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Antimicrobial Agents and Chemotherapy, January 2000, p. 19-23, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Therapeutic Efficacy of Human Macrophage
Colony-Stimulating Factor, Used Alone and in Combination with
Antifungal Agents, in Mice with Systemic Candida
albicans Infection
Tetsuya
Kuhara,1,*
Katsuhisa
Uchida,2 and
Hideyo
Yamaguchi2
Biochemical Research Laboratory, Morinaga
Milk Industry Co., Ltd., Kanagawa,1 and
Research Center for Medical Mycology, Teikyo University,
Tokyo,2 Japan
Received 8 February 1999/Returned for modification 31 July
1999/Accepted 9 October 1999
 |
ABSTRACT |
We examined the in vivo activity of human macrophage
colony-stimulating factor (hM-CSF) against lethal Candida
albicans infection in mice. In C. albicans-infected
mice which had been immunosuppressed with cyclophosphamide, treatment
with hM-CSF at a daily dose of 8 × 105 units/kg of
body weight or greater slightly but significantly prolonged survival.
Furthermore, the therapeutic efficacy of amphotericin B (AMPH-B) in
infected mice was enhanced by its combined use with hM-CSF, while that
of fluconazole (FLCZ) was not. The activities of peritoneal macrophages
and neutrophils from mice administered hM-CSF plus AMPH-B in
combination for inhibition of hyphal growth of C. albicans
cells and intracellular phagocytosis and killing of the cells were
greater than those of comparable phagocytic cells from control mice to
which hM-CSF plus AMPH-B was not administered. These results suggest
that intravenous administration of hM-CSF augments the efficacy of
AMPH-B by enhancing the antifungal activities of macrophages and
neutrophils. Therefore, it is expected that therapy with the
combination AMPH-B and hM-CSF could improve the efficacy of AMPH-B and
reduce the therapeutic dose of the antifungal drug that is required.
| |
INTRODUCTION |
It is widely accepted that
immunocompromised hosts, particularly those with impaired phagocytic
cell function (mainly neutrophils and/or monocytes/macrophages) are at
high risk of infections caused by Candida,
Aspergillus, and several other opportunistic fungal pathogens. The survival, growth, and differentiation of progenitor cells of these phagocytes are known to be controlled by hemopoietic colony-stimulating factors (CSFs), of which four types of CSFs have
been recognized: granulocyte CSF (G-CSF), granulocyte/macrophage CSF
(GM-CSF), macrophage colony-stimulating factor (M-CSF), and multicolony-stimulating factor (interleukin-3 [IL-3]).
M-CSF is a hematopoietic glycoprotein that stimulates the proliferation
and differentiation of mononuclear progenitors into mature cells
(18, 30, 35) and promotes the production of other cytokines
(9, 13, 20, 32) by monocytes/macrophages. These properties
are indispensable to antimicrobial host defense, and there are an
increasing number of reports describing the in vitro or in vivo
antifungal effect of M-CSF (4, 14, 21, 22, 27, 28, 31).
Although some reports of clinical trials with human M-CSF (hM-CSF)
mentioned that it is useful as an adjunctive therapy in patients with
invasive fungal infections treated with conventional antifungal agents
(23, 24), there is limited backup information about the
usefulness of M-CSF in combination with antifungal agents against
fungal infections, and the clinical significance of M-CSF in
combination with antifungal agents is still unclear.
The present studies were designed to evaluate the potential usefulness
of hM-CSF in combination with two major antifungal drugs, amphotericin
B (AMPH-B) and fluconazole (FLCZ), against Candida albicans
infection in mice with immunosuppression induced by cyclophosphamide
(CY). The results showed that the administration of hM-CSF in
combination with AMPH-B markedly enhanced the preventive and
therapeutic effects of the antifungal drug against Candida infection, while hM-CSF administered to mice in combination with FLCZ
resulted in lower levels of enhancement of the effects of the
antifungal drug. We further showed that the anti-Candida
activities of hM-CSF-activated macrophages and neutrophils were
enhanced by AMPH-B when it was administered together with M-CSF.
| |
MATERIALS AND METHODS |
Animals.
Male inbred C3H/HeN mice (specific pathogen free)
were obtained from Charles River Japan, Kanagawa, Japan. The mice were
6 weeks of age at the time of the experiments.
