JP2004250441A - Large platelet aggregate formation inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicament capable of inhibiting the formation of a large aggregate of platelets. <P>SOLUTION: The medicament as a large platelet aggregate formation inhibitor contains a substance selected from the group consisting of aminoalkoxybibenzyls expressed by general formula (1) [R<SP>1</SP>is H, a halogen, a 1-5C alkoxy or a 2-6C dialkylamino; R<SP>2</SP>is H, a halogen or a 1-5C alkoxy; R<SP>3</SP>is H, hydroxy, O-(CH<SB>2</SB>)<SB>n</SB>-COOH ((n) is an integer of 1 to 5) or O-CO-(CH<SB>2</SB>)<SB>l</SB>-COOH ((l) is an integer of 1 to 3); R<SP>4</SP>is N(R<SP>5</SP>)(R<SP>6</SP>) (R<SP>5</SP>and R<SP>6</SP>are each H or a 1-8C alkyl), or the like; and (m) is an integer of 0 to 5], either one of their pharmaceutically acceptable salts or esters, their solvates and their hydrates as an active ingredient. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

The present invention relates to a medicament for inhibiting the formation of large aggregates of platelets.

Platelet aggregation caused by epinephrine, ADP, etc., consists of the formation of small aggregates (comprising several to about 10 platelets) that occur at the beginning of the aggregation process and the subsequent large aggregates (which consist of more than 100 platelets). ) Is known to proceed in two steps. It is known that these two steps can be clearly distinguished by a particle measurement method using laser scattered light (Journal of the Japanese Society of Thrombosis and Hemostasis, Vol. 8, pp. 55-61, 1997). It has also been shown to proceed by different mechanisms.

For example, when cyclic AMP in platelets is increased by prostacyclin (PGI ₂ ), the formation of both small aggregates and large aggregates is suppressed, but when the formation of thromboxane A ₂ is inhibited by acetylsalicylic acid, large aggregates are reduced. Only the formation of small aggregates is not suppressed (see above). The formation of small aggregates is inhibited by anti-glycoprotein IIb IIIa antibody, suggesting that the binding of platelet membrane glycoprotein IIb IIIa to fibrinogen is involved in this step. On the other hand, since the formation of large aggregates is inhibited not only by acetylsalicylic acid but also by a thromboxane A ₂ antagonist, production of thromboxane A ₂ is considered to be important in this step.

で表される塩酸サルポグレラートに代表される特定構造のアミノプロポキシビベンジル類は５HT₂受容体に高い選択性を示し、血圧にほとんど影響を与えないことが報告されており、さらに、重篤な副作用もほとんどなく、高い安全性を示す薬剤である。塩酸サルポグレラートについては、これまで脳循環障害、虚血性心疾患、末梢循環障害等の疾患における、血栓生成及び血管収縮に基づく種々の微小循環障害の改善に有効であることが知られている（特開平２−３０４０２２号公報）。 On the other hand, the following equation (2):

It has been reported that aminopropoxybibenzyls having a specific structure represented by sarpogrelate hydrochloride represented by the formula have high selectivity for 5HT ₂ receptor and have little effect on blood pressure, and further, serious side effects. There is almost no drug that shows high safety. Sarpogrelate hydrochloride is known to be effective in improving various microcirculatory disorders based on thrombus formation and vasoconstriction in diseases such as cerebral circulatory disorders, ischemic heart disorders, and peripheral circulatory disorders (particularly). JP-A-2-304022).

In the clinic, sarpogrelate hydrochloride has been used to improve ischemic symptoms associated with chronic arterial occlusion, but its action is to inhibit platelet aggregation and vasoconstriction via 5HT ₂ receptors present on platelets and vascular smooth muscle. ("New Development of Serotonin Research in the Cardiovascular Area", Chapter III. Effects on Serotonin Vascular System 3. Platelet Aggregation ", p.59-66, supervised by Mitsuhiro Yokoyama, published by Medical Review, 2002) . The above publication describes that serotonin-induced platelet aggregation is inhibited by sarpogrelate hydrochloride, and that the process was measured by a highly sensitive particle counting method. No inhibition is suggested or taught.

Problems to be solved by the invention and means for solving the problems

An object of the present invention is to provide a medicament having an action of inhibiting formation of a large aggregate of platelets. The present inventors have conducted intensive studies in order to solve the above-mentioned problems. As a result, aminopropoxybibenzyls having a specific structure known as 5HT ₂ receptor antagonists have an effect of inhibiting the formation of large aggregates of platelets. I found that. The present invention has been completed based on the above findings.

〔式中、Ｒ¹ は水素原子、ハロゲン原子、Ｃ₁〜Ｃ₅のアルコキシ基、又はＣ₂〜Ｃ₆のジアルキルアミノ基を表わし、Ｒ²は水素原子、ハロゲン原子又はＣ₁〜Ｃ₅のアルコキシ基を表わし、Ｒ³は水素原子、ヒドロキシル基、−Ｏ−（ＣＨ₂）_n−ＣＯＯＨ（式中、ｎは１〜５の整数を表わす。）、又はＯ−ＣＯ−（ＣＨ₂）_l−ＣＯＯＨ（式中、ｌは１〜３の整数を表わす。）を表わし、Ｒ⁴は−Ｎ（Ｒ⁵）（Ｒ⁶）（式中、Ｒ⁵及びＲ⁶はそれぞれ独立して水素原子又はＣ₁〜Ｃ₈のアルキル基を表わす。）又は

