EP2456446A2 - Plasmaadaptierte und balancierte gelatinelösung - Google Patents
Plasmaadaptierte und balancierte gelatinelösungInfo
- Publication number
- EP2456446A2 EP2456446A2 EP10734480A EP10734480A EP2456446A2 EP 2456446 A2 EP2456446 A2 EP 2456446A2 EP 10734480 A EP10734480 A EP 10734480A EP 10734480 A EP10734480 A EP 10734480A EP 2456446 A2 EP2456446 A2 EP 2456446A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- gelatin
- pharmaceutical preparation
- physiologically acceptable
- mmol
- preparation according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Definitions
- the present invention relates to a pharmaceutical preparation comprising an aqueous composition comprising gelatin and / or a physiologically acceptable gelatin derivative.
- the pharmaceutical preparation is suitable for the prophylaxis and therapy of hypovolemia.
- the present invention relates to uses of the pharmaceutical preparation as a volume replacement agent and as erythrocyte-protective washing solution.
- Circulatory failure is one of the most commonly observed clinical states of shock. It is characterized by decreased circulating blood volume (hypovolaemia), which may be due to absolute losses of blood, plasma or extracellular fluids on the one hand, or relative deficits (distributional disorders) on the other hand.
- the losses of blood or plasma either have traumatic causes (haemorrhagic trauma) or are due to increased blood loss as a result of surgical procedures.
- Primary extravascular fluid deficits which also affect the circulating blood volume to an appropriate extent, are due to decreased fluid intake or abnormal fluid loss (e.g., excessive sweating, vomiting, gastrointestinal loss).
- Vasoactive substances as well as diverse interactions between mediators and hormones which may also be caused by traumatic events or serious illnesses, lead to relative volume deficiencies or distributional disorders through vasodilation; In addition, they also contribute to the maintenance of a possibly existing shock condition.
- volume deficits may develop from generalized dysfunction of the vascular endothelium which causes extravasation, i. cause the passage of plasma fluid across the endothelial barrier into the surrounding tissues, e.g. in inflammatory diseases such as sepsis.
- hypovolemia Depending on the extent of the volume deficit and the influence of the mediators, the heart function is reduced. If the hypovolemia lasts longer, the compensatory abilities of the myocardium, which for example consist in an increase in contractility and heart rate, are no longer sufficient, so that the circulatory failure takes a progressive course.
- Hypovolemia or failure of the large circulation, ie the macrocirculation has the consequence, among other things, that the microcirculation, ie the perfusion of the tissues and organs, is also affected; the resultant deficiency of blood of one or more organs, called ischemia, leads to an undersupply of oxygen in the tissues of interest and to a restriction of the cellular metabolism. With a corresponding duration of the deficiency occurs by the death of cells to damage the organ and the initially reversible, eventually irreversible organ failure.
- the restoration of the circulating blood volume is the highest therapeutic goal in all forms of hypovolemic circulatory failure or shock. This is done by infusion of crystalloid or colloidal volume replacement solutions or - in case of extensive blood loss and correspondingly reduced oxygen transport capacity - by transfusion of blood or blood components.
- the volume substitution and the concomitant filling of the circulation increase the venous return of the blood to the heart and improve the cardiac ejection performance; As a result of the increasing perfusion of the tissues, their reduced supply of oxygen during ischemia is reversed and the metabolism is restarted.
- crystalloid isotonic electrolyte solutions
- colloidal volume replacement solutions solutions which additionally contain a high molecular weight constituent, a so-called hydrocolloid, in an electrolyte-containing medium
- hydrocolloids find on the one hand either endogenous proteins use such as human albumin or chemically modified proteinaceous substances such as certain modifications of gelatin, which in turn comes from collagenous material.
- the colloids contained in the volume replacement solutions can be polysaccharides (dextrans) or, in turn, chemically modified derivatives of polysaccharides, as is the case with hydroxyethyl starch (HES).
- colloidal volume replacement solutions In contrast to the crystalloid solutions, they provide for a more pronounced and sustained binding of fluid in the circulation, ie for a stronger and longer-lasting volume or filling effect.
- the reason for this is mainly to be seen in the molecular size of the hydrocolloids, whose effect is further enhanced by electrical charge carriers and / or the presence of large hydrate shells on the hydrocolloid.
- the distribution of colloidal volume replacement solutions initially limited only to the circulation, ie the intravascular space, while the components of the crystalloid solutions can permeate the vascular barrier freely, so that they distribute a priori in the entire extracellular space, which is about four times as large intravascular space.
