WO2005110450A1 - 医薬組成物及び治療方法 - Google Patents
医薬組成物及び治療方法 Download PDFInfo
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- WO2005110450A1 WO2005110450A1 PCT/JP2005/008944 JP2005008944W WO2005110450A1 WO 2005110450 A1 WO2005110450 A1 WO 2005110450A1 JP 2005008944 W JP2005008944 W JP 2005008944W WO 2005110450 A1 WO2005110450 A1 WO 2005110450A1
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- inflammatory disease
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- 239000000454 talc Substances 0.000 description 1
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- 230000002588 toxic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
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Classifications
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- compositions and methods of treatment are provided.
- the present invention relates to a pharmaceutical composition for preventing, ameliorating or treating an inflammatory disease and a method for treating the same.
- Interleukin-18 is a gram-positive bacillus
- Propionibacterium acnes was found as an interferon ⁇ (IFN ⁇ or interferon ⁇ ) production inducer that appeared in blood when a small amount of lipopolysaccharide (LPS) was intravenously injected into mice pre-administered with heat-killed bacteria .
- IFNy enhances cellular immunity by activating macrophage NK cells, and increases resistance to infection by pathogens such as bacteria.
- LPS lipopolysaccharide
- IL-18 induces IFNy production by activating CD8 cells, NK cells, and TH-1 cells.
- IL-18 is expressed at low levels even in normal times. However, for infection by pathogens (viruses, prokaryotes, eukaryotes), expression is increased, rendering cells resistant to pathogens. For example, administering IL-18 before infecting mice with HSV can significantly improve mouse survival. In addition, administration of IL-18 suppresses the growth of the fungal Cryptococcus neoformans, which is a cause of the disease, and makes it resistant to Candida infection.
- mice with anti-IL-18 antibody impairs resistance to the intracellular microorganism Salmonella typhimurium.
- IL-18 administration to mice lethally infected with the toxic strain Salmonella Decreases bacterial counts and lethality in tissues (Joost J. Oppenheim, Marc Feldmann, Scott K. Durum, eds.), “Site Force in 'Reference: Sites in Host Defense” Overview of Force-In and Other Mediators (Cytokine Reference: A ompendium of cytokines and Other Mediators of Host Defense), (USA), / Academic Press, 2000, p.338-350 " ).
- IL-18 is known to induce cytokines other than IFN ⁇ , chemokines, among which inflammatory IL-8, TNF, and IL-6.
- IL-18 knockout mice are resistant to LPS administration that induces inflammatory cytokines, it can be seen that IL-18 is an essential factor for LPS-induced inflammatory site force-in.
- IL-18 is known as a mediator of the immune response, and was considered to have an important role in inducing inflammatory cytotoxicity.
- the present inventors have discovered a new action of IL-18 to suppress inflammation. Therefore, the present invention, based on the discovery of this new action of IL-18, contains IL-18 and contains s ⁇ RS (systemic inflammatory response syndrome: systemic inflammatory response syndromeE
- An object of the present invention is to provide a pharmaceutical composition and a therapeutic method for preventing, ameliorating or treating sexual diseases.
- IL-18 Low levels of expression of IL-18 are also observed in normal times.
- the present inventors have found that the expression level of IL-18 decreases when serious burns are inflicted, and that when a small amount of IL-18 is administered to mice with severe burns, the survival rate is reduced. It has been found that significant improvements are seen.
- the mouse spleen The isolated spleen cells secrete inflammatory site force-in in response to LPS under culture conditions, but found that secretion was suppressed in IL-18-administered mice. It came to success.
- the pharmaceutical composition according to the present invention is a pharmaceutical composition for preventing, ameliorating or treating an inflammatory disease, characterized by containing interleukin-18.
- the inflammatory disease may be SIRS, sepsis syndrome, or sepsis.
- the inflammatory disease may be acute lung injury or multiple organ failure secondary to SIRS. Moreover, it may act independently of interferon ⁇ .
- the inflammatory disease to be treated by the pharmaceutical composition may be one that reduces interleukin-18 concentration in the liver.
- the pharmaceutical composition according to the present invention does not increase the interleukin-18 concentration in the liver, which has been reduced in the inflammatory disease, above a normal value.
- the normal value is measured in a healthy person. It is a fixed value and usually has a certain range.
