U.S. patent application number 10/487224 was filed with the patent office on 2004-12-30 for hdl for the treatment of stroke and other ischemic conditions.
Invention is credited to Hubsch, Alphonse, Lang, Markus G, Lerch, Peter G, Paterno, Roberto.
Application Number | 20040266660 10/487224 |
Document ID | / |
Family ID | 26076691 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040266660 |
Kind Code |
A1 |
Hubsch, Alphonse ; et
al. |
December 30, 2004 |
Hdl for the treatment of stroke and other ischemic conditions
Abstract
The present invention relates to a method for the prophylaxis
and/or treatment of stroke and other ischemic injury, wherein HDL
is administered to a subject in need thereof, particularly by
intravenous infusion.
Inventors: |
Hubsch, Alphonse;
(Zollikofen, CH) ; Lang, Markus G; (Biel-Benken,
CH) ; Lerch, Peter G; (Bern, CH) ; Paterno,
Roberto; (Napoli, IT) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Family ID: |
26076691 |
Appl. No.: |
10/487224 |
Filed: |
August 2, 2004 |
PCT Filed: |
August 20, 2002 |
PCT NO: |
PCT/EP02/09294 |
Current U.S.
Class: |
514/200 ;
514/171; 514/7.4 |
Current CPC
Class: |
A61K 38/17 20130101;
A61K 38/1709 20130101; A61P 9/10 20180101; A61P 25/00 20180101;
A61P 9/00 20180101 |
Class at
Publication: |
514/002 ;
514/171 |
International
Class: |
A61K 038/17; A61K
031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 20, 2001 |
EP |
01120026.8 |
Aug 20, 2001 |
US |
60/313605 |
Claims
1. Use of HDL for the manufacture of an agent for the prophylaxis
and/or treatment of ischemia or reperfusion injury.
2. The use of claim 1 for the prophylaxis and/or treatment of a
disorder selected from ischemic stroke, ischemic tissue injury,
cardiac ischemia, cardiac reperfusion injury, and complications
resulting from organ transplantation or cardio-pulmonary bypass
surgery.
3. The use of claim 1 wherein HDL is administered by intravenous
infusion and/or injection.
4. The use of claim 1 wherein HDL is administered as a
prophylaxis.
5. The use of claim 1 wherein HDL is administered as a
treatment.
6. The use of claim 1 wherein HDL is administered before the start
of ischemia and/or during ischemia.
7. The use of claim 1 wherein HDL is administered at or after
reperfusion.
8. The use of any of claim 1 wherein HDL is administered in a
dosage of from 10-200 mg HDL (weight based on apolipoprotein) per
kg body weight per treatment.
9. The use of claim 1 wherein HDL is administered as a bolus
injection and/or as an infusion for a clinically necessary period
of time.
10. The use of claim 1 wherein the HDL has a molar ratio of
protein, e.g. apolipoprotein A-1 to phospholipids in the range of
1:50-1:250 and optionally additional lipids such as cholesterol,
cholesterol esters, trigylcerides and/or sphingolipids are present
in a molar ratio of up to 1:20 based on the protein.
11. The use of claim 1, wherein the HDL is selected from nascent
HDL, reconstituted HDL (rHDL), recombinant HDL or mixtures
thereof.
12. The use of claim 1, wherein HDL is administered in combination
with other pharmaceutical agents.
13. A method for prophylaxis and/or treatment of ischemia or
reperfusion injury comprising administering a subject in need
thereof an effective amount of HDL.
14. The method of claim 13, wherein the HDL is selected from
nascent HDL, reconstituted HDL (rHDL), recombinant HDL or mixtures
thereof.
15. The method of claim 13, wherein the subject is a human.
16. A composition for the prophylaxis and/or treatment of ischemia
or reperfusion injury comprising HDL as an active ingredient.
Description
[0001] The present invention relates to a method for the
prophylaxis and/or treatment of stroke and other ischemic
conditions, wherein HDL particles, as exemplified by reconstituted
HDL (rHDL) particles are administered to a subject in need thereof,
particularly by intravenous infusion.
