CA2106172C - Use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid for the treatment of restenosis associated with coronary intervention - Google Patents
Use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid for the treatment of restenosis associated with coronary intervention Download PDFInfo
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- CA2106172C CA2106172C CA002106172A CA2106172A CA2106172C CA 2106172 C CA2106172 C CA 2106172C CA 002106172 A CA002106172 A CA 002106172A CA 2106172 A CA2106172 A CA 2106172A CA 2106172 C CA2106172 C CA 2106172C
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- treatment
- restenosis
- coronary intervention
- ptca
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
This invention provides a pharmaceutical composition for the treatment or prevention of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethyoxycinnamoyl)aminobenzoic acid or a pharmaceutically acceptable salt thereof and the use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment or prevention of restenosis associated with coronary intervention. A 600 mg dosage of 2-(3,4-dimethoxy-cinnamoyl)aminobenzoic acid for a treatment period of three consecutive months after coronary intervention lowers the incidence of restenosis, and reduces the degree of stenosis in patients.
Description
Use of 2-f3,4-Dimethoxycinnamoyl)aminobenzoic Acid For the Treatment of Restenosis Associated With Coron_ ary Intervention The present invention relates to 2-(3,4-dimethoxy cinnamoyl)aminobenzoic acid (Tranilast) which is useful as therapeutic agent for the treatment or prevention of restenosis associated with coronary intervention.
Mare particularly, the present invention relates to a pharmaceutical composition for the treatment or prevention of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid (Tranilast) or a pharmaceutically acceptable salt thereof, represented by the formula:
CH3O ~ ~ CONH
(->
The present invention also relates to the use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid (Tranilast), or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment or prevention of restenosis associated with coronary intervention.
Tllustrative of pharmaceutically acceptable salts are inorganic salts such as sodium or calcium salt, or organic salts formed with amines such as morpholine, piperidine, arginine, and the like.
As coronary intervention in the present invention, for example, Percutaneous Transluminal Coronary Angioplasty (PTCA), Direction Coronary Atherectomy and Scent can be included.
Coronary intervention is a surgical approach to the treatment of ischemic heart diseases such as angina pectoris and myocardial infarction. Coronary intervention technically involves mechanical revascularization of a stenosed lesion in a coronary _1_ artery by means of a balloon catheter, an atherectomy catheter and the like. As a consequence, coronary intervention often causes restenosis due to damaged intima cells.
Up to the present time, there has not been any effective drug for the treatment or prevention of restenosis associated with coronary intervention.
Tranilast is sold cammercially as a drug for the treatment of allergic diseases, e.g., allergic to bronchitis, allergic asthma, atopic dermatitis, and the like, based on the activity exhibited by the drug for inhibiting release of chemical mediators [The Journal of Allergy and Clinical Immunology, Vol. 57, No. 5, pp. 396-407, (1976)].
Recently, in Biochemical Pharmacology, Vol. 36, No. 4, pp. 469-474 (1987), it was reported that Tranilast inhibits fibroblast proliferation and collagen accumulation.
There is also a report in Japanese College of Cardiology (1988) describing the treatment of patients subjected to PTCA surgery with Tranilast in a daily oral dose of 300 mg for 30 consecutive days after PTCA
surgery. The clinical data did not indicate any significant efficacy for preventing a restenosis effect associated with PTCA surgery.
Summary of the Invention One feature of the present invention is a pharmaceutical composition for the prevention or treatment of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.
Another feature of the present invention is the use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid, or-a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the prevention or treatment of restenosis associated with coronary intervention.
It is documented that restenosis associated with coronary intervention occurs within a period of about six months after coronary intervention. The clinical test data described above in the Japanese College of Cardiology (1988) document were obtained over a test period of 30 consecutive days after the PTCA surgery.
It was speculated by the present inventors that the lack of any significant efficacy for preventing a restenosis effect with Tranilast might be due to the relatively short 30 day duration of the drug treatment after PTCA
surgery.
