Note: Descriptions are shown in the official language in which they were submitted.
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USE OF A CORTICOSTEROID TO REDUCE THE ADVERSE t~t~lS OF A PERFLUOROCHEMICAL
EMULSION
Background of the Invention
Field of the Invention
This invention is directed to the use of corticosteroids,
and more particularly, to the use of corticosteroids for reducing or
attenuating the adverse effects of a perfluorochemical emulsion on
the hemostatic system and serum chemistry parameters of an
animal.
Description of the Related Art
Perfluorochemical (PFC) emulsions are being developed
for many different uses. Because PFCs have a high intrinsic
solubility for gases, including ~2 and C02, they are especially useful
as 02/C02 transport agents, artificial bloods, and red blood cell
substitutes. PFC emulsions also are being developed as contrast
agents for biological imaging. However, one of the drawbacks in
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using PFC emulsions in animals is that these emulsions produce
certain undesirable side effects.
Side effects from the intravenous infusion of a PFC
emulsion have been reported in both human and animal studies.
Two groups of side effects have been observed in human volunteers
receiving a perfluorooctylbromide (PFOB) emulsion. PFOB, also
known as Perflubron, is a PFC under development as a component of
a blood-pool imaging agent known as Imagent BP. Imagent BP is a
phospholipid emulsion containing ninety (90%) percent w/v
Perflubron and having a mass median particle size of approximately
0.2 ~. The first group of side effects occurs within the first 2 hours
after injection of the PFC emulsion. These acute effects are
characterized primarily by skin flushing and back~che. The second
group of side effects occurs later than 2 hours post-injection and
lasts generally for about a day. These delayed effects, described as
a "flu-like syndromen, include fever, dizziness, and occasional
nausea. S. F. Flaim, et al., "Characterization and Mechanism of Side
Effects of Imagent BP (Highly Concentrated Fluorocarbon Emulsion)
In Swinen, Vol. 26, Investigative Radiologv, November Supplement
1991, S122-S124.
PFC emulsions also induce adverse side effects in
swine. As with the human volunteers! intravenous administration of
a PFOB emulsion produced both an acute and a delayed response in
swine. The acute response included a rise in mean pulmonary artery
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pressure (mPAP) and severe skin flushing, both of which resolved
~ completely by 2 hours post-injection. The delayed side effect was a
febrile response characterized by a 1 - 2~C increase in body
temperature which peaked at 4 hours post-injection and resolved
over the next 2 to 24 hours. The early rise in mPAP is believed to
be related to the activation of pulmonary intravascular macrophages,
while the skin flushing is attributed to the substantial release of
Prostaglandins upon macrophage activation. S. F. Flaim, et al.,
"Characterization and Mechanism of Side Effects of Imagent BP
(Highly Concentrated Fluorocarbon Emulsion) In Swine", Vol. 26,
Investigative Radiologv, November Supplement 1991, S122-S124.
Further research with swine has shown that these
particular clinical side effects may be effectively prophylaxed with
dexamethasone, ibuprofen, or indomethacin. For example, the
acute, transient rise in mPAP and skin flushing both were blocked
successfully by prophylaxis with any one of these three
compositions. In addition, the delayed febrile response also was
blocked successfully by prophylaxis with dexamethasone, ibuprofen,
or indomethacin. /d.
Despite the advances made by these animal and human
studies, they do not identify other problems or side effects which
might be associated with intravenous infusion of PFC emulsions.
Given the increase in clinical use of such emulsions, it would be
desirable to identify other potential side effects. Furthermore, once
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those side effects have been identified, it would be highly beneficial
to identify ways in which those side effects might be alleviated or
even prevented.
Summarv of the Invention
This invention is directed to a method of improving the
adverse effects of a perfluorochemical emulsion on the hemostatic
system and serum chemistry of an animal. The method includes
intravenously administering a corticosteroid to an animal prior to
intravenous administration of a perfluorochemical emulsion. The
corticosteroid is administered in an amount sufficient tO improve the
adverse effects of the perfluorochemical upon the hemostatic system
and serum triglyceride/enzyme levels of the animal. After
administration of the corticosteroid, the perfluorocarbon emulsion is
administered intravenously.
Preferably, the corticosteroid is administered at a dose
of from about 0.2 mg/kg of body weight to about 6 mg/kg of body
weight, and more preferably, at a dose of about 1 mg/kg. The
perfluorochemical used in the perfluorochemical emulsion preferably
is administered at a dose of from about 0.5 to about 10 ml/kg of
body weight.