Reagents.
hM-CSF was purified from human urine as described
previously (10). The specific activity was 2.8 × 108 U/mg of protein, as determined by a mouse bone marrow
colony formation assay (19), and the endotoxin content of
the preparation containing 100 µg of hM-CSF was less than 0.03 endotoxin units as measured by the Limulus assay (Limulus
HS-Single Test; Wako Pure Chemicals, Osaka, Japan). hM-CSF was
dissolved to the required concentration in sterile saline before use.
Commercially available intravenous (i.v.) preparations of AMPH-B
(Fungizone) and FLCZ (Diflucan) were purchased from Bristol-Myers
Squibb Co. (Tokyo, Japan) and Pfizer Inc. (Tokyo, Japan), respectively.
The former was dissolved in 5% glucose immediately before use.
Microorganism.
C. albicans TIMM1768 (2),
isolated from a patient with systemic candidiasis, was used in this
study. The yeast was cultured on Sabouraud glucose agar. At the time of
use, a small colony was taken from a subculture and inoculated into YPG
broth (0.5% yeast extract, 1% polypeptone, 2% D-glucose)
and was grown with shaking (200 rpm) for 16 h at 37°C. Yeast
cells were harvested and washed three times with sterile saline by
centrifugation at 500 × g for 5 min. The number of
yeast cells in a suspension was measured with a hemocytometer, and the
yeast cells were adjusted to a suitable concentration with sterile saline.
In vivo study.
Mice were injected intraperitoneally (i.p.)
with 100 mg of CY (Shionogi Pharmaceuticals, Osaka, Japan) per kg of
body weight. The immunosuppressed mice were infected i.v. with a lethal
dose of C. albicans (5 × 104 cells per
mouse) 5 days after CY injection. Beginning on the next day, the mice
were administered the indicated i.v. doses of hM-CSF or vehicle sterile
saline, alone and in combination with subcutaneous (s.c.) doses of
AMPH-B (100 µg/kg) or FLCZ (500 µg/kg), once a day for 5 days. To
detect the enhancing effect of hM-CSF, the minimal effective doses of
AMPH-B and FLCZ were used. In some experiments, mice were administered
an i.v. dose of M-CSF once a day for 4 days, beginning 1 day after CY
injection. The animals were subsequently infected with C. albicans and were administered s.c. doses of antifungal drugs for
5 days, beginning 1 day after the infection. The number of animals
surviving in each group was determined every day until the end of the
3-week experimental period. These experiments were repeated five or six times with groups of five mice each time. The total number of mice
tested is indicated in the figure legends.
Preparation of neutrophils and macrophages.
hM-CSF and/or
AMPH-B was injected into healthy mice in the same manner as described
above for the in vivo study. To isolate murine neutrophils
(1), the mice were injected i.p. with 2 ml of an 8% casein
sodium (Tokyo Kasei, Tokyo, Japan) solution in saline. Six hours later,
peritoneal cells were collected, washed with phosphate-buffered saline
(PBS), and suspended in Tris-buffered ammonium chloride (1 mM
Tris-acetate [pH 7.5], 0.833% ammonium chloride) to lyse the
erythrocytes. The residual cells were resuspended in RPMI 1640 (Flow
Laboratories, Inc., McLean, Va.) containing 7.5% heat-inactivated
fetal calf serum and 100 µg of penicillin-streptomycin per ml, which
was designated a complete medium, and then the cell suspension was
layered onto 10 ml of 90% Ficoll Hypaque (Pharmacia Fine Chemicals,
Piscataway, N.J.). After centrifugation at 300 × g for
30 min at room temperature, a neutrophil-rich pellet was obtained,
washed with PBS, and resuspended in complete medium. The final cell
suspension routinely consisted of more than 95% neutrophils, as
confirmed by Diff-Quick staining (American Scientific Products, McGaw
Park, Ill.).
To prepare murine macrophages, mice into which hM-CSF and/or AMPH-B was
injected were i.p. administered 2 ml of 4% Brewer thioglycolate medium
(Difco Laboratories, Detroit, Mich.). Four days later, the peritoneal
cells were collected, and after lysing of the erythrocytes, the
peritoneal cells were resuspended in complete medium. They were
adjusted to 106 cells/ml with the same medium and were
seeded in flat-bottom microplates (105 cells/well). After
incubation for 1 h at 37°C in a 5% CO2 incubator, nonadherent cells were removed. Adherent cells consisting of over 95%
macrophages were designated peritoneal macrophages (29).
