close

Вход

Забыли?

вход по аккаунту

?

000070618

код для вставкиСкачать
Pharmacology
Chemotherapy 2003;49:126–131
DOI: 10.1159/000070618
Received: September 11, 2002
Accepted after revision: February 14, 2003
Comparative Effects of Cidofovir and Cyclic
HPMPC on Lethal Cowpox and Vaccinia Virus
Respiratory Infections in Mice
Donald F. Smee Kevin W. Bailey Robert W. Sidwell
Department of Animal, Dairy and Veterinary Sciences, Institute for Antiviral Research, Utah State University,
Logan, Utah, USA
Abstract
Background: Cidofovir is approved for the treatment of
cytomegalovirus retinitis in humans. Although highly
effective, the drug can cause renal toxicity in patients.
There is much interest in cidofovir as a potential treatment for smallpox, monkeypox and other orthopoxvirus
infections. A cyclic phosphonate form of cidofovir,
1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), was reported to be less
nephrotoxic than cidofovir in animals. Thus, it was
deemed important to directly compare the activities of
cidofovir and cyclic HPMPC against poxvirus infections
in mouse models. Methods: The compounds were evaluated by intraperitoneal and intranasal infection routes
using multiple doses of each agent, with single doses of
compound given 24 h after virus challenge. Results: By
intraperitoneal route, cidofovir protected mice from mortality at 40, 80 and 160 mg/kg, whereas cyclic HPMPC
was similarly protective only at 160 mg/kg. By intranasal
route, cidofovir was active down to 5 mg/kg, compared
to cyclic HPMPC efficacy at 20 and 40 mg/kg. Intraperito-
ABC
© 2003 S. Karger AG, Basel
0009–3157/03/0493–0126$19.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Accessible online at:
www.karger.com/che
neal doses of 40, 80 and 160 mg/kg cidofovir significantly
reduced mortality from vaccinia virus infections, compared to doses of 80 and 160 mg/kg cyclic HPMPC. Intranasal treatment with cidofovir at 5–40 mg/kg was comparably effective to cyclic HPMPC doses of 20 and
40 mg/kg in vaccinia virus infections. Active doses significantly reduced lung virus titers and lung consolidation.
Overall, the potency of cyclic HPMPC was about 4 times
less than that of cidofovir. Conclusions: Although cyclic
HPMPC is reported to exhibit reduced nephrotoxicity in
vivo, it is also less potent than cidofovir against orthopoxvirus infections. For this reason, cyclic HPMPC may
not offer any advantage over cidofovir in treating these
infections in humans.
Copyright © 2003 S. Karger AG, Basel
Introduction
Cidofovir has been shown to be active in the treatment
of lethal respiratory infections caused by cowpox and vaccinia viruses [1–3]. This drug, approved for the treatment
of cytomegalovirus retinitis in humans, is also effective
against many other DNA viruses. De Clercq [4] recently
reviewed the activity of this compound for the treatment
of various poxvirus infections. Orthopoxviruses such as
Donald F. Smee
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences
5600 Old Main Hill, Utah State University
Logan, UT 84322-5600 (USA)
Tel. +1 435 797 2897, Fax +1 435 797 3959, E-Mail dsmee@cc.usu.edu
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
Key Words
Cowpox virus W Vaccinia virus W Cidofovir W Cyclic
HPMPC W Antiviral treatment
Materials and Methods
Viruses and Cells
Cowpox virus (Brighton strain) was obtained from John Huggins,
U.S. Army Medical Research Institute of Infectious Diseases (Ft.
Detrick, Frederick, Md., USA). The virus originated from the Centers for Disease Control and Prevention (Atlanta, Ga., USA). Vaccinia virus (WR strain) was purchased from the American Type Culture
Collection (ATCC; Manassas, Va., USA). The viruses were propagated in African green monkey kidney (MA-104) cells (BioWhittaker,
Walkersville, Md., USA). Plaque assays of the viruses were done in
African green monkey kidney (Vero) cells (from ATCC). The MA104 cells were cultured in Eagle’s medium (MEM) containing 9%
fetal bovine serum (FBS), whereas the Vero cells were grown in
Medium 199 with 5% FBS. MEM with 2% FBS and gentamicin
(50 Ìg/ml) was used for viral propagation and plaque assays.