With respect to the hemostatic system, the method
may be conducted for reducing perfluorochemical-induced adverse
side effects upon prothrombin time and activated partial
thromboplastin time, and for inhibiting perfluorochemical-induced
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thrombocytopenia. With respect to serum chemistry, the ",ell,o~
~ may be conducted for reducing perfluorocarbon-induced adverse side
effects upon aspartate amino transferase enzyme activity, lactate
dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone, while
the perfluorochemical preferably is selected from the group
consisting of: perfluorodichlorooctane, perfluorodecalin,
perfluoromethyldecalin, perfluorodimethyldecalin,
perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-~
methyl-octahydroquinolidizine, perfluoro-N-methyl-
decahydroquinoline, F-methyl-1-oxa-decalin, perfluoro-
bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine, perfluoro-5,6-
dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene, chlorinated
perfluorocarbons, and mixtures thereof. Most preferably, the
perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the
perfluorochemical in an amount of from about 15 v/v% to about 70
v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps,
administration of the perfluorochemical emulsion preferably is begun
within several hours after administering the corticosteroid, and can
t also be administered immediately following administration of the corticosteroid .
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This invention offers several benefits to animals being
treated with PFC emulsions. For example, corticosteroid
pretreatment attenuates or prevents adverse PFC-induced side
effects on the coagulation system. Pretreatment virtually eliminates
the PFC-induced adverse effects on prothrombin time and activated
partial thromboplastin time, and significantly inhibits PFC-induced
thrombocytopenia .
Corticosteroid pretreatment also attenuates or
eliminates adverse PFC-induced side effects on several serum
chemistry parameters. For example, pretreatment inhibits PFC-
induced increases in serum triglycerides and bilirubin, as well as in
aspartate amino transferase enzyme activity and lactate
dehydrogenase enzyme activity.
Detailed Desc.iulion of the Invention
This invention is directed to a method of improving the
adverse effects of a perfluorochemical emulsion on the hemostatic
system and serum chemistry of an animal. The method includes
intravenously administering a corticosteroid to an animal prior to
intravenous administration of a perfluorochemical emulsion. The
corticosteroid is administered in an amount sufficient to improve the
adverse effects of the perfluorochemical upon the hemostatic system
and serum triglyceride/enzyme levels of the animal. After
administration of the corticosteroid, the perfluorocarbon emulsion is
administered intravenously.
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Preferably, the corticosteroid is administered at a dose
of from about 0.2 mg/k~ of body weight to about 6 mg/kg of body
weight. At low doses of about 0.1 mg/kg, ptel,eal.,.enl with
dexamethasone has li~tle impact on PFC-induced side efreol:.; while
doses above about 6.0 mg/kg present safety issues in that such
doses may result in undesired changes in the hypothalamic-pituitary-
adrenal axis physiology. More preferably, the co~icosleroid is
administered at a dose of about 1 mg/kg. The perfluorochemical
used in the perfluorochemical emulsion preferably is administered at
a dose of from about 0.5 to about 10 ml/kg of body weight.
With respect to the hemostatic system, the method
may be conducted for reducing perfluorochemical-induced adverse
side effects upon prothrombin time and activated partial
thromboplastin time, and for inhibiting perfluorochemical-induced
thrombocytopenia. With respect to serum chemistry, the method
may be conducted for reducing perfluorocarbon-induced adverse side
effects upon aspartate amino transferase enzyme activity, lactate
dehydrogenase enzyme activity and bilirubin.
The corticosteroid preferably is dexamethasone. The
perfluorochemical preferably is selected from the group consisting of
perfluorodichlorooctane, perfluorodecalin, perfluoro"-~ yldecalin,
. perfluorodimethyldecalin, perfluorodimethyladamantane,
perfluorooctylbromide, perfluoro-~methyl-octahydroquinolidizine,
perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxa-decalin,
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perfluoro-bicyclo(5.3.0)decane, perfluorooctahydroquinolidizine,
perfluoro-5,6-dihydro-5-decene, and perfluoro-4,5-dihydro-4-octene,
chlorinated perfluorocarbons, and mixtures thereof. Most preferably,
the perfluorochemical used in the method is perfluorodichlorooctane.
