WO1996004921A1 - TNFα-SECRETION INHIBITOR CONTAINING SYRINGIN OR ITS AGLYCONE - Google Patents

TNFα-SECRETION INHIBITOR CONTAINING SYRINGIN OR ITS AGLYCONE Download PDF

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Publication number
WO1996004921A1
WO1996004921A1 PCT/KR1994/000110 KR9400110W WO9604921A1 WO 1996004921 A1 WO1996004921 A1 WO 1996004921A1 KR 9400110 W KR9400110 W KR 9400110W WO 9604921 A1 WO9604921 A1 WO 9604921A1
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Prior art keywords
syringin
tnfα
aglycone
secretion
secretion inhibitor
Prior art date
Application number
PCT/KR1994/000110
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French (fr)
Inventor
Hong Keun Chung
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Hong Keun Chung
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 Hong Keun Chung filed Critical Hong Keun Chung
Priority to PCT/KR1994/000110 priority Critical patent/WO1996004921A1/en
Priority to AU74680/94A priority patent/AU7468094A/en
Publication of WO1996004921A1 publication Critical patent/WO1996004921A1/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages

Definitions

  • the present " invention relates to a tumor necrosis factor (TNF) ⁇ -secretion inhibitor and, more particularly, to a TNF ⁇ - secretion inhibitor containing syringin or syringin aglycon as an active ingredient.
  • TNF tumor necrosis factor
  • immune-suppresive agents such as cyclosporin A and dexamethason are known to inhibit TNF ⁇ secretion, these agents are being used very limitedly for the treatment of the above diseases because they induce overall immune suppression and involve various side effects.
  • syringin blocks the inhibitory action of diabetic beta-lipoprotein [Lek. Sredtava Dal nego Vostoka 11, 56-59, 1972].
  • syringin is administered to rat in a dose of 0.5mg/kg, a good anti-stress effect is observed [Lloydia, 32, 46-50(1969)].
  • syringin is effective for the treatment of psychogenic behavior disorder.
  • syringin has a hypnosis- inducing action.
  • Syringin is extracted by lower alcohols and then, the extract is separated and purified by column chromatography and high performance liquid chromatography.
  • Syringin is a colorless needle-shaped crystal and soluble in distilled water and methanol. Its aqueous solution has an ultraviolet absorption at 220 and 265nm, and melting point 192°C.
  • syringin or its aglycone inhibits effectively the secretion of TNF ⁇ from macrophage.
  • edema of the test animals induced by hypersensi ivity was dose- dependently reduced by syringin or its aglycone. Also, it showed the activity toward auto-immune diseases by suppressing inflammation of uveitis.
  • Figure 1 shows severe infiltration of inflammatory cells into retina of the eye of a control rat [Experiment 3].
  • Figure 2 shows little infiltration of inflammatory cells into retina of the eye of a rat treated with syringin [Experiment 3] .
  • the bark of Eucommia ulmoides was boiled in water for two hours, filtered through gauze and extracted with butanol.
  • the butanol fraction was evaporated under the reduced pressure and dissolved in a small amount of water and then, the aqueous solution was applied to a HPLC C18 column (2.2 x 50cm) and eluted with 30% methanol at a flow rate of 14 ml/min.