Mouse Infection Studies
Female BALB/c mice (13–15 g) were purchased from B & K Universal (Fremont, Calif., USA) for the studies. The animals were quarantined 48 h before use. An infectious vaccinia virus challenge of
5 ! 105 plaque-forming units (about 10 50% lethal doses) per mouse
was used for the experiments. This was based upon previously conducted lethality titrations with the viruses in mice. Virus was administered i.n. in a 50-Ìl volume following anesthesia with ketamine
(100 mg/kg given by i.p. injection). A single i.p. treatment with cidofovir, cyclic HPMPC or placebo was given 24 h after virus exposure.
This regimen using cidofovir was shown to be effective against cowpox [1] and vaccinia (WR strain) [2, 3] virus respiratory infections.
Alternatively, single i.n. treatments, proven to be effective using
cidofovir against cowpox virus [23], were also given in separate
experiments. Animals were individually weighed every 2–3 days and
deaths were recorded for 21 days. There were 10 mice per group held
for death determinations and 5 mice per group sacrificed per day for
virus titer determinations. Uninfected toxicity control animals were
not used in these experiments since single doses have been reported
as nontoxic [1–3, 23].
Lungs from sacrificed cowpox virus-infected mice were removed
and frozen at –80 ° C on day 6 of the infection for virus titer determinations. Lung infection parameters for the vaccinia virus experiments were determined in a manner similar to those reported for
influenza virus [24] in groups of infected mice. On day 5 of the vaccinia virus infection (mice died more rapidly with this infection than
with the cowpox virus infection, thus the difference in day of sacrifice), lungs from sacrificed mice were collected, given a severity score
based upon lung discoloration ranging from 0 (normal) to 4 (100% of
lung area exhibiting a plum coloration), weighed and frozen for later
virus titration. With the cowpox virus infection, lungs did not
become enlarged or discolored as they did with the vaccinia virus
infection, and thus were not scored. Virus titers from lung samples
were determined by plaque assay in Vero cells as described previously [2].
Antiviral Compounds
Norbert Bischofberger and Mick Hitchcock of Gilead Sciences
(Foster City, Calif., USA) kindly provided cidofovir and cyclic
HPMPC, respectively. The compounds were dissolved in sterile
saline at a maximum concentration of 22.4 mg/ml for intraperitoneal
(i.p.) injection or at a maximum concentration of 11.2 mg/ml for
intranasal (i.n.) instillation into 14-gram mice. Treatment volumes
were 0.1 or 0.05 mg/mouse for these respective treatments. Sterile
saline served as the placebo control.
Statistical Methods
Statistical comparisons were made between the drug-treated
groups and the placebo controls by two-tailed analyses. The Fisher
exact test was used to interpret differences in numbers of survivors.
Mean day of death, mean lung virus titers, mean lung scores and
mean lung weight comparisons were statistically analyzed by the
Mann-Whitney U test. Calculations were made using the InStat computer program (GraphPad Software, San Diego, Calif., USA).
Effects of Cidofovir and Cyclic HPMPC
Chemotherapy 2003;49:126–131
127
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
smallpox and monkeypox have become a concern due to
their bioterrorism potential [5–8]. Treatments for progressive vaccinia [9], molluscum contagiosum [10–13]
and orf virus infections [14] are also being sought.
Although cidofovir is a very effective drug against cytomegalovirus infections in humans, it is not orally active
and may cause renal toxicity [15, 16]. Derivatives of cidofovir are being investigated that may be safer and orally effective. One such compound, 1-[((S)-2-hydroxy-2oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), is a cyclic phosphonate derivative of cidofovir that has been reported to have reduced nephrotoxicity in rodents [17–19] and in humans [20]. Certain salicylate ester prodrugs of cyclic HPMPC have been synthesized that exhibit up to 46% oral bioavailability [21].