The perfluorochemical emulsion preferably contains the
perfluorochemical in an amount of from about 15 v/v~/0 to about 70
v/v%, and more preferably, in an amount of about 40 v/v%.
With respect to the timing of the method steps,
administration of the perfluorochemical emulsion preferably is begun
within several hours after administering the corticosteroid, and can
also be administered immediately following administration of the
corticosteroid .
Examr~le
Study Design and Protocol
A study was conducted to assess the responses
associated with an acute intravenous exposure of a 40 v/v%
perfluorodichlorooctane ~PFDC0) emulsion in male adult baboons
/Papio cynocephalus~ with and without treatment with 1 mg/kg of
dexamethasone. Dose levels of the 40 v/v% PFDC0 emulsion were
selected to impart minimal, reversible side errecls in the baboon that
would be efficacious with respect to intravascular gas transport.
The dexamethasone pretreatment regimen was administered
intravenously at a dose level intended to elicit anti-infla",.,~alory
effects. The 40 v/v% PFDC0 emulsion included a PFDC0 stem
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emulsion, as well as a 23.4% saline annex solution. The specific
composition of the stem emulsion, saline annex and final formulation
is shown in Table 1.
Table 1
Formulation of the 40 v/v% PFDCO Emulsion
Component PFDCO 23.4% Saline Final Formula-
Stem Emulsion Annex tion for IV
Administration
PFDCO (v/v%) 40 - 39
Lecithin 2 - 1.95
~w/v%)
Safflower Oil 2 - 1.95
(w/v%)
Na2CO3 0.01 5
(w/v%)
NaCI (w/v%) - 23.4 0.466
Water for q.s q.s q.s
Injection
Twelve adult male baboons (P~pio cynocephalus~ were
selected after being given complete health examinations by
veterinary personnel and approved for the study. The animals
ranged in age from 8 - 20 years, were either feral or colony born,
and were clinically in excellent health.
The twelve animals were divided into four L~eal-~ent
groups with three animals in each group. The group I and ll animals
each received 1.0 ml/kg PFCDO (2.5 ml/kg stem emulsion annexed
with 23.4% sodium chloride), with the Group ll animals also
receiving 1 mg/kg dexamethasone intravenously immediately prior to
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infusion of PFDC0. The Group lll and IV animals each received 2.0
ml/kg PFDC0 (5.0 ml/kg stem emulsion mixed with 23.4% sodium
chloride), while the Group IV animals also received 1 mg/kg
dexamethasone intravenously immediately prior to infusion.
The baboons were sedated for dexamethasone and
PFDC0 infusion with ketamine HCI (IM) supplemented with valium,
and additional doses of ketamine HCI were administered when
required to maintain sedation. Following sedation and pretreatment
blood collection, a 16-20 gauge indwelling angiocatheter was placed
and secured into a saphenous vein for infusion of the respective
emulsions. The doses of the 40 v/v% PFDC0 emulsion were
administered at a rate of approximately 4-6 ml per minute.
Blood samples were drawn and analyzed over a thirty
(30) day period following administration of the PFDC0 emulsion.
The baboons were sedated for all blood sampling procedures with
ketamine HCI (IM) supplemented with valium, and additional doses
of ketamine HCI were administered when required to maintain
sedation. Indirect systemic blood pressure was measured using a
non-invasive blood pressure unit, and body temperature was
monitored using a rectal thermometer. In addition, respiratory rate
was measured directly by monitoring the inspiratory excursions of
the thoracic or abdominal wall, while heart rate was deterrnined by
palpation of a peripheral pulse or chest auscultation. Blood samples
were collected percutaneously via a peripheral vein.
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Data Analvsis Methodologv
For parameters having multiple baseline and/or pre-
infusion measurements, an average baseline value for each animal
~i
was calculated. The change in response from the average baseline
was statistically evaluated, and between-group comparisons at each
dose level of PFC with and without dexamethasone pretreatment
were performed at each sample time. A one-factor analysis of
variance (ANOVA) was used to test for significance within and
between groups over time. The levels of significance were defined
as P<.05 and P<.01.
The results presented below were compared to normal
values for the adult male baboon as listed in Brenda M. Hainsey, et
al., Clinical Parameters of the Normal Baboons (Papio species) and
Chimpanzees (Pan troglodytes)", Vol. 43, No. 3, Laboratorv Animal
Science, June, 1993. For analysis of Factor Vlll, the results were
compared to the normal range for baboons as reported in Hollace M.