  • Fractions containing syringin were collected and evaporated under the reduced pressure which in turn was dissolved in a small amount of water.
  • the aqueous solution was subjected to HPLC again.
  • syringin was purified by recrystalization in hot water.
  • the structure of recrystallized substance was determined with NMR and Mass spectrophotography to be syringin.
  • the melting point of this material was 192°C.
  • RAW 264.7 murine raacrophage cell line was grown to confluence in RPMI 1640 medium containing 10% bovine calf serum(BCS) and 50 ⁇ g/ml gentamycin in 24-well plate. After the culture supernatant was removed by suction, each well received one of four kinds of medium : 0.2 ml of the medium containing 1 ⁇ g/ml lipopolysaccharide(LPS) , 1 ⁇ g/ml LPS + 5 ⁇ g/ml syringin, l ⁇ g/ml LPS +50 ⁇ g/ml syringin or none additive. The plate was incubated for 4 hours in a CO-, incubator at 37°C. Thereafter the culture supernatant was harvested by centrifugation.
  • LPS lipopolysaccharide
  • L-929 mouse fibroblast cell line was cultured in DMEM supplemented with 50 ⁇ g/ml gentamycin and 10% BCS. The cells were trypsinized and suspended in the 6/04921 PCI7KR94/00110
  • the cells at a density of 3xl ⁇ ⁇ -lml/well in 96-well plate were incubated at 37°C for 24 hours.
  • each well received 90 ⁇ l of the medium containing actinomycin D (1 ⁇ g/ml) and 10 ⁇ l of serially diluted RAW 264.7 culture supernatant.
  • RAW 264.7 murine macrophages were stimulated by LPS with or without syringin. As shown in Table I, the cells secreted 377 units of TNF ⁇ without stimulation, but LPS alone stimulated the cells to secrete 1600 units. The combination of LPS and 5 ⁇ g/ml syringin reduced the secretion to 801 units and the combinataion of LPS and 50 ⁇ g/ml syringin, to 406 units.
  • mice Male mice(Balb/c) were used for the test of contact hypersensitivity. The abdomens were shaved using a ' small animal clipper. Two hundred microliters of 1% FITC [ 1 g of fluorescein 5-isothiocyanate/100ml of acetone-dibutyl phthalate(l:1) ] was epicutaneously applied onto the shaved abdomens.
  • mice After 5 days, the four groups of animals each (40 mice) received orally twice daily one of the following treatments ; 70 ⁇ g of syringin/kg, 700 ⁇ g of syringin/kg, 7000 ⁇ g of syringin/kg or water for three days.
  • the baseline ear thickness of the animal's right ear was measured using a dial thickness gauge. Immediately after ear measurement, each side of the right ear was treated with 10 ⁇ l of 1% FITC (20 ⁇ l total) .
  • ear thickness was measured in the sensitized animals.
  • the relative swelling of mouse ear was expressed by (ear thickness after the induction of hypersensitivity - baseline ear thickness / baseline ear thickness) x 100.
  • the figure represents a relative swelling(%) of mouse ear expressed by(ear thickness after the induction of hypersensitivity-baseline ear thickness / baseline ear thickness) x 100
  • the control group showed the relative swelling of 40.5% at 24 hours after the sensitization but the administration of syringin reduced dose-dependently the swelling to 31.6% (70 ⁇ g/kg) , to 23.1% (700 ⁇ g/kg) , and to 3.2% (7000 ⁇ g/kg) .
  • the data from the control group, 700 ⁇ g/ml syringin-treated group and 7000 ⁇ g/ml syringin-treated group were treated with Tukey's studentized range test. The differences between the control group and syringin-treated groups were statistically significant.
  • syringin inhibited effectively the contact hypersensitivity.
  • Contact hypersensitivity is a simple in vivo assay of cell-mediated immune function.
  • the murine model presented in this experiment is an excellent model for human allergic contact dermatitis.
  • Bovine S-antigen was prepared using bovine retinas according to the method of Dorey et al. [ Dorey C. , Cozette J. and Faure J.P., Ophthalmic Res. 14:249, 1982 ].
  • the antigen (lmg/ml) was emulsified(1:1) in complete Freund's adjuvant.
  • a total volume of O.lml/rat was injected into foot pads of Lewis rats.
  • syringin(4mg/kg, BID) was orally administered to one group (6 rats) " and water, to a control group (6 rats) . The administration was continued until the animal experiment was completed.
  • Fig.l histochemical staining showed severe infiltration of inflammatory cells into iris, ciliary body, retina and vitreous of an eye of a control rat, but little infiltration of inflammatory cells into an eye of a syringin- treated rat (Fig.2). Similar phenomena were observed in the rest of rats, which indicated that syringin suppressed effectively the inflammation of rat eyes.
  • Preparation 1 One gram of syringin obtained as above Example 1 is homogeneously mixed with 1400 g of lactose and 450 g of starch and then, the mixture is also homogeneously mixed with 100 g of aqueous hydroxypropyl cellulose solution. In accordance with a conventional method, wet granules were prepared. The dried granules were packed in a sachet by 2 grams (syringin content: lmg) .
  • syringin is homogeneously mixed with 1400 g of lactose , 600 g of crystalline cellulose and 15 g of magnesium stearate. Granule formation is conducted with this mixture and 200 g of starch and 15 g of magnesium stearate are added. Tablet of 500mg (syringin content: 0.22 mg) is prepared.
  • Preparation 3 Syringin aglycone corresponding to one gram of syringin is dissolved in 1000 ml of sterilized saline for injection, and 1000ml of additional sterilized saline is added to the mixture. After ultrafiltration, the solution is filled in each 1 ml ampoul.
  • the pharmaceutical composition of the present invention having syringin as active ingredient may be administered orally or parenterally (e.g. injectable form) .
  • syringin may be prepared by mixing some excipients such as binders, diluents, etc.
  • the excipients for oral administration e.g. powders, tablets, emollients, granules, etc.
  • lactose include lactose, starch, dextrin, calcium phosphate, calcium carbonate, silicic aluminum, magnesium stearate, sodium bicarbonate, dried yeast, etc.
  • the excipients for liquid-type oral administration e.g.
  • elixirs, syrups, etc. include distilled water, glycerin, propylene glycol, ethanol, fat oil, ethylene glycol, polyethylene glycol, sorbitol, etc.
  • the excipient for injectable form include saline.