Thus, prodrug forms of cyclic HPMPC hold the promise
of exhibiting both oral bioavailability and reduced nephrotoxicity relative to the parent drug cidofovir. Such a
compound may be useful in treating orthopoxvirus infections.
Recently, Bray et al. [22] reported on the activities of
cidofovir and cyclic HPMPC by aerosol route to treat
cowpox virus infections in mice. Although it is difficult to
accurately quantify drug uptake by this treatment method
(the dosages were reported as ranges rather than as discrete mg/kg doses), the authors concluded that cyclic
HPMPC was less potent than cidofovir in the treatment
of the infections. In the present studies, we evaluated the
activities of the two compounds under more stringent
treatment regimens in order to determine differences in
potency. This would help determine if increases in the
safety of cyclic HPMPC (due to decreased renal toxicity)
would be negated by decreases in potency against infection (i.e. more drug would be needed to counteract the
infection). The results of the present studies indicate that
cyclic HPMPC is indeed less potent than cidofovir against
infections caused by cowpox and vaccinia viruses in
mice.
Table 1. Effects of i.p. treatment with
cidofovir and cyclic HPMPC on a cowpox
virus respiratory infection in mice
Compound
Dose
mg/kg
Survivors/
total
Mean day
of death B SD
Mean lung
virus titer B SD
Cidofovir
160
80
40
20
160
80
40
20
–
10/10***
10/10***
10/10***
0/10
8/10***
4/10
3/10
0/10
0/10
–
–
–
14.1B3.6***
10.0B1.4
16.7B2.7***
12.7B3.0***
10.4B1.7*
8.7B1.2
7.7B0.3**
7.8B0.1**
8.1B0.1**
7.8B0.1**
7.9B0.3*
8.0B0.3*
8.2B0.2
8.2B0.3
8.5B0.2
Cyclic HPMPC
Placebo
Treatment was given as a single injection 24 h after virus exposure. The mean day of death
was recorded in those mice that died prior to day 21. Mean lung virus titer was determined as
log10 plaque-forming units/g (5 mice/group) on day 6 of the infection.
* p ! 0.05; ** p ! 0.01; *** p ! 0.001.
Table 2. Effects of i.n. treatment with
cidofovir and cyclic HPMPC on a cowpox
virus respiratory infection in mice
Compound
Dose
mg/kg
Survivors/
total
Mean day
of death B SD
Mean lung
virus titer B SD
Cidofovir
40
20
10
5
40
20
10
5
–
8/10***
8/10***
10/10***
8/10***
9/10***
8/10***
0/10
2/10
0/10
17.5B3.5*
9.5B0.7
–
9.0B0.0
10.0B0.0
10.0B0.0
12.1B2.7*
11.0B2.2*
8.5B0.5
5.7B0.7***
7.1B0.6**
6.9B0.4**
7.5B0.2**
6.8B0.6**
7.6B0.4**
7.5B0.1**
8.0B0.5
8.5B0.2
Cyclic HPMPC
Placebo
Treatment was given as a single dose 24 h after virus exposure. The mean day of death was
recorded in those mice that died prior to day 21. Mean lung virus titer was determined as
log10 plaque-forming units/g (5 mice/group) on day 6 of the infection.
* p ! 0.05; ** p ! 0.01; *** p ! 0.001.
Effect of i.p. Treatment on Cowpox Virus Infection
Intraperitoneal treatment with cidofovir at 40, 80 and
160 mg/kg prevented mortality by 100% and significantly
reduced cowpox virus titers in lungs on day 6 of the infection (table 1). At the 20 mg/kg dose, all of the mice died,
but the time to death was delayed over 5 days relative to
deaths in the placebo group. Cyclic HPMPC at 160 mg/kg
protected 80% of mice from death. At 80 mg/kg, there
were 40% survivors, which was not quite significantly different from the placebo group. At 160 and 80 mg/kg, virus
128
Chemotherapy 2003;49:126–131
titers were reduced compared to the placebo group. Mice
dying the 20, 40 and 80 mg/kg cyclic HPMPC groups
lived significantly longer than placebo controls. Cidofovir
was approximately 4 times more potent than cyclic
HPMPC against the infection.
