L. infantum used in our laboratory. For the sake of completeness, since a direct extrapolation of the drug doses from mice to humans is unreliable, it should be noted that in cancerology the recommended therapeutic dose of HDPC in humans has been established to be 2 to 3 mg/kg of body weight/day (35, 36, 49).
We next demonstrated the short-term efficacy of HDPC against a Leishmania infection which evolved for 6 weeks prior to drug administration. This phase of murine leishmaniasis corresponds to the end of the acute phase of the disease (9) and is characterized by a spontaneous decrease of the hepatic and a steady increase of the splenic parasite burdens (9, 32, 38, 51). In spite of the notable reduction of the amastigote load in the spleen, the splenomegaly was as important in HDPC-treated mice as in control groups, suggesting that there was no direct activity of HDPC on inflammation.
We then examined the stability of the effects of HDPC against the
infection. HDPC therapy was administered during the acute phase, and
the mice were examined 10, 31, and 52 days after the end of the
treatment. The amastigote loads were significantly lower in the spleens
and livers of HDPC-treated animals than in those of the controls at all
time points tested. Moreover, the progression of the splenomegaly and
the increase of the splenic load were found to be significantly lower
in HDPC-treated mice than in controls, demonstrating that parasite
suppression and the inhibition of growth persisted for at least 7 to 8 weeks after the end of the HDPC uptake. Although our data do not
provide a direct measure of the parasite killing (1 [amastigote load at the end of the treatment/amastigote load before
the start of the treatment]), they support the notion (26)
that HDPC induces effective leishmanicidal activity.
The spleen is one of the major sites of Leishmania multiplication in the natural infection. In BALB/c mice, the splenic parasite burden is initially quite low, but it increases steadily for at least 3 months, and unlike the hepatic burden, it does not decline spontaneously without treatment. The splenic efficacy of HDPC should be emphasized, since until recently splenectomy was performed as the last recourse for cases of antimony-resistant leishmaniasis. The efficacy of HDPC in the spleen is compatible with the available data on its tissue distribution. In the rat (29, 37), a steady-state level of the drug was achieved in several organs, and maximal concentrations of HDPC were found in the spleen, the kidney, and the adrenal glands. The prolonged effect of HDPC on parasite growth suggests a low catabolism and/or slow clearance, resulting in a long biological half-life for the drug. To our knowledge there is no available in vivo data on these issues. In cultured tumor cells (41), HDPC was detectable 48 h after its removal from the medium.
The mechanism of antileishmanial activity of HDPC is unknown. Part of HDPC's effects could be mediated by its stimulatory activity of the immune system. It was previously suggested (26) that HDPC could act as a costimulator for the interleukin 2-mediated activation of T cells (48). HDPC was shown to enhance gamma interferon, interleukin 3, and granulocyte-macrophage colony-stimulating factor (4, 23) expression and gamma interferon secretion in human mononuclear cells (23). More recently it was reported by several groups that HDPC had the capacity to induce macrophage activation and to stimulate NO release and tumor necrosis factor alpha production in human (18) and murine cells (54, 55). But a leishmanicidal activity against the promastigote form of L. infantum and L. donovani was also shown in in vitro assays (12, 26), and thus a direct killing of amastigotes cannot be excluded. This could be achieved by the interference of HDPC, whose uptake seems mediated via a receptor-independent endocytotic mechanism (20), with membrane lipid metabolism at various sites (7, 21, 50) and/or by its interference with signal transduction (6, 28) in host cells.
On the basis of these results and considered together with at least partial knowledge of its safe doses and side effects, and its administration by the oral route, HDPC appears to be a promising candidate for the treatment of human VL.
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ACKNOWLEDGMENTS |
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This work was supported, in part, by grants from the Ministry of Education and Research and from the University of Nice.
We thank Georgette Pagliardini for technical and administrative assistance, Clothilde Roptin for all intravenous injections, and Gilbert Dabbene for taking care of our animal facility.
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FOOTNOTES |
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* Corresponding author. Mailing address: Groupe de Recherche en Immunopathologie de la Leishmaniose, Laboratoire de Parasitologie, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 02, France. Phone: 33 4 93 37 76 84. Fax: 33 4 93 37 76 84. E-mail: kubar{at}unice.fr.
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