Further clinical testing of patients was conducted to determine if an extended period of Tranilast treatment might be effective for lowering the incidence of post-surgery restenosis associated with PTCA. It was found that Tranilast dosage of patients for a duration of at least about three months (i.e., a term of at least about 90 consecutive days of treatment) reduced the incidence of restenosis associated with the PTCA surgery.
In one clinical study, when patients were administered Tranilast in a daily oral dose of 600 mg for three consecutive months after PTCA surgery, the incidence of restenosis was less than about 200.
The incidence of restenosis associated with PTCA
surgery usually is about 40%, as reported in Percutaneous Transluminal Coronary Angioplasty, page 179 (1990).
Thus, the present invention demonstrates that Tranilast dosage of patients after PTCA surgery is effective for reducing the incidence of restenosis during the treatment period. In patients in which the incidence of restenosis occurs when under Tranilast treatment, the mean degree of ~~~~1~~
stenosis is minimized. The need for a second PTCA
intervention is significantly reduced.
When Tranilast or a pharmaceutically acceptable salt thereof is employed therapeutically, it can be administered orally or parenterally in appropriate dosage forms, such as powder, granules, tablets, capsules, injectable solutions, and the like.
A Tranilast pharmaceutical composition can be formulated by admixing suitable carriers such as excipients, disintegrators, binders, brighteners, and the like, and preparing in accordance with conventional molding methods and dosage forms.
For example, a powder dosage form can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, binders, brighteners, and the like.
Tablets can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, disintegrators, binders, brighteners, and the like, and compressing the mixture with conventional molding equipment. The tablets also can be coated to provide film-coated tablets, sugar-coated tablets, enteric coated tablets, and the like.
Capsules can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, brighteners, and the like, and filling the mixture in capsules, or by forming granules containing Tranilast or a pharmaceutically acceptable salt thereof with conventional molding equipment, and filling the formed granules in capsules.
When a pharmaceutical compasition of the present invention is employed therapeutically, the dosage of Tranilast or a pharmaceutically acceptable salt thereof as an active ingredient can be in a range between about 300-1,000 mg. A preferred dosage is between about 300-600 mg per adult patient by oral administration on a daily basis for a treatment period of about 3-6 consecutive months after coronary intervention. The dosage and a term of administration are changed depending upon the weight and age and sex of the patient, the severity of the condition to be treated, and the like.
The present invention is further illustrated in more detail by way of the following Examples.
EXAMPLE I
This Example demonstrates the efficacy of the invention method for treatment of restenosis associated with PTCA surgery.
One hundred and forty nine patients with a partial occlusion, underwent successful PTCA procedures with smooth dilation, and enrolled in this study. These patients were divided into two groups, and both groups did not differ significantly with sex, distribution of coronary artery and ratio of lesions restenosed after PTCA; One group (49 patients) received Tranilast in a daily dose of 600 mg (hereinafter identified as the R
group), and the other group (100 patients) did not receive Tranilast (hereinafter identified as the C
group). In addition, all patients were also given calcium antagonists, nitrites and anti-platelets. These drugs were administered for 3 consecutive months after PTCA and follow-up coronary angiography was performed in 3 months after PTCA.
The measurements were made in two projections using a direct caliper system, and all measurements (before and immediately after PTCA and at final follow-up) were made in the same projection for more accurate comparison.
_5_ Diameter stenosis was calculated as the mean of measurements, and restenosis was defined as a loss of at least 50a of the initial gain in luminal diameter accomplished by dilation.
A. The ratio of female-to-male, distribution of coronary vessel, and the ratio of lesions restenosed after PTCA were as follows.