Effect of i.n. Treatment on Cowpox Virus Infection
It has been previously shown that i.n. cidofovir treatment of cowpox virus infections requires much less compound for efficacy than by i.p. administration [23]. Also,
the suppression of lung virus titers in mice treated i.n. was
greater than in i.p. treated mice. In the present study, i.n.
Smee/Bailey/Sidwell
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
Results
Table 3. Effects of i.p. treatment with cidofovir and cyclic HPMPC on a vaccinia virus respiratory infection in
mice
Compound
Cidofovir
Cyclic HPMPC
Dose
mg/kg
Survivors/
total
Mean day of
death B SD
160
80
40
20
160
80
40
20
0
7/10**
7/10**
7/10**
3/10
6/10*
6/10*
2/10
0/10
0/10
3.3B2.3
6.7B0.6
6.0B0.0
9.4B2.8**
6.5B0.6
8.8B2.1*
7.1B2.0
7.6B1.8
6.4B0.8
Mean lung parameters B SD
score
weight, mg
virus titer,
log10 PFU/g
0.3B0.4*
0.3B0.3**
0.6B0.7*
1.3B0.6
0.8B0.8
1.1B0.8
0.9B0.5
2.5B0.4
2.1B0.9
208B90
190B37*
188B79
218B61
214B104
226B68
174B76*
266B34
292B49
7.8B1.3*
8.6B0.2
8.3B1.4
8.5B1.1
8.2B0.3*
8.5B0.2
8.5B0.2
8.8B0.1
8.8B0.2
Treatment was given as a single injection 24 h after virus exposure. The mean day of death was recorded in those
mice that died prior to day 21. Mean lung parameters were determined from 5 mice per group on day 5 of the
infection. Lung consolidation scores ranged from 0 (normal) to 4 (entire lung discolored). PFU = Plaque-forming
units. * p ! 0.05; ** p ! 0.01.
Effect of i.p. Treatment on Vaccinia Virus Infection
Intraperitoneal treatment with cidofovir administered
at 40, 80 and 160 mg/kg prevented mortality by 70% and
significantly reduced vaccinia virus titers in lungs at the
160 mg/kg dose on day 6 of the infection (table 3). Lung
consolidation scores were significantly reduced at the top
three doses. Reductions in lung weights were evident
compared to the placebo group, but lung weights were
only significantly different at the 80 mg/kg dose. Lung
weights were quite variable from animal to animal, which
impacted on statistical significance. Cyclic HPMPC prevented mortality by 60% at 80 and 160 mg/kg. In these
groups of mice, lung virus titers were not significantly different from those in placebo controls. Lung consolidation
scores differed from those in placebos at 40, 80 and
160 mg/kg, but the results were not statistically signifi-
Effects of Cidofovir and Cyclic HPMPC
cant. At 40 mg/kg, the lung weights differed significantly
from placebo animals. Cyclic HPMPC was less protective
to the lungs than was cidofovir, based upon lung scores. In
this experiment and based upon mortality results, cidofovir was approximately 2 times more potent than cyclic
HPMPC against the infection.