- crystalloid volume replacement solutions must also be used in approximately four times the amount of colloidal solutions to achieve the same circulatory filling, which also lasts less time or requires more frequent post infusions than with colloidal solutions. Due to the simultaneous fluid influx in the extracellular space - when infused crystalloid solutions - there is a risk that accumulate fluid (edema) there; and when the ability to excrete salt and fluid is reduced, as may often be the case after trauma on surgery or in severe disease, the use of crystalloid solutions is associated with the risk of fluid overload. For these reasons, for the purpose of intravascular volume replacement, colloidal solutions are generally preferred over crystalloids.
- gelatine and gelatin derivatives in the human organism can be broken down into smaller fragments by enzyme systems present there (mainly proteases) and finally eliminated renally as soon as the size of the fragments has fallen below the renal threshold.
- enzyme systems present there mainly proteases
- the recovery rate in urine is approximately 60% of a given dose; Over the course of a week, it rises to over 95%.
- other artificial colloids used as volume replacement agents e.g., hydroxyethyl starch.
- gelatin and the gelatin derivatives are not stored in the organism or predestined organs, so that no organ complications are to be expected from this side. It is also advantageous in comparison with other artificial colloids less or completely missing influence of blood clotting, which allows gelatin or gelatin derivatives in higher dosages to infuse intravenously than is the case with other artificial colloids or the volume replacement agents produced therefrom.
- gelatin or its derivatives is commonly used in the well-known art in the production of hard and soft capsules and also in infusion solutions for the treatment of volume deficiency shock.
- available as a volume replacement following gelatin preparations with gelatin or a gelatin derivative having an average molecular weight from 20,000 to 35,000 are available: for oxypolygelatin example Gelifundol ®, for urea crosslinked gelatin, for example Haeamaccel ® and succinylated gelatin ® example Gelafundin (also referred to as Gelofusine ®), Gelafusal ® and Thomaegelin ®.
- volume replacement solutions In medicine, however, the use of gelatin-containing volume replacement solutions is not uncritical. For example, some of the gelatin solutions currently in use contain too high a chloride content, which is associated with the risk of Development of hyperchloraemic acidosis. Volume replacement solutions, whether containing gelatin or other colloids, have their major indications in the treatment of hypovolemic circulatory failure and shock. The inferior tissue perfusion associated with these clinical conditions inevitably produces acidosis, which is rapidly eliminated by the infusion of volume replacements, but in no way enhanced or even prolonged by their azidotic properties. All the more so as the severity of acidosis correlates with the occurrence of coagulopathy, to which also the traumatic or surgical blood losses contribute as the main cause of hypovolemic shock states.
- hyperchloraemic metabolic acidosis include electrolyte imbalances that delay the resumption of diuresis following trauma and surgery, or neurological dysfunctions such as: Somnolence or postoperative nausea and vomiting (PONV) may be associated.
- PONV postoperative nausea and vomiting
- An object of the present invention is thus an aqueous pharmaceutical preparation comprising: a) 20 to 80 g / L gelatin and / or a physiologically acceptable gelatin derivative and / or a gelatinous protein and / or gelatinous polypeptide,
- the preparation according to the invention contains, in addition to the abovementioned electrolytes, 1 to 2 mmol / L of phosphate.
- Phosphates for the purposes of the present invention include both the PO 4 3 " and hydrogen phosphates and dihydrogen phosphates and phosphate derivatives, such as glycerophosphate.
- Gelatin is the degradation product of a mammalian protein, collagen, which is readily available and inexpensive to isolate and can be stored for long periods of time without degradation. Despite its protein nature, gelatine shows only a very low antigenic potential. Due to its high molecular weight, native gelatine has the property of forming highly viscous solutions which gel at lower temperatures and are therefore not suitable for the production of parenteralia. By chemical modification or derivatization of gelatin, however, this disadvantage can be avoided.
- Gelatin derivatives can also be prepared by decalcifying gelatin, condensing with glyoxal and oxidizing with hydrogen peroxide. These are so-called oxypolygelatins, whose preparation has been described by Campbell, DH et al., Texas Rep. Biol. Med. 9, 235 (1951), Bonhard, K., Arzneim. -Forsch. 21, 1667 (1971) as well as Nitschmann and Stoll, Pharm. Ztg. 42, 1594 (1968). In Recently, gelatin or gelatinous proteins and polypeptides have also been synthesized recombinantly and proposed as such for use in the preparation of parenteralia, especially volume replacement agents (DE 60207053T2).