Feingold, et al., "Coagulation Assays and Platelet Aggregation
Patterns in Human, Baboon, and Canine Blood", Vol. 47, No. 10,
American Journal of Veterinary Research, October, 1986.
Imnact of Dexamethasone ~et,aal---ent
- on the Hemostatic Svstem
Prothrombin time (PTJ is shown for the four treatment
groups over the length of the study in Table 2. In the low dose PFC
animals, there was evidence of a rise in the PT at six hours post-
infusion, which remained elevated one day after infusion. However,
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in the low dose animals preL~aaLed with dexamethasone, there were
no significant changes in the PT over the course of the study. In the
high dose baboons, the PT was significantly elevated at 4 hours, 6
hours, and 1 day post-infusion when compared to the baseline and
the high dose animals pretreated with dexamethasone. At 2 days
following dosing, the PT of the high dose animals remained
significantly prolonged when compared to the baseline. For the
pretreated high dose animals, the only significant change in the PT
from baseline occurred at thirty (30) days post-infusion; however,
this elevation was not considered to be biologically significant.
The activated partial thromboplastin time (aPTT) results
are presented in Table 3. On day 1 post-infusion, the low dose
animals showed a significantly higher aPTT when compared with the
pretreated low dose animals. In the high dose baboons, the aPTT
was significantly elevated at 4 hours, 6 hours, and 1 day post-
infusion when compared to the baseline and the pretreated high dose
animals. On day 7, the aPTT of the high dose animals decreased
significantly from baseline, although this was not considered to be
biologically significant. Meanwhile, in the high dose animals
pretreated with dexamethasone, there was no significant change in
the aPTT from baseline, and the clotting times were all within normal
range for the baboon.
The Factor Vlll (FVIII) results are summarized in Table 4.
FVIII levels of the low dose and pretreated low dose groups showed
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some scdll~red significant differences from baseline and between
~,edl",ents, however, all of the values were within the normal range
for baboons. The FVIII levels of the high dose animals exceeded the
upper limit of the normal range on days Z, 4, 7, and 14 post-dosing.
Values for the pretreaLed high dose animals also exceeded the upper
limit of the normal range, but only at six hours, 1 day and 2 days
post-dosing, coming back into the normal range much sooner than
the values for the untreated animals.
The plasma fibrinogen values for the various lrt:al",en
groups are shown in Table 5. In the low dose baboons, the
fibrinogen concentration exceeded the upper limit of the normal
range (214 mg/dl) on days 1 and 2, and was significantly different
from baseline on day 2. The fibrinogen concentrations in the
pretreated low dose baboons also exceeded the upper limit of the
normal range on days 1 and 2, however, these changes were not
considered to be biologically significant. The fibrinogen
concentration of the high dose group decreased significantly with
respect to baseline at six hours post-infusion, and this concentration
was below the lower limit of normal (118 mg/dl) for baboons.
Meanwhile, fibrinogen levels in the pre~redLed high dose group
increased significantly from baseline on days 1 and 2 and exceeded
the upper limit of riormal on days 1, 2, and 4.
Intravenous administration of PFDC0 also induced
thrombocytopenia in the u"lrealed study groups. The platelet count
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data for the four study groups in shown in Table 6. The normal
range for a baboon platelet count is 164,000-394,000/mm3, with
values below this range indicative of thrombocytopenia. In
comparison to the low end of the normal range, the low dose
baboons were moderately to mildly thrombocytopenic on days 4 and
7 post-infusion. Meanwhile, the pretreated low dose animals were
not considered to be thrombocytopenic since the platelet count
values for these animals were within the normal range during the
entire study. Meanwhile, both high dosed study groups exhibited
signs of thrombocytopenia. However, the untreated high dose
animals were thrombocytopenic between days 2 and 14, whereas
the thrombocytopenia in the treated high dose group was not visible
until day 4.
Imnact of Dexamethasone Pretrealment
on Serum Chemistrv Parameters
Clinical chemistry parameters were analyzed only for
the two high dose study groups.
Serum triglyceride (TG), total bilirubin, and direct
bilirubin values are shown in Tables 7 and 8. With respect to serum
triglycerides, elevations in the high dose animals exceeded the upper
- limit (94 mg/dl) of the normal range for baboons on days 1, 2, and
4, whereas increases in the dexamethasone pretreated group where
well within the normal range for the baboon. The TG increases were
probably related to the infusion of exogenous triglycerides contained
in the corticosteroid and/or PFC emulsion and the number of
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chemical sedation procedures required for blood sampling and
monitoring of vital signs in the first 4 days post-infusion.
