Combination therapy of dacomitinib and nintedanib for the prevention or treatment of pulmonary fibrosis

Abstract

This invention relates to a combination therapy of dacomitinib and nintedanib for the prevention or treatment of pulmonary fibrosis.

Description

Technical Field

[0001] The present invention relates to a combined therapy of dacomitinib and nintedanib for preventing or treating pulmonary fibrosis.

Background Art

[0002] Pulmonary fibrosis means a state in which normal lung structure is destroyed and lung tissue is hardened and deteriorated due to the growth of fibrous connective tissue in the lungs.

[0003] In particular, idiopathic pulmonary fibrosis is a disease in which chronic inflammatory cells invade the alveolar wall, cause various changes, harden the lungs, cause profound structural changes in lung tissue, and sequentially deteriorate lung function. There is no effective treatment method yet.

[0004] In addition, radiotherapy is frequently used for NSCLC tumor patients who cannot undergo resection, but it often causes radiation-induced pulmonary fibrosis (RIPF).

[0005] To date, as a compound with a certain degree of effect, Ofev of Boehringer Ingelheim containing nintedanib as an active ingredient is known to delay the decline of lung function, but the need to develop a more effective drug is increasing.

Summary of the Invention

Problems to be Solved by the Invention

[0006] As a result of intensive efforts to develop a more effective drug for preventing or treating pulmonary fibrosis, the present inventors confirmed the effect of preventing or treating pulmonary fibrosis of the combined therapy of dacomitinib and nintedanib, and completed the present application.

Means for Solving the Problems

[0007] The present invention aims to provide a therapy for the prevention, improvement, or treatment of pulmonary fibrosis, comprising the combined use of dacomitinib or a pharmaceutically acceptable salt or solvate thereof with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0008] Furthermore, the present invention aims to provide a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pharmaceutical composition is administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0009] Furthermore, the present invention aims to provide a pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising nintedanib or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pharmaceutical composition is administered in combination with dacomitinib or a pharmaceutically acceptable salt or solvate thereof.

[0010] Furthermore, the present invention aims to provide a combination comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof, and nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0011] Furthermore, the present invention aims to provide a pharmaceutical composition for the prevention, improvement, or treatment of pulmonary fibrosis, comprising the aforementioned combination.

[0012] Furthermore, the present invention aims to provide a pharmaceutical kit for the prevention, improvement, or treatment of pulmonary fibrosis, comprising the aforementioned combination.

[0013] Furthermore, the present invention aims to provide a method for preventing, improving, or treating pulmonary fibrosis, comprising the step of administering and / or using the aforementioned combination, pharmaceutical composition, or pharmaceutical kit to an individual requiring the aforementioned combination, pharmaceutical composition, or pharmaceutical kit.

[0014] Furthermore, the present invention aims to provide a method for preventing, improving, or treating pulmonary fibrosis, comprising the step of co-administering and / or co-using a composition containing a pharmaceutically effective amount of dacomitinib or a pharmaceutically acceptable salt or solvate thereof to an individual requiring a composition containing nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0015] Furthermore, the present invention aims to provide the above combinations, pharmaceutical compositions, or pharmaceutical kits for use in the prevention, improvement, or treatment of pulmonary fibrosis, and / or for the manufacture of drugs for the prevention, improvement, or treatment of pulmonary fibrosis. [Effects of the Invention]

[0016] The combination therapy of the present invention has improved efficacy compared to monotherapy and is useful for the prevention or treatment of pulmonary fibrosis. [Brief explanation of the drawing]

[0017] [Figure 1] This figure shows the effect of suppressing radiation-induced pulmonary fibrosis in mice that were administered nintedanib, dacomitinib, or a combination of nintedanib and dacomitinib, as confirmed by micro-CT imaging. [Figure 2]This graph shows the degree of inflammation and fibrosis confirmed by H&E and Masson's Trichrome staining in mice in which pulmonary fibrosis was induced by radiation, and who were administered nintedanib, dacomitinib, or a combination of nintedanib and dacomitinib. [Modes for carrying out the invention]

[0018] These will be explained in detail below. Note that each description and embodiment disclosed in this invention applies to other descriptions and embodiments. That is, any combination of the various elements disclosed in this invention is included. Furthermore, this invention is not limited to the following specific descriptions.