Effect of i.n. Treatment on Vaccinia Virus Infection
In this experiment, i.n. drug doses of 5, 10, 20 and
40 mg/kg prevented mortality in 70–80% of the animals
(table 4). At the 20 and 40 mg/kg doses, mice dying from
the infection lived several days longer than those dying in
the placebo group. Virus titers were reduced in lungs of
mice treated with all of these doses compared to virus in
lungs of placebo-treated mice. Treatment with cidofovir
at 20 and 40 mg/kg significantly reduced lung scores and
lung weights. Cyclic HPMPC was effective in preventing
death by 50 and 70% at doses of 20 and 40 mg/kg, respectively. Doses of 5 and 10 mg/kg did not prevent mortality,
however. Virus titers were reduced by treatments of 5–
40 mg/kg. The highest two doses of cyclic HPMPC were
not as effective as the highest doses of cidofovir in reducing lung virus titers, lung consolidation scores and lung
weights. Cidofovir was approximately 4 times more potent than cyclic HPMPC against the infection.
Chemotherapy 2003;49:126–131
129
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
drug doses of 5, 10, 20 and 40 mg/kg prevented mortality
in 80–100% of the animals (table 2). Greater virus titer
reductions were seen in lungs compared to lungs of mice
treated i.p. (table 1). Cyclic HPMPC was effective at 20
and 40 mg/kg in preventing mortality and reducing lung
virus titers. Reductions in lung virus titers with cyclic
HPMPC at 20 and 40 mg/kg were similar to those
achieved by HPMPC at 5 and 10 mg/kg. In this experiment, cidofovir was approximately 4 times more potent
than cyclic HPMPC against the infection.
Table 4. Effects of i.n. treatment with cidofovir and cyclic HPMPC on a vaccinia virus respiratory infection in
mice
Compound
Cidofovir
Cyclic HPMPC
Dose
mg/kg
Survivors/
total
Mean day of
death B SD
40
20
10
5
40
20
10
5
0
8/10***
7/10**
8/10***
7/10**
7/10**
5/10*
0/10
0/10
0/10
12.0B0.0***
8.7B1.2**
8.5B2.1
8.3B1.5
7.7B1.5
10.8B4.6
8.8B1.5
7.8B0.6
6.9B0.3
Mean lung parameters B SD
score
weight, mg
virus titer,
log10 PFU/g
0.5B0.0***
0.5B0.0***
3.3B0.3
3.0B0.4
3.0B0.1*
2.4B0.9*
2.1B1.0*
3.3B0.4
3.5B0.4
154B9***
180B35***
288B76
252B85*
230B54***
220B41***
238B36***
306B130
384B38
6.4B0.6***
7.9B0.3***
8.6B0.2*
8.4B0.3**
8.1B0.2***
8.3B0.2***
8.1B0.3***
8.4B0.3**
8.9B0.1
Treatment was given as a single dose 24 h after virus exposure. The mean day of death was recorded in those mice
that died prior to day 21. Mean lung parameters were determined from 5 mice per group on day 5 of the infection.
Lung consolidation scores ranged from 0 (normal) to 4 (entire lung discolored). PFU = Plaque-forming units. * p !
0.05; ** p ! 0.01; *** p ! 0.001.
Direct efficacy comparisons of cidofovir and cyclic
HPMPC were made against cowpox and vaccinia viruses
using two treatment regimens previously found to be
effective against cowpox and vaccinia virus infections in
mice [1–3, 23]. Cyclic HPMPC demonstrated decreased
potency relative to HPMPC by 4-fold in three of the studies and 2-fold in one study. Bray et al. [22] presented data
indicating that cidofovir was more potent than cyclic
HPMPC against cowpox virus infections by aerosol administration. In those studies, it was difficult to precisely
quantify the drug dose because of the route of administration. Thus, more precise comparisons of the effects of the
two compounds were made herein.
The responses of mice to antiviral treatment of the
cowpox and vaccinia virus infections were similar, although vaccinia infections were harder to treat due to
more rapid occurrence of death, more severe lung consolidation and higher lung virus titers than occurred in the
cowpox virus infections. Thus, the overall numbers of survivors of the cowpox virus infections treated with cidofovir were greater than those with the vaccinia virus infections. Intranasal treatment of the cowpox virus infection
with cidofovir reduced lung virus titers to a greater extent
than similar treatments of the vaccinia virus infection.