[0002] Stroke can be classified into thrombo-embolic and
hemorrhagic forms and is the third largest cause of death in
western countries, after heart disease and cancer. In the United
States each year 600 000 people suffer a new or recurrent stroke
(about 500 000 are the first attacks) and approximately 29% of them
die within the first year (1). The incidence of stroke increases
with age, and in the elderly it is the leading cause of serious,
long-term disability in the US accounting for total costs of 51.3
billion $/year (1). Although the death rate from stroke has been
decreasing in recent years, largely due to the increased awareness
and better control of risk factors such as hypertension,
hypercholesterolemia, arrhythmia or diabetes, the actual number of
stroke deaths is rising because of an increasing elderly
population. However, when prevention measures fail only limited and
risky thrombolytic approaches exist, e.g. t-PA (tissue plasminogen
activator). Neuronal protection could become a new and safer
strategy for stroke treatment in the future (2-4).
[0003] One common cause of circulatory shock is severe blood loss
associated with trauma. Despite improvements in intensive care
medicine, mortality from hemorrhagic shock remains high (5, 6).
Thus, there is still a great need for new approaches to improve
therapy and outcome of patients with hemorrhagic shock (6). In
clinical practice, hemorrhagic shock leads to a delayed vascular
decompensation (resulting in severe hypotension) and, in
approximately 25% of patients, in the dysfunction or failure of
several organs including lung, kidney, gut, liver and brain (7).
Organ dysfunction can also occur from an ischemic event, caused by
a reduction in blood supply as a result of a blockage as distinct
from a hemorrhage. There is also evidence that reperfusion (during
resuscitation) also plays a role in the pathophysiology of the
multiple organ dysfunction syndrome (MODS)(8).
[0004] According to WO 01/13939 and (21) rHDL used in a rat
hemorrhagic shock model demonstrated a significant reduction of
organ damage. Hemorrhagic shock comprises a generalized reduction
in blood supply to the whole body which results in hypoxic damage
that affects all organs and tissues. In contrast, ischemia
describes a localized depletion of blood supply to specific organs
and tissues, resulting in a rapid onset of anoxia in these affected
regions. The mechanisms of damage are therefore quite distinct.
[0005] rHDL has been shown to stimulate cholesterol efflux from
peripheral cells in a process better known as reverse cholesterol
transport. Furthermore, rHDL dose-dependently binds bacterial
lipopolysaccharides (LPS) and inhibits LPS-induced cytokine
production as well as adherence of PMNs (polymorphonuclear
leukocytes) to endothelial cells (21). rHDL has anti-inflammatory
and free oxygen radical scavenger activity. rHDL also decreases the
rate and the extent of platelet aggregation. More recently it was
demonstrated that rHDL acutely restores endothelial function and in
turn normalizes blood flow in hypercholesterolemic patients by
increasing nitric oxide bioavailability as determined by forearm
plethysmography (9).
[0006] The pathophysiology of stroke is characterized by a wide
range of homoeostatic, hemodynamic and metabolic abnormalities such
as thrombus formation, impaired endothelial function and an
activated inflammation cascade, i.e. increased cytokine production
and expression of adhesion molecules (10-15). Another hallmark of
stroke is the augmented oxidative stress after reperfusion which is
thought to play a detrimental role in the progression of the
disease.
[0007] Prolonged ischemia results in an elevation of intracellular
Ca.sup.++ and the consequent activation of proteases and
phospholipases results in formation of numerous potentially
damaging products of membrane lipid breakdown. These include
arachiodonic acid metabolites, which, in the presence of oxygen
during reperfusion, provide a source of free radical formation
(e.g. superoxide and hydroxyl anions). These free radicals induce
blood brain barrier destruction and neuronal apoptosis and/or
necrosis. Apoptosis is a form of cell death that eliminates
compromised or superfluous cells with no inflammatory response and
is differentiated from necrosis by many morphological and
biochemical characteristics. The feature of apoptosis can be found
in both neurons and glia after ischemic injuries. Neurons in the
ischemic penumbra, that are not exposed to lethal ischemia, may
undergo delayed apoptosis (16). The so called penumbra is a brain
area where blood flow is reduced to a level that interrupts
neuronal function and the consequent electrical activities, yet
permits maintenance of membrane pumps and preservation of ion
gradients. This brain area has two characteristics that explain its
potential clinical importance: 1) the interruption of clinical and
electrical function that characterizes this area is fundamentally
reversible, but 2) the reversibility is time-limited and linked to
reperfusion.