- the therapeutic method of the present invention is characterized by administering an effective amount of IL-18 to a patient suffering from an inflammatory disease.
- the inflammatory disease may be SIRS, sepsis syndrome, or sepsis.
- the inflammatory disease may be acute lung injury or multiple organ failure secondary to SIRS. Further, it may act independently of interferon ⁇ .
- the inflammatory disease that is the subject of the treatment method may decrease interleukin-18 concentration in plasma or in the liver.
- the interleukin-18 concentration in either the plasma or the liver, which has been reduced in the inflammatory disease is not increased to a value higher than the normal value.
- the treatment method according to the present invention is a treatment method for treating a human or a non-human vertebrate individual suffering from an inflammatory disease, wherein the vertebrate individual contains interleukin-18. And administering a pharmaceutical composition.
- the inflammatory disease may be one that reduces interleukin-18 levels in either the plasma or the liver. Further, it is possible to administer an amount of the pharmaceutical composition containing interleukin-18 in such a manner that the concentration of interleukin-18 in either the plasma or the liver, which has been reduced in the inflammatory disease, is not increased to a normal value or higher. preferable.
- FIG. 1 is a graph showing IL-18 content in liver and lung of each mouse group of a control group and a burn group over time after burn treatment in one example of the present invention.
- FIG. 2 is a graph showing the IL-18 content in human plasma with time after burns in one example of the present invention.
- FIG. 3 is a graph showing the survival rate after LPS administration in each mouse group of a control group, a non-administration group, and an IL-18 administration group over time in one example of the present invention.
- FIG. 4 is an image of a tissue section of a lung after LPS administration in a mouse group of a control group, a non-administration group, and an IL-18 administration group in one example of the present invention.
- FIG. 5 In one example of the present invention, various sites obtained by stimulating in vitro spleen cells isolated from each of a control group, a non-administration group, and an IL-18 administration group with an anti-CD3 antibody It is the figure which showed the secretion amount of force in.
- FIG. 6 In one example of the present invention, in vitro, spleen cells isolated from a control group, a non-administration group, and an IL-18 administration group of various spleen cells were stimulated with LPS in various cytoplasmic forces. It is a figure showing the secretion amount of.
- FIG. 7 is a graph showing the secretion amount of pulmonary cytokin after LPS administration in each mouse group of a control group, a non-administration group, and an IL-18 administration group in one example of the present invention.
- the pharmaceutical composition of the present invention is a pharmaceutical composition containing IL-18 for preventing, ameliorating, or treating an inflammatory disease.
- inflammatory diseases include SIRS (systemic inflammatory response syndrome). This is the concept of the inflammatory response jointly defined by the American Society of Thoracic Diseases and the Intensive Care Society in 1991. SIRS is defined as meeting two or more of the following four items. 1) Body temperature 38 ° C or more or 36 ° C or less, 2) Pulse 90 / min or more, 3) Respiratory rate 20 / min, or PaCO
- SIRS Systemic inflammation without infection, such as trauma, burns, knee inflammation, and highly invasive post-operative, and systemic inflammation with infection;! Positive, sepsis syndrome). Furthermore, sepsis syndrome is classified into those with bacterial infection in the blood (sepsis) and others.
- the pharmaceutical composition of the present invention can treat all these inflammatory diseases.
- the affected area is infected with bacteria, and the proliferated bacteria enter the blood, leading to sepsis.
- Sepsis causes acute lung injury (ALI) and may also lead to multiple organ failure (MODS).
- the pharmaceutical composition of the present invention can also treat such serious injuries by exerting an anti-inflammatory effect.
- IL-18 or a pharmacologically acceptable salt thereof is administered to humans, for example, at a dose of about 8 mg / kg (body weight) per day, the dose may be administered once or several times It is preferable to administer, but the dose and the frequency of administration can be appropriately changed depending on the symptoms, age, administration method and the like.
- IL-18 and its pharmacologically acceptable salt can be administered orally in the form of tablets, capsules, granules, powders, syrups, liniments, etc., or administered directly to the affected area. Or in the form of injections, suppositories, etc., intraperitoneally, intravenously, intraarterially, intramuscularly, subcutaneously, etc. Parenteral administration can also be achieved by injection into the parent. It may be made into a liquid form and applied or sprayed on the skin, mucous membranes, affected areas, etc., or inhaled through the nasal mucosa or throat mucosa.