Abstract

The present invention relates to a TNFα-secretion inhibitor, more particularly to a TNFα-secretion inhibitor containing syringin or syringin aglycone as active ingredient. Syringin or syringin aglycone purified from Fraxinus spp. or Eucommia ulmoides shows TNFα-secretion inhibiting effect without considerable toxicity. It also shows anti-hypersensitivity effect and anti-inflammatory effect toward autoimmune disease such as uveitis.

Description

TITLE OF THE INVENTION
TNFα-SECRETION INHIBITOR CONTAINING SYRINGIN OR ITS AGLYCONE
TECHNICAL FIELD
The present "invention relates to a tumor necrosis factor (TNF) α-secretion inhibitor and, more particularly, to a TNFα- secretion inhibitor containing syringin or syringin aglycon as an active ingredient.
BACKGROUND ART
Recently, over-production of TNFα has been observed in allergy or various auto-immune diseases, and attempts to develop the materials specifically inhibiting the secretion of TNFα as therapeutic agents for the above diseases have been intensively made.
Although immune-suppresive agents such as cyclosporin A and dexamethason are known to inhibit TNFα secretion, these agents are being used very limitedly for the treatment of the above diseases because they induce overall immune suppression and involve various side effects.
Therefore, the present inventor gave attention to syringin and its aglycone having various pharmacological effects with little toxicity among natural products isolated from plants. Various pharmaceutical actions of syringin have been reported. Syringin blocks the inhibitory action of diabetic beta-lipoprotein [Lek. Sredtava Dal nego Vostoka 11, 56-59, 1972]. When syringin is administered to rat in a dose of 0.5mg/kg, a good anti-stress effect is observed [Lloydia, 32, 46-50(1969)]. According to Japanese Patent Laid-Open No. Sho 59-33221, syringin is effective for the treatment of psychogenic behavior disorder. According to another Japanese Patent Laid-Open No. Hei 3-145426, syringin has a hypnosis- inducing action.
DISCLOSURE OF INVENTION
After conducting a long-term intensive research, the present inventor found that syringin and its aglycone have TNFα-secretion inhibiting effect, anti-hypersensitivity effect as well as anti-inflammatory effect on auto-immune disease like uveitis. Thus this invention has come to be completed.
Syringin is extracted by lower alcohols and then, the extract is separated and purified by column chromatography and high performance liquid chromatography. Syringin is a colorless needle-shaped crystal and soluble in distilled water and methanol. Its aqueous solution has an ultraviolet absorption at 220 and 265nm, and melting point 192°C. In in vitro experiment, syringin or its aglycone inhibits effectively the secretion of TNFα from macrophage. And edema of the test animals induced by hypersensi ivity was dose- dependently reduced by syringin or its aglycone. Also, it showed the activity toward auto-immune diseases by suppressing inflammation of uveitis.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 shows severe infiltration of inflammatory cells into retina of the eye of a control rat [Experiment 3].
Figure 2 shows little infiltration of inflammatory cells into retina of the eye of a rat treated with syringin [Experiment 3] . BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in more detail based upon the following Examples, Experiments and Preparations.
Example 1
The bark of Eucommia ulmoides was boiled in water for two hours, filtered through gauze and extracted with butanol. The butanol fraction was evaporated under the reduced pressure and dissolved in a small amount of water and then, the aqueous solution was applied to a HPLC C18 column (2.2 x 50cm) and eluted with 30% methanol at a flow rate of 14 ml/min. Fractions containing syringin were collected and evaporated under the reduced pressure which in turn was dissolved in a small amount of water. The aqueous solution was subjected to HPLC again. Finally, syringin was purified by recrystalization in hot water. The structure of recrystallized substance was determined with NMR and Mass spectrophotography to be syringin. The melting point of this material was 192°C.
Experiment 1