[0019] Furthermore, a person with ordinary skill in the art would be able to recognize and confirm many equivalents of the specific embodiments of the present invention described herein using only ordinary experiments. Moreover, these equivalents are also intended to be included in the present invention.

[0020] Furthermore, numerous papers and patent documents are referenced throughout this specification, and their citations are indicated. The disclosures of the cited papers and patent documents are incorporated in their entirety as references within this specification, thereby more clearly explaining the level of the art to which the present invention belongs and the content of the present invention.

[0021] One aspect of the present invention is a therapy for the prevention, improvement, or treatment of pulmonary fibrosis, comprising the combined use of dacomitinib or a pharmaceutically acceptable salt or solvate thereof with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0022] Another aspect of the present invention is a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains dacomitinib or a pharmaceutically acceptable salt or solvate thereof, and the pharmaceutical composition is characterized in that it is administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0023] Still another aspect of the present invention is a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains nintedanib or a pharmaceutically acceptable salt or solvate thereof, and the pharmaceutical composition is characterized in that it is administered in combination with dacomitinib or a pharmaceutically acceptable salt or solvate thereof.

[0024] Dacomitinib of the present invention is also referred to as PF-00299804 or Vizimpro (trade name), etc., and is a commercially available compound, and has the structure of Chemical Formula 1.

[0025]

Chemical Formula

[0026] The IUPAC Name of the above dacomitinib is (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide.

[0027] Dacomitinib is an inhibitor of human (pan-human) epidermal growth factor receptors (EGFR / HER1, HER2, HER4), and is known to be used for mutant EGFR having a deletion in exon 19 or an L858R substitution in exon 21.

[0028] Nintedanib of the present invention is also referred to as BIBF 1120, Vargatef, Ofev (trade name), etc., and is a commercially available compound, and has the structure of Chemical Formula 2.

[0029] [ka]

[0030] The IUPAC name for the aforementioned nintedanib is Methyl(3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate

[0031] Furthermore, the compounds of the present invention include not only compounds having a specific structural formula, but also their clathrates, hydrates, solvates, or polymorphs. Also, unless otherwise specified, the compounds of the present invention include pharmaceutically acceptable salts of the compounds of the present invention. In one example, the compounds of the present invention exist as stereoisomerically pure compounds (for example, those substantially free of other stereoisomers (e.g., 85% ee or higher, 90% ee or higher, 95% ee or higher, 97% ee or higher, or 99% ee or higher)), but are not limited thereto.

[0032] "Hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0033] "Clathrate" refers to the compound or salt thereof of the present invention in the form of a crystal lattice containing spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0034] "Pharmaceutically acceptable" means that a compound, substance, composition, and / or dosage form is suitable for use as a pharmaceutical preparation and can be used in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of sound medical judgment, and is used to indicate a reasonable benefit / risk ratio.

[0035] In this invention, "pharmaceutically acceptable salt" means a derivative of a compound obtained by the parent compound being modified to produce an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts of the present invention include, but are not limited to, salts commonly used in the pharmaceutical field, such as hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, sulfonate, citrate, camphorate, maleate, acetate, lactate, nicotinate, nitrate, succinate, phosphate, malonate, malate, salicylate, phenylacetate, stearate, formate, fumarate, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamate, methylamino acid, methanesulfonate, picrate, p-toluenesulfonate, naphthalenesulfonate, tartrate, triethylamino acid, dimethylamino acid, and tri(hydroxymethyl)aminomethane.

[0036] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the compound in the form of a free acid or base with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile, or a mixture thereof.

[0037] A "solvate" or "pharmaceutically acceptable solvate" means a solvate formed by the bonding of at least one solvent molecule with a compound. Solvates include hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

[0038] The pharmaceutical composition according to the present invention can be manufactured by conventional methods in the pharmaceutical field. The pharmaceutical composition may be compounded with a suitable pharmaceutically acceptable carrier depending on the dosage form, and may further contain, as necessary, excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. The suitable carrier, etc., does not inhibit the activity and properties of the compound according to the present invention, and different carriers may be selected depending on the administration form and dosage form.