- the preparation according to the invention contains gelatinous proteins and / or polypeptides produced by recombinant means.
- Urea-crosslinked gelatin is prepared by subjecting the gelatin strands resulting from the alkali and hot water treatment, which have a molecular weight of 12,000-15,000, to a treatment with hexamethylene diisocyanate. This leads to condensation between a free carboxyl and a free amino group, resulting in a peptide bond between individual GelatinestrBooken.
- the resulting condensation product has a number average molecular weight of 24,500 at a range of about 5000-50,000 daltons.
- the polypeptide chains from which the synthesis of succinylated gelatin originates have a molecular weight above 20,000 and are reacted with succinic anhydride. Unlike the urea-crosslinked gelatin, however, there is no cross-linking of the strands and their molecular weight consequently remains unchanged. Since the chemical modification replaces a basic amino group with an acidic carboxyl group, a derivative with a lower isoelectric point and a stronger negative charge results. It is this stronger negative charge and not an increased molecular weight which, at physiological pH values - inter alia due to the Donnan effect on the vascular endothelium - leads to a prolongation of the residence time in the circulation.
- the physiologically acceptable gelatin derivatives to be used according to the invention may be urea-crosslinked or-preferably-succinylated gelatin derivatives.
- MFG modified liquid gelatin
- M n weight average
- M n number average
- the starting material for succinylation or crosslinking with urea is gelatin from bovine bone; this is commercially available, for example via Gelita AG, Ebersbach (Germany), or Rousselot SAS, Isle sur Ia Sorgue (France).
- Preferred embodiments of the present invention include physiologically acceptable gelatin derivatives such as succinylated gelatin derivatives, non-succinylated gelatin derivatives, urea crosslinked gelatin derivatives, oxypolygelatins and gelatin polysuccinate, and recombinant gelatinous proteins and / or polypeptides.
- physiologically acceptable gelatin derivatives such as succinylated gelatin derivatives, non-succinylated gelatin derivatives, urea crosslinked gelatin derivatives, oxypolygelatins and gelatin polysuccinate, and recombinant gelatinous proteins and / or polypeptides.
- the pharmaceutical preparation according to the invention contains 20 to 80 g / L gelatin and / or a physiologically acceptable gelatin derivative and / or a gelatinous protein and / or a gelatinous polypeptide, preferably 30 to 60 g / L and particularly preferably 40 to 50 g / L, for example 40g / L.
- the isotonic aqueous pharmaceutical preparations according to the invention are infused intravenously and are therefore present in a preferred embodiment as an infusion solution.
- salts are used which are selected from the group consisting of sodium chloride, sodium acetate x 3 H 2 O, sodium hydrogen phosphate x 2 H 2 O, sodium hydroxide, D-gluconic acid sodium salt, potassium chloride, potassium acetate, calcium D-gluconate x H 2 O, calcium chloride x 2 H 2 O and magnesium chloride x 6 H 2 O comprises.
- the pharmaceutical preparations according to the invention are preferably sterile-filtered or heat-sterilized.
- sterile filtration in particular fine-pored filter cartridges, such as are commercially available from various manufacturers, are suitable. Suitable examples are filter cartridges with a pore diameter of 0.2 to 3.0 microns.
- the pharmaceutical preparations according to the invention can be heat-sterilized without decomposition of the ingredients.
- the heat sterilization is carried out at a temperature above 100 0 C, more preferably between 105 and 150 0 C, in particular between 110 and 130 0 C, wherein - depending on the container material - either a temperature of for example 121 0 C, over a period of up to to 30 minutes, preferably up to 28 minutes, in particular between 23 and 25 minutes or a temperature of for example 112 0 C, over a period of up to 100 minutes, in particular between 70 and 90 minutes is used.
- Volume substitutes are used to replenish intravascular fluid deficits in humans and animals. They find special application for the prophylaxis and therapy of hypovolemia. It does not matter whether the hypovolemia results from the immediate loss of blood or body fluids such as acute bleeding, trauma, surgery, burns etc. or distribution disorders between macro and microcirculation such as in sepsis, or whether it is a regionally limited, for. B. artificially induced interruption of blood flow is as in the clamping of vascular sections or the creation of a tourniquet barrier.
- Another object of the present invention is the use of the pharmaceutical preparation as a volume replacement agent.