Doses of either compound that caused a positive effect
130
Chemotherapy 2003;49:126–131
against cowpox virus were also effective against vaccinia
virus. Against both infections, i.n. treatments were more
effective than i.p. treatments in reducing the severity of
the various infection parameters. This is understandable,
since i.n. treatment deposited the drug directly at the site
of the infection.
In cell culture studies, cidofovir was reported to be 3.8
times more potent than cyclic HPMPC against cowpox
virus and 2.6 times more potent against vaccinia virus
(Copenhagen strain) in mouse 3T3 cells [25]. These differences may explain the potency differences seen in vivo.
For this to be true, mouse lung cells must behave similarly
to 3T3 cells, and the WR strain of vaccinia virus must act
similarly to the Copenhagen strain in terms of responses
to cyclic HPMPC treatment. In a pharmacokinetic study
of cyclic HPMPC performed in humans, the cidofovir
excreted in urine in 24 h was only 9.4% of the total cyclic
HPMPC dose, indicating low conversion to the active
antiviral form [20]. This could contribute negatively to
the compound’s antiviral efficacy in man. The authors of
that report indicated that cyclic HPMPC had a lower
potential for nephrotoxicity in humans compared to cidofovir. Previous investigations showed that cidofovir accumulated in kidneys of rats at a level 20 times higher than
that of cyclic HPMPC, whereas the level of radioactive
compound in other tissues was similar for both drugs [18].
Cidofovir was reported to be at least 13 times more toxic
Smee/Bailey/Sidwell
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
Discussion
to mice than cyclic HPMPC [17]. Taking into account the
reduced efficacy of cyclic HPMPC relative to cidofovir
against poxviruses with the greater safety profile in mice,
cyclic HPMPC may only have a safety margin about 3
times better than cidofovir. The results of human pharmacokinetic data of the conversion rate of cyclic HPMPC
to cidofovir suggest that cyclic HPMPC may prove to be
no better than the parent drug.
Acknowledgements
This work was supported by contracts N01-AI-65291 and N01AI-15435 from the Virology Branch, National Institute of Allergy
and Infectious Diseases, National Institutes of Health.
References
Effects of Cidofovir and Cyclic HPMPC
12 Ibarra V, Blanco JR, Oteo JA, Rosel L: Efficacy
of cidofovir in the treatment of recalcitrant
molluscum contagiosum in an AIDS patient.
Acta Derm Venereol 2000;80:315–316.
13 Toro JR, Wood LV, Patel NK, Turner ML:
Topical cidofovir: A novel treatment for recalcitrant molluscum contagiosum in children infected with human immunodeficiency virus 1.
Arch Dermatol 2000;136:983–985.
14 Geerinck K, Lukito G, Snoeck R, De Vos R, De
Clercq E, Vanrenterghem Y, Degreef H, Maes
B: A case of human orf in an immunocompromised patient treated successfully with cidofovir cream. J Med Virol 2001;64:543–549.
15 Wachsman M, Petty BG, Cundy KC, Jaffe HS,
Fisher PE, Pastelak A, Lietman PS: Pharmacokinetics, safety and bioavailability of HPMPC
(cidofovir) in human immunodeficiency virusinfected subjects. Antiviral Res 1996;29:153–
161.
16 Naesens L, Snoeck R, Andrei G, Balzarini J,
Neyts J, De Clercq E: HPMPC (cidofovir),
PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: A review of their
pharmacology and clinical potential in the
treatment of viral infections. Antiviral Chem
Chemother 1997;8:1–23.
17 Bischofberger N, Hitchcock MJM, Chen MS,
Barkhimer DB, Cundy KC, Kent KM, Lacy
SA, Lee WA, Li Z-H, Mendel DB, Smee DF,
Smith JL: 1-[((S)-2-Hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, an intracellular prodrug for (S)-1,(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved
therapeutic index in vivo. Antimicrob Agents
Chemother 1994;38:2387–2391.