- the content of IL-18 or a pharmacologically acceptable salt thereof (active ingredient) in the preparation can be varied between 1 and 90% by weight.
- the active ingredient in the case of tablets, capsules, granules, powders and the like, the active ingredient is preferably contained in an amount of 5 to 80% by weight.
- liquid preparations such as syrup preparations, it is preferable to contain 1-30% by weight of the active ingredient.
- parenteral injection it is preferable to contain 1 to 10% by weight of the active ingredient.
- Formulation of IL-18 and its pharmacologically acceptable salts can be carried out using excipients (sugars such as lactose, sucrose, glucose, mannitol, starch such as potato, wheat, corn, calcium carbonate).
- excipients such as lactose, sucrose, glucose, mannitol, starch such as potato, wheat, corn, calcium carbonate.
- Inorganic substances such as calcium sulfate, sodium hydrogen carbonate, crystalline cellulose, etc.
- Binders starch paste, gum arabic, gelatin, sodium alginate, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, carmellose, etc.
- lubricants magnesium stearate, talc, hydrogenated
- Vegetable oil macrogol, silicone oil
- disintegrant starch, agar, gelatin powder, crystalline cellulose, CMC'Na, CMC'Ca, calcium carbonate, sodium hydrogen carbonate, sodium alginate, etc.
- flavoring agent lactose, Sucrose, glucose, mannitol, aromatic essential oils, etc.
- solvents water for injection, sterile purified water, sesame oil, soybean oil, corn oil, olive oil, cottonseed oil, etc.
- stabilizers nitrogen, carbon dioxide, etc.
- Chelating agents such as inert gas, EDTA, thioglycolic acid, sulfite water Sodium, sodium, sodium, sodium,
- the pharmacologically acceptable salt of IL-18 is, for example, an organic salt such as a quaternary ammonium salt, or a metal salt such as an alkali metal. There is no restriction.
- an organic salt such as a quaternary ammonium salt
- a metal salt such as an alkali metal.
- mice Seven-week-old male Balb / c mice (weighing 23-28 grams) were placed in a cage and allowed free access to water and food for approximately one week. Then, it divided into the control group and the burn group.
- Day 0 One day before the experiment (Day 0), the mice were shaved on the back under pentobarbital anesthesia (50 mg / kg).
- Day 1 On the following day (Day 1), all mice were anesthetized with ether, and for the burned mice, hot steam was applied to the shaved spine for 5 seconds to remove about 15% of the total body surface area. The layer was burned. Control mice were not exposed to hot steam. Thereafter, all mice immediately regained consciousness with 4 ml of saline.
- IL-12 is a site power-in classified as a Th-1 site power-in involved in Th-1 cell sorting.
- Th-1 site power-in involved in Th-1 cell sorting.
- mice Twenty-four hours after the burn treatment, the mice were anesthetized by intraperitoneal administration of pentobarbital, and the lungs and liver were excised. To the removed lung and liver, 10 or 50 times their weight of PBS (phosphate buffered saline) was added, homogenized, centrifuged, and the supernatant was collected.
- PBS phosphate buffered saline
- Figure 1 shows the results.
- the site force-in concentration was compared after analysis of variance (ANOVA) by using the Scheffe's comparison test (the significant difference was judged as p ⁇ 0.05. The following comparison of the site force-in concentration was also performed).
- IL-18 levels in humans with severe burns were measured at several time points after burns.
- the animals were classified into divided groups on days 3, 6-8, and 9-11.
- the measurement was performed using an ELISA kit (BD Biosciences) in the same manner as in Example 2.
- the average value of the measured values of a plurality of IL-18 concentrations measured in each divided group was also calculated for each divided group.
- the IL-18 concentration in each divided group was subjected to statistical processing using Fisher's PLSD method after analysis of variance using this average value (significant difference was judged by p ⁇ 0.05).
- the IL-18 concentration significantly decreases on the second to third days after the burn, and reaches a peak of the decrease on the 6th to 8th days.
- the kinetics of this IL-18 concentration is the same as the change in IL-18 content in the liver of the burn group mice of Example 2. In this way, it was confirmed that the IL-18 concentration decreased in humans after burns.