RAW 264.7 murine raacrophage cell line was grown to confluence in RPMI 1640 medium containing 10% bovine calf serum(BCS) and 50μg/ml gentamycin in 24-well plate. After the culture supernatant was removed by suction, each well received one of four kinds of medium : 0.2 ml of the medium containing 1 μg/ml lipopolysaccharide(LPS) , 1 μg/ml LPS + 5 μg/ml syringin, lμg/ml LPS +50 μg/ml syringin or none additive. The plate was incubated for 4 hours in a CO-, incubator at 37°C. Thereafter the culture supernatant was harvested by centrifugation.
For the bioassay of TNFα, L-929 mouse fibroblast cell line was cultured in DMEM supplemented with 50 μg/ml gentamycin and 10% BCS. The cells were trypsinized and suspended in the 6/04921 PCI7KR94/00110
medium.
The cells at a density of 3xlθ θ-lml/well in 96-well plate were incubated at 37°C for 24 hours.
After the culture supernatant was removed, each well received 90 μl of the medium containing actinomycin D (1 μg/ml) and 10 μl of serially diluted RAW 264.7 culture supernatant.
After 16 hours, viable cells were stained by the addition of 10 μl of a chromogen, 3-(4,5-dimethylthiazol-2-yl) -2,5- diphenyltetrazolium bromide ( 5 mg/ml of PBS) . After 3 hours, the culture supernatant was removed from each well and 100 μl of dimethylsulfoxide (DMSO) was added.
The absorbances at 570/690 nm were measured by using an automated enzyme-linked immunosorbent assay (ELISA) plate reader. The results are shown in the following Table I.
Table I : Inhibitory effect of syringin on secretion of TNFα from macrophage
Treatment TNFα unit
None 377 ± 23
LPS 1600 ± 82
LPS + Syringin (5μg/ml) 801 ± 63 LPS + Syringin (50μg/ml) 406 ± 63
RAW 264.7 murine macrophages were stimulated by LPS with or without syringin. As shown in Table I, the cells secreted 377 units of TNFα without stimulation, but LPS alone stimulated the cells to secrete 1600 units. The combination of LPS and 5 μg/ml syringin reduced the secretion to 801 units and the combinataion of LPS and 50 μg/ml syringin, to 406 units.
Thus syringin inhibited effectively the secretion of TNFα from macrophages. Experiment 2
Male mice(Balb/c) were used for the test of contact hypersensitivity. The abdomens were shaved using a' small animal clipper. Two hundred microliters of 1% FITC [ 1 g of fluorescein 5-isothiocyanate/100ml of acetone-dibutyl phthalate(l:1) ] was epicutaneously applied onto the shaved abdomens.
After 5 days, the four groups of animals each (40 mice) received orally twice daily one of the following treatments ; 70 μg of syringin/kg, 700 μg of syringin/kg, 7000 μg of syringin/kg or water for three days.
After 24 hours from the administration, the baseline ear thickness of the animal's right ear was measured using a dial thickness gauge. Immediately after ear measurement, each side of the right ear was treated with 10 μl of 1% FITC (20 μl total) .
After 24 hours and 48 hours, ear thickness was measured in the sensitized animals. The relative swelling of mouse ear was expressed by (ear thickness after the induction of hypersensitivity - baseline ear thickness / baseline ear thickness) x 100.
The results are shown in the following Table II.
Table II : Inhibitory effect of syringin on contact hypersensitivity
Treatment 24 Hours 48 Hours
Water *40.5 ± 19.1 (%) 24.4 ± 9.9 (%) Syringin(7Oμg/kg) 31.6 ± 23.9 19.2 ± 12.4 Syringin(700μg/kg) 23.1 ± 14.9 10.3 ± 10.0 Syringin(7000μg/kg) 3.2 ± 4.9 0.7 ± 3.4
* : The figure represents a relative swelling(%) of mouse ear expressed by(ear thickness after the induction of hypersensitivity-baseline ear thickness / baseline ear thickness) x 100
As shown in Table II, the control group showed the relative swelling of 40.5% at 24 hours after the sensitization but the administration of syringin reduced dose-dependently the swelling to 31.6% (70 μg/kg) , to 23.1% (700 μg/kg) , and to 3.2% (7000 μg/kg) . The data from the control group, 700 μg/ml syringin-treated group and 7000 μg/ml syringin-treated group were treated with Tukey's studentized range test. The differences between the control group and syringin-treated groups were statistically significant. Thus syringin inhibited effectively the contact hypersensitivity. Contact hypersensitivity is a simple in vivo assay of cell-mediated immune function. The murine model presented in this experiment is an excellent model for human allergic contact dermatitis.