The total bilirubin values exceeded or were at the upper
limit (0.40 mg/dl) of normal for baboons at 4 hours, 6 hours, and 1
day in the high dose animals, and were at this upper limit at 4 hours
and 6 hours in the pretreated animal group. These rises probably
were due to altered hemoglobin metabolism secondary to
phagocytosis of the emulsion particles by the hepatic
reticuloendothelial (Kupffer) cells. With respect to direct bilirubin,
the high dose group exceeded the normal range for baboons
(0.20mg/dl) at 6 hours and 1 day post-infusion, whereas all of the
values in the pretreatment group were within the normal range.
Aspartate amino transferase (AST) enzyme activity
values are shown in Table 9. The AST enzyme activity exceeded the
upper limit (62 U/L) of the normal range for baboons in both the high
dose and pretreated high dose study groups at 4 hours, 6 hours, 1
day, 2 days and 4 days post-infusion. However, the AST values for
the high dose group were significantly greater than the values of the
pretreatment high dose group at 6 hours, 1 day and 2 days post-
infusion.
The lactate dehydrogenase (LDH) serum enzyme activity
values also are shown in Table 9. In the high dose animals, there is
a significant elevation of LDH during several measurement times
post-infusion, and all of the LDH values between 4 hours and 4 days
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were above the upper limit ( 438 U/L) of the normal range for
baboons. In the pretreated high dose group, LDH values exceeded
the upper limit of the normal range only on days 1 and 2.
Furthermore, in this group, there were no significant changes in the
LDH level from baseline over the course of the entire study.
This invention offers several benefits to animals being
treated with PFC emulsions. For example, corticosteroid
pretreatment attenuates or prevents adverse PFC-induced side
effects on the coagulation system. Pretreatment virtually eliminates
the PFC-induced adverse effects on prothrombin time and activated
partial thromboplastin time, and significantly inhibits PFC-induced
thrombocytopenia .
Corticosteroid pretreatment also attenuates or
eliminates adverse PFC-induced side effects on several serum
chemistry parameters. For example, pretreatment inhibits PFC-
induced increases in serum triglycerides and bilirubin, as well as in
aspartate amino transferase enzyme activity and lactate
dehydrogenase enzyme activity.
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Table 2
..
F~oll.ro...b;n Time
(seconds)
1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg
PFC Dexam PFC PFC
Dexam
R ~s - ' .eMean 12.8 12.4 12.8 13.2
Std 0.0 0.5 0.3 0.5
n 3 3 3 3
4 Hour Mean 12.5 12.3 14.3t@ 12.8
Std 0.0 0.3 0.6 0.6
n 3 3 3 3
6 Hour Mean 14.2 13.7 18.0t@ 13.7
Std 1.2 1.5 0.9 0.8
n 3 3 3 3
1 Day Mean 14.4* 13.5 16.0t@ 14.0
