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Antimicrobial Agents and Chemotherapy, March 1999, p. 471-475, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Activities of NS-718, a New
Lipid Nanosphere Incorporating Amphotericin B, against
Aspergillus fumigatus
Takakazu
Otsubo,1
Shigefumi
Maesaki,1
Mohammad Ashraf
Hossain,1
Yoshihiro
Yamamoto,1
Kazunori
Tomono,1
Takayoshi
Tashiro,1
Junzo
Seki,2
Yoshifumi
Tomii,2
Satoru
Sonoke,2 and
Shigeru
Kohno1,*
The Second Department of Internal Medicine, Nagasaki
University School of Medicine, 1-7-1 Sakamoto, Nagasaki
852-8501,1 and Research Laboratories,
Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchicho, Kisshoin,
Minami-ku, Kyoto, 601-8550,2 Japan
Received 27 August 1998/Returned for modification 1 October
1998/Accepted 4 December 1998
 |
ABSTRACT |
We evaluated the in vitro and in vivo potencies of a new lipid
nanosphere that incorporates amphotericin B (AmB), NS-718, against
Aspergillus fumigatus. The in vitro activity of NS-718 (the
MIC at which 90% of strains are inhibited [MIC90], 0.25 µg/ml) against 18 isolates of A. fumigatus was similar to
that of deoxycholate AmB (D-AmB; Fungizone; MIC90, 0.25 µg/ml), but NS-718 was more potent than liposomal AmB (L-AmB;
AmBisome; MIC90, 1.0 µg/ml). The in vivo efficacy of
NS-718 in a rat model of invasive pulmonary aspergillosis was compared
with those of D-AmB and L-AmB. A low dose (1 mg/kg of body weight) of
L-AmB was ineffective (survival rate, 0%), although equivalent doses
of D-AmB and NS-718 were more effective (survival rate, 17%). However,
a higher dose of NS-718 (3 mg/kg) was more effective (survival rate,
100%) than equivalent doses of D-AmB and L-AmB (survival rate, 0%).
To explain these differences, pharmacokinetic studies showed higher
concentrations of AmB in the plasma of rats treated with NS-718 than in
the plasma of those treated with D-AmB. Our results suggest that
NS-718, a new preparation of AmB, is a promising antifungal agent with activity against pulmonary aspergillosis.
| |
INTRODUCTION |
The incidence of deep-seated mycosis
has increased, probably due to an increase in the number of compromised
hosts, e.g., patients with human immunodeficiency virus infection or
patients who have undergone organ transplantation. Despite the
introduction of new azole antifungal agents, such as fluconazole and
itraconazole, amphotericin B (AmB) is still the first choice for the
treatment of severe and refractory mycoses, particularly for invasive
pulmonary aspergillosis (IPA). However, the clinical usefulness of AmB
is often limited due to its adverse effects, including its
nephrotoxicity. In order to improve the therapeutic activity and lower
the toxicity of AmB, new drug delivery systems such as the lipid
microsphere (LM) that incorporates AmB (LM-AmB) (9),
liposomal AmB (L-AmB; AmBisome) (6, 10, 13), AmB colloidal
dispersion (Amphocil) (3), and AmB lipid complex (Abelcet)
(1) have been developed in the last 10 years. These new
forms of AmB are less toxic than deoxycholate AmB (D-AmB; Fungizone).
The lipid nanosphere (LNS), a new drug career, is composed of purified
soybean oil and purified egg yolk lecithin, and its structure and
composition are similar to those of LM, which is used as a carrier of
prostaglandins (15), steroids (16), and certain
anti-inflammatory drugs (17). LNS is smaller (25 to 50 nm)
than LM (200 nm). LNS was developed as a drug carrier by Nippon
Shinyaku Co., Ltd., Kyoto, Japan (20).
In the present study, we investigated the efficacy of an LNS that
incorporates AmB (NS-718) in vitro and in vivo in experimental IPA
caused by Aspergillus fumigatus.
| |
MATERIALS AND METHODS |
Fungal strains, antifungal agents, and MIC measurement.
We
used 18 clinical isolates of A. fumigatus isolated from the
sputum of patients with pulmonary aspergillosis at Nagasaki University
Hospital. The Aspergillus strains were identified by morphological methods and electrophoretic comparison of enzymes (12). D-AmB (Fungizone; Bristol-Myers Squibb K.K., Tokyo,
Japan), L-AmB (AmBisome; NeXstar Pharmaceuticals, Cambridge, United
Kingdom), and NS-718 (Nippon Shinyaku Co., Ltd.) were used in this
study. NS-718 is a lyophilized preparation and is composed of 10 mg of AmB, 1 g of soybean oil, 1 g of purified egg yolk lecithin,
and 2 g of maltose in a vial. After reconstitution with water, the average particle diameter was 25 to 50 nm, as determined by laser dynamic scattering analysis. D-AmB, L-AmB, and NS-718 were dissolved in
sterile distilled water.