Experiment 3
Bovine S-antigen was prepared using bovine retinas according to the method of Dorey et al. [ Dorey C. , Cozette J. and Faure J.P., Ophthalmic Res. 14:249, 1982 ]. The antigen (lmg/ml) was emulsified(1:1) in complete Freund's adjuvant. A total volume of O.lml/rat was injected into foot pads of Lewis rats. After 5 days from the immunization, syringin(4mg/kg, BID) was orally administered to one group (6 rats) "and water, to a control group (6 rats) . The administration was continued until the animal experiment was completed.
After two weeks from the S-antigen immunization; eyes of rats were examined with a slit lamp microscope. Boosting with the same antigen was conducted on the rats at 18 days after the immunization. Eyes were examined again after two weeks from the boosting and then the animals were sacrificed.
The eyes removed were histochemically stained and examined. The results are shown in the following Table III.
Table III : Anti-inflammatory effect of syringin on uveitis of Lewis rats induced by bovine eye S-antigen
Beginning of Observation at Observation at
Lewis rats oral treat- 2 weeks after 2 weeks after ments(BID) the immuniza- the boosting at 5 days tion after the immunization
1 d.p.v.
3 d.p.v. 5 d.p.v. with posterior synechia control 1ml of water 4 d.p.v. 5 d.p.v. group(6)
2 d.p.v. 2 d.p.v.
1 d.p.v. with 4 d.p.v. with fibrinous fibrinous membrane membrane
1 d.p.v. 2 d.p.v.
drug- 1ml of syrin- 1 d.p.v. 2 d.p.v. treated gin group(6) (4mg/kg)
1 d.p.v.
d.p.v. : dilated pupillary vessel
As shown in Table III, after two weeks from the immunization, eyes of rats were examined with a slit lamp microscope. The control rats each showed 1-5 dilated pupillary vessels except in one rat, but the syringin-treated group showed only one dilated pupillary vessel in one rat. After two weeks from the boosting, the number of dilated pupillary vessel increased by 1-2 in each of control rats.
In addition, in one rat and in another rat, severe posterior synechia and fibrinous membrane were observed respectively but syringin-treated group showed only one more dilated pupillary vessels.
As shown in Fig.l, histochemical staining showed severe infiltration of inflammatory cells into iris, ciliary body, retina and vitreous of an eye of a control rat, but little infiltration of inflammatory cells into an eye of a syringin- treated rat (Fig.2). Similar phenomena were observed in the rest of rats, which indicated that syringin suppressed effectively the inflammation of rat eyes.
Preparation 1 One gram of syringin obtained as above Example 1 is homogeneously mixed with 1400 g of lactose and 450 g of starch and then, the mixture is also homogeneously mixed with 100 g of aqueous hydroxypropyl cellulose solution. In accordance with a conventional method, wet granules were prepared. The dried granules were packed in a sachet by 2 grams (syringin content: lmg) .
Preparation 2
One gram of syringin is homogeneously mixed with 1400 g of lactose , 600 g of crystalline cellulose and 15 g of magnesium stearate. Granule formation is conducted with this mixture and 200 g of starch and 15 g of magnesium stearate are added. Tablet of 500mg (syringin content: 0.22 mg) is prepared.
Preparation 3 Syringin aglycone corresponding to one gram of syringin is dissolved in 1000 ml of sterilized saline for injection, and 1000ml of additional sterilized saline is added to the mixture. After ultrafiltration, the solution is filled in each 1 ml ampoul.
INDUSTRIAL APPLICABILITY
The pharmaceutical composition of the present invention having syringin as active ingredient may be administered orally or parenterally (e.g. injectable form) . Based upon its objective, syringin may be prepared by mixing some excipients such as binders, diluents, etc. The excipients for oral administration (e.g. powders, tablets, emollients, granules, etc.) include lactose, starch, dextrin, calcium phosphate, calcium carbonate, silicic aluminum, magnesium stearate, sodium bicarbonate, dried yeast, etc. Further, the excipients for liquid-type oral administration (e.g. elixirs, syrups, etc.) include distilled water, glycerin, propylene glycol, ethanol, fat oil, ethylene glycol, polyethylene glycol, sorbitol, etc. The excipient for injectable form include saline.

Claims

WHAT IS CLAIMED IS :
1. TNFα-secretion inhibitor containing syringin or syringin aglycone as an active ingredient.
2. Anti-hypersensitivity agent containing syringin or syringin aglycone as an active ingredient.
3. Anti-inflammatory agent containing syringin or syringin aglycone as an active ingredient.
PCT/KR1994/000110 1994-08-13 1994-08-13 TNFα-SECRETION INHIBITOR CONTAINING SYRINGIN OR ITS AGLYCONE WO1996004921A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/KR1994/000110 WO1996004921A1 (en) 1994-08-13 1994-08-13 TNFα-SECRETION INHIBITOR CONTAINING SYRINGIN OR ITS AGLYCONE
AU74680/94A AU7468094A (en) 1994-08-13 1994-08-13 Tnfalpha-secretion inhibitor containing syringin or its aglycone

Applications Claiming Priority (1)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028808A1 (en) * 1996-02-12 1997-08-14 The Scripps Research Institute Methods of inhibiting leaderless protein export using cardiac glycosides or aglycones therefrom and derivatives
WO1998037880A1 (en) * 1997-02-26 1998-09-03 Ciblex Corporation Inhibitors of leaderless protein export
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
WO2007102440A1 (en) * 2006-03-03 2007-09-13 Kobayashi Pharmaceutical Co., Ltd. Agent for improvement in adipocytokine production

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JPS5933221A (en) * 1982-08-19 1984-02-23 Wakunaga Seiyaku Kk Remedy for psychogenic asynodia
EP0163270A2 (en) * 1984-05-23 1985-12-04 Green Cross Corporation A lipoxygenase inhibitor
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JPH03145426A (en) * 1989-10-30 1991-06-20 Morinaga Milk Ind Co Ltd Sleeping promoter
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EP0163270A2 (en) * 1984-05-23 1985-12-04 Green Cross Corporation A lipoxygenase inhibitor
JPS6299324A (en) * 1985-10-25 1987-05-08 Wakunaga Pharmaceut Co Ltd Improver for cerebral circulation metabolism
JPH03145426A (en) * 1989-10-30 1991-06-20 Morinaga Milk Ind Co Ltd Sleeping promoter
US5306732A (en) * 1989-11-24 1994-04-26 Xenova Limited Tumor necrosis factor antagonist

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Title
P.H. LIST, L. HOERHAMMER, "Hagers Handbuch Der Pharmazeutischen Praxis", Fourth Edition, Volume VI B, BERLIN, HEIDELBERG, NEW YORK: SPRINGER VERLAG, 1979, pages 713-714. *
PATENT ABSTRACTS OF JAPAN, Vol. 11, No. 315 (C-451), 1987; & JP,A,62 099 324 (WAKUNAGA PHARMACEUT. CO. LTD.). *
PATENT ABSTRACTS OF JAPAN, Vol. 15, No. 361 (C-867), 1991; & JP,A,03 145 426 (MORINAGA MILK IND. CO. LTD.). *
PATENT ABSTRACTS OF JAPAN, Vol. 8, No. 122 (C-227), 1984; & JP,A,59 033 221 (WAKUNAGA SEIYAKU K.K.). *
Volume III, BERLIN, HEIDELBERG, NEW YORK: SPRINGER VERLAG, 1972, pages 785-786. *
Volume IV, BERLIN, HEIDELBERG, NEW YORK: SPRINGER VERLAG, 1973, page 861. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997028808A1 (en) * 1996-02-12 1997-08-14 The Scripps Research Institute Methods of inhibiting leaderless protein export using cardiac glycosides or aglycones therefrom and derivatives
US5891855A (en) * 1996-02-12 1999-04-06 The Scripps Research Institute Inhibitors of leaderless protein export
EP0941733A2 (en) * 1996-02-12 1999-09-15 The Scripps Research Institute Methods of inhibiting leaderless protein export using cardiac glycosides and derivatives
EP0941733A3 (en) * 1996-02-12 1999-12-01 The Scripps Research Institute Methods of inhibiting leaderless protein export using cardiac glycosides and derivatives
WO1998037880A1 (en) * 1997-02-26 1998-09-03 Ciblex Corporation Inhibitors of leaderless protein export
US6083706A (en) * 1997-02-26 2000-07-04 Ciblex Corporation Inhibitors of leaderless protein export
US6306613B1 (en) 1997-02-26 2001-10-23 Ciblex Corporation Modulators of leaderless protein export and methods for identifying and using the same
WO2007102440A1 (en) * 2006-03-03 2007-09-13 Kobayashi Pharmaceutical Co., Ltd. Agent for improvement in adipocytokine production
JP2007262061A (en) * 2006-03-03 2007-10-11 Kobayashi Pharmaceut Co Ltd Adipocytokine production improver

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