CA2000650A1 - Product and process for the treatment and prevention of intravascular thrombi and atherosclerosis - Google Patents
Product and process for the treatment and prevention of intravascular thrombi and atherosclerosisInfo
- Publication number
- CA2000650A1 CA2000650A1 CA 2000650 CA2000650A CA2000650A1 CA 2000650 A1 CA2000650 A1 CA 2000650A1 CA 2000650 CA2000650 CA 2000650 CA 2000650 A CA2000650 A CA 2000650A CA 2000650 A1 CA2000650 A1 CA 2000650A1
- Authority
- CA
- Canada
- Prior art keywords
- heparin
- treatment
- atherosclerosis
- prevention
- vascular
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 14
- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 10
- 230000002265 prevention Effects 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 9
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229920000669 heparin Polymers 0.000 claims abstract description 32
- 229960002897 heparin Drugs 0.000 claims abstract description 32
- 210000003462 vein Anatomy 0.000 claims description 10
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 230000002792 vascular Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 6
- 230000003412 degenerative effect Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 210000001367 artery Anatomy 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000007850 degeneration Effects 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000011287 therapeutic dose Methods 0.000 claims 3
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 5
- 230000003143 atherosclerotic effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000003038 endothelium Anatomy 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000010171 animal model Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000037516 chromosome inversion disease Diseases 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The invention provides for the use of heparin in the treatment and prevention of intravascular thrombi and atherosclerosis by oral administration.
heparin
The invention provides for the use of heparin in the treatment and prevention of intravascular thrombi and atherosclerosis by oral administration.
heparin
Description
Back~round of the Invention ~ his invention relates to the use o~ heparin for a new use, namely, in the treatment and prevention of intravascular thrombi and atherosclerosis by oral administration.
Heparin, which was discovered over 30 years ago, is a highly sulfated dextrorotatory mucopolysaccharide. See British Pharmacopia 1973, standard preparation and units defined British Pharmacopia A112 (1973). Heparin is commercially available and its method of preparation is well known in the art. See Merck Index 10th Ed., 4538.
It is known that coronary thrombosis and the development of arterial plaques as a result of athexosclerosis is based upon the effect of lipid lesions ~ormed within arterial walls by plasma lipoproteins and cholesterol deposits.
A study group of the World Health Organization has defined atherosclerosis as a "variable combination of changes of the intima of arteries consisting of the focal accumulation of lipids, complex carbohydrates, blood and blood products, fibrous tissue and calcium deposits, etc." (WHO Tech Report Sex. 143).
As discussed by Kenneth W. Walton in "The Pathophysiology of Arterial Deposition" (Angeolgie, Vol~ 41, 4 pp 121-130~ "atherosclerotic lesions arise, in general, because certain reactive proteins appear to insude into the intima and interact with charged components of the connective tissue gel".
For 30 years inves~igators have shown intravenous z~
administration of heparin can halt and reverse degenerative conditions of the cardiovascular system such as atherosclerosis.
It was also believed that heparin was not absorbed by the gastrointestinal tract and could not be orally administered.
Thus, heparin has not be used clinically for treatment of cardiovascular disease since long term treatment generally requires effective oral administration.
Summary of the Invention It has been found that heparin is rapidly and almost completed absorbed in animals, particularly mammals, by oral administration and can be an effective treatment for vascular degenerative condition such as atherosclerosis or thrombosis of a vein or artery.
It has now been found that heparin is rapidly absorbed by the body upon oral administration and is in fact sequestered by the endothelium of the respective bodily tissues so that only a very small proportion remains in the blood or plasma.
The resulting concentration of heparin in the endothelium of arterial cell walls likely serves to retard or prevent the formation of thrombi and eliminate or retard the formations of atherosclerotic deposits.
The present invention provides a pharmaceutical composition in dosage form suitable for administration for the treatment and prevention of conditions of vascular degeneration such as thrombosis or atherosclerosis which comprises an active 2~
ingredient heparin or a pharmaceutically acceptable salt thereo~
in an amount effective to reduce the severity of the said conditions in humans, in admixture with a suitable pharmaceutically acceptable diluent or carrier.
Although the existence of heparin is known, ik is both new and surprising that heparin is useful in the treatment of thrombotic and related atherosclerotic conditions by oral administration.
Description of the Preferred Embodiment In accordance with the present invention, it has been found that the oral administration o~ heparin is an effective treatment for vascular degenerative diseases such as thrombosis or atherosclerosis and that heparin is also a suitable treatment for prevention for such diseases. Preferably heparin is administered along with a suitable pharmaceutically acceptable diluent or carrier. Dosages for use in accordance with the invention would range from about .1 to about 10 grams per day.
