Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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FILE, P~k+N-~HIS A~f
T.F~TRANSLATION
ThP U'se of Human al-Acid Glycvprotein for
1?roducing a Pharmaceutical Preparation
The invention relates to riew medical uses of
orosomucoid.
cxl -Acid glycopr_otein (AGP) , also called
orosomucoid, is a substance recovered from plasma,
hawing a molecular weight of 40,000 Daltons, and
aamprising a carbohydrate portion of. between 30 and
50 %. AGP consists of a single polypeptide chain of 183
amino acids and compx-ises two disulfide bands.
Furthermore, it comprises five earb4hydratP chains alb
located in the first half of the peptide chain. These
carbohydrate groups consist of about 14% of neutral
hexoses, 14% of hexosamines, 11% of sialic acid and 2%
of fructose. Depending on the source of the AGP
preparatxvn and or'1 the recovery or characterisation
methods used, AGP appears in different forms which 19
attributed to differences in the polypeptide chain as
well ag to differences in Lhe carbohydrate chain.
The properties and biological Lunctions of
orosomucoid have been described in the survey articles
by Schmid (in ~~The Plasma Proteins Structure Function
and Genetic Control~~, Vol. 1 (1975), Academic Press,
Ed. Frank A. Putnam, 2nd Edition, pp. 183-228) and
Kremer et al. (Pharmacological Revzews ~0 (1988), pp.
1-47).
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xn the medical field, AGP so far has been
considered as an essentza~. carrier substance for
predominantly basic medicaments in plasma (cf. Kremer
et al . ) .
furthermore, orasomucoid could be democlsl:rated to
have a positive effect on inflammatory reactions. Thus,
Denko et al. (Agents and Actions l5, s/6 (1984), 539-
540) have described an anLiinflammatory effect of AGP
in orate crystal inflammations in rats. Libert et al_
(J. Exp. Med. 18Q (1994), 1571-1575) proved that a
similar indication lies in pre~crenting septic shock a.n
connection with the effect df TNF-a or lipopoly-
saccharides_
To improve perfusion disturbances, in particular of
microcirculation, as well as reperfusion damages so far
either vasoactive substances or special blood factors
which influence hemostasis or fibrinolysis,
respectively, in particular anticoagulants or
thrombolytically active fa4'LOrS have beers administered,
or a correspdndi.ng volume substitution has been carr~.ed
out.
'ro treat hypovolemic shock conditions occurzing
independently of inflammatory reactions, volume
substitution has been effected so far, whereby albumin
solutions Commonly having been used.
It is the object of the present invention to
provide new medical indication9 for orosomucoid.
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Surprisingly it-has been found that. oxosomucoid i.s
suitable for the treatment of disturbed circulation, or
mic~cocircu7.ation, .respectively, ref the non-inflammatory
type. Thus, it can be used tn v.mprove perfusion
disturbances, in particular a disturbed
microcirculation, as well as reperfusivn injuries, and,
above all, in shock conditions, for a better supply of
the vital organs, such as bra~.n, lung, heart, liver and
kidney_
These indications are all of the non--inflammatory
type, i.e. the disturbances are indicated if they do
not occur in connection with SzRS («systemic
inflammatory response syndxome~~ ) . l,''or a definition of
SIRS, cf. Critical Care Medicine 20 (6), 864-874
(1992). Due to inflammations, cells and tissue are
directly damaged, and as a consequence the permeability
of the vessels and the circulation are disturbed. With
the inventive use of AGP fox producing a pharamceutical
preparation for the trEatment of disturbances of
circulation, arad microcirculatlo~rl, respectively,
however, these disturbances are of the non-inflaauttdLory
type and thus have different causes. Among these pauses
are altered pressure conditions, particularly in
connection with a reduction of intravasal volume. If
not treated, the circulatory disorders triggered
thereby will lead to hypovolemic shock. Triggering
mechanisms in this case are considered to be aoute
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hemorrhages, excessive Joss of liquid, such as by
vomiting, diarrhoea, extreme sweating, dehydration,
excessive discharge of urine, peritonitis,
pancreatitis, ischemias in the splanchnic region,
ileus, gangrene, blunt traumas, damage of large groups
of muscles, or burns.