Assay for Candida hyphal growth inhibition by
phagocytes.
To determine neutrophil- or macrophage-mediated
inhibition of C. albicans hyphal growth, we used a
[3H]glucose incorporation assay technique (6).
One hundred microliters of a neutrophil suspension or macrophage
suspension (1 × 106 cells/ml) in complete medium was
seeded into triplicate wells of flat-bottom microplates (100 µl/well), and then 100 µl of a C. albicans suspension
(4 × 104 cells/ml) was added to these wells, yielding
an effector cell:target cell (E/T) ratio of 25:1. After the cell
mixtures were incubated for 16 h at 37°C in a humidified
atmosphere of 5% CO2, the culture supernatants were
removed and replaced by 50 µl of [3H]glucose (specific
activity, 40 Ci/mmol [1,480 GBq/mmol]; ART 312, Glucose D-L5,
6-3H; American Radiolabeled Chemicals Inc., St. Louis, Mo.)
diluted to 10 µCi/ml in sterile water. After an additional 1.5 h
of incubation, 50 µl of 5.25% sodium hypochlorite was added to the
incubation mixture. The growing Candida cells containing
[3H]glucose in each well were collected with a MASH
harvester, and [3H]glucose incorporation was measured
with a scintillation counter. The percent growth inhibition of C. albicans was calculated as follows: 1 
(counts per minute
of C. albicans incubated with effector cells/counts per
minute of C. albicans incubated alone) × 100.
Assay of phagocytosis and C. albicans killing by
macrophages.
For the phagocytosis assay, C. albicans
cells were added to wells of flat-bottom microplates containing
macrophages, yielding an E/T ratio of 2:1. The plates were centrifuged
at 500 × g for 10 min. After a 30-min incubation, the
wells were washed thoroughly and a 0.05% deoxycholic acid solution in
sterile water was added to the wells to lyse the macrophages. To
determine fungicidal activity, complete medium was added to the wells
of the plate, which was then incubated for a further 5 h before
the macrophages were lysed. After dilution with sterile water, the
numbers of viable C. albicans cells in the wells were
determined by the conventional plate count method on Sabouraud glucose
agar as described above. The phagocytotic ability and fungicidal rate
were calculated as follows: phagocytotic ability (in percent) = (number of remaining viable Candida cells in or on
macrophages at 30 min of incubation/total number of Candida
cells added) × 100, and fungicidal rate (in percent) = [1 (number of viable Candida cells at 30 min number of viable yeast cells at 5 h)/number of viable
Candida cells at 30 min] × 100.
Statistical analysis.
Survival rates were evaluated by
Kaplan-Meyer analysis and the Wilcoxon signed-rank test. The
statistical significance of differences between groups of other data
was determined by an analysis of variance by the Tukey-Kramer test. The
difference was significant if P was <0.05.
| |
RESULTS |
Effect of hM-CSF against Candida infection.
In the
present study, mice with CY-induced leukopenia were infected with
C. albicans. When mice were treated with CY at a single i.p.
dose of 100 mg/kg, the total number of leukocytes in the peripheral
blood decreased to approximately 60% of that for untreated control
animals 4 days after the injection and then gradually returned to the
normal level within 2 or 3 days (data not shown). Consistent with this,
CY-treated animals were found to be highly susceptible to relatively
small numbers of C. albicans cells (5 × 104 cells per mouse) 4 days after CY injection. All such
mice infected with C. albicans died within 8 days, with a
median survival time (MST) of 5.0 days (Fig.
1). CY-treated mice administered hM-CSF showed a slight but significant resistance to C. albicans.
As seen in Fig. 1, mice receiving hM-CSF at a daily dosage of 8 × 105, 4 × 106, or 2 × 107 U per kg for 5 days from day 1 to day 5 postinfection
had a slight but statistically significantly prolonged survival time
compared with the survival times for the vehicle-treated controls. The greatest efficacy was obtained with 4 × 106 U of the
cytokine per kg, with an MST of 9.0 days, although all the animals had
died by 14 days.
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FIG. 1.