18 Cundy KC, Bidgood AM, Lynch G, Shaw JP,
Griffin L, Lee WA: Pharmacokinetics, bioavailability, metabolism, and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC
in rats. Drug Metab Dispos 1996;24:745–752.
19 Bourne N, Bravo FJ, Bernstein DI: Cyclic
HPMPC is safe and effective against systemic
guinea pig cytomegalovirus infection in immune compromised animals. Antiviral Res
2000;47:103–109.
20 Cundy KC, Barditch-Crovo P, Petty BG, Ruby
A, Redpath M, Jaffe HS, Lietman PS: Clinical
pharmacokinetics of 1-[((S)-2-hydroxy-2-oxo1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine
in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1999;43:
271–277.
21 Oliyai R, Arimilli MN, Jones RJ, Lee WA:
Pharmacokinetics of salicylate ester prodrugs
of cyclic HPMPC in dogs. Nucleoside Nucleotides Nucleic Acids 2001;20:1411–1414.
22 Bray M, Martinez M, Kefauver D, West M,
Roy C: Treatment of aerosolized cowpox virus
infection in mice with aerosolized cidofovir.
Antiviral Res 2002;54:129–142.
23 Smee DF, Bailey KW, Wong M-H, Sidwell
RW: Intranasal treatment of cowpox virus respiratory infections in mice with cidofovir. Antiviral Res 2000;47:171–177.
24 Sidwell RW, Huffman JH, Barnard DL, Bailey
KW, Wong M-H, Morrison A, Syndergaard T,
Kim CU: Inhibition of influenza virus infections in mice by GS4104, an orally effective
influenza virus neuraminidase inhibitor. Antiviral Res 1998;37:107–120.
25 Smee DF, Bray M, Huggins JW: Antiviral activity and mode of action studies of ribavirin
and mycophenolic acid against orthopoxviruses in vitro. Antiviral Chem Chemother
2002;12:327–335.
Chemotherapy 2003;49:126–131
131
Downloaded by:
Vanderbilt University Library
129.59.95.115 - 10/26/2017 4:59:49 PM
1 Bray M, Martinez M, Smee DF, Kefauver D,
Thompson E, Huggins JW: Cidofovir
(HPMPC) protects mice against lethal aerosol
or intranasal cowpox virus challenge. J Infect
Dis 2000;181:10–19.
2 Smee DF, Bailey KW, Sidwell RW: Treatment
of lethal vaccinia virus respiratory infections in
mice with cidofovir. Antiviral Chem Chemother 2001;12:71–76.
3 Smee DF, Bailey KW, Wong M-H, Sidwell
RW: Effects of cidofovir on the pathogenesis of
a lethal vaccinia virus respiratory infection in
mice. Antiviral Res 2001;52:55–62.
4 De Clercq E: Cidofovir in the treatment of poxvirus infections. Antiviral Res 2002;55:1–13.
5 Breman JG, Henderson DA: Poxvirus dilemmas – monkeypox, smallpox and biological terrorism. N Engl J Med 1998;339:556–559.
6 Hooper C: Poxvirus dilemmas. N Engl J Med
1998;339:2027–2028.
7 Orent W: Excape from Moscow. Sciences (New
York) 1998;38:26–31.
8 Peters CJ: Many viruses are potential agents of
bioterrorism. ASM News 2002;68:168–173.
9 Kesson AM, Ferguson JK, Rawlinson WD,
Cunningham AL: Progressive vaccinia treated
with ribavirin and vaccinia immune globulin.
Clin Infect Dis 1997;25:911–914.
10 Meadows KP, Tyring SK, Pavia AT, Rallis
TM: Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol 1997;133:987–990.
11 Davies EG, Thrasher A, Lacey K, Harper J:
Topical cidofovir for severe molluscum contagiosum. Lancet 1999;353:2042.
Документ
Категория
Без категории
Просмотров
0
Размер файла
62 Кб
Теги
000070618
1/--страниц
Пожаловаться на содержимое документа