Std 1.7 1.3 0.5 0.5
n 3 3 3 3
2 Day Mean 13.2 13.2 14.2t 14.0
Std 0.8 1.0 0.8 0.5
n 3 3 3 3
4 Days Mean 12.5 12.7 12.8 13.8
Std 0.5 0.8 0.3 0.3
n 3 3 3 3
7 Days Mean 13.0 12.5 12.3 13.0
Std 0.5 0.5 0.3 0.5
n 3 3 3 3
14 Days Mean 13.0 12.7 13.0 13.3
Std 0.5 0.6 0.5 0.6
n 3 3 3 3
30 Days Mean 13.0 12.8 13.7 14.2
Std 0.5 0.3 0.3 0.8
n 3 3 3 3
~Denotes a sig--irica--l dirrerenGe from Lase" ~e (p50.05)
Denotes a siy.-irica-.l Jirr_lence within a PFC dose group with and ~;ll-o.Jl
t p.t l.eaL---e--l (p50-05)
tDenotes a .;yniricanl dirr.,.~nce from ~?S-'- .e (ps0.01)
@Denotes a sig.-iricarl dirrerence within a PFC dose group with and
without ~,.el-eal---ent (p s 0.01)
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Table 3
A~ F - ' Parbal Tl' "r 6 ~ Time (arl r)
(5~CG. .~ls)
1 ml/kg1 ml/kg PFC 2 ml/kg2 ml/kg
PFC Dexam PFC PFC
Dexam
P~a~-' .eMean 31.4 29.3 32.9 33.1
Std 0.8 1.6 4.1 1.6
n 3 3 3 3
4 Hour Mean 29.3 28.3 39.5@ 29.2
Std 2.5 1.9 6.1 1.8
n 3 3 3 3
6 Hour Mean 33.3 31.7 44.5t@ 31.5
Std 4.1 2.0 9.0 1.3
n 3 3 3 3
1 Day Mean 36.2 29.7 43.7t@ 32.2
Std 7.7 3.4 6.8 2.0
n 3 3 3 3
2 Day Mean 30.5 28.3 35.2t 29.5
Std 3.0 3.0 5.0 1.3
n 3 3 3 3
4 Days Mean 26.7 29.3 27.2 32.0
Std 1.3 2.6 2.6 2.2
n 3 3 3 3
7 Days Mean 28.3 28.7 26.0* 31.8
Std 2.0 Z.3 2.6 3.5
n 3 3 3 3
14 Days Mean 30.5 31.7 29.8 31.3
Std 1.8 2.5 3.3 3.5
n 3 3 3 3
30 Days Mean 31.7 30.7 31.3 33.5
Std 2.9 2.0 3.3 1.7
n 3 3 3 3
*Denotes a s;g.~;ricanl dirrerence from b~ e (pC0.05)
Denotes a ~iy..irica,.l Jirro~e....,G within a PFC dose group with and without
.aal~ l (p s 0.05)
tDenotes a ;,;g..;ficanl dirt~rGnce from basel;ne (ps0.01)
@Denotes a significant .lirrerOnce within a PFC dose group with and
without Fi,el-Gal.,.enl (pcO.01)
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Table 4
Factor Vlll (FVIII)
~%)
.
1 ml/kg1 ml/kg PFC2 ml/kg 2 ml/kg
PFC Dexam PFC PFC
Dexam
R~se! )e Mean 64.5 77.0 63.2 61.7
Std 10.7 4.8 5.8 18.9
n 3 3 3 3
4 Hour Mean 77.3 89.3 74.0 87.0
Std 8.6 20.5 16.6 43.6
n 3 3 3 3
6 Hour Me~n 89.3~ 65.7 89.0 105.0*
Std Z.5 21.2 38.0 33.0
n 3 3 3 3
1 Day Mean 58.3 92.0 61.0 100.7
Std 16.5 25.0 8.5 38.6
n 3 3 3 3
2 Day Mean 76.3 87.0 98.7 116.7*
Std 13.4 15.0 8.7 23.4
n 3 3 3 3
4 Days Mean 78.7 70.7 105.0~ 77.0
Std 11.6 3.2 7.5 22.1
n 3 3 3 3
7 Days Mean 67.0 93.3 113.3~ 83.0
Std 8.7 15.5 7.8 29.5
n 3 3 3 3
14 Days Mean 60.7 54.3~ 98.0 87.7
Std 7.1 6.0 17.1 41.0
n 3 3 3 3
30 Days Mean 63.0 82.0 89.3 78.3
Std 6.0 19.1 2.5 25.0
n 3 3 3 3
*Denotes a ,;ynirica-.l dirrerence from ' ~s-' .e (psO.05)
_Denotes a siynirica.-l dirrcr~llce within a PFC dose group with and without
p.~l,a~ -enl (p50.05)
tDenotes a ~iyr.iricanl .lirrorë"ce from Las-'- ~e (psO.01)
@Denotes a siyniricsrl dirrere.-ce within a PFC dose group with and
-' without p.el.eal,.. ent (psO.01)
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Table 5
hL ~