The fungal isolates were cultured on potato dextrose agar plates
(Nissui Seiyaku, Tokyo, Japan) at 30°C for 2 weeks. The spores were
harvested with 1 ml of sterile saline containing 0.05% Tween 80 (Wako
Chemical, Tokyo, Japan). The final concentration of the spores in the
inoculum was adjusted to 3 × 103 CFU/ml. The MICs of
the antifungal agents were determined by a microdilution method
modified from the method of the National Committee for Clinical
Laboratory Standards (18) by using a round-bottom 96-well
plate. The plates were incubated at 30°C for 72 h and the
endpoint was defined as the point at which no growth was observed.
In vivo efficacy in rats with IPA.
Male Sprague-Dawley rats
(age, 5 weeks) were purchased from Charles River Japan (Yokohama,
Japan). Experimental IPA was induced in rats by the method described in
our previous report (14). Briefly, the rats were
immunosuppressed by subcutaneous injection of 150 mg of cortisone
acetate (Wako Pure Chemical Industries, Osaka, Japan) per kg of body
weight three times per week and were provided a low-protein diet (8%
protein diet; Oriental Yeasts Industries, Chiba, Japan). Cortisone was
continued for 1 week before and after inoculation (i.e., 1 week prior
to antifungal therapy). The low-protein diet was continuously provided
until the end of the study (28 days after inoculation). Tetracycline hydrochloride (250 mg/800 ml; Achromycin; Lederle Japan, Tokyo, Japan)
was added to the drinking water throughout the experiment to prevent
bacterial infection. A. fumigatus MF-13, which was isolated
from the sputum of a patient with pulmonary aspergilloma, was used for
infection. The experimental protocol was approved by the Ethics Review
Committee for Animal Experimentation of Nagasaki University School of Medicine.
Fungal isolates were cultured on potato dextrose agar plates at 30°C
for 4 days, and the conidia were harvested with 0.02% Tween 80. After
the conidia were washed, they were suspended in sterile saline and
counted in a hemocytometer. Three days after the third cortisone
acetate injection, the immunosuppressed rats were infected by
intratracheal inoculation of 105 spores in 0.1 ml of saline
by tracheostomy while they were under general anesthesia with enflurane
(Ethrane; Abbott Laboratories, Chicago, Ill.). One hundred microliters
of D-AmB, L-AmB, NS-718, or 5% dextrose (as control) was injected
through the lateral tail vein once daily for 8 days starting at 2 h after inoculation. For mycological studies, the animals were killed
after 1 or 3 days of inoculation, and the lungs were removed and
homogenized and were then suspended in sterile saline. One hundred
microliters of the suspension was inoculated onto Sabouraud dextrose
agar (BBL, Cockeysville, Md.), and the plates were incubated at 30°C for 48 h, followed by counting of the colonies.
Concentration of AmB in plasma.
D-AmB, L-AmB, or NS-718 was
administered (at 3.0 mg/kg) on the third day after infection, and a
laparotomy was performed while the rats were under general anesthesia
to exsanguinate and collect the whole blood through the inferior vena
cava. Determination of the AmB concentration by high-pressure liquid
chromatography (HPLC) was based on the method of Granich et al.
(5), with some modifications. Plasma samples (0.1 ml) were
combined with 1.0 ml of methanol containing 1.0 µg of the internal
standard 1-amino-4-nitronaphthalene (Aldrich, Milwaukee, Wis.) per ml, and the components were mixed by vortexing. After centrifugation at
3,000 rpm for 10 min, the supernatant was dried under reduced pressure
followed by redissolution with 0.2 ml of methanol for injection into
the high-pressure liquid chromatograph. The high-pressure liquid
chromatography system consisted of an SLC-10A system controller, an
LC-10AD pump, an SIL-10A autosampler with a 20-µl sampler loop, an
SCL-10A UV-visible detector set at 408 nm, a CTO-10AC column oven kept
at 40°C, and a C-R5A chromatopac data station (Shimadzu, Kyoto,
Japan). Analysis was performed with an L-column ODS (4.6 by 150 mm;
Chemicals Inspection and Testing Institute, Tokyo, Japan) equipped with
a LiChroCART guard cartridge (E. Merck, Darmstadt, Germany). The mobile
phase was a mixture of acetonitrile and 10 mM sodium acetate buffer (pH
4.0) (11:17; vol/vol), and the flow rate was 1.0 ml/min. The
concentration of AmB was determined from the ratio between the peak
height of AmB to that of the internal standard.
Biochemical study with immunosuppressed rats.