Therapeutic effect of hM-CSF on C. albicans
infection in CY-treated mice. Mice were inoculated i.v. with C. albicans (5 × 104 yeast cells per mouse) 5 days
after CY injection. Vehicle or hM-CSF was given i.v. to the mice once
daily for 5 days starting 1 day after infection. The total number of
mice in each group was as follows: vehicle, n = 30;
hM-CSF at 8 × 105 U/kg, n = 25;
hM-CSF at 4 × 106 U/kg, n = 30;
hM-CSF at 2 × 107 U/kg, n = 25. *,
P < 0.05 (significant difference among the
treatments).
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|
Effect of hM-CSF in combination with antifungal drugs against
Candida infection.
To study the potential usefulness
of combination therapy of antifungal drugs with hM-CSF as an
immunotherapeutic agent, experiments were conducted with the two major
antifungal drugs, AMPH-B and FLCZ, which were administered to C. albicans-infected leukopenic mice, alone and in combination with
hM-CSF, starting on day 1 postinfection. Low doses of the antifungal
drugs which did not show a remarkable efficacy when they were used
alone were chosen; daily doses of 100 µg of AMPH-B per kg and 500 µg of FLCZ per kg were given s.c. to mice once a day for 5 days
starting 1 day after infection. Figure 2A
shows the results of an experiment in which AMPH-B was administered
alone and/or in combination with hM-CSF. That dose of AMPH-B was
slightly efficacious in prolonging survival (MST, 9.0 days, versus 5.0 days for vehicle-treated controls). As indicated in Fig. 1,
administration of the most effective dosage of hM-CSF (4 × 106 U/kg/day for 5 days) was begun 1 day after C. albicans infection. As shown in Fig. 2A, when hM-CSF treatment was
combined with AMPH-B therapy, remarkable efficacy against
Candida infection was evident. The MST was prolonged over 21 days (cf. MSTs of 9.0 days for AMPH-B alone and hM-CSF alone), and the
survival rate over a 3-week period reached 73.3% (cf. survival rates
of 13.3% for AMPH-B alone and 0% for hM-CSF alone). Figure 2B shows
the results of FLCZ injection alone and/or in combination with hM-CSF.
FLCZ alone was about as effective as AMPH-B alone in respect to MST (no
significance was detected by the Tukey-Kramer test). The combined use
of FLCZ with hM-CSF also significantly prolonged the MST to 12.0 days but did not increase the survival rate during the experimental period.
These results demonstrate that therapy with AMPH-B in combination with
hM-CSF is significantly more effective than AMPH-B monotherapy and
that, in combination therapy with hM-CSF, the efficacy of AMPH-B
treatment is significantly greater than that of FLCZ treatment.
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FIG. 2.
Combined therapeutic effect of hM-CSF with AMPH-B (A) or
FLCZ (B) administration on C. albicans infection in
CY-treated mice. Mice were given hM-CSF (4 × 106
U/kg) as described in the legend to Fig. 1. AMPH-B (100 µg/kg) or
FLCZ (500 µg/kg) was given s.c. to the mice once daily for 5 days
concurrently with hM-CSF administration. The total number of mice in
each group was 30. *, P < 0.05 (significant
difference among the treatments).
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|
Figure
3 shows the results of experiments
which were conducted under the same conditions as those for the
experiments whose
results are presented in Fig.
2, except that the
administration
of hM-CSF (4 × 10
6 U/kg/day for 4 days) was started 4 days before infection. As
seen in Fig.
3, AMPH-B
(Fig.
3A) and FLCZ (Fig.
3B) administered
alone significantly prolonged
the survival times (MSTs, 9.5 and
9.0 days, respectively) compared with
that for the vehicle-treated
control mice (MST, 5.0 days). The extent
of survival was similar
between groups of animals treated with AMPH-B
and FLCZ alone (the
difference was not significant). Pretreatment with
hM-CSF rendered
the mice more resistant to lethal
Candida
infection compared with
the resistance of control mice treated with the
vehicle (MSTs,
9.0 versus 5.0 days). In hM-CSF-pretreated mice,
subsequent administration
of AMPH-B and FLCZ significantly protected
the animals from infection,
as determined by prolongation of the
survival time (MSTs, >21.0
days for AMPH-B-treated mice and 12.5 days
for FLCZ-treated mice)
and the survival rate (70% for AMPH-B-treated
mice).