[0008] Surprisingly, it was found that the size of the lesions in
animal models for stroke (excitotoxicity and cerebral artery
occlusions) is reduced by administration of HDL. These data show
that HDL can improve the outcome following excitotoxic and
ischemic/reperfusion neuronal damage, particulary apoptosis and/or
necrosis in the ischemic area and in the penumbra. Further, it was
shown in an animal model for hemorrhagic shock that HDL reduces the
PMN infiltration and prevents organ injury and dysfunction. At
present, the mechanism of action is unknown. While not wishing to
be bound by theory, it is possible that HDL might act as a free
oxygen radical scavenger, vasodilator, e.g. via improvement of NO
bioavailability resulting in an improvement of collateral blood
flow or it may exhibit an anti-inflammatory effect. Thus, HDL may
act as a neuroprotective drug particularly in cerebrovascular
diseases. It might also work by a combination of all these
activities, achieving a clinical efficacy not yet seen in current
therapies.
[0009] The invention generally relates to the use of HDL for the
prophylaxis and/or treatment of ischemia or reperfusion injury.
Ischemia to an organ occurs as a result of interruption to its
blood supply, and in its broadest sense may result in organ
dysfunction or damage, especially heart, cerebral, renal, liver or
lung. It is a local event/interruption that leads to complete or
partial and in some cases reversible damage. Reperfusion injury
occurs as a consequence of rapid return of oxygenated blood to the
area following ischemia and is often referred to in cardiovascular
and cerebral misadventures.
[0010] Thus, a subject matter of the present invention is the use
of HDL for the manufacture of an agent for the prophylaxis and/or
treatment of ischemia or reperfusion injury. Particularly, HDL may
be used for the prophylaxis and/or treatment of a disorder selected
from ischemic stroke, ischemic tissue injury, e.g. ischemic injury
of organs, cardiac ischemia, cardiac reperfusion injury and
complications resulting from organ transplantation, e.g. kidney,
heart and liver or cardio-pulmonary bypass surgery and other
disorders. Even more surprisingly, it has been found that HDL can
have a beneficial effect when a transient or a permanent occlusion
is in place. As a result, it is not a prerequisite for efficacy
that the clot or other entity causing the occlusion be dissolved or
otherwise removed. Moreover, administration of HDL shows benefits
even 6 or more hours after an ischemic event. A further surprising
observation has been the beneficial effect of HDL administration
before an ischemic event.
[0011] A further embodiment of the invention relates to the use of
HDL for prophylaxis and/or treatment of transient ischemic attacks
(TIA). TIAs are common and about one third of those affected will
develop a stroke some time later. The most frequent cause of TIA is
the embolization by a thrombus from an atherosclerotic plaque in a
large vessel (typically a stenosed atheromatous carotid artery). As
HDL has anti-atherosclerotic properties, as shown in studies
looking at endothelial function through the restoration of
bioavailability of nitric oxide, regulation of vascular tone and
structure (9) it is thought that HDL may play a role in stabilizing
an atheromatous plaque causing TIAs thereby reducing the risk of a
major stroke. Current therapy for TIAs include antiplatlet therapy,
aspirin, ticlopidin and surgical intervention such as
endoarterectomy. However, none of these provide, as yet, a
substantial reduction in morbidity.
[0012] Yet a further embodiment relates to the prophylactic
administration of HDL to risk patient groups such as patients
undergoing surgery. Administration of HDL may reduce the incidence
and/or severity of new strokes. Prophylactic administration of HDL
could also be useful in patients with TIAs, atrial fibrillation and
asymptomatic carotid stenosis.
[0013] The use of HDL for the treatment of the above diseases,
particularly for the treatment of stroke and transient ischemic
attacks fulfills an as yet unmet clinical need. It provides a
clinically effective neuroprotective therapy for individuals with
traumatic brain injury.
[0014] The term "HDL" as used in the present invention relates to
particles similar to high density lipoproteins and comprises
nascent HDL or reconstituted HDL (rHDL) or any mixture thereof.
Such particles can be produced from a protein or peptide component,
and from lipids. The term "HDL" also includes within its breadth
any recombinant HDL or analogue thereof with functional
relationship to nascent or reconstituted HDL.
[0015] The proteins are preferably apolipoproteins, e.g. human
apolipoproteins or recombinant apolipoproteins, or peptides with
similar properties. Suitable lipids are phospholipids, preferably
phosphatidyl choline, optionally mixed with other lipids
(cholesterol, cholesterol esters, triglycerides, or other lipids).
The lipids may be synthetic lipids, naturally occurring lipids or
combinations thereof.
[0016] Administration of HDL may result, on one hand, in a short
term effect, i.e. an immediate beneficial effect on several
clinical parameters is observed and this may occur not only within
3 hours of onset of stroke, but even 6 hours or possibly even
longer and, on the other hand, a long term effect, a beneficial
alteration on the lipid profile may be obtained. Furthermore, HDL
resembles very closely substances naturally occuring in the body
and thus the administration of HDL is free of side effects.
[0017] HDL is preferably administered by infusion, e.g. by
arterial, intraperitoneal or preferably intravenous injection
and/or infusion in a dosage which is sufficient to obtain the
desired pharmacological effect. For example, HDL may be
administered before the start of ischemia (if foreseeable, e.g.
before an organ transplantation) and/or during ischemia, before
and/or shortly after reperfusion, particularly within 24 h-48
h.
[0018] The HDL dosage ranges preferably from 10-200 mg, more
preferably 40-80 mg HDL (weight based on apolipoprotein) per kg
body weight per treatment. For example, the dosage of HDL which is
administered may be about 20-100 mg HDL per kg body weight (weight
based on apolipoprotein) given as a bolus injection and/or as an
infusion for a clinically necessary period of time, e.g. for a
period ranging from a few minutes to several hours, e.g. up to 24
hours. If necessary, the HDL administration may be repeated one or
several times.
[0019] Reconstituted high density lipoprotein (rHDL) may be
prepared from human apolipoprotein A-I (apoA-I), e.g. isolated from
human plasma, and soybean-derived phosphatidylcholine (PC), mixed
in molar ratios of approximately 1:150 apoA-1:PC.
[0020] According to the present invention, an HDL, e.g. nascent
HDL, rHDL, recombinant HDL or an HDL-like particle is particularly
preferred which has a molar ratio of protein (e.g. apolipoprotein
A-1) and phospholipid in the range of 1:50 to 1:250, particularly
about 1:150. Further, rHDL may optionally contain additional lipids
such as cholesterol, cholesterol esters, triglycerides and/or
sphingolipids, preferably in a molar ratio of up to 1:20, e.g. 1:5
to 1:20 based on the apolipoprotein. Preferred rHDL is described in
EP-A-0663 407.
[0021] The administration of HDL may be combined with the
administration of other pharmaceutical agents such as thrombolytic
agents, anti-inflammatory agents, neuro- and/or cardioprotective
agents.
[0022] Furthermore, the present invention relates to a method for
prophylaxis and/or treatment of ischemia or reperfusion injury
comprising administering a subject in need thereof an effective
amount of HDL. Preferably, HDL is administered to a human
patient.
[0023] Further, the present invention shall be explained in detail
by the following examples:
EXAMPLE 1
[0024] Excitotoxic Lesion:
[0025] Experiments were performed in Sprague-Dawley rats
anesthetized with chloral hydrate (400 mg/kg ip). A femoral vein
was cannulated for infusion of rHDL. Rats were placed into a
stereotaxic apparatus and, after a midline incision, received a
unilateral injection of N-methyl-D-aspartate (NMDA) or vehicle into
the right striatum: coordinates: 0.2 mm posterior, 3 mm lateral,
5.5 mm ventral to the bregma. Five minutes after insertion of the
needle the solution was injected over a period of 6 minutes using a
Hamilton syringe pump at a rate of 0.5 ml/min. 5 minutes after
injection has been completed, the needle was removed.