The rats
(Sprague-Dawley male rats; age, 5 weeks) in each group were
immunosuppressed but not infected and were treated by the regimen (AmB
at 3.0 mg/kg intravenously daily) for 8 days. Laparotomy was done
24 h after the last injection while the rats were under general
anesthesia. Blood was collected from the inferior vena cava for
measurement of serum glutamic oxalacetic transaminase (SGOT), serum
glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), and
creatinine levels by standard procedures.
Statistical analysis.
Data are expressed as means ± standard deviations. The effect of treatment on the survival rate was
tested by the generalized Wilcoxon test. Differences in the number of
fungi between organs were tested by Scheffe's multiple comparison
test. Differences in the serum biochemical profiles were tested by
Student's t test or the Welch test. A P value of
<0.05 was considered statistically significant.
| |
RESULTS |
In vitro activity of NS-718.
The MICs of D-AmB, L-AmB, and
NS-718 for 18 isolates of A. fumigatus are presented in
Table 1. The MIC of NS-718 (the MIC at
which 90% of strains are inhibited [MIC90], 0.25 µg/ml) was similar to that of D-AmB (MIC90, 0.25 µg/ml)
and was fourfold less than that of L-AmB (MIC90, 1.0 µg/ml).
In vivo activity of NS-718 against IPA.
As shown in Fig.
1, all control rats died within 6 days
after infection. The survival rate was less than 20% in all groups when a low dose of the drug (1.0 mg/kg) was used. NS-718 was
significantly more effective than L-AmB (survival rate, 0%;
P < 0.05). The efficacy of the high-dose therapy (3.0 mg/kg) is indicated in Fig. 2. NS-718 was
significantly more effective (survival rate, 100%) than D-AmB (survival rate, 0%; P < 0.05) and L-AmB (survival
rate, 0%; P < 0.05).
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FIG. 1.
Survival rates for rats with IPA treated with an
intravenous injection of 5% dextrose (×), NS-718 (), D-AmB ( ),
or L-AmB ( ) (dose, 1.0 mg of AmB per kg of body weight). Six rats
were used in each group. The study of the survival of rats with IPA was
repeated twice.
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FIG. 2.
Survival rates for rats with IPA treated with an
intravenous injection of 5% dextrose (×), NS-718 (), D-AmB (),
or L-AmB () (dose, 3.0 mg of AmB per kg of body weight). Six rats
were used in each group. The study of the survival of rats with IPA was
repeated twice.
|
|
Table
2 indicates the number of
aspergilli in the lungs of rats with IPA at 24 and 72 h after
inoculation. At 24 h after
inoculation, the numbers of aspergilli
in the lungs of rats treated
with L-AmB were similar to those in the
lungs of control rats.
The cell count in rats treated with NS-718 after
the same time
interval was significantly lower than that in control
rats. The
numbers of aspergilli in the lungs of rats 72 h after
treatment
with L-AmB were significantly lower than the numbers in
control
rats. The cell counts in NS-718- or D-AmB-treated rats after
the
same time period were significantly lower than the cell counts
in
those treated with L-AmB.
Concentration of AmB in the plasma of rats with IPA.
The
concentration of AmB in plasma measured 3 h after a single
administration of 3 mg of NS-718 per kg was higher than that measured
3 h after the administration of D-AmB, but the concentration decreased 12 h after injection and was similar to that in
D-AmB-treated rats. However, the plasma AmB concentration in
L-AmB-treated rats tended to be higher than those of the two other
forms of AmB 6 h after injection (Fig.
3).
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FIG. 3.
Concentrations of AmB in plasma after a single
administration of one of three forms of AmB (3.0 mg/kg) to rats with
IPA. , NS-718; , D-AmB; , L-AmB.
|
|
Study of the serum biochemical profile for immunosuppressed
rats.
The results of the study of the serum biochemical profile
for immunosuppressed rats treated with NS-718, D-AmB, or L-AmB are summarized in Table 3. Renal
insufficiency was evident in rats treated with D-AmB. In the rats in
the NS-718-treated group, BUN and creatinine levels were increased
compared with those in the rats in the control and L-AmB-treated
groups. The highest elevations of SGOT and SGPT levels were observed in
rats after the administration of L-AmB; however, the difference was not
significant compared with the values for the control group.
| |
DISCUSSION |
In the present study, we compared the in vitro and in vivo
potencies of NS-718, D-AmB, and L-AmB against A. fumigatus.
The A. fumigatus strains were more susceptible to NS-718
that to L-AmB; i.e., a smaller dose of NS-718 was required to inhibit
fungal growth. In our previous study, among three AmB formulations
NS-718 was found to be the most efficacious against Cryptococcus
neoformans isolates in vitro (7). NS-718 was also found
to be more effective than D-AmB or L-AmB against clinical isolates of
Candida albicans in our previous study (8); thus,
NS-718 has a broad spectrum of antifungal activity. Our results in this
study indicate that NS-718 was efficacious in the treatment of rat IPA,
which correlates with the results of the in vitro study. NS-718 at a
dose of 3.0 mg/kg inhibited the growth of aspergilli in the lung, but
the antifungal activity of L-AmB was weaker than that of NS-718.
It is necessary to study the toxicity of NS-718 in mammalian cells
since at a high dosage AmB has harmful side effects. Lysis of
erythrocytes has occasionally been observed with D-AmB but not with
NS-718 (4). This phenomenon indicates that the effective therapeutic dose of NS-718 used for the treatment of deep-seated mycoses, including aspergillosis, has a low level of toxicity. According to the results obtained from study of the serum biochemical profile, the level of renal insufficiency was the highest in
D-AmB-treated rats. We speculated that all rats died rapidly after
therapy with a high dose of D-AmB (3.0 mg/kg) because of the acute
toxicity of AmB, but equivalent doses of NS-718 were well tolerated,
indicating a reduction in toxicity with the lipid formulation.
One of the reasons for the differences in the antifungal potencies and
toxicities among AmB formulations was suggested by Espuelas et al.
(2). Their formulation, which is an AmB-poly (
-caprolacton) nanosphere, was less toxic than D-AmB and was more
toxic than L-AmB. Their preliminary results indicated that their
nanoparticles containing AmB were more potent in vitro against C. albicans than D-AmB. They mentioned that if the high degree of
stability of L-AmB can explain its lower level of toxicity, it is also
responsible for the decreased efficacy reported by several
investigators (11, 19, 21).
In terms of the efficacy of NS-718 against fungal cells, we also
speculated that the facilitation of AmB release and contact with the
fungal cell surface might improve the MIC and potency of the lipid
formulation. The release of AmB from L-AmB might be slow and slight
because the transition temperatures of the gel-liquid crystal phases of
the lipids used in L-AmB, hydrogenated soy lecithin and
distearoylphosphatidylglycerol, are higher than the body temperature.
This means that the liposomal particles of L-AmB are relatively rigid
and tight at the body temperature and hold AmB molecules within the
liposomal particles. In contrast, because NS-718 is composed of soybean
oil and egg lecithin as liquid-like lipid particles, with the release
of AmB from the lipid particles, it may be easy for the AmB to move to
fungal cells, which have ergosterol as a membrane component, and it may be relatively hard for the AmB to move to mammalian cells, which do not
contain ergosterol as a membrane component. Further investigations of
physicochemical preparations should be done to confirm this hypothesis.
In the pharmacokinetic study, the concentrations of NS-718 in plasma
were higher than those of D-AmB. The pharmacokinetic character of
NS-718 suggested that a lower dose of AmB encapsulated in LNS could be
as efficacious as D-AmB for the treatment of IPA. In our previous
study, the concentration of AmB in pleural exudate after the
intravenous injection of NS-718 was higher than that obtained after the
injection of D-AmB (4, 20). The results indicated that
NS-718 was retained in the blood circulation and easily permeated leaky
blood vessels at the site of inflammation by a mechanism called the
passive targeting effect. Although the injection of L-AmB resulted in
high plasma AmB concentrations, a higher dose of L-AmB might be
required for efficacy similar to that of NS-718 for the treatment of
IPA in rats because of the low intrinsic potency of L-AmB, as discussed above.
NS-718 was less nephrotoxic than D-AmB but was more toxic than L-AmB in
our study. However, SGOT and SGPT levels increased in rats injected
with L-AmB. The reason for the liver insufficiency could not be
explained clearly. In rats injected with NS-718, SGOT and SGPT levels
increased less than those in rats injected with L-AmB, and there was no
statistical difference compared with the results for the control rats.
In conclusion, the results obtained in the present study suggest that
NS-718 may represent a more appropriate choice for patients with
aspergillosis because of the good balance between efficacy and
toxicity. Because NS-718 was more efficacious than L-AmB and had a
lower level of toxicity than D-AmB, NS-718 may serve as an effective
novel antifungal drug delivery system for the treatment of patients
with IPA.
| |
ACKNOWLEDGMENTS |
We thank Yoshitsugu Miyazaki for academic support. We also thank
F. G. Issa, Department of Medicine, University of Sydney, Sydney,
Australia, for careful reading and editing of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: The Second
Department of Internal Medicine, Nagasaki University School of
Medicine, Sakamoto 1-7-1, Nagasaki 852-8501, Japan. Phone:
81-95-849-7271. Fax: 81-95-849-7285. E-mail:
sk1227{at}net.nagasaki-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, March 1999, p. 471-475, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