Experimentation was carried out utilizing rats as the animal model. In particular, a bovine lung heparin supplied by the Upjohn Company was used. The heparin was administered to rats at a dosage o~ 60 mg/kg. The dose was in the form of an aqueous solution placed in the stomach by means of a gastric tube.
The total amount of the drug absorbed was determined in plasmas and endothelium by the optical density of the complax 2~ S~
with toluidine blue in agarose gel ~lectrophoresis. Uptake of the drug was rapid and almost ~otally complete within 6 minutes.
0.5% or less was found in the plasma.
From the plasma and endothelial values after inserkion in to the stomach, it was evident that these values were considerable in as early as 2.4 minutes with the highest values in about 6 minutes. Thereafter, the concentration became diminished after 15 mi~utes and gradually further with time, although some could still be detected after 1 hour.
The rates of absorption may be illustrated as follows:
Oral Heparin Time A~ter Heparin Heparin and Administration in Plasma in Endothelium -min. % of administered dose 2.4 ~0.01 18 6 0.4 56 0.5 <3 In order to determine the efficacy of heparin in preventing vascular thrombosis, the drug was orally administered to rats ~mmediately after treatment to produce thrombosis in the right jugular veins of each by the method described by Blake et al ~J. Clinl. Path. 12, 118, (1959)].
s~
In accordance with the Blake procedure, the right jugular vein of a rat, under anesthetic, was exposed by an incision and 3 drop~ of formalin in 65~ methyl alcohol was applied. The incision was then closed. 50me time later (in this case 4 hours) the rat was anesthetized, the incision opened and the vein examined to determine whether thrombosis has occurred and whether the vein is plugged. }Iistological examination of these plugs shows that they are a typical mixed thrombus composed of large masses of platelets and fibrin. To determine whether flow of blood i9 being obstructed, the vein need not be incised to determine whether a plug has formed. If a Q-tip is pressed lightly on the vein, a clear vein will empty and refill when the pressure is removed. This does not happen if there is a plug.
Further with a plug, the vein is evident and on lifting with a probe, solid masses are seen in the plugged vein with no evidence of flow.
Accordingly groups of rats were selected. Group A - 25 rats receiving the formalin treatment as a control. Group B ~ 25 rats receiving heparin at a dosage of 60 mg/kg administered orally in saline solution with a stomach tube immediately after incision and insertion of the formalin. After 4 hours the incidence of thrombi or plugs in each group of rats was determined.
The results obtained were as follows:
Control Group A out of 25 rats plugs found in 20 rats = 80%
2~
Group B - out o~ 24 rats treated with heparin - Zero plugs, veins clear, normal blood ~low = 0%.
These rasults clearly demonstrate the surprising result that thrombotic and related atherosclerotic conditions can be prevented or removed in the presence of the heparin.
The results obtained by the oral administration of the heparin as described above would be applicable to other animal models (mammals) including humans.
The Food and Drug Administration (U.s.) accepts results in rats, such as those referred to herein, as indicative of the effect of the substance on humans. Similarly, persons skilled in this art accept effects in rats as applicable to humans.
The heparin which is usually obtained as the sodium salts thereoP in the form of white granular powders readily soluble in w~ter are readily formulated in solutions, tablets or capsules for oral administration with pharmaceutically acceptable excipients etc. as well known in the pharmaceutical art. In the case of oral administration the heparin would preferably be packaged in a soft gelatin capsule. The dosages will vary somewhat depending upon the animal specias. For human therapy a preferred daily dosage range would be from 20 80 mg/kg or preferably about 0.1 - 10 grams per day for the average parson usually in divided spaced doses.
The pharmaceutically acceptable diluents and/or carriers will depend on the selected route of administration and .
Heparin, which was discovered over 30 years ago, is a highly sulfated dextrorotatory mucopolysaccharide. See British Pharmacopia 1973, standard preparation and units defined British Pharmacopia A112 (1973). Heparin is commercially available and its method of preparation is well known in the art. See Merck Index 10th Ed., 4538.
It is known that coronary thrombosis and the development of arterial plaques as a result of athexosclerosis is based upon the effect of lipid lesions ~ormed within arterial walls by plasma lipoproteins and cholesterol deposits.
A study group of the World Health Organization has defined atherosclerosis as a "variable combination of changes of the intima of arteries consisting of the focal accumulation of lipids, complex carbohydrates, blood and blood products, fibrous tissue and calcium deposits, etc." (WHO Tech Report Sex. 143).