(1) The ratio of female-to-male R group . 180 ; C group . 290 (2) Distribution of coronarv vessel (R group and C group) left anterior descending artery:
left circumflex artery . right coronary artery =
1 . 1 . 1 (3) The ratio of lesions restenosed after PTCA
R group . 49.0% ; C group . 35.6%
B. The results of examination were as follows.
(1) The chance of stenosis diameter Pre-PTCA
R group . 68.40 ~ 12.3% ;
C group . 71.1% ~ 11.5%, ns Post-PTCA
R group . 14.8% ~ 11.6% ;
C group . 18.50 ~ ll.Oo, ns Three months after PTCA
R group . 25.8% ~ 18.2% ;
C group . 41.2a ~ 26.80, (p < 0.001) (2) The incidence of restenosis R group . 12.20 ; C group . 38.Oo (p < 0.01) The comparative clinical data demonstrates the efficacy of 3 month Tranilast treatment for the prevention of restenosis in patients after PTCA surgery.
The following comparative Example demonstrates that a one month Tranilast treatment is not effective for reducing restenosis in patients after PTCA surgery.
EXAMPLE II
This Example illustrates a one month treatment of patients with Tranilast which is not effective for reducing the incidence of restenosis associated with PTCA
surgery.
Three hundred and fifty two patients having lesions with a partial occlusion, underwent successful PTCA
procedures with smooth dilation, and enrolled in this study. These patients were divided into two groups, and both groups did not differ significantly with sex, age, number of diseased vessels, distribution of coronary artery and mean degree of stenosis (%) before PTCA; One group (100 patients) received Tranilast in a daily dose of 300 mg for 30 consecutive days (hereinafter identified as the R' group), and the other group (252 patients) did not receive Tranilast (hereinafter identified as the C' group). In addition, all patients were also given calcium antagonists, vasodilators and anti-platelets for 3 consecutive months after PTCA. Follow-up coronary angiography was performed in 3 months after PTCA.
The measurements were made in two projections using a direct caliper system, and all measurements (before and immediately after PTCA and at final follow-up) were made in the same projection for more accurate comparison.
Diameter stenosis was calculated as the mean of measurements, and restenosis was defined as a loss of at ' least 50% of the initial gain in luminal diameter ~. accomplished by dilation.
The results of examination were as follows.
(1) The change of stenosis diameter Pre-PTCA
R' group . 86.10 ; C' group . 78.70, ns Post-PTCA
R' group . 78.40 ; C' group . 22.50, ns Three months after PTCA
R' group . 78.4% ; C' group . 74.9%, ns (2) The incidence of restenosis R' group . 32.1% ; C' group . 36.10, ns The one month treatment with a 300 mg dosage did not have a significant effect in reducing the incidence of restenosis inpatients after PTCA surgery.
_g_
Mare particularly, the present invention relates to a pharmaceutical composition for the treatment or prevention of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid (Tranilast) or a pharmaceutically acceptable salt thereof, represented by the formula:
CH3O ~ ~ CONH
(->
The present invention also relates to the use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid (Tranilast), or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment or prevention of restenosis associated with coronary intervention.
Tllustrative of pharmaceutically acceptable salts are inorganic salts such as sodium or calcium salt, or organic salts formed with amines such as morpholine, piperidine, arginine, and the like.
As coronary intervention in the present invention, for example, Percutaneous Transluminal Coronary Angioplasty (PTCA), Direction Coronary Atherectomy and Scent can be included.
Coronary intervention is a surgical approach to the treatment of ischemic heart diseases such as angina pectoris and myocardial infarction. Coronary intervention technically involves mechanical revascularization of a stenosed lesion in a coronary _1_ artery by means of a balloon catheter, an atherectomy catheter and the like. As a consequence, coronary intervention often causes restenosis due to damaged intima cells.
Up to the present time, there has not been any effective drug for the treatment or prevention of restenosis associated with coronary intervention.
Tranilast is sold cammercially as a drug for the treatment of allergic diseases, e.g., allergic to bronchitis, allergic asthma, atopic dermatitis, and the like, based on the activity exhibited by the drug for inhibiting release of chemical mediators [The Journal of Allergy and Clinical Immunology, Vol. 57, No. 5, pp. 396-407, (1976)].
Recently, in Biochemical Pharmacology, Vol. 36, No. 4, pp. 469-474 (1987), it was reported that Tranilast inhibits fibroblast proliferation and collagen accumulation.
There is also a report in Japanese College of Cardiology (1988) describing the treatment of patients subjected to PTCA surgery with Tranilast in a daily oral dose of 300 mg for 30 consecutive days after PTCA
surgery. The clinical data did not indicate any significant efficacy for preventing a restenosis effect associated with PTCA surgery.
Summary of the Invention One feature of the present invention is a pharmaceutical composition for the prevention or treatment of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid or a pharmaceutically acceptable salt thereof, together with a suitable diluent or carrier.
Another feature of the present invention is the use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid, or-a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical for the prevention or treatment of restenosis associated with coronary intervention.
It is documented that restenosis associated with coronary intervention occurs within a period of about six months after coronary intervention. The clinical test data described above in the Japanese College of Cardiology (1988) document were obtained over a test period of 30 consecutive days after the PTCA surgery.
It was speculated by the present inventors that the lack of any significant efficacy for preventing a restenosis effect with Tranilast might be due to the relatively short 30 day duration of the drug treatment after PTCA
surgery.
Further clinical testing of patients was conducted to determine if an extended period of Tranilast treatment might be effective for lowering the incidence of post-surgery restenosis associated with PTCA. It was found that Tranilast dosage of patients for a duration of at least about three months (i.e., a term of at least about 90 consecutive days of treatment) reduced the incidence of restenosis associated with the PTCA surgery.
In one clinical study, when patients were administered Tranilast in a daily oral dose of 600 mg for three consecutive months after PTCA surgery, the incidence of restenosis was less than about 200.
The incidence of restenosis associated with PTCA
surgery usually is about 40%, as reported in Percutaneous Transluminal Coronary Angioplasty, page 179 (1990).
Thus, the present invention demonstrates that Tranilast dosage of patients after PTCA surgery is effective for reducing the incidence of restenosis during the treatment period. In patients in which the incidence of restenosis occurs when under Tranilast treatment, the mean degree of ~~~~1~~
stenosis is minimized. The need for a second PTCA
intervention is significantly reduced.
When Tranilast or a pharmaceutically acceptable salt thereof is employed therapeutically, it can be administered orally or parenterally in appropriate dosage forms, such as powder, granules, tablets, capsules, injectable solutions, and the like.
A Tranilast pharmaceutical composition can be formulated by admixing suitable carriers such as excipients, disintegrators, binders, brighteners, and the like, and preparing in accordance with conventional molding methods and dosage forms.
For example, a powder dosage form can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, binders, brighteners, and the like.
Tablets can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, disintegrators, binders, brighteners, and the like, and compressing the mixture with conventional molding equipment. The tablets also can be coated to provide film-coated tablets, sugar-coated tablets, enteric coated tablets, and the like.
Capsules can be formulated by admixing Tranilast or a pharmaceutically acceptable salt thereof with suitable excipients, brighteners, and the like, and filling the mixture in capsules, or by forming granules containing Tranilast or a pharmaceutically acceptable salt thereof with conventional molding equipment, and filling the formed granules in capsules.
When a pharmaceutical compasition of the present invention is employed therapeutically, the dosage of Tranilast or a pharmaceutically acceptable salt thereof as an active ingredient can be in a range between about 300-1,000 mg. A preferred dosage is between about 300-600 mg per adult patient by oral administration on a daily basis for a treatment period of about 3-6 consecutive months after coronary intervention. The dosage and a term of administration are changed depending upon the weight and age and sex of the patient, the severity of the condition to be treated, and the like.
The present invention is further illustrated in more detail by way of the following Examples.
EXAMPLE I
This Example demonstrates the efficacy of the invention method for treatment of restenosis associated with PTCA surgery.
One hundred and forty nine patients with a partial occlusion, underwent successful PTCA procedures with smooth dilation, and enrolled in this study. These patients were divided into two groups, and both groups did not differ significantly with sex, distribution of coronary artery and ratio of lesions restenosed after PTCA; One group (49 patients) received Tranilast in a daily dose of 600 mg (hereinafter identified as the R
group), and the other group (100 patients) did not receive Tranilast (hereinafter identified as the C
group). In addition, all patients were also given calcium antagonists, nitrites and anti-platelets. These drugs were administered for 3 consecutive months after PTCA and follow-up coronary angiography was performed in 3 months after PTCA.
The measurements were made in two projections using a direct caliper system, and all measurements (before and immediately after PTCA and at final follow-up) were made in the same projection for more accurate comparison.
_5_ Diameter stenosis was calculated as the mean of measurements, and restenosis was defined as a loss of at least 50a of the initial gain in luminal diameter accomplished by dilation.
A. The ratio of female-to-male, distribution of coronary vessel, and the ratio of lesions restenosed after PTCA were as follows.
(1) The ratio of female-to-male R group . 180 ; C group . 290 (2) Distribution of coronarv vessel (R group and C group) left anterior descending artery:
left circumflex artery . right coronary artery =
1 . 1 . 1 (3) The ratio of lesions restenosed after PTCA
R group . 49.0% ; C group . 35.6%
B. The results of examination were as follows.
(1) The chance of stenosis diameter Pre-PTCA
R group . 68.40 ~ 12.3% ;
C group . 71.1% ~ 11.5%, ns Post-PTCA
R group . 14.8% ~ 11.6% ;
C group . 18.50 ~ ll.Oo, ns Three months after PTCA
R group . 25.8% ~ 18.2% ;
C group . 41.2a ~ 26.80, (p < 0.001) (2) The incidence of restenosis R group . 12.20 ; C group . 38.Oo (p < 0.01) The comparative clinical data demonstrates the efficacy of 3 month Tranilast treatment for the prevention of restenosis in patients after PTCA surgery.
The following comparative Example demonstrates that a one month Tranilast treatment is not effective for reducing restenosis in patients after PTCA surgery.
EXAMPLE II
This Example illustrates a one month treatment of patients with Tranilast which is not effective for reducing the incidence of restenosis associated with PTCA
surgery.
Three hundred and fifty two patients having lesions with a partial occlusion, underwent successful PTCA
procedures with smooth dilation, and enrolled in this study. These patients were divided into two groups, and both groups did not differ significantly with sex, age, number of diseased vessels, distribution of coronary artery and mean degree of stenosis (%) before PTCA; One group (100 patients) received Tranilast in a daily dose of 300 mg for 30 consecutive days (hereinafter identified as the R' group), and the other group (252 patients) did not receive Tranilast (hereinafter identified as the C' group). In addition, all patients were also given calcium antagonists, vasodilators and anti-platelets for 3 consecutive months after PTCA. Follow-up coronary angiography was performed in 3 months after PTCA.
The measurements were made in two projections using a direct caliper system, and all measurements (before and immediately after PTCA and at final follow-up) were made in the same projection for more accurate comparison.
Diameter stenosis was calculated as the mean of measurements, and restenosis was defined as a loss of at ' least 50% of the initial gain in luminal diameter ~. accomplished by dilation.
The results of examination were as follows.
(1) The change of stenosis diameter Pre-PTCA
R' group . 86.10 ; C' group . 78.70, ns Post-PTCA
R' group . 78.40 ; C' group . 22.50, ns Three months after PTCA
R' group . 78.4% ; C' group . 74.9%, ns (2) The incidence of restenosis R' group . 32.1% ; C' group . 36.10, ns The one month treatment with a 300 mg dosage did not have a significant effect in reducing the incidence of restenosis inpatients after PTCA surgery.
_g_
Claims (5)
1. The use of 2-(3,4-dimethoxycinnamoyl)amino-benzoic acid or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment or prevention of restenosis associated with coronary intervention.
2. The use of 2-(3,4-dimethoxycinnamoyl)amino-benzoic acid or a pharmaceutically acceptable salt thereof for the treatment or prevention of restenosis associated with coronary intervention.
3. The use according to claim 2 wherein the use is continued for a period of at least three months.
4. The use according to claim 3 wherein the use is on a daily basis.
5. A pharmaceutical composition for use in the treatment or prevention of restenosis associated with coronary intervention, containing, as an active ingredient, 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4288086A JP2617407B2 (en) | 1992-09-14 | 1992-09-14 | Preventive and therapeutic agent for intimal cell hyperproliferative disease |
| JP288086/92 | 1992-09-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2106172A1 CA2106172A1 (en) | 1994-03-15 |
| CA2106172C true CA2106172C (en) | 2001-01-02 |
Family
ID=17725612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002106172A Expired - Fee Related CA2106172C (en) | 1992-09-14 | 1993-09-14 | Use of 2-(3,4-dimethoxycinnamoyl)aminobenzoic acid for the treatment of restenosis associated with coronary intervention |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5385935A (en) |
| EP (1) | EP0588518B1 (en) |
| JP (1) | JP2617407B2 (en) |
| KR (1) | KR100252410B1 (en) |
| CA (1) | CA2106172C (en) |
| DE (1) | DE69310065T2 (en) |
| HK (1) | HK1005425A1 (en) |
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| US6613083B2 (en) * | 2001-05-02 | 2003-09-02 | Eckhard Alt | Stent device and method |
| AU2003280437A1 (en) * | 2002-06-27 | 2004-01-19 | Microport Medical (Shanghai) Co., Ltd. | Drug eluting stent |
| US20080306126A1 (en) * | 2004-01-05 | 2008-12-11 | Fonseca Vivian A | Peroxisome proliferator activated receptor treatment of hyperhomocysteinemia and its complications |
| US7473738B2 (en) * | 2004-09-30 | 2009-01-06 | Johnson & Johnson Vision Care, Inc. | Lactam polymer derivatives |
| CA2670590C (en) * | 2006-12-01 | 2018-06-12 | Wake Forest University Health Sciences | Medical devices incorporating collagen inhibitors |
| WO2010147184A1 (en) | 2009-06-17 | 2010-12-23 | 国立大学法人熊本大学 | Prophylactic and/or therapeutic agent for dysmenorrhea |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4070484A (en) * | 1973-01-18 | 1978-01-24 | Kissei Pharmaceutical Co., Ltd. | Antiallergic composition containing aromatic carboxylic amide derivatives and method of using the same |
| JPS5640710B2 (en) * | 1973-01-18 | 1981-09-22 | ||
| US4337270A (en) * | 1980-05-21 | 1982-06-29 | Hisamitsu Pharmaceutical Co., Inc. | Novel anthranilic acid derivatives |
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1992
- 1992-09-14 JP JP4288086A patent/JP2617407B2/en not_active Expired - Fee Related
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1993
- 1993-08-26 EP EP93306787A patent/EP0588518B1/en not_active Expired - Lifetime
- 1993-08-26 DE DE69310065T patent/DE69310065T2/en not_active Expired - Fee Related
- 1993-09-07 US US08/116,701 patent/US5385935A/en not_active Expired - Lifetime
- 1993-09-13 KR KR1019930018347A patent/KR100252410B1/en not_active IP Right Cessation
- 1993-09-14 CA CA002106172A patent/CA2106172C/en not_active Expired - Fee Related
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1998
- 1998-05-27 HK HK98104564A patent/HK1005425A1/en not_active IP Right Cessation
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|---|---|
| US5385935A (en) | 1995-01-31 |
| CA2106172A1 (en) | 1994-03-15 |
| KR100252410B1 (en) | 2000-05-01 |
| JPH06135829A (en) | 1994-05-17 |
| JP2617407B2 (en) | 1997-06-04 |
| DE69310065T2 (en) | 1997-11-20 |
| EP0588518A1 (en) | 1994-03-23 |
| KR940006578A (en) | 1994-04-25 |
| DE69310065D1 (en) | 1997-05-28 |
| HK1005425A1 (en) | 1999-01-08 |
| EP0588518B1 (en) | 1997-04-23 |
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| EEER | Examination request | ||
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