So far, these conditions commonly have been treated
with dextrane solutions, hydroacy ethyl starch, R~.nger's
lactate or albumin solutions. I~owevcr, these sub9tances
do nol possess any a~ntiimflammatory properties, azzd
thus it has been surprising that orosomucoid which had
been used for the treatment of inflammations could
assume this function in the indications accaz~ding tv
the invention.
According to the invention, orosomucoid can also be
used in case of a relative hypovalemia. The latter is
found if the absolute blood volume is not reduced, yet
there exists an undersupply of the organs. The reason
for this may reside in a vasodilatory change which may
be neurogenic, metabolic, toxic or trumoral. A further
reason is an increased vessel permeability, possibly of
the anaphylactic type or caused by diverse snake
venoms.
Likewise, a pump failure may be the cause of
hypovolemic shock, caused by an acute myocardial
infarction, myocarditis, or a highly reduced output
performance, acute valvular incompetence, myocardial
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rupture, septum perforation, arrhythmia:,, such as
bradycardia, tachyCardia or fibrillation, or a
mechanical compression o~ the heart, respectively, yr
physical obstacles, e.g. thrombi or embolisms.
The present invention therefore also relates to the
use of lf.GP for producing a preparation for the
treatment of hemorrhagic and/or hypovolemic shock and
for stabilizing the intravasal volume, in particular in
case of acute hemorrhages, excessive liquid loss, or
vasodilation, respectively.
According to the invention, AGP can also be used Lo
prevent reperfusion damages as a consequence of a
stroke, in particular for reducing cerebral oedema.
Reperfusion injuries occur primarily after removal of a
flew obstacle, e.g. cacc~.usion of a vessel due to
deposzts or blood clots. Such injuries are particularly
found as a consequence of a stroke, w)nere a cerebral
oedema is formed, leading to neurological dysfunctions.
Tissue damage in transplanted organs possibly occurring
due to x'e-started perfusion are also among the
reperfusion i_nju~~aes.
A further disturbance of microci_xculation which,
according to the invention, can be r.r_eatPd by AGP, are
the microcirculation disturbances in vital c.r_gan.s, in
particular in the kidney, which may, e.g., directly
cause proteinuria.
Microcirculation disturbances in organs may,
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however, also be caused by oedemas. Therefore, the
present invention a~.so relates to the use of
orosomucoid for producing a pxepax~ation for the
prevention or treaCment, respectively, of oedemas.
The nuode c~L production pf AGF 1s known (e.g. from
WO 95/07703). As the source of human AGP, preferably
human p7.asma or a pl.amsma fraction, respectively, a_g_
a CORN fraction, such as COHIV z'tt or CoHN v, will be
used. According to the invention, the preparation
advantageously is produced as a storage-stable infusion
solution, and preferably it is provided as a
lyophilisate.
The dose used will depend on the respective
indication and also on the severity of the patient s
condition, e.g. on the amount of blood last. As a rule,
a single dose in the range of from 70 mg/kg body weight
to 5 g/kg will be used, the range from x_00 to 700 mg/kg
being particularly prefexz-ed.
The application according to the invention may be
of any type, preferred are i.v., e.c., i.m_ and a local
application.
Advantageously, the pharmaceutical, preparation used
contains at least 50a orosomucois3, preferabJ.y more than
70%, in particular more than 90%, based on the total
protein. As a further component, the pharmaceutical
preparation according to the invention may furthermore
contain albumin and A1AT (al-antitrypsin).
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Preferably, a stabilizer, in particular sodium
caprylate and, optionally, tensidee are admixed to the
pharmaceutical preparation before ~.ts uee according too
the invention, so as to increase its storage stability
and its stability during a heat treatment,
reapcctively_
It is also suitable to treat the pharmaceutical
preparation for an i:'nactivation or depletion of
viruses, respectively, in particular by at least one
physical treatment, such as a heat treatment and/or
filtration. Tv inactivate viruses, a number of
physical, chemical yr chemical-physical. methods are
known, such as, e.g., a heat treatment, e.g. according
to EP 0 159 311 A or EP 0 G37 451 A, a hydrolase
treatment according to EP 0 247 99& A, or a radiatyon
treatment ox' a treatment with an argan~.c solvent auzd/or
tansides, e.g. according to EP 0 131 740 A. Further
suitable virus inactivation ~t~g$ lI1 the production ref
the preparations according to the invention are
described irt EP 0 506 651 A or in WO 94/13329 A.
For certaa.n indicaCions, i.e. in particular
hypcwolemic or neurvgenic shock, the admi_ni st=ration of
orosomucoid advantagPOUSly is combined witY~. C-ne
administration of vasoaotive substances iconstringent
or dilating), which may be administered either Logether
or in parallel.
Therefore, according to a further aspect, the
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present ~.xlventic~n iwlttLes to an ~.llfusion preparation
for the tx~eatmmlL of shock conditions, containing AGP
arid a vasoactive substance as active components_
According to the invention, this infusion
preparation is provided in the form of a kit which
cr_irn~5rises
- AGP in a pharmaceutical prtrpdrat:ion, and
- a v2~soactive substance, optionally in separate
containers_
Application of ACP ao4oxding to the invention may
be prophylactic, yet, primarily, therapeutic.
The invention Will now be explained in more detail
by way of the following Examples and the drawing
figures, to which, however, it shall not be restricted.
Figs. 7. to 5 show the results of the trea~ment of
hemQrrhagic shock in the rat model;
Figs. 6 to 8 show the results in the prevention of
cerebral oedema in the stroke mode7_ can the rat; and
Fig. 9 shows the results of the treatment of
proteinuria in a rat model.
E x a m p 1 a 1 . 'treatment of hemorrhac,~ic shock
in the rat model (at present
con8idered by applicant tc~ by
the best mode of carry~.ng out
the invcant~.on)
These experiments have been carried out in a manner
analogous to Wang and Chaudry (J. Surg_ Res 50 (1991),
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163-169?. The animals wez~e fasted over nigfut, yet had
free access to water. As an introduction to anesthesia,
the ar~imals were injected i_m. with 60 mg/kg
pentobarbir_al_ Anesthesia was maintained by 5 mg of
pentotaa rlair_al per animal every 1 . S h, s . c . . The trachea
was cannu7arPd for artificial respiration in
emergencies. A pc~7.yer_hylen catheter was provided in the
left juc,~ular vein for infusions (volume substitution)
and injections. A second catheter was inr_raduced via
the right jugular vein into the right atrium to inject
cold isotonic saline (s 2D°C; thermvdilution method)_
Via the right carotid., a thermocouple was advancRd lTlt~c~
the aorta arch to take the blond temperature. Both
femoral arteries were cannulated, one for delrermining
the blood pre9sure, the other one for withdrawing
blood. During the entire experiment, the body
temperature wag maintained at 36_5 by using a rectal
thermometer which was connected to an infrared lamp. 'fo
aet a trauma prior to bleeding, after depilation, a 5
Cm laparotomy was carried out in the linea alba by
means of an electrocauteriser. 'this cut subsequently
was closed in layers.
1 IU of heparin/g body weight was injected.
Subsequently, the mean arteris.l blood pressure was
lowered to 40 mmHg within 10 min by withdrawing blood
from the femural artery. The blood pressure was
maintained for a maximum of 80 min at 40 mmHg either by
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furL_her withdrawing of blood or by injecLlUi1 Uf
IW_nger~s solution in a total volume not exceeding 40ro
of the lost blood. After these 80 mzn yr earlier (it
the blood pressure could no longer be kept above
mmHg) , volz~me substitution was started by Lepldc:izig the
3-fold volume of the total blood loss witk~ Ringer s
solution during 60 min. volume substitutive was
followed by an observation period of 4 h. The surviving
animals were sacrificed with an overdose of
pentobarLital, i.v..
The mean arterial blood pressure was continuously
registered by means of a polygraph by using an
eleGtromcohanical pressure transducer_ The heart rate
was continuously recorded by pulse waves_ The cardiac
output per minute was~determined by means of the
thermodilution method, ~OV ~.1 of cold saline being
in~eeted into the right atrium. $y taking the blood
temperature in the aorta arch, the thex~modilut~_o~ri curve
was integrated by means of a Cardiomax II (Model 85,
Columbus rnstrumexzts), and the cardiac output per
minute was given in ml/min. The systolic volume and r_he
entire pezipheral vascular resistance were calculated
by dividing the cardiac output per minute by the heart
rate, or by dividing the blood pressure by the cardiac
output per minute, this ratio being multiplied by 103
(mml-Ig_ml_min'1.103). Initial values were indicated as
the natuxal values. All ether values were given in % of
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the x'espective initial value (As)_ Mean values ~
standard erx'or were also calculated_ The significance
of the differences betwccn initial values and all other
values was verified by the t-tcst for paired
observations. For a Comparison between the groups, the
"double-side t-test" was employed.