- Example 2 and 3 indicate that the ability to reduce the concentration of Th-1 site force-in after burns may have an important role in inflammatory diseases such as sepsis and acute lung injury caused by severe burns. it was thought. Therefore, using inflammation model mice in which acute inflammation was induced by administering endotoxin (LPS) to mice after burns, administration of a small amount of IL-18 was performed using the survival rate by LPS administration as an index. The effect was investigated.
- LPS endotoxin
- mice in the burn group prepared according to Example 1 were divided into an IL-18 administration group and a non-administration group,
- mice in the IL-18 administration group received 0.2 ⁇ g of recombinant IL-18 (MBL) every other day for 10 days after the burn, and no administration in the non-administration group.
- MBL recombinant IL-18
- dayl2 eleventh day of the burn treatment
- all mice in the three groups were intravenously administered with a saline solution containing 3 mg / kg body weight of LPS (Escherichia coli 0111: B4 endotoxin; Sigma) in 10 ml of saline. Induced inflammation. Thereafter, surviving individuals in each group were examined every 12 hours up to 72 hours.
- Figure 3 is a graph showing the results. The survival rates between groups were compared by the Wilcoxon-Gehan test (significant difference was judged by p ⁇ 0.05).
- IL-18 has an anti-inflammatory effect, and is considered to be useful as a pharmaceutical composition for preventing, ameliorating, or treating inflammatory diseases such as systemic inflammatory response syndrome including sepsis.
- inflammatory diseases such as systemic inflammatory response syndrome including sepsis.
- Example 5 Effect of IL-18 administration on pulmonary edema
- Example 4 In the inflammation model mouse of Example 4, the lung was excised, the upper lung lobe was fixed with a 4% formaldehyde solution, a noraffin section was prepared, stained with hematoxylin-eosin, and pathological examination was performed. As shown in FIG. 4, in the non-administration group (FIG. 4B), severe pulmonary edema (severe pulmonary edema) was induced and neutrophils were increased as compared with the control group (FIG. 4A). This is a condition similar to acute lung injury and can be a model. On the other hand, in the IL-18 administration group (Fig. 4C), improvement of these symptoms such as pulmonary edema and neutrophil increase was observed.
- IL-18 is useful for preventing, ameliorating or treating diseases such as acute lung injury and multiple organ failure secondary to SIRS.
- the spleen cells were isolated from the inflammation model mouse capilla of Example 4 and administered under culture conditions with an anti-CD3 antibody or LPS to activate the spleen cells and reduce the amount of secreted cytokin. It was measured. Stimulation of spleen cells with an anti-CD3 antibody activates the immune response through T cells, and stimulation of spleen cells with LPS activates mainly macrophages and secretes inflammatory cytokines.
- the spleen taken out was subdivided into RPMI 1640 containing 5% fetal calf serum (FCS) and filtered through a nylon mesh.
- FCS fetal calf serum
- the cells were treated with a 0.84% salt blood ammonia solution for removing red blood cells.
- the spleen cells were resuspended in RPMI 1640/5% FCS, and 1 ⁇ g / mL anti-CD3 antibody (MAb clone 145-2C11, BD Biosciences) or 10 g / mL LPS was added. Soak and add 5% CO, 37 ° C for 24 hours or
- Example 4 revealed that the administration of IL-18 significantly improved the survival rate of inflammation model mice. Therefore, the following experiment was conducted to examine the power of IL-18 in relation to the secretion amount of cytoforce in inflammation model mice.
- lungs of an inflammatory model mouse 12 hours after LPS administration in Example 4 were isolated, and PBS (phosphate-buffered saline) 10 or 50 times the weight of the lung was added. After homogenization and centrifugation, the supernatant was recovered. TNF a, IFN y, IL-4, IL-10, IL-12, IL-18, MIP-2 sandwich ELISA using ELISA kit (BD Biosciences or Wako Pure Chemical Industries, Ltd.) was used to determine the concentration of each cytokine in the supernatant of the lung.
- Figure 7 shows the results.
- the site force-in concentration was compared by analysis of variance (ANOVA) and then using the Scheffe's comparison test (the significant difference was determined as p ⁇ 0.05).
- the secretion amounts of all the inflammatory force, Th-1 force, and Th-2 force in the non-administration group were significantly increased as compared with the control group.
- the IL-18 treatment group significantly reduced the secretion of inflammatory cytotoxicity (TNFa and MIP-2). I let you. This therefore indicates that IL-18 has an anti-inflammatory effect at the level of cytodynamic force.
- the present invention provides a pharmaceutical composition containing IL-18 for preventing, ameliorating, or treating inflammatory diseases such as SIRS.
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Abstract
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US11/596,674 US20090016987A1 (en) | 2004-05-18 | 2005-05-17 | Pharmaceutical composition and therapeutic method |
EP05741471A EP1752159A4 (en) | 2004-05-17 | 2005-05-17 | MEDICAL COMPOSITION AND THERAPEUTIC PROCEDURE |
CA002566877A CA2566877A1 (en) | 2004-05-17 | 2005-05-17 | Medicinal composition and therapeutic method |
JP2006513602A JPWO2005110450A1 (ja) | 2004-05-17 | 2005-05-17 | 医薬組成物及び治療方法 |
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JP2004-145971 | 2004-05-17 |
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EP (1) | EP1752159A4 (ja) |
JP (1) | JPWO2005110450A1 (ja) |
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WO (1) | WO2005110450A1 (ja) |
Citations (3)
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JP2001502330A (ja) * | 1996-10-11 | 2001-02-20 | ワーナー―ランバート・コンパニー | スルホンアミド置換アスパラギン酸インターロイキン―1β変換酵素阻害剤 |
JP2002504091A (ja) * | 1997-03-18 | 2002-02-05 | ベーアーエスエフ アクツィエンゲゼルシャフト | コルチコステロイドに対する応答性を調整するための方法及び組成物 |
WO2002092008A2 (en) * | 2001-05-16 | 2002-11-21 | Yeda Research And Development Co., Ltd. | Use of il-18 inhibitors for the treatement or prevention of sepsis |
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WO2004002519A1 (en) * | 2002-06-27 | 2004-01-08 | Smithkline Beecham Corporation | Methods of treating or preventing ibd with il-18 |
ATE359088T1 (de) * | 2002-12-27 | 2007-05-15 | Universitaetsklinikum Muenster | Verwendung von interleukin-18 zur behandlung von uv-assoziierten hautkrankheiten |
-
2005
- 2005-05-17 JP JP2006513602A patent/JPWO2005110450A1/ja not_active Withdrawn
- 2005-05-17 CA CA002566877A patent/CA2566877A1/en not_active Abandoned
- 2005-05-17 EP EP05741471A patent/EP1752159A4/en not_active Withdrawn
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JP2001502330A (ja) * | 1996-10-11 | 2001-02-20 | ワーナー―ランバート・コンパニー | スルホンアミド置換アスパラギン酸インターロイキン―1β変換酵素阻害剤 |
JP2002504091A (ja) * | 1997-03-18 | 2002-02-05 | ベーアーエスエフ アクツィエンゲゼルシャフト | コルチコステロイドに対する応答性を調整するための方法及び組成物 |
WO2002092008A2 (en) * | 2001-05-16 | 2002-11-21 | Yeda Research And Development Co., Ltd. | Use of il-18 inhibitors for the treatement or prevention of sepsis |
Non-Patent Citations (5)
Title |
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ENDO S. ET AL.: "Interleukin 18 (il-18) levels in patients with sepsis.", JOURNAL OF MEDICINE., vol. 31, no. 1-2, 2000, pages 15 - 20, XP008052610 * |
IKUTA S. ET AL.: "Interleukin-18 concentration in the peritoneal fluid correlates with the severity of peritonitis.", AMERICAN JOURNAL OF SURGERY., vol. 185, 2003, pages 550 - 555, XP002990191 * |
MUHL H. ET AL.: "Inhibition of lippopolysaccharide/ATP-induced release of interleukin-18 by KN-62 and glyburide.", EUROPEAN JOURNAL OF PHARMACOLOGY., vol. 482, 2003, pages 325 - 328, XP002990189 * |
NAKAMURA S. ET AL.: "IFN-Gamma-Dependent and - Independent Mechanisms in Adverse Effects Caused by Concomitant Adminsitration of IL-18 and IL-12.", JOURNAL OF IMMUNOLOGY., vol. 164, 2000, pages 3330 - 3336, XP002990190 * |
See also references of EP1752159A4 * |
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CA2566877A1 (en) | 2005-11-24 |
JPWO2005110450A1 (ja) | 2008-03-21 |
EP1752159A4 (en) | 2009-07-01 |
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