As discussed by Kenneth W. Walton in "The Pathophysiology of Arterial Deposition" (Angeolgie, Vol~ 41, 4 pp 121-130~ "atherosclerotic lesions arise, in general, because certain reactive proteins appear to insude into the intima and interact with charged components of the connective tissue gel".
For 30 years inves~igators have shown intravenous z~
administration of heparin can halt and reverse degenerative conditions of the cardiovascular system such as atherosclerosis.
It was also believed that heparin was not absorbed by the gastrointestinal tract and could not be orally administered.
Thus, heparin has not be used clinically for treatment of cardiovascular disease since long term treatment generally requires effective oral administration.
Summary of the Invention It has been found that heparin is rapidly and almost completed absorbed in animals, particularly mammals, by oral administration and can be an effective treatment for vascular degenerative condition such as atherosclerosis or thrombosis of a vein or artery.
It has now been found that heparin is rapidly absorbed by the body upon oral administration and is in fact sequestered by the endothelium of the respective bodily tissues so that only a very small proportion remains in the blood or plasma.
The resulting concentration of heparin in the endothelium of arterial cell walls likely serves to retard or prevent the formation of thrombi and eliminate or retard the formations of atherosclerotic deposits.
The present invention provides a pharmaceutical composition in dosage form suitable for administration for the treatment and prevention of conditions of vascular degeneration such as thrombosis or atherosclerosis which comprises an active 2~
ingredient heparin or a pharmaceutically acceptable salt thereo~
in an amount effective to reduce the severity of the said conditions in humans, in admixture with a suitable pharmaceutically acceptable diluent or carrier.
Although the existence of heparin is known, ik is both new and surprising that heparin is useful in the treatment of thrombotic and related atherosclerotic conditions by oral administration.
Description of the Preferred Embodiment In accordance with the present invention, it has been found that the oral administration o~ heparin is an effective treatment for vascular degenerative diseases such as thrombosis or atherosclerosis and that heparin is also a suitable treatment for prevention for such diseases. Preferably heparin is administered along with a suitable pharmaceutically acceptable diluent or carrier. Dosages for use in accordance with the invention would range from about .1 to about 10 grams per day.
Experimentation was carried out utilizing rats as the animal model. In particular, a bovine lung heparin supplied by the Upjohn Company was used. The heparin was administered to rats at a dosage o~ 60 mg/kg. The dose was in the form of an aqueous solution placed in the stomach by means of a gastric tube.
The total amount of the drug absorbed was determined in plasmas and endothelium by the optical density of the complax 2~ S~
with toluidine blue in agarose gel ~lectrophoresis. Uptake of the drug was rapid and almost ~otally complete within 6 minutes.
0.5% or less was found in the plasma.
From the plasma and endothelial values after inserkion in to the stomach, it was evident that these values were considerable in as early as 2.4 minutes with the highest values in about 6 minutes. Thereafter, the concentration became diminished after 15 mi~utes and gradually further with time, although some could still be detected after 1 hour.
The rates of absorption may be illustrated as follows:
Oral Heparin Time A~ter Heparin Heparin and Administration in Plasma in Endothelium -min. % of administered dose 2.4 ~0.01 18 6 0.4 56 0.5 <3 In order to determine the efficacy of heparin in preventing vascular thrombosis, the drug was orally administered to rats ~mmediately after treatment to produce thrombosis in the right jugular veins of each by the method described by Blake et al ~J. Clinl. Path. 12, 118, (1959)].
s~
In accordance with the Blake procedure, the right jugular vein of a rat, under anesthetic, was exposed by an incision and 3 drop~ of formalin in 65~ methyl alcohol was applied. The incision was then closed. 50me time later (in this case 4 hours) the rat was anesthetized, the incision opened and the vein examined to determine whether thrombosis has occurred and whether the vein is plugged. }Iistological examination of these plugs shows that they are a typical mixed thrombus composed of large masses of platelets and fibrin. To determine whether flow of blood i9 being obstructed, the vein need not be incised to determine whether a plug has formed. If a Q-tip is pressed lightly on the vein, a clear vein will empty and refill when the pressure is removed. This does not happen if there is a plug.
Further with a plug, the vein is evident and on lifting with a probe, solid masses are seen in the plugged vein with no evidence of flow.
Accordingly groups of rats were selected. Group A - 25 rats receiving the formalin treatment as a control. Group B ~ 25 rats receiving heparin at a dosage of 60 mg/kg administered orally in saline solution with a stomach tube immediately after incision and insertion of the formalin. After 4 hours the incidence of thrombi or plugs in each group of rats was determined.