[0026] In this series of experiments rats received intravenous
infusion of saline (n=5) (5 .mu.l/min) over 4 h. After 2 h,
unilateral injection of NMDA (75 nM in 3 ml of phosphate-buffered
saline pH 7.4) was performed into the right striatum. After
twenty-four hours, rats were sacrificed and the brain was removed
for histological analysis. In another group of experiments, rats
received intravenous infusion of rHDL (n=5) (5 .mu.l/min) at a dose
of 120 mg/kg over 4 h. After 2 h, unilateral injection of NMDA (75
nM in 3 ml of phosphate-buffered saline pH 7.4) was applied into
the right striatum and intravenous infusion of rHDL continued for
an additional 2 h. Twenty-four hours later the rats were sacrificed
and the brain was removed for histological analysis. The results
are shown in Table 1.
1TABLE 1 lesion volume in mm.sup.3 rat control rHDL 1 50.27 16.54 2
47.05 18.86 3 41.28 17.44 4 38.5 17.51 5 51.66 19.86 n 5 5 MEAN
45.75 18.04 SD 5.69 1.31 SEM 2.55 0.59
[0027] In this experiment a dramatic reduction of the brain
necrotic volume in rHDL treated animals by 60.6% compared to
controls was observed.
[0028] In a further series of experiments rHDL (120 mg/kg) or
placebo (saline) infusion was administered over 4 h starting 3 h
after NMDA injection. The infarct size was measured histologically
after 24 h. The results are shown in Table 2.
2 TABLE 2 Saline + NMDA rHDL + NMDA lesion vol. (mm.sup.3) lesion
vol. (mm.sup.3) 175 77 101 83 105 133 180 121 149 51 115 66 mean
137 88 SD 35 32 % reduction -36% p (Students t test) 0.03
[0029] In this experiment a reduction of infarct size by 36% was
found.
EXAMPLE 2
[0030] Middle Cerebral Artery Occlusion:
[0031] 2.1 Administration Before Occlusion
[0032] Experiments were performed in Sprague-Dawley rats
anesthesized with chloral hydrate (400 mg/kg ip). The trachea were
cannulated and the animals were mechanically ventilated with air
and supplemental oxygen to maintain blood gases within normal
ranges. Rectal temperature was continually monitored and maintained
at 37.degree. C. Catheters were placed into the femoral artery to
measure systemic blood pressure and to monitor blood gases. A
femoral vein was cannulated for infusion of drug. A neck midline
incision was made and the right common carotid artery was exposed.
Following coagulation of its branches, the external carotid artery
(ECA) was distally opened. A nylon thread (diameter 0.22 mm) which
has a distal cylinder of silicon (2 mm long, diameter 0.38 mm) of
thermofusible glue was inserted in the lumen of ECA and advanced
into the internal carotid artery up the origin of MCA. To restore
the MCA blood flow, the nylon thread was removed and cut thirty
minutes later.
[0033] Histological analysis: Twenty-four hours after the surgery
euthanasia was performed. The brains were rapidly removed, frozen
in isopentane at -50.degree. C. and stored at -80.degree. C.
Cryostat cut coronal brain sections (20 .mu.m) were stained with
thionine and analyzed using an image analyzer. The lesioned areas
were delimited by the paleness of histological staining in
alterated tissue compared to the color of healthy tissue. Regions
of interest were determined through the use of a stereotaxic atlas
for the rat and an image analysis system was used to measure the
lesioned area.
[0034] In this series of experiments rats received an intravenous
infusion of saline (n=5) (5 .mu.l/min) over 4 h. After 2 h the MCA
of rats was occluded for 30 minutes followed by reperfusion. After
twenty-four hours, rats were sacrified for histological analysis of
the brain. In another group of experiments, rats received
intravenous infusion of rHDL (n=5) (5 .mu.l/min) at a dose of 120
mg/kg over 4 h. After 2 h the MCA of rats were occluded for 30
minutes followed by reperfusion. Twenty-four hours later the rats
were sacrificed for histological analysis of the brain. The results
are shown in Table 3.
[0035] In the MCA occlusion model, the following results were
obtained:
3TABLE 3 Lesion volume in mm.sup.3 rat control rHDL 1 158.94 54.18
2 229.78 35.27 3 201.52 37.64 4 193.02 34.64 5 210.24 76.74 n 5.00
5.00 MEAN 198.70 47.69 SD 26.08 18.11 SEM 11.66 8.10
[0036] rHDL reduced brain necrotic volume by 76% as compared to
control rats.
