CA2283580A1 - Use of human .alpha.1-acid glycoprotein for producing a pharmaceutical preparation - Google Patents

Abstract

The invention relates to the use of human .alpha.1-acid glycoprotein (AGP) for producing a pharmaceutical preparation for the treatment of non-inflammatory disturbances of the circulation or microcirculation.

Description

_ SE>-08-99 07:3T +43 1 512 9B 05 P.49 R-612 Job-264 08/x9 '99 13:51 FAa +4a 1 512 98 05 PAT.ATT.VIENNA ~ 049 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).

SE°-08-99 07:37 +43 1 512 98 05 P.50 R-612 Job-264 08/09 '99 13:52 FAg +43 1 512 98 05 PAT.ATT.VIENNA X1050 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.
-SEp-08-99 OT:37 +43 1 512 98 05 P.51 R-612 Job-264 08/09 '99 13:52 FAa +45 1 512 98 05 PAT.ATT.VIENNA ~J051 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 SEE-06-99 07:37 +43 1 512 96 05 P.52 R-612 Job-264 08/09 '99 13:52 FAQ +43 1 512 98 05 PAT.ATT.VIENNA X1052 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 SEF-06-99 07:37 +43 1 512 9B 05 P.53 R-612 Job-264 08/09 '99 13:53 FAX +43 1 512 98 05 PAT.ATT.VIENNA ~ 053 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, SEP-08-99 OT:3T +43 1 512 98 05 P.54 R-612 Job-264 08/09 '99 13:53 FAZ +43 1 512 98 05 PAT.ATT.VIENNA ~J054 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).
-SEP-08-99 08:01 +43 1 512 98 05 P.O1 R-613 Job-265 08/,09 '99 13:58 FAg +43 1 512 98 05 PAT.ATT.VIENNA I~]001 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 7 _ SEP-08-99 08:01 +43 1 512 9B 05 P.02 R-613 Job-265 08/09 '99 19:58 FAX +4a 1 512 98 05 PAT.ATT.VIENNA X1002 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), _ g _ SEP-08-99 08:01 +43 1 512 98 05 P.03 R-613 Job-265 08/09 '99 15:58 FAg +43 1 512 98 05 PAT.ATT.VIENNA ~ 005 163-169?. 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 SEP-06-99 08:01 +43 1 512 9B 05 P.04 R-613 Job-265 08/09 '99 15:58 FAX +4a 1 512 98 05 PAT.ATT.VIENNA ~ 004 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 5EP-08-99 08:01 +43 1 512 98 05 P.05 R-613 Job-265 08/09 '99 13:59 FAX +4~ 1 512 98 05 PAT.ATT.VIENNA ~ 005 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 SEP-06-99 06:01 +43 1 512 96 05 P.06 8-613 Job-265 08/09 '99 13:59 FAg +43 1 512 98 05 PAT.ATT.VIENNA x]006 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 SEP-06-99 08:01 +43 1 512 96 05 P.07 R-613 Job-265 08/09 '99 14:00 FAX +45 1 512 98 05 PAT.ATT.VIENNA 0 007 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 SEP-Ofi-99 06:01 +43 1 512 98 05 P.08 R-613 Job-265 08/09 '99 14:00 FAg +43 1 512 98 05 PAT.ATT.VIENNA X1008 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.

SEP-08-AA 06:01 +43 1 512 96 05 P.08 R-613 Job-265 08/09 ' 99 14 : 00 FAlt +43 1 512 98 05 PAT. ATT. VIENNA ~J 009 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 SEP-08-99 08:01 +43 1 512 96 05 P.10 R-613 Job-265 08%09 '99 14:00 FAX +45 1 512 98 05 PAT.ATT.VIENNA f~010 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_ SEP-08-99 08:01 +43 1 512 98 05 P.11 R-613 Job-265 08/09 '99 14:01 FAQ +45 1 512 98 05 PAT.ATT.VIENNA ~J011 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) .
_ 17 _

Claims (19)

Claims:

1. The use of human ~1 -acid glycoprotein for producing a pharmaceutical preparation for treating non-inflammatory disturbances of circulation or micro-circulation, respectively.

2. The use according to claim 1, characterized in that the preparation is suitable for the treatment of hemorrhagic shock and/or hypovolemic shock.

3. The use according to claim 2, characterized in that the preparation is suitable for stabilizing the intravasal volume, in particular in case of acute hemorrhages, excessive loss of liquid or vasodilation, respectively.

4. The use according to claim 1, characterized in that the preparation is suitable for preventing reperfusion damages occurring in connection with a reduced perfusion.

5. The use according to claim 4, characterized in that the preparation is suitable for preventing reperfusion damages as a consequence of a stroke, in particular for reducing cerebral oedema.

6. The use according to claim 1, characterized in that the preparation is suitable for treating microcirculatory disturbances in organs, in particular in the kidney.

7. The use according to claim 6, characterized in that the preparation is suitable for treating proteinuria.

8. The use according to claim 6, characterized in that the preparation is suitable for preventing or treating, respectively, oedemas.

9. The use according to any one of claims 1 to 8, characterized in that the pharmaceutical preparation is produced as a storage-stable infusion solution.

10. The use according to any one of claims 1 to 9, characterized in that the pharmaceutical preparation is produced as a lyophilisate.

11. The use according to any one of claims 1 to 10, characterized in that the pharmaceutical preparation is used in a dose ranging from 70 mg/kg to 5 g/kg, in particular ranging from 100 to 700 mg/kg.

12. The use according to any one of claims 1 to 11, characterized in that the pharmaceutical preparation comprises at least 50% of ~1 -acid qlycoprotein, in particular more than 70%, preferably more than 90%, based on the total protein.

13. The use according to any one of claims 1 to 12, characterized in that the pharmaceutical preparation further comprises albumin.

14. The use according to any one of claims 1 to 13, characterized in that the pharmaceutical preparation comprises a stabilizer, in particular sodium caprylate.

15. The use according to any one of claims 1 to 14, characterized in that the pharmaceutical preparation is treated for virus inactivation or virus depletion, respectively, in particular by at least one physical treatment, such as heat treatment and/or filtration.

16. The use according to claim 2, characterized in that the treatment comprises an administration of vasoactive substances, in particular catechol amines.

17. The use according to claim 16, characterized in that the vasoactive substances are administered together or in parallel.

18. Infusion preparation for treating shock conditions, comprising ~1 -acid glycoprotein and a vasoactive substance as its active components.

19. A kit for treating shock conditions, comprising a) .alpha.1 -acid glycoprotein in a pharmaceutical preparation, and b) a vasvactitre substance.