- Another object of the invention is therefore the pharmaceutical preparation according to the invention for improving the microcirculation.
- the pharmaceutical preparation Due to the special properties of the pharmaceutical preparation, it is particularly suitable as erythrocyte-protective washing solution.
- Another object of the present invention relates to the use of the pharmaceutical preparation according to the invention as erythrocyte-protective washing solution.
- Table 1 shows by way of example the composition of a pharmaceutical preparation according to the invention.
- composition shown in Table 1 can be obtained by weighing and dissolving in auqa ad iniectibilia ad 100O mL: 40 g gelatin polysuccinate, 95 mmol sodium chloride, 24 mmol sodium acetate, 4 mmol potassium chloride, 1.5 mmol calcium gluconate, 1.25 mmol magnesium gluconate, 1 , 5 mmol sodium glycerophosphate [glycerol-l (2) dihydrogen phosphate mixture of disodium salts] and about 35 mmol of sodium hydroxide (the exact need for sodium hydroxide results from adjusting the pH to 7.4 (7.1-7 , 7) required amount.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102009034132A DE102009034132A1 (de) | 2009-07-20 | 2009-07-20 | Plasmaadaptierte und balancierte Gelatinelösung |
PCT/EP2010/060210 WO2011009797A2 (de) | 2009-07-20 | 2010-07-15 | Plasmaadaptierte und balancierte gelatinelösung |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2456446A2 true EP2456446A2 (de) | 2012-05-30 |
Family
ID=43334706
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10734480A Withdrawn EP2456446A2 (de) | 2009-07-20 | 2010-07-15 | Plasmaadaptierte und balancierte gelatinelösung |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP2456446A2 (pt) |
KR (1) | KR20120046160A (pt) |
CN (1) | CN102470147A (pt) |
BR (1) | BR112012001229A2 (pt) |
DE (2) | DE102009034132A1 (pt) |
IN (1) | IN2012DN00419A (pt) |
MX (1) | MX2012000957A (pt) |
RU (1) | RU2012105925A (pt) |
WO (1) | WO2011009797A2 (pt) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2651717B1 (es) * | 2016-07-26 | 2018-11-16 | Lara OLLER DUQUE | Solución acuosa cristaloide isotónica |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA702706B (en) * | 1969-04-28 | 1971-12-29 | Knox Gelatine Inc | Blood plasma substitute |
EP0223906A3 (en) * | 1982-10-29 | 1989-02-01 | Synthetic Blood Corporation | Gelatin based synthetic whole blood and a process for preparing the same |
EP1238675A1 (en) | 2001-03-06 | 2002-09-11 | Fuji Photo Film B.V. | Recombinant gelatin-like proteins for use as plasma expanders |
-
2009
- 2009-07-20 DE DE102009034132A patent/DE102009034132A1/de not_active Withdrawn
-
2010
- 2010-07-15 CN CN2010800330764A patent/CN102470147A/zh active Pending
- 2010-07-15 DE DE202010018349.9U patent/DE202010018349U1/de not_active Expired - Lifetime
- 2010-07-15 MX MX2012000957A patent/MX2012000957A/es not_active Application Discontinuation
- 2010-07-15 BR BR112012001229A patent/BR112012001229A2/pt not_active IP Right Cessation
- 2010-07-15 RU RU2012105925/15A patent/RU2012105925A/ru unknown
- 2010-07-15 EP EP10734480A patent/EP2456446A2/de not_active Withdrawn
- 2010-07-15 WO PCT/EP2010/060210 patent/WO2011009797A2/de active Application Filing
- 2010-07-15 KR KR1020127000796A patent/KR20120046160A/ko not_active Application Discontinuation
-
2012
- 2012-01-16 IN IN419DEN2012 patent/IN2012DN00419A/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO2011009797A2 * |
Also Published As
Publication number | Publication date |
---|---|
DE202010018349U1 (de) | 2015-10-28 |
BR112012001229A2 (pt) | 2016-03-01 |
DE102009034132A1 (de) | 2011-01-27 |
MX2012000957A (es) | 2012-03-06 |
RU2012105925A (ru) | 2013-08-27 |
WO2011009797A3 (de) | 2011-08-25 |
IN2012DN00419A (pt) | 2015-05-15 |
CN102470147A (zh) | 2012-05-23 |
WO2011009797A2 (de) | 2011-01-27 |
KR20120046160A (ko) | 2012-05-09 |
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