Img/dl)
1 mllkg1 mllkg PFC 2 ml/kg 2 ml/kg
PFC Dexsm PFC PFC
Dexam
B~s~" .eMean 207.8 218.7 187.5 190.0
Std 33.5 23.6 19.8 13.0
n 3 3 3 3
4 Hour Mean 175.3 200.0 159.3 193.3
Std 21.9 Z7.8 37.6 17.6
n 3 3 3 3
6 Hour Mean 170.3 187.7 113.0t@ 200.0
Std 4.0 55.1 51.1 18.0
n 3 3 3 3
1 Day Mean 247.0 248.7 146.7@ 260.0t
Std 86.2 59.0 39.5 17.3
n 3 3 3 3
2 Day Mean 276.7~ 238.3 187.7 253.3
Std 58.4 42.5 36.6 30.6
n 3 3 3 3
4 Days Mean 201.7 210.0 210.0 230.0
Std 16.1 27.8 34.6 43.6
n 3 3 3 3
7 Days Mean 156.0 192.7 183.3 195.7
Std 1.7 21.9 10.4 33.9
n 3 3 3 3
14 Days Mean 148.5 173.3 163.3 190.7
Std 17.6 22.5 19.3 20.6
n 3 3 3 3
30 Days Mean 150.0 166.7 152.3 169.0
Std 13.2 14.4 5.9 15.9
n 3 3 3 3
~Denotes a ~;y..irica..l Jirre~enca from baseline (p50.05)
_Denotes a a;y..iricanl dirrerence within a PFC dose group with and without
prel,eal...ent (p50.05)
tDenotes a siy~irica~l dirrercnce from tase'i )e (pso.ol~
@Denotes a significant .lirrerence within a PFC dose group with and
without ~,rel.aal...anl (psO.01)
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Table 6
~,
Platelet Count
(#Imm3)
1 ml/kg1 ml/kg PFC 2 ml/kg 2 ml/kg
PFC Dexam PFC PFC
Dexam
Baseline Mean 293,667 384,667 256,667 245,000
Std 73,059 87,719 21,808 10,851
n 3 3 3 3
4 Hour Mean 350,000 375,000 249,333 282,667
Std 110,000 72,111 31,770 51,433
n 3 3 3 3
6 Hour Mean 347,333 374,000 228,667 273,000
Std 137,147 82,018 31,134 61,579
n 3 3 3 3
1 Day Mean 313,333 387,000 218,667@ 370,667
Std 119,316 77,660 15,503 170,694
n 3 3 3 3
2 Day Mean 159,000 268,000 108,333t 223,333
Std 54,617 112,468 64,485 75,593
n 3 3 3 3
4 Days Mean71,667~@ 193,333~ 45,333t 86,000t
Std 16,803 146,401 14,012 21,703
n 3 3 3 3
7 Days Mean132,667~ 213,333~ 87,000t 65,000t
Std 32,578 72,058 23,302 17,346
n 3 3 3 3
14 Days Mean 264,333 311,333 148,000~ 136,000
Std 51,082 72,858 31,225 3,464
n 3 3 3 3
30 Days Mean 337,667 283,333 203,000 242,333
Std 56,518 72,009 98,240 77,526
n 3 3 3 3
~Denotes a s;y.,iricd.,l Jirr~r~,nce from i ~s ~J ", IpsO.05)
- Denotes a s;g"ilicanl .lirrerence within a PFC dose group with and without
~J.el,cdl."a"l (psO.05)
tDenotes a ~;g"ilicanl dirr~.cnce from ' -s~ ,e (psO.Ol)
@Denotes a ~;g,.;rica"l dirr~rcnce within a PFC dose group with and
without ,6,cl-cal",ent (psO.01)
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-22-
Tablo 7
T.;5~1y~.;~s
(mg/dl)
2 ml/kg 2 ml/kg
PFC PFC
Dexam
R? ;~ ~eMean 45-5 33.8
Std 17.7 24.9
n 3 3
4 Hour Mean 47.0 40.7
Std 11.3 16.7
n 3 3
6 Hour Mean 51.0 31.7
Std 16.7 15.1
n 3 3
1 Day Mean 107.7~ Z5.0
Std 51.1 11.3
n 3 3
2 Day Mean 132.7~ 87.3
Std 26.5 15.0
n 3 3
4 Days Mean 115.0~ 89.3
Std 22.6 23.9
n 3 3
7 Days Mean 68.3 45.7
Std 2.5 25.9
n 3 3
14 Days Mean 54.7 54.7
Std 18.9 19.5
n 3 3
30 Days Mean 40.3 40.0
Std 5.0 15.6
n 3 3
~Denotes a ~;y"iricdnl Jirferel)cc from ~as~' .e (psO.05)