It has been shown that in all animals (n - 30), the
amount of blood withdrawn was 7.0 ~ 2.9 m~., to reduce
the mean axterial blood pressure to 40 mml3g_ The blood
pressure could be kept at this low level for 77.8 ~ s.5
min. The blood pressure drop was accompanied by a
lowering of the cardiac output per minute, systolic
volume, and the entire peripheral vascular resistance.
The heart rate dropped in all three groups, with an
init3.al rise in r.he AGP-treated group.
Volume substitution in control animals (n.--- 13)
with Ringer's solution i.v_ (volume: 3 times the amount
of lost blood) could not re-establish the mean arterial
blood pressure which had dropped significaz~tly over the
entire observation period (range -50.5 ~ 2.3 % Lo -63.6
f 10.3 %). A slight drop in the heart rate could also
be observed which became signifa.cant 180 to 240 min
after volume substitution (maximum: -29_9 t 8.8 % at
240 min). The cardiac output per minute could be
returned to the initial values immediately upon volume
substitution, yet between 30 and 240 min thereafter it
was significantly 7.owered (range -25.9 ~ 5.5 % to -51_4
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t 7.4 %). The same course over time could be observed
for the systolic volume (range of drop: -26.'7 ~ 8.8 %
to -31.1 + 9.9 ~). The entire per7.pheral vascular
resistance dropped durxr~g the observation period (~'ange
-19.1 ~ 18.2 % to 39.7 ~ 9.9 °s) , the differences beiz7.g
significant 30 Lo 120 min after reanimation. Thrcc
animals died s 150 min after substitution of the volume
and were not included in the evaluation_ Further three
animals died after 180 min.
~,ro further groups were treated by using AGF or a
placebo formulation, respectively, instead of Ringer s
solution. The ~rGP solution (200 mg/kg) , pur~.fied from
COFRV fraction v from human plasma by precipitation and
further pasteurization at 60~C for 10 h, and the
ana7.ogous amount of placebo formulation (albumin
solution from human albumin, zoo, by separat~.ng
orosomucoid) were diluted with Ringer's solutioz~ to the
three-fold amount of the inidividual blood loss.
AGP was tested on I4 animals; -2 rat died during
treatment (volume substitution), 3 rats died within
less than 150 min after treatment, arid 1 animal died
180 min after, volume substitution. The placebo
formulation was administered to 18 animals. Four of
these animals died during treatment, tour died Hrithin
lass than 150 min after treatment, four animals died
alter more than 1.80 min after volume substitution. Rats
which died within less than 150 min after treatment
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were noL included in the evaluation_
A comparison of the results obtained by Ringer's
solution with these obtained by the placebo formulation
showed that equal or lower values of the mean arterial
blood pressure, hearC rate and entire peripheral
vascular resistance were obtained with the placebo
formulation treatment. The ~ralues for cardiac output
per minute and systolic volume were equal or higher in
the placebo formulation group than in the Ringer's
solution group.
In animals which had been treated with AGP, the
blood pressure rose initially arid then dropped
gradually (cf. Fig. 1). Complete restoration of the
blood pressure, however, could not b~ achieved. All the
values in the observation period were _'Lower than the
initial values (p ~ 0.001). As regards the heart rate
(Fig. 2), no change in the period after volume
substitution as compared. to the initial values could be
observed (p > 0.05). 'rhe card~_ac output per minute
(Fig. 3) was higher than the initial values immediately
after volLime substitution (p a O.O1), yet re-adjuStPd
to the initial values (+30 to +90 min; p ~ 0_05), arid
finally dropped to below the initial values (p < 0.05
or s 0.01).
For the systolic value, the situation was similar
(Fig. 4), except that the values during the fixst 120
min were statistically not different from the initial
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valuee_ The entire pPri.pheral vascular resistance
(Fig. 5) was lower over the entire observation period
as compared to the initial values; however, a
significance was not reached at +30, -X90 and +la0 min.
Figs. 1 to 5 show also the comparison between
anima~.s whioh had been treated with AGP and placebo
formulation. The mean arterial blood pressure is
significantly higher at all points of measurement after
volume substitution in the AGP-treated group (Fig. 1).