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FIG. 3.
Combined prophylactic effect of hM-CSF with AMPH-B (A)
or FLCZ (B) administration on C. albicans infection in
CY-treated mice. Mice were inoculated i.v. with C. albicans
(5 × 104 yeast cells per mouse) 5 days after CY
injection. Vehicle or hM-CSF (4 × 106 U/kg) was given
i.v. to mice once daily for 4 days starting 1 day after CY injection
until 1 day before infection. AMPH-B (100 µg/kg) or FLCZ (500 µg/kg) was given s.c. to the mice once daily for 5 days after
infection. The total number of mice in each group was 10. *,
P < 0.05 (significant difference among the
treatments).
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|
Effect of hM-CSF, alone and in combination with AMPH-B, on
macrophage function in ex vivo assays.
The possible
immunopotentiating activity of hM-CSF, alone and in combination with
AMPH-B, against macrophages was studied with ex vivo assay systems in
which the growth-inhibitory activities, phagocytic activities, and
fungicidal activities of macrophages from mice treated with 4 × 106 U of the cytokine per kg and/or 100 µg of AMPH-B per
kg against C. albicans were tested. As shown in Table
1, macrophages harvested from mice that
had been treated with hM-CSF in combination with AMPH-B significantly
inhibited C. albicans hyphal growth compared with the
inhibition caused by the corresponding cells from mice treated with
vehicle or AMPH-B alone. Table 1 also shows that treatment with AMPH-B
alone did not significantly enhance the fungal growth-inhibitory
activities of macrophages but that the ability of hM-CSF to increase
the antifungal activities of macrophages did appear, although to a
slight extent, to be enhanced by the use of AMPH-B in combination.
Furthermore, as shown in Table 2, macrophages from mice treated with hM-CSF in combination with AMPH-B
were more active than the corresponding cells from vehicle-treated mice
in the phagocytosis and intracellular killing of Candida cells. These abilities of macrophages from mice treated with hM-CSF and
AMPH-B in combination were more prominent than those of macrophages from mice treated with the cytokine alone or AMPH-B alone (Table 2).
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TABLE 1.
Effect of treatment of mice with hM-CSF and AMPH-B on in
vitro C. albicans growth-inhibitory activities
of macrophagesa
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TABLE 2.
Effect of treatment of mice with hM-CSF and AMPH-B on in
vitro phagocytic and fungicidal activities
of macrophagesa
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|
Effect of hM-CSF, alone and in combination with AMPH-B, on
neutrophil function in ex vivo assays.
Since neutrophils are known
to be more potent than macrophages as direct effector cells against
C. albicans, the fungal growth-inhibitory activities of
neutrophils harvested from mice that had been treated with hM-CSF,
alone and in combination with AMPH-B, were investigated by using ex
vivo assay systems which were essentially the same as those used to
test macrophages. Table 3 shows that the
hyphal growth-inhibitory activities of neutrophils, which appeared to be more potent than those of macrophages (Table 1), were significantly increased by in vivo treatment with hM-CSF in combination with AMPH-B
compared with the activities after vehicle treatment, as was the case
for macrophages.
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TABLE 3.
Effect of treatment of mice with hM-CSF and AMPH-B on in
vitro C. albicans growth-inhibitory activities
of neutrophilsa
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| |
DISCUSSION |
Only a limited number of papers have reported that M-CSF-treated
monocytes increase the host's capability to kill fungal cells intracellularly (14, 35) and that the administration of
M-CSF to neutropenic mice infected with fungal microorganisms
significantly improved the survival of the animals compared with the
survivals obtained for placebo-treated controls (5). These
data suggest, however, that M-CSF directly enhances host resistance to
fungal infection by functionally activating monocytes or macrophages. One of the aims of the present study was to confirm these abilities of
hM-CSF by using both in vivo and ex vivo assay systems.
The results of the in vivo study demonstrate that hM-CSF restores the
reduced resistance of mice with CY-induced leukopenia to fungi. Our
findings are similar to those presented in previous papers in which the
effectiveness of recombinant hM-CSF against C. albicans
infection in rats or mice was described (5, 31). In this
connection, it has been demonstrated that hM-CSF enhances the
fungicidal activities of macrophages by augmenting phagocytosis (12, 14) and superoxide production (27). The
therapeutic efficacy of exogenous hM-CSF in the animal model of
systemic candidiasis may also be associated with its capabilities to
increase the number of monocytes/macrophages in the peripheral blood
(31) and to enhance the number and activities of neutrophils
by stimulating CSF (32) and IL-8 (9) production.