_An u "Jersco.2d value denoles a s;g..;rica"l dirrt:,e"ce within a PFC dose
group with and without ~Jrelreal~ent (p50.05)
tDenotes a s;yniricar,l Jirrer~nce from ~as~' )e (psO.01)
@Denotes a s;g";rica"l Jirra~ancc within a PFC dose group with and
without ~ e~,l"~enl (pC0.01)
CA 02202989 1997-04-17
WO 96/13268 PCT/US95/13714
Table 8
~,
To~tal '' 1,l' ' Direct r~ ~
(mg/d) (mg/d)
2 ml/kg2 ml/kg PFC2 ml/kg2 ml/kg
PFC Dexam PFC PFC
Dexam
Baseline Mean 0.2 0.2 0.2 0.2
Std 0.0 0.1 0.0 0.1
n 3 3 3 3
4 HourMean 0.6~ 0.4~ 0.5~ 0.2
Std 0.3 0.1 0.5 0.1
n 3 3 3 3
6 HourMean 0.4~ 0.4* 0.3 0.1
Std 0.1 0.1 0.1 0.0
n 3 3 3 3
1 DayMean 0.4* 0.2 0.4 0.1
Std 0.2 0.0 0.4 0.0
n 3 3 3 3
2 DayMean 0.3 O.Z 0.3 0.1
Std 0.2 0.1 0.2 0.0
n 3 3 3 3
4 DaysMean 0.2 0.2 0.2 0.2
Std 0.1 0.1 0.1 0.1
n 3 3 3 3
7 DaysMean 0.3 0.1 0.1 0.1
Std 0.1 0.1 0.0 0.0
n 3 3 3 3
14 DaysMean 0.3 0.2 0.1 0.1
Std 0.1 0.1 0.0 0.1
n 3 3 3 3
30 DaysMean 0.2 0.1 0.1 0.1
Std 0.1 0.1 0.0 0.0
n 3 3 3 3
*Denotes a s;y"iricanl dirr~.ence from l~aseline (pC0,05J
_An u~duscOrëd value denoles a aiy"iricar,l dirr1renca within a PFC dose
group with and without p,el,~al",e.,l (p~0.05)
tDenotes a aiy.,iri.,a"l dirr~r~.,ce from La~ e (psO.01)
@Denotes a signiricanl dirrelence within a PFC dose group with and
without ,~,.el,èal",anl (p~0.01)
CA 02202989 1997-04-17
WO 96113268 PCT/US95/13714
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Table 9
SGOT-AST LDH
(U/L) ~U/L)
2 ml/kg2 ml/kg PFC2 ml/kg 2 ml/kg
PFC Dexam PFC PFC
Dexam
R= ~ .eMean 32.8 27.8 165.2 124.8
Std 12.5 1.8 17.9 58.5
n 3 3 3 3
4 Hour Mean 143.3 89.3 743.3 311.0
Std 28.9 51.7 167.3 127.2
n 3 3 3 3
6 Hour Mean 270.7t 127.0 1289t 492.0
Std 53.0 54.0 448.7 119.7
n 3 3 3 3
1 Day Mean 549.0t 166.7~ 3791.3t 520.0
Std Z40.2 61.8 1604.2 126.1
n 3 3 3 3
2 Day Mean 304.0t 172.3* 1588.3t 558.7
Std 150.7 56.3 1155.5 303.0
n 3 3 3 3
4 Days Mean 73.7 81.3 451.7 299.0
Std 29.7 31.5 112.6 118.9
n 3 3 3 3
7 Days Mean 33.0 40.0 313.7 213.7
Std 7.0 8.5 60.7 62.7
n 3 3 3 3
14 Days Mean 22.3 25.3 228.0 164.3
Std 1.2 5.7 85.5 64.8
n 3 3 3 3
30 Days Mean 22.7 21.7 163.7 122.0
Std 0.6 2.1 36.2 3.2
n 3 3 3 3
~Denotes a siy.-iric~nl Jirralance from l~asel;ne (ps0.05)
An ul-derscGracl value denoles a :.;y..irica-.l dirrarance within a PFC dose
group without and without p~ e.-~ enl (ps0.05
tDenotes a significant dirtarence from Laseli.-e Ips0.01)
@Denotes a sig..iricanl .lirrt~ nce within a PFC dose group with and
without ~rt~ dllll~ (ps0.01)
CA 02202989 1997-04-17
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-25-
The embodiments presented in the detailed descripLion
.;.
i ~ are provided by way of illustration only, and are not intended to limit
the scope of the invention. Rather, this invention is defined by the
appended claims and any equivalents thereto.
WHAT IS CLAIMED IS:
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