The heart rate is equal or significantly higher in the
AGp-gzoup. Differences, however, are very small (Fig.
2). The cardiac output per minute is significantly
higher in the AGP-treated group, except for the point
of measurement "240 min" after volume substitution
(Fig. 3). The systolic volume is significantly higher
after treatment with AGP at 30 to 150 min.after volume
substitution (Fig. 4). The entire peripheral vascuJ.ar
resistance is increased in the AGP-group - as compared
tv the placebo formulation - at 60 to 120 min after
infusion (Fig. 5).
These experiments demonstrate the superiority of a
treatment wa,th prGP ag compared tv a placebo formulation
(containing the same protein amount in the form of
albumin which is free from AGP) or Ringer's solution.
I3ence it follows that AGP can maintain the perfusion of
vital organs in case of hypvvolemie shock.
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Tr x a, m p 1 a 2 _ Prevention of cerebral oederaa
in the etrohe model on rat
A global cerebral ischemia ("stroke") waN Caused by
clamping both Carotids and withdrawing 5 ml of bl.ood_
Aftex 30 min of ischemia, the carotids were re-opened,
and the withdrawn blood was re-infused. 23.5 h later
the animals were sacrificed and the water content of
the two halves of the cerebrum was determined.
In previous expez3mex~ts it had been found that
orosomucoid at 600 mg/kg i_v. is capab3.e of preventing
the formation of cerebral oedema following global
cerebral ischemia. The formulation buffer had remained
without such effect. In the present e7cample, a dose
response and time effect relal:ionship is set up for the
oedema~pxeventix~g effect of orosomucoid.
orosomucoid which had also been used in example i
was tested on rats at 20o mg/kg i.v., with simultaneous
blood reperfusivn. The resulee appear from Fig. 6. It
has been shown that pseudo-operated animaJ.s (C, n = 121
dp not have a cerebral oedema, while isehemic, saline-
treated animals exhibit massive cerebral oedema (B, n
8)_ Iechamic animals which had been treated with
oroeomuoo~.d iA, n = il) again behaved like the sham-
operated animals.
However, when the dose was reduced to 50 mg of
orosomucoid per kg, i.v_, a protecti~re effect could no
longer be found (af. column A in Fig. 7), whereby the
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dose dependence of the effect has been pro~rer~.
On account of the therapeutic situation in human ;t-
has been interesr_i.ng to check whether orosomucoid,
adminiotered afte7~ a stroke has occurred, iS St=ill
effcctive_ Therefore, the dose of 200mg/kg i_v_ found
above to be effective was administered 30 minute: afr_er
the end of isehemia_ As is apparent from Fig. 8 (column
Ay, orosomucoid is fully effective even in this
situation.
A protective action of orosomucoid against tire
cerebral oedema forming as a a4nsequence of a stroke
Chas has been, proven iz~ the animal model..
R x a m p 1 a 3 . Treatment of proteinur~.a is a
rat model
Rats were treated i.p. with 100 mg/kg of puromyain
aminonucleoside on day 0. Controls received isotonic
saline (negative control) in an analogous manner. In
metabolie cages, the 24 h urine was collected for
protein determination.
Thp puromycin-treated animals received 200 mg/kg
orvsvmucoid i.v. on the 6th, 7th. 8th and gth test day,
off' isotonic saline in analogous manner (positives
controls).
On day 10, the animals were weighed and sacrificed
by heart puncture for plasma recovery. Kidney wet
weight was determined, arid Creatir~irie and urea were
measured from pla.sma_
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In, dc~illg so, the following paramPi~r~r-s ware found:
total protein of urine (mg/24 h) , pla~;ma c~.rear_inine
(mg/dl), blood urea (mg/dl) and the kidney i~idex
(kidney weight in % of body weight)
Fig_ 9 shawl the proteinuria values of_ r_he first
test rLlri_ Animals which had been tx'eated wi.r_h isotonic
saline on day 0 exhibited slight, physiological
proteinuria (full diamonds). Zn animals treated with
puromycin, the protein in lVhe urine rose from the r_hird
day onwards. In animals treated with isoton~.c saline on
days 6 to 9, >the total prr~tein reached 500 to X00 mg/24
h (open triangles). Tn an~.mals treated with orosomucaid
on days ~ to 9, the protein secr~r.ion dropped
practically to the control ~craluee (full squares) .
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