[0037] 2.2 Administration after Occlusion
[0038] rHDL was administered 3 h after injury in the MCAo (middle
cerebral artery occlusion) model. In 12 rats temporary occlusion of
the middle cerebral artery (MCA) was attained by inserting a nylon
thread through the carotid artery and blood flow was restored 30
minutes later. After 3 hours they received an intravenous infusion
of either rHDL (120 mg/kg over 4 h, 6 ml/kg over 4 h) or saline (6
ml/kg over 4 h). The rats were randomly assigned to the rHDL or the
control group. In four additional rats the same procedure of MCA
occlusion was performed but the nylon thread was halted in the
internal carotid artery, without interfering with carotid blood
flow, and was removed thirty minutes later (Sham MCAo group). After
3 hours two rats of this group received rHDL and two received
saline intravenously (6 ml/kg over 4 h). 24 h later, all rats were
sacrificed and the brains were removed for histological analysis.
The necrotic area was delimited by the paleness of the histological
staining as compared to the color of healthy tissue. Regions of
interest were determined by use of a stereotaxic atlas for the rat
and an image analysis system (NIH Image) was used to measure the
necrotic area.
[0039] In the sham MCAo group there was no lesion.
[0040] After MCA occlusion in the other 12 rats, treated
intravenously with saline or rHDL, the results from the image
analysis are presented in Table 4. The results show that infusion
of rHDL 3 hours post occlusion resulted in a 60% reduction in
infarct volume (mm.sup.3).
4 TABLE 4 lesion area in mm.sup.3 rat control rHDL 1 88.94 87 2
118.9 46.91 3 110.06 43.91 4 121.09 43.13 5 224.14 36.65 6 157.45
35.63 mean 136.8 48.9 SD 48.2 19.2 % reduction 64% p (Students t
test) 0.0020
[0041] The necrotic volume was reduced by 64% as compared to
control rats.
[0042] Conclusion: In both models, a dramatic reduction of the
infarct volume was seen in rHDL treated animals, as compared to
placebo treated controls: Excitotoxic model: 60.6% or 36% reduction
of necrotic volume; MCA occlusion model: 76% or 60% reduction.
EXAMPLE 3
[0043] Administration of rHDL in a Rat Model for Stroke (MCA
Occlusion Model)
[0044] Method
[0045] 120 male Sprague-Dawley rats were used in this study. 100
rats received either a transient occlusion or permanent occlusion.
20 rats served as surgical and rHDL controls. rHDL (120 mg/kg/4 h)
was infused starting 2 h before or 3 or 6 h after induction of
stroke. The same thread occlusion method as in Example 2 was
used.
[0046] Rats were grouped into three treatment arms. Group 1
received a prophylactic dose of rHDL 2 hours before receiving a
transient MCA occlusion (2 hour) and continued receiving treatment
during the occlusion. The artery was then reperfused.
[0047] Group 2 received a transient MCA occlusion followed by
reperfusion. Treatment with HDL was given either 3 hours or 6 hours
later.
[0048] Group 3 received a permanent MCA occlusion and received
treatment 3 hours or 6 hours after occlusion.
[0049] Following the above protocol the rats were examined for
neurological change using four standard motor neurological tests,
namely forelimb flexion, torso twisting, lateral push and mobility.
The scores were added for each of the tests and the results
presented in FIG. 1.
[0050] From this Figure it is clear that rHDL given both as a
pretreatment and as a dose 3 or 6 hours post occlusion (both
transient and permanent) resulted in a better neurological score
than untreated rats.
[0051] Following the neurological analyis the rats were sacrificed
and their brain removed. Sections of rat brain were examined using
a ballistic light technique that measured infact area by the
reflection of light. The results for rHDL treated permanent and
transient MCAo are shown in FIGS. 2 and 3.
[0052] These graphs show that if rHDL is given to rats (i) 2 hours
before occlusion there is a reduction in total infarct volume of
54% (ii) 3 hours post transient occlusion there is a reduction of
65% and (iii) 6 hours post transient occlusion a reduction of 62%.
A similar reduction of 59% was observed for permanent occlusion at
both treatment times.
[0053] Thus, the administration of rHDL is efficacious as a
prophylactic treatment before occlusion and as a therapeutic
treatment at two different points of time after occlusion. More
particularly, a prophylactic and therapeutic treatment may be
combined.
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