[0039] The pharmaceutical compositions of the present invention may further contain suitable carriers, excipients, or diluents commonly used in the manufacture of pharmaceutical compositions. Compositions containing pharmaceutically acceptable carriers are in various oral or parenteral dosage forms. When formulated, they are prepared using commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, or other diluents or excipients. Examples of oral solid formulations include tablets, pills, powders, granules, and capsules, which are prepared by mixing at least one compound with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to common excipients, lubricants such as magnesium stearate and talc are also used. Examples of oral liquid formulations include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives are used. Parenteral formulations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, tween 61, cocoa butter, lauric acid butter, and glycerol gelatin.

[0040] Furthermore, although not limited to these, the pharmaceutical compositions of the present invention have any dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, lyophilized preparations, and suppositories.

[0041] Each component of the pharmaceutical composition according to the present invention is included in the pharmaceutical composition in a pharmaceutically effective amount.

[0042] "Pharmacologically effective dose" means an amount sufficient to suppress or mitigate the increase in vascular permeability with a reasonable benefit / risk ratio applicable to medical use. The effective dose level is determined by factors including the individual's species and severity, age, sex, drug activity, sensitivity to the drug, administration time, route of administration and elimination rate, duration of treatment, any drugs used concurrently, and other factors known in the medical field.

[0043] The effective dose level of the pharmaceutical composition is determined by the intended use, the patient's age, sex, weight and health status, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the elimination rate, the duration of treatment, the elements of the drugs included in the formulation or used simultaneously, and other elements known in the medical field. For example, although not constant, it is generally 0.001 to 100 mg / kg, and as an example, 0.01 to 10 mg / kg may be administered once a day or in several divided doses. The above dosage does not limit the present invention in any way.

[0044] The pharmaceutical composition can be appropriately administered to an individual by target or, if necessary, by conventional methods, routes of administration, and dosages used in the art. Examples of routes of administration include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, while parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Furthermore, an appropriate dosage and number of administrations can be selected by methods known in the art, and the actual amount and number of administrations of the pharmaceutical composition of the present invention can be appropriately determined based on various factors such as the type of symptom to be treated, route of administration, sex, health status, diet, age and weight of the individual, and severity of the disease.

[0045] "Administration" means introducing the pharmaceutical composition of the present invention into a subject by any appropriate method, and the route of administration can be any of the various routes, oral or parenteral, as long as it can be delivered to the target tissue.

[0046] The pharmaceutical composition can be administered to any animal in which pulmonary fibrosis may occur, and such animals include, for example, humans and primates, as well as livestock such as cattle, pigs, horses, and dogs. In one embodiment, the animal may be any animal other than a human.

[0047] The pharmaceutical composition can be administered via an appropriate route of administration depending on the formulation, and can be administered orally or parenterally via various routes, as long as it can be delivered to the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, topical application, intrarespiratory inhalation, intradural, or intraventricular injection.

[0048] In this invention, "combined administration," "being used in combination," and "combined use" do not merely mean simultaneous administration, but may also refer to a dosage regimen in which dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate thereof act together on an individual, with each substance performing a function equivalent to or greater than its original function. Therefore, in this invention, "combined use" should be understood to mean simultaneous, individual, sequential, or reversed administration, and the order may be any. In the case of sequential, reversed, or individual administration, the order of administration is not particularly limited, but the interval between secondary component administrations must not lose the advantageous effect of the combination.

[0049] In the present invention, (i) a composition comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof, and (ii) a composition comprising nintedanib or a pharmaceutically acceptable salt or solvate thereof, are administered in the following forms, but are not limited thereto.

[0050] a) administered as a mixture of (i) dacomitinib or a pharmaceutically acceptable salt or solvate thereof, and (ii) nintedanib or a pharmaceutically acceptable salt or solvate thereof, or b) (i) Dacomitinib or a pharmaceutically acceptable salt or solvate thereof, and (ii) Nintedanib or a pharmaceutically acceptable salt or solvate thereof, administered in an isolated form, but not limited to these.

[0051] (i) dacomitinib or a pharmaceutically acceptable salt or solvate thereof and (ii) nintedanib or a pharmaceutically acceptable salt or solvate thereof are in separate forms, and (i) and (ii) may be formulated into separate formulations and administered simultaneously, individually, sequentially, or in reverse order.

[0052] The therapeutically effective dose of each active ingredient used in combination therapy varies depending on the specific compound or pharmaceutical composition used, the mode of administration, the symptoms being treated, the severity of the symptoms, the species, body weight, sex, diet, and age of the homeothermic animal. Therefore, the dosage regimen using the compounds of the present invention is selected according to the route of administration and various factors, including the patient's renal and hepatic function. Surgeons, clinicians, or veterinarians in the art can easily determine and prescribe the effective amount of drug required to prevent, manage, or halt the progression of symptoms. Optimal accuracy in obtaining drug concentrations within an efficient range without toxicity requires dosage regimens based on the dynamics of drug usability targeting specific sites. This includes considering the distribution, balance, and removal of the drug. Therefore, dosage regimens, i.e., the administration levels and frequencies of any individual component of the present invention, are adjusted to provide the optimal therapeutic response.

[0053] A further aspect of the present invention is a combination comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0054] In this invention, "combination" means having a use for co-administration of dacomitinib or a pharmaceutically acceptable salt or solvate thereof with nintedanib or a pharmaceutically acceptable salt or solvate thereof, and is used in the same sense as "combined used." This includes, but is not limited to, the form of pharmaceutical compositions and pharmaceutical kits characterized by the co-administration of dacomitinib or a pharmaceutically acceptable salt or solvate thereof with nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0055] The “kit” in the present invention may include a combination or composition according to the present invention for co-administration of dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate thereof. Specifically, the kit of the present invention may include dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate formulated into a single formulation, or it may include individual formulations of dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate thereof. The kit may further include substances necessary for the co-administration of the two substances, but is not necessarily limited thereto.

[0056] Pulmonary fibrosis refers to a respiratory disease in which lung tissue hardens, causing severe respiratory impairment. Pulmonary fibrosis can be caused by various factors, including radiation, tuberculosis, syphilis, pneumoconiosis, and viral infections, but it can also be caused by unknown factors. All of these types of pulmonary fibrosis are included in the definition of pulmonary fibrosis in this invention.

[0057] In one embodiment of the present invention, pulmonary fibrosis may be selected from pulmonary fibrosis caused by radiation exposure, acute pulmonary fibrosis, and idiopathic pulmonary fibrosis.

[0058] In this invention, "idiopathic pulmonary fibrosis" or "idiopathic pulmonary fibrosis" (IPF) refers to an interstitial lung disease of unknown cause in which recurrent inflammation due to alveolar damage leads to fibrosis and respiratory failure in the patient.

[0059] In one embodiment of the present invention, pulmonary fibrosis may be a side effect of radiation therapy caused by exposure of normal tissue to radiation during radiation therapy for cancer, or it may be a side effect of drug therapy for anti-cancer treatment.

[0060] Radiation therapy or drug therapy for cancer that causes pulmonary fibrosis includes, but is not limited to, the treatment of breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, oral cancer, oropharyngeal cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, endometrial cancer, cervical cancer, vaginal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer, liver cancer, colorectal cancer, or brain tumors.

[0061] In one embodiment, the pharmaceutical composition of the present invention may be administered before or after radiation exposure.

[0062] "Treatment" means any action that improves or favorably alters the symptoms of fibrosis by administering the pharmaceutical composition, and "prevention" means any action that suppresses or delays the onset of fibrosis by administering the pharmaceutical composition.

[0063] In the present invention, "improvement" means any action by which the administration of the composition of the present invention reduces, at least, parameters related to pulmonary fibrosis, such as the severity of symptoms.

[0064] A further aspect of the present invention is a method for preventing, improving, or treating pulmonary fibrosis, comprising the step of administering and / or using a combination, pharmaceutical composition, or pharmaceutical kit comprising dacomitinib or a pharmaceutically acceptable salt or solvate thereof and nintedanib or a pharmaceutically acceptable salt or solvate thereof to an individual requiring such a combination.

[0065] A further aspect of the present invention is a method for preventing, improving, or treating pulmonary fibrosis, comprising the step of co-administering and / or co-using a composition comprising a pharmaceutically effective amount of dacomitinib or a pharmaceutically acceptable salt or solvate thereof to an individual requiring a composition comprising nintedanib or a pharmaceutically acceptable salt or solvate thereof.

[0066] Further embodiments of the present invention include compositions comprising a pharmaceutically effective amount of dacomitinib or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions comprising nintedanib or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical kits, for use in the prevention, improvement, or treatment of pulmonary fibrosis, and / or for the manufacture of pharmaceuticals for the prevention, improvement, or treatment of pulmonary fibrosis.

[0067] Dacomitinib or compositions comprising a pharmaceutically acceptable salt or solvate thereof, nintedanib or a pharmaceutically acceptable salt or solvate thereof, and the treatment of pulmonary fibrosis, are as described above. [Examples]

[0068] The present invention will be described in more detail below with reference to examples and experimental cases. However, these examples and experimental cases are merely illustrative of the present invention, and the present invention is not limited to these examples and experimental cases. [Examples]

[0069] Confirmation of the effect of suppressing radiation-induced pulmonary fibrosis. Seven-week-old male mice from C57BL / 6 were orally administered one hour before stereotactic body radiation therapy (SBRT, 90 Gy, 4 mm collimator) to one of three groups: a group receiving nintedanib, an FDA-approved pulmonary fibrosis inhibitor; a group receiving dacomitinib, an EGFR TKI; or a group receiving a combination of both drugs. Two weeks after radiation exposure, the degree of pulmonary fibrosis and the effect of suppressing radiation-induced lung damage were observed.

[0070] In the nintedanib group, a concentration of 60 mg / kg was administered daily, in the dacomitinib group, a concentration of 10 mg / kg was administered, and in the combination therapy group, nintedanib was administered at 60 mg / kg and dacomitinib at 10 mg / kg. All drugs were administered orally daily. Figure 1 shows the results of micro-CT scans taken two weeks after radiation exposure. In addition, H&E staining and Masson's Trichrome staining were performed to analyze the degree of inflammation and fibrosis. Figure 2 shows the pulmonary fibrosis rank and the degree of collagen deposition in a graph.

[0071] The experimental results showed that in the group without drug treatment, the degree of fibrosis worsened two weeks after radiation exposure. Compared to the group without drug treatment, the degree of fibrosis was reduced in the nintedanib-treated group and the dacomitinib-treated group, respectively. In the group that received both drugs in combination, pulmonary fibrosis was significantly reduced.

[0072] From the above description, those skilled in the art in the field to which the present invention pertains will understand that the present invention can be implemented in other specific forms without altering its technical idea or essential features. It should be understood that the above embodiments are merely illustrative and not limiting. The present invention should be interpreted as encompassing all modified or altered forms derived from the meaning and scope of the claims and their equivalent concepts, rather than the specification.

Claims

1. A pharmaceutical composition for the prevention or treatment of pulmonary fibrosis, comprising a pharmaceutically effective amount of dacomitinib or a pharmaceutically acceptable salt or solvate thereof, The aforementioned pharmaceutical composition is characterized by being administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof. Pharmaceutical composition.

2. The aforementioned dacomitinib is a compound represented by the following chemical formula 1. The pharmaceutical composition according to claim 1. 【Chemistry 1】

3. The aforementioned nintedanib is a compound represented by the following chemical formula 2. The pharmaceutical composition according to claim 1. 【Chemistry 2】

4. The composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition according to claim 1.

5. The aforementioned dacomitinib or a pharmaceutically acceptable salt or solvate thereof is administered in combination with nintedanib or a pharmaceutically acceptable salt or solvate thereof, either simultaneously, sequentially, or in reverse order. The pharmaceutical composition according to claim 1.

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