The results obtained were as follows:
Control Group A out of 25 rats plugs found in 20 rats = 80%
2~
Group B - out o~ 24 rats treated with heparin - Zero plugs, veins clear, normal blood ~low = 0%.
These rasults clearly demonstrate the surprising result that thrombotic and related atherosclerotic conditions can be prevented or removed in the presence of the heparin.
The results obtained by the oral administration of the heparin as described above would be applicable to other animal models (mammals) including humans.
The Food and Drug Administration (U.s.) accepts results in rats, such as those referred to herein, as indicative of the effect of the substance on humans. Similarly, persons skilled in this art accept effects in rats as applicable to humans.
The heparin which is usually obtained as the sodium salts thereoP in the form of white granular powders readily soluble in w~ter are readily formulated in solutions, tablets or capsules for oral administration with pharmaceutically acceptable excipients etc. as well known in the pharmaceutical art. In the case of oral administration the heparin would preferably be packaged in a soft gelatin capsule. The dosages will vary somewhat depending upon the animal specias. For human therapy a preferred daily dosage range would be from 20 80 mg/kg or preferably about 0.1 - 10 grams per day for the average parson usually in divided spaced doses.
The pharmaceutically acceptable diluents and/or carriers will depend on the selected route of administration and .
3~
will be apparent to those acquainted with this art.
It should be understood by those skilled in the art that various modifications may be made in the present invention but not departing from the spirit and scope thereof as described in the specification and defined in the appending claims. While the invention has been described by reference to specific embodiments, this was for the purpose of illustration only and should not be construed to limit the spirit or scope of the invention.
will be apparent to those acquainted with this art.
It should be understood by those skilled in the art that various modifications may be made in the present invention but not departing from the spirit and scope thereof as described in the specification and defined in the appending claims. While the invention has been described by reference to specific embodiments, this was for the purpose of illustration only and should not be construed to limit the spirit or scope of the invention.
Claims (8)
1. A method for the prevention and treatment of vascular degenerative conditions in animals which comprises the oral administration of therapeutic doses of heparin.
2. The method according to Claim 1 wherein the vascular condition is thrombosis of a vein or artery.
3. The method according to Claim 1 wherein the vascular condition is atherosclerosis.
4. The method according to Claim 1 wherein the therapeutic doses range from 0.1 - 10 grams per day.
5. A therapeutic agent according to Claim 4 which is incorporated in a pharmaceutically acceptable carrier.
6. A therapeutic agent according to Claim 4 which is administered in aqueous solution.
7. A pharmaceutical composition in dosage form suitable for administration for the treatment and prevention of conditions of vascular degeneration such as thrombosis or atherosclerosis which comprises an active ingredient, heparin or a pharmaceutically acceptable salt thereof in an amount effective to reduce the severity of the said conditions in humans, in admixture with a suitable pharmaceutically acceptable diluent or carrier.
8. A method of treatment of a mammal suffering from vascular degenerative conditions comprising the oral administration of a therapeutic dose of heparin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2000650 CA2000650A1 (en) | 1989-10-13 | 1989-10-13 | Product and process for the treatment and prevention of intravascular thrombi and atherosclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2000650 CA2000650A1 (en) | 1989-10-13 | 1989-10-13 | Product and process for the treatment and prevention of intravascular thrombi and atherosclerosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2000650A1 true CA2000650A1 (en) | 1991-04-13 |
Family
ID=4143324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2000650 Abandoned CA2000650A1 (en) | 1989-10-13 | 1989-10-13 | Product and process for the treatment and prevention of intravascular thrombi and atherosclerosis |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2000650A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922690A (en) * | 1996-04-25 | 1999-07-13 | Van Gorp; Cornelius L. | Dermatan disulfate, an inhibitor of thrombin generation and activation |
| US6409987B1 (en) | 1999-04-07 | 2002-06-25 | Intimax Corporation | Targeted agents useful for diagnostic and therapeutic applications |
| US6518244B2 (en) | 2000-03-09 | 2003-02-11 | Intimax Corporation | Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof |
-
1989
- 1989-10-13 CA CA 2000650 patent/CA2000650A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922690A (en) * | 1996-04-25 | 1999-07-13 | Van Gorp; Cornelius L. | Dermatan disulfate, an inhibitor of thrombin generation and activation |
| US6409987B1 (en) | 1999-04-07 | 2002-06-25 | Intimax Corporation | Targeted agents useful for diagnostic and therapeutic applications |
| US6518244B2 (en) | 2000-03-09 | 2003-02-11 | Intimax Corporation | Combinations of heparin cofactor II agonist and platelet IIb/IIIa antagonist, and uses thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |