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WO1996005855A1 - Traitement des maladies des cartilages - Google Patents

Traitement des maladies des cartilages Download PDF

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Publication number
WO1996005855A1
WO1996005855A1 PCT/JP1995/000121 JP9500121W WO9605855A1 WO 1996005855 A1 WO1996005855 A1 WO 1996005855A1 JP 9500121 W JP9500121 W JP 9500121W WO 9605855 A1 WO9605855 A1 WO 9605855A1
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WO
WIPO (PCT)
Prior art keywords
hgf
cartilage
arthritis
cells
active ingredient
Prior art date
Application number
PCT/JP1995/000121
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English (en)
Japanese (ja)
Inventor
Masahiro Iwamoto
Sumihare Noji
Toshikazu Nakamura
Original Assignee
Sumitomo Pharmaceuticals Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sumitomo Pharmaceuticals Co., Ltd. filed Critical Sumitomo Pharmaceuticals Co., Ltd.
Priority to CA002197869A priority Critical patent/CA2197869C/fr
Publication of WO1996005855A1 publication Critical patent/WO1996005855A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/4753—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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

  • the present invention relates to an agent useful for treating and preventing cartilage disease. More specifically, the present invention relates to a therapeutic agent for cartilage disorders, a chondrocyte proliferation promoter and a proteoglycan production promoter containing HGF (Hepatocyte Growth Factor) as an active ingredient.
  • HGF Hepatocyte Growth Factor
  • Cartilage is connective tissue consisting of chondrocytes and the matrix surrounding it, and is found in joints, spinal discs, costal cartilage, auricles, ear canals, pubic connections, and epiglottis.
  • Cartilage is composed of chondrocytes and cartilage matrix produced by chondrocytes.
  • the cartilage matrix is mainly composed of fibrous components such as collagen fibers, proteoglycans and water.
  • the cartilage is mixed with the cartilage matrix to produce hyaline cartilage (costum).
  • cartilage Disc cartilage, pubic cartilage, articular cartilage, etc.
  • collagen fibers are involved in rigidity and strength of cartilage against tension and shear force
  • proteoglycans are involved in strength against compressive force
  • water has never before been characterized as a viscoelastic body of living tissue.
  • articular cartilage water accounts for 78.6% of cartilage mass
  • collagen accounts for 20%
  • proteoglycan accounts for 7%.
  • the effects of cartilage include reduction of epiphyseal friction (cartilage between bones), retention of elasticity (such as auricular cartilage), and motor function (such as costal cartilage and pubic cartilage).
  • cartilage has an important effect in maintaining the function of a living body, and various diseases caused by cartilage disorders have been known, for example, dyschondrodysplasia, osteoarthritis, deformation Examples include intervertebral disc disease, fracture repair, and poor healing.
  • various diseases caused by cartilage disorders include intervertebral disc disease, fracture repair, and poor healing.
  • HGF has an effect of promoting the growth of chondrocytes and the production of proteoglycan, and has been shown to inhibit various diseases caused by cartilage disorders.
  • the present inventors have found that they are effective for treatment and completed the present invention.
  • HGF is a protein found as a factor for growing hepatocytes in vitro (Biochem Biophys Res Commun, 122, 1450, 1984, Proc. Natl. Acad. Sci. USA, 83, 6489, 1986, FEBS Letter, 224, 311, 1987, Nature, 342, 440, 1989, Proc. Natl. Acad. Sci. USA, 87, 3200, 1990).
  • HGF which was discovered as a factor that specifically promotes hepatocyte proliferation, has been shown to have various activities such as tissue injury healing and the like in vivo by recent research results by many researchers including the present inventors. The results are clear, and expectations are high for its application not only as a research target but also as a therapeutic drug for humans and animals.
  • HGF is produced by cells of the mesenchymal system in life, and it has been clarified that a so-called paracrine mechanism has been established in which HGF is supplied from neighboring cells as needed. I have. However, when liver and spine are injured, HGF production is also increased in uninjured organs, such as lungs, so that it is considered that HGF is also supplied by the so-called endocrine mechanism.
  • the present invention is a remedy for cartilage disorders comprising HGF as an active ingredient.
  • Another aspect of the present invention provides a chondrocyte proliferation promoting agent comprising HGF as an active ingredient; a proteoglycan production promoting agent comprising HGF as an active ingredient; and administering an effective amount of HGF. And a method for treating cartilage disorders in a human or mammal.
  • the above HGF may be derived from human or animal tissues or blood components, or may be produced by genetic recombination.
  • HGF which is an active ingredient, has the effect of promoting the proliferation of chondrocytes and the production of proteoglycan, and is therefore effective for the treatment and prevention of various diseases caused by cartilage disorders.
  • Figure 1 is a micrograph showing the expression of HG FmRNA in the limb buds of early nascent mice (bright field on the left and corresponding dark field on the right).
  • a to D are 10.5-day-old fetuses
  • E to H are longitudinal section sections of the 11-day-old fetus.
  • Figure 2 is a photomicrograph showing the expression of HG FmRNA in the limb buds of the mouse during finger formation (bright field on the left, corresponding ⁇ field on the right).
  • a and B are sections of a 12.5 day old fetus
  • C to F are sections of a 13 day old fetus
  • G to J are sections of a 14 day old fetus.
  • Fe is the femur
  • Fi is the fibula
  • Ta indicates a tarsal bone
  • I to V indicate finger numbers.
  • FIG. 3 is a micrograph showing the expression of HGF mRNA in the limb buds and thorax of a developing mouse (the bright field is on the left, and the corresponding dark field is on the right).
  • a and B show cross sections of hind limbs of a 6-day-old fetus; C and D show 13-day- ⁇ fetuses, and E and F show longitudinal-section sections of the thorax of 14-day-old fetuses.
  • Ta indicates tarsal bone
  • Ti indicates tibia
  • Rib indicates pre-cartilaginous accumulation of rib cartilage.
  • FIG. 4 is a micrograph showing the scatter activity of HGF on chondrocytes.
  • A indicates control (non-HGF processing) and B indicates HGF processing.
  • FIG. 5 shows the effect of HGF on chondrocyte proliferation.
  • A shows the effect on DNA synthesis of articular chondrocytes
  • B shows the effect on DNA synthesis of peritoneal cells
  • C shows the effect on proliferation (cell number) of articular chondrocytes.
  • FIG. 6 is a diagram showing the effect of HGF on proteoglycan production.
  • FIG. 7 is a graph showing the effects of HGF on DNA synthesis (FIG. 7A) and production of open-ended theoglycans (FIG. 7B) in the presence of an anti-HGF antibody.
  • FIG. 8 is an electrophoretic photograph showing the expression of HGF receptor mRNA in chondrocytes. BEST MODE FOR CARRYING OUT THE INVENTION
  • HGF used in the present invention those prepared by various methods can be used as long as they are purified to the extent that they can be used as pharmaceuticals.
  • HGF HGF-like growth factor
  • organs such as bone marrow, brain, back, placenta, etc.
  • blood cells such as platelets, leukocytes, plasma, serum, etc. It can be obtained by extraction and purification (see FEBS Letter, 224, 312, 1987, Proc. Natl. Acad. Sci. USA, 86, 5844, 1989, etc.).
  • HGF primary cultured cells and cell lines that produce HGF are cultured and cultured.
  • HGF can be isolated and purified from culture supernatants, cultured cells, etc., or HGF-encoding genes can be incorporated into an appropriate vector by genetic engineering techniques and inserted into an appropriate host.
  • HGF recombinant HGF from the culture supernatant of this transformant (for example, Nature, 342, 440, 1989, Japanese Patent Application Laid-Open No. 5-111383). Gazette, Biochem. Biophys. Res. Commun., 163, 967, 1989).
  • the above host cells are not particularly limited, and various host cells conventionally used in genetic engineering techniques, for example, Escherichia coli, Bacillus subtilis, yeast, filamentous fungi, plants, or animal cells can be used.
  • a method for extracting and purifying HGF from living tissue for example, a method of intraperitoneally administering carbon tetrachloride to a rat, extracting and crushing the liver of the rat in a hepatitis state, and crushing the S-sepharose
  • the protein can be purified by conventional protein purification methods such as gel column chromatography such as heparin sepharose and HPLC.
  • animal cells such as Chinese hamster ovaries (eg, Chinese hamster ovaries), are obtained by using an expression vector in which a gene encoding the amino acid sequence of human HGF has been incorporated into a vector such as sipapilloma virus DNA using a genetic recombination method.
  • CHO CHO cells, mouse C127 cells, monkey COS cells, etc. can be transformed and obtained from the culture supernatant.
  • HGF HGF
  • a part of the amino acid sequence is deleted or replaced by another amino acid, or another amino acid sequence is partially inserted.
  • one or more amino acids may be bound to the N-terminus and / or C-terminus, or the sugar chain may be similarly deleted or substituted.
  • the therapeutic agent and accelerator of the present invention contain the above-mentioned HGF as an active ingredient, and HGF promotes the growth of chondrocytes and the production of proteoglycan, as shown in the test examples described later. Furthermore, since HGF does not act on undisturbed cartilage tissue and acts only on impaired cartilage tissue, HGF has a feature that it is less likely to cause side effects. Therefore, the therapeutic agent and the accelerator of the present invention are useful for treating various diseases caused by cartilage disorders. It is effective for prevention, and these include, for example, the following diseases.
  • the therapeutic agent and enhancer of the present invention are useful for the treatment and prevention of various diseases caused by cartilage disorders in mammals (for example, horses, horses, pigs, sheep, dogs, cats, etc.) in addition to humans. Applied.
  • the therapeutic agent and enhancer of the present invention can be used in various forms (for example, liquids, solids, capsules, etc.).
  • the injection can be prepared by a conventional method. For example, after dissolving HGF in an appropriate solvent (for example, sterilized water, buffer, physiological saline, etc.), sterilize by passing through a filter or the like. Then, it can be prepared by filling in a sterile container.
  • the HGF content in the injection is usually adjusted to about 0.002 to 0.2 (W / V5, preferably about 0.001 to 0.1 (W / V%).
  • Suppositories can also be prepared by a conventional method using a conventional base (for example, cacao butter, laurin butter, glycemic gelatin, macrocrogol, witepsol, etc.).
  • Inhalants should also be prepared in accordance with the usual pharmaceutical procedures. Can be.
  • the HGF content in the preparation can be appropriately adjusted according to the dosage form, the disease to be applied and the like.
  • a stabilizer is preferably added.
  • the stabilizer include albumin, globulin, gelatin, glycine, mannitol, glucose, dextran, sorbitol, ethylene glycol and the like.
  • the preparation of the present invention may contain additives necessary for preparation, for example, excipients, solubilizers, antioxidants, soothing agents, isotonic agents and the like.
  • a liquid preparation it is desirable to store it after freezing or freezing it to remove water.
  • the lyophilized preparation is reconstituted with distilled water for injection and used before use.
  • the therapeutic agent and enhancer of the present invention can be administered by an appropriate route depending on the form of the preparation.
  • it can be administered in the form of an injection into a vein, artery, subcutaneous, intramuscular, or the like.
  • the dose is adjusted appropriately depending on the patient's condition, age, weight, etc., but is usually 0.05 mg to 500 ing, preferably lmg to 100 mg as HGF, and is divided into once or several times a day. It is appropriate to administer.
  • HGF which is an active ingredient, has the effect of promoting the growth of chondrocytes and promoting the production of priteoglycan. Therefore, the therapeutic agent and the promoting agent of the present invention are useful for the treatment and prevention of the above-mentioned various diseases caused by cartilage disorders. Furthermore, since HGF acts only on damaged cartilage tissue, it is possible to obtain a drug with few side effects.
  • Rat HG F-cDNA (RBC1 clone) (Proc. Natl. Acad.
  • the sections were washed with 0.1 XSSC solution at 50 ° C for 1 hour, treated with RNAase A (20 g / m]) at 37 ° C for 30 minutes, and then treated with 2XSSC solution. Washing was performed twice at 37T for 10 minutes.
  • the sections were immersed in the emulsion (11 Kodak NBT-2 diluted solution) and exposed for 2 weeks. The sections were developed and fixed on Kodak D-19 and stained with hematoxylin and eosin.
  • Chondrocytes were isolated from 23-day-old fetuses and 4-week-old newborns of New Zealand white herons according to the method described in the literature (J. Cell. Physiol., 133, 491, 1987). Articular cartilage was isolated from femoral articular cartilage of the knee, and costal cartilage was isolated from hyaline cartilage of the rib (Dev. Biol., 136, 500, 1989). Meningeal fibroblasts were isolated from the meningeal tissue of the knee joint. The minced synovial tissue fragments were cultured in DMEM containing 10% FBS for 10 days, and cells grown by trypsin treatment were collected. According to the method described in the literature (Exp.
  • fetal mesenchymal cells were isolated from leg muscle tissues of fetal rats on day 20.
  • Leg bud mesenchymal cells were isolated from rat embryos at 10.5 days. Leg buds are surgical
  • the cells were cut out under a microscope for use, treated with 0.25% tribcine for 30 minutes, and then pitted to obtain isolated cells with nylon gauze. All cells except Asymmetric cells, 1 0% FBS, 6 0 ⁇ DM EM ( hereinafter, referred to as medium A) containing g / 1 of kanamycin 3 7 ° at C, 5% C 0 2/ 9 5% air Maintained below.
  • DNA synthesis rate is 10 ° /.
  • [3 H] to T CA insoluble cell sedimentation - thymidine.. [6 - 3 H ] - thymidine, Amersham, 2 0 C immo 1) of was evaluated by measuring the incorporation (J. Clin Invest, 85, 626, 1990).
  • Cells were seeded at a density of 1.5 11 per 96-mm plate in a 96-well plate ( ⁇ density) and cultured until confluent. To stop the growth, cells were incubated with 0.3% FBS. .. containing preincubation with 0.
  • Chondrocytes were seeded at a density of 1.5 x 1 ( ⁇ ) per 6 mm well and maintained in 0.1 ml medium A. When cells reached confluence, they contained 0.3% FBS. Preincubation was performed for 24 hours in 0.1 ml DMEM, followed by incubation for 24 hours in 0.1 ml DMEM containing 0.3% FBS and HGF. ae S] The monosulfate group was added 20 hours before the end of the incubation. The proteoglycan synthesis was based on [ 3 'S] of the precipitate on cetylpyridinium chloride after protease digestion. —Evaluated by measuring sulfate uptake (Exp. Cell Res., 130, 73, 1980).
  • RNA from cartilage was prepared by a modification of the method described in the literature (Anal. Biochem., 203, 352, 1992). Freshly isolated tissue fragments (0.1 g wet weight) were prepared using 4 M guanidine thiosinate, 0.1 MT ris hydrochloric acid (pH 7.5), 1% 2-mercaptoethanol in 4 MGITC solution 2 The homogenization was performed quickly at m 1. The homogenate was mixed with 10% SDS 1001 and centrifuged for 5 minutes in a microcentrifuge.
  • first-strand cDNA was synthesized from 0.5 ⁇ g of total RNA using Supersrcript revertase (Gibco-BRL) and an antisense primer in the downstream region. Subsequently, PCR expansion was performed. Proliferation is for 30 cycles at 94 ° C for 30 seconds, 58 for 1 minute, and 72 ° C for 5 minutes for 35 cycles (for chondrocytes) or 40 cycles (for cartilage tissue). I went in.
  • the primer base sequence for PCR amplification is 5 'for rat and mouse c-Met (Oncogene, 2, 593, 1988).
  • CA GT A / G
  • Fig. 1 shows the expression of HG FmRNA in the limb buds of mice in early development, and is a photomicrograph of a longitudinal section of the hind limb. The corresponding dark field (right) was taken after in situ hybridization, autoradiography and staining.
  • a to D are sections of a 10.5 day old fetus
  • E to H are sections of an 11 day old fetus.
  • Figure 2 shows the expression of HG FmRNA in the limb buds of the mouse during finger formation.
  • a and B are sections of a 12.5 day old fetus
  • CF are sections of a 13 day old fetus
  • GJ are sections of a 14 day old fetus.
  • Fe represents a femur
  • Fi represents a fibula
  • Ta represents a tarsal bone
  • I to V represent finger numbers.
  • Figure 3 is a micrograph showing the expression of HG FmRNA in the limb buds and rib cage of the developing mouse.
  • the bright field (left) and the corresponding dark field (right) are in situ hybridization and autoradio. It was taken after the graphic and dyeing.
  • a and B show cross-sections of hind limbs of 16-day-old fetuses; C and D show 13-day-old fetuses, and E and F show longitudinal cross-sections of thorax of 14-day-old fetuses.
  • Ta indicates a tarsal bone
  • Ti indicates a tibia
  • R ib indicates pre-cartilaginous accumulation of rib cartilage.
  • HGF mRNA expression was observed in the joint area of the wrist malleolus and elbow Z knee when the base leg, the joint leg, and the self-leg portion were formed on Day 2.5 (see FIGS. 2A and B. For convenience). , Knees and ankles). Late (days 13 to 14), HGF mRNA was expressed in adjacent and restricted mesenchymal cells of the cartilage accumulation in the wrist Z ankle and elbow / knee joint regions (Fig. 2C-J See).
  • HG FmRNA was localized to limited mesenchymal cells adjacent to tarsal cartilage (see FIGS. 3A and B). HG Limb expression levels of FmRNA decreased with differentiation. No HG FmRNA was detected in the growth plates of the limbs throughout the study.
  • Example 2
  • HG FmRNA was expressed in the intercostal mesenchymal tissue around the tip of the intercostal elongated pre-cartilaginous accumulation. No signal of hybridization was detected in pre-cartilaginous accumulation.
  • chondrocytes from knee joint cartilage and costal cartilage, synovial cells from knee joint, and fibroblasts grown from limb muscle tissue Cultured cells were prepared, and the effect of exogenously added HGF on these cells was examined.
  • perforated articular chondrocytes were seeded at a density of 3 ⁇ 10 3 cells in 16-mm wells and maintained in medium A for 2 days. Thereafter, the cells were treated with HGF for 2 days. At the end of the incubation, phase contrast micrographs were taken. Fig. 4 shows the results.
  • articular chondrocytes collected from 4 weeks old egrets were cultured. After the configurator Ruen Bok cells became 24 hours serum withdrawal treatment, were treated with HG F at various concentrations, by the method described in Materials and Methods [a H] - uptake of thymidine was measured . In addition, a similar test was performed on the heron membrane fibroblasts. The results are shown in FIGS. 5A (articular chondrocytes) and B (synovial fibroblasts). The results show the average soil standard deviation of three tests (the same applies to Figs. 5C, 6 and Figs. 7A and B).
  • HG F is Usagi articular cartilage into cells [3 H] - increased thymidine incorporation in a dose-dependent manner, enhancement of DNA synthesis, a growth promoting effect on immediate Chi articular chondrocytes It was shown to have. DNA synthesis showed a 3-fold increase in HGF at 1 ng / ml over control. On the other hand, as shown in FIG. 5B, meningeal fibroblasts did not respond to HGF.
  • ⁇ ⁇ in 101 8 111] increased the cell number by about 1.8 times compared to the control.
  • IGF Insulin-like growth factor
  • PTH Parathyroid hormone
  • FIG. 6 shows the results. As shown in FIG. 6, HGF dose-dependently increased 6 S] -sulfate uptake. The maximum increase was obtained with 1 ng / ml of HGF. This effect is due to TG F— / 3 (J. Cell Physiol.,
  • HGF is generally considered to act on target cells by a paracrine mechanism, and the results of the in situ hybridization described above are considered to support this idea. Therefore, in order to confirm this point, it was examined whether the HGF polyclonal antibody changes the function of chondrocytes.
  • the confluent Egret articular chondrocytes were cultured with 25 ⁇ g / ml anti-HGF polyclonal antibody (IgG fraction purified by affinity) in the presence or absence of 3 ng Zml of HGF. ) Treated or non-treated. Thereafter, the materials and methods described in the Methods Nyori, [a H] - thymidine or [36 S] - labeled with sulfate group was measured DN A synthesis or proteoglycans generation. The results are shown in FIGS. 7A (DNA synthesis) and B (proteoglycan generation). In the figure, Ab indicates an anti-HGF polyclonal antibody.
  • HGF receptor 1 HGF receptor 1
  • the above substance was dissolved in 0.01 M PBS having a pH of 7.0, the total amount was adjusted to 20 ml, and after sterilization, 2 ml was dispensed into vials and sealed by freeze-drying.
  • the above substance was dissolved in physiological saline for injection, the total volume was adjusted to 2 Oml, and after sterilization, 2 ml was dispensed into vials and sealed by freeze-drying.

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Abstract

Remède ou maladie des cartilages, accélérateur de croissance des cellules de cartilage et accélérateur de formation de protéoglycane, renfermant chacun un facteur de croissance des hépatocytes (HCF) comme principe actif, et méthode de traitement des maladies des cartilages humains et mammaliens par administration d'une dose efficace de HGF. En tant que principe actif, le HGF accélère la croissance des cellules de cartilage et la formation de protéoglycane. Ce remède et ces accélérateurs sont ainsi utiles pour la prévention et le traitement de diverses maladies des cartilages.
PCT/JP1995/000121 1994-08-19 1995-01-30 Traitement des maladies des cartilages WO1996005855A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002197869A CA2197869C (fr) 1994-08-19 1995-01-30 Agent therapeutique pour maladies du cartilage

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JP6/218164 1994-08-19
JP21816494A JP3737532B2 (ja) 1994-08-19 1994-08-19 軟骨障害治療剤

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US08793121 A-371-Of-International 1997-04-21
US09/921,874 Continuation US6756358B2 (en) 1994-08-19 2001-08-06 Therapeutic agent for cartilaginous diseases

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072134A1 (fr) * 2001-02-28 2002-09-19 Mitsubishi Pharma Corporation Remedes pour l'arthrite deformante et pour l'arthrite rhumatoide
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05132426A (ja) * 1991-02-15 1993-05-28 Takeda Chem Ind Ltd 骨組織の形成促進剤
JPH0625010A (ja) * 1991-05-15 1994-02-01 Toshiichi Nakamura 抗ガン剤
JPH06172207A (ja) * 1992-10-08 1994-06-21 Toshiichi Nakamura 肺傷害治療剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05132426A (ja) * 1991-02-15 1993-05-28 Takeda Chem Ind Ltd 骨組織の形成促進剤
JPH0625010A (ja) * 1991-05-15 1994-02-01 Toshiichi Nakamura 抗ガン剤
JPH06172207A (ja) * 1992-10-08 1994-06-21 Toshiichi Nakamura 肺傷害治療剤

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601365B2 (en) 2000-08-28 2009-10-13 Damavand Wound, AB Synergetic effects of HGF and antibacterial treatment
WO2002072134A1 (fr) * 2001-02-28 2002-09-19 Mitsubishi Pharma Corporation Remedes pour l'arthrite deformante et pour l'arthrite rhumatoide

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JP3737532B2 (ja) 2006-01-18

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