Our greater interest was on the potential of M-CSF to improve the
clinical outcome of therapy when used in combination with certain
antifungal drugs. Antifungal chemotherapy is generally required for
patients with fungal infections, and at present the main treatment is
AMPH-B or FLCZ. However, the clinical usefulness is hampered by the
serious side effects of AMPH-B and the limited efficacy of FLCZ,
particularly in immunocompromised patients. Therefore, some supportive
therapy with immunotherapeutic agents is believed to be necessary for
the immunological improvement of such patients.
Like G-CSF and GM-CSF, M-CSF is a promising candidate as an
immunotherapeutic agent for antifungal therapy. Prophylactic
administration of M-CSF to mice infected with C. albicans
following chemotherapy resulted in longer survival times
(5). When F344 rats with established C. albicans
infection were treated with a combination of FLCZ and M-CSF, there was
an increase in the survival time compared with that for rats receiving
FLCZ alone (31).
Similarly, it would appear that combination therapy of AMPH-B, a
"gold standard" antifungal drug, with M-CSF enhances the therapeutic efficacy of AMPH-B without increasing the dose and/or lowers the toxicity of AMPH-B by reducing the dose of the antifungal drug that is needed. However, there is little information about the
usefulness of M-CSF in combination with AMPH-B against fungal infections. Thus, we were tempted to investigate the therapeutic efficacy of AMPH-B, as well as that of FLCZ, when the drugs were used
in combination with hM-CSF against C. albicans infection in
CY-induced neutropenic mice. The results of this study demonstrate that
the therapeutic administration of hM-CSF improved survival and that
when hM-CSF was combined with AMPH-B, survival was remarkably prolonged. When given with hM-CSF, FLCZ also increased the survival significantly, but to a lesser degree than AMPH-B did, while both agents applied alone exhibited a lower degree of efficacy than when
they were applied with hM-CSF. Several investigators have shown the
synergistic benefits of FLCZ combined with M-CSF (4, 22,
31), as well as with G-CSF (26, 37) or IL-1
(15), in fighting fungal infections. The mechanism of the
synergistic action between FLCZ and M-CSF or some other cytokine by
which fungal growth is inhibited remains to be answered. Since FLCZ does not have substantial immunomodulating activity (3, 7, 25), it looks likely that it and cytokines may not act
synergistically on phagocytes to potentiate their antifungal activities
but that FLCZ concentrated in phagocytes may directly inhibit the
phagocytized fungi (33). In contrast, AMPH-B has a potent
immunostimulatory effect on macrophages and/or polymorphonuclear
leukocytes (8, 34, 36). Its stimulation of the antifungal
activities of macrophages is believed to be due to activation of an
oxidative burst upon phagocytosis (34),
NO2
production (11), and tumor
necrosis factor alpha production (17). Apart from this, as
macrophages also function as a concentrated reservoir of AMPH-B, those
into which the antibiotic is incorporated can be more active against
Candida than macrophages into which AMPH-B is not
incorporated (16). On the other hand, it is possible that
some pharmacokinetic interactions between hM-CSF and FLCZ or AMPH-B
could result in the potentiation of the activities of the antifungal
drugs through an intervention of the macrophages on the level and/or
retention time of the drugs in the blood and tissues. Pharmacokinetic
studies on this issue are warranted.
The present ex vivo studies demonstrated that AMPH-B plus hM-CSF
enhanced the growth-inhibitory activities of both of the two major
types of effector cells, macrophages and neutrophils, against
Candida. Clinical evaluation of the combination therapy with
AMPH-B plus hM-CSF in the treatment of patients with disseminated candidiasis and other deep-seated mycoses is thus warranted.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Biochemical
Research Laboratory, Morinaga Milk Industry Co., Ltd., 5-1-83 Higashihara, Zama, Kanagawa 228-8583, Japan. Phone: 81-462-52-3069. Fax: 81-462-52-3075. E-mail: t_kuhara{at}morinagamilk.co.jp.
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Abstract
Introduction