（式中、Ａはカルボキシル基で置換されていてもよいＣ₃〜Ｃ₅のアルキレン基を表わす。）を表わし、ｍは０〜５の整数を表わす。〕 That is, the present invention is selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. An object of the present invention is to provide a platelet large aggregate formation inhibitor containing a substance as an active ingredient.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom or a C ₁ -C ₅ R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (where n represents an integer of 1 to 5), or O—CO— (CH ₂ ) ₁ -COOH (wherein, l represents. an integer of 1 to 3) represent, R ⁴ is ^{-N (R 5) (R 6} ) ( wherein, R ⁵ and R ⁶ are each independently hydrogen or Represents a C ₁ -C ₈ alkyl group) or

(In the formula, A represents a C ₃ -C ₅ alkylene group which may be substituted with a carboxyl group.), And m represents an integer of 0-5. ]

アミノアルコキシビベンジル類が下記（３）で表わされる化合物である上記の阻害剤；

及び塩酸塩の形態の上記の阻害剤が提供される。 According to a preferred embodiment of the above invention, the inhibitor wherein the aminoalkoxybibenzyl is a compound represented by the following (2):

The above-mentioned inhibitor, wherein the aminoalkoxybibenzyl is a compound represented by the following (3):

And in the form of the hydrochloride salt.

From still another viewpoint, the above-mentioned inhibitor used for the prevention and / or treatment of a disease associated with the formation of a large aggregate of platelets; the prevention and / or treatment of a disease caused by the formation of a large aggregate of platelets; The above-mentioned inhibitors for use in the present invention are provided by the present invention. In addition, aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof for the production of the above inhibitors The use of a substance selected from the group consisting of is also provided by the present invention.

Further, a substance selected from the group consisting of aminoalkoxybibenzyls represented by the general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof is used as an active ingredient. The present invention also provides a medicament for treating and / or preventing a disease associated with formation of large platelet aggregates or a disease caused by formation of large platelet aggregates, including the present invention. According to a preferred embodiment of the present invention, there is provided the above drug, wherein the aminoalkoxybibenzyl is in the form of a compound represented by the above formula (2) or (3), preferably a hydrochloride. Preferably, the disease is chronic arterial occlusion, intermittent claudication, ischemic cerebrovascular disease (preferably transient cerebral ischemic attack and cerebral infarction, etc.), angina pectoris (preferably chronic stable angina and unstable Angina pectoris), myocardial infarction, and pain.

Further, the above-mentioned medicine for co-administration with a drug selected from the group consisting of a platelet aggregation inhibitor, an anticoagulant, and a fibrinolytic agent; and a group consisting of a platelet aggregation inhibitor, an anticoagulant, and a fibrinolytic agent The present invention also provides the above-mentioned medicament for administration after discontinuation of administration of a drug selected from the group consisting of: The platelet aggregation inhibitor is preferably an aspirin preparation, ticlopidine hydrochloride or ozagrel sodium, the anticoagulant is preferably warfarin potassium or urokinase, and the fibrinolytic agent is preferably urokinase, alteplase or monteplase.

From yet another aspect, the present invention relates to a method for inhibiting the formation of large aggregates of platelets, comprising administering to a mammal, including a human, an aminoalkoxybibenzyl represented by the above general formula (1), a pharmaceutically acceptable salt or A method comprising the step of administering an effective amount of a substance selected from the group consisting of an ester thereof, a solvate thereof, and a hydrate thereof; a method for preventing and / or treating a disease associated with formation of a large aggregate of platelets. It comprises aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof in mammals including humans. A method comprising administering a prophylactically and / or therapeutically effective amount of a substance selected from the group; and a method for preventing and / or treating a disease caused by formation of a large aggregate of platelets, A substance selected from the group consisting of aminoalkoxybibenzyls represented by the above general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. And administering a prophylactically and / or therapeutically effective amount of

The inhibitor of the present invention is selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. Contains selected substances as active ingredients.

R ¹ is a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C _{1 to} C ₅ alkoxy group such as a methoxy group, an ethoxy group or a butoxy group; a C ₂ group such as a dimethylamino group, a diethylamino group or a methylethylamino group. shows a dialkylamino group -C _6. R ² represents a hydrogen atom; a halogen atom such as a chlorine atom or a fluorine atom; a C ₁ -C ₅ alkoxy group such as a methoxy group, an ethoxy group or a butoxy group. R ³ is a hydrogen atom; a hydroxyl _{group; -O- (CH 2) 2 -COOH} , -O- (CH 2) 3 -COOH, etc. -O- (CH ₂₎ in _n -COOH (wherein, n is 1 to 5 represents an integer of); - O-CO- (CH 2) 2 -COOH, -O-CO- (CH 2) 3 -O-CO- (CH 2 -COOH, etc.) in _l -COOH (wherein, l represents an integer of 1 to 3). R ⁴ is an amino group or an alkyl group having 1 to 8 carbon atoms such as a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a diethylamino group, and a methylethylamino group. A 4- to 6-membered polymethyleneamino group which represents an amino group having 2 to 2 carbon atoms, or a ring such as a trimethyleneamino group, a pentamethyleneamino group, or a 3-carboxypentamethyleneamino group which may be substituted with a carboxyl group Represents

Table 1 shows some of the compounds included in the general formula (1) that are preferably used in the present invention.

Among these, a compound in which an aminoalkoxy group —OCH ₂ C (R ³ ) H— (CH ₂ ) _m —R ⁴ is bonded to the 2-position of the phenyl group is preferable. R ¹ is preferably a hydrogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, R ² is preferably a hydrogen atom, and R ⁴ is at least one C ₁ -C _8. Is preferably an amino group having an alkyl group or a 4- to 6-membered polymethyleneamino group having a trimethylene group or a pentamethylene group, and m is preferably an integer of 0 to 2. Particularly preferred are ^{No. 1 wherein} R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a dimethylamino group. No. 15 (hereinafter, this compound may be referred to as “M-1” in the present specification) and its succinic ester No. 15 14 compounds.

Examples of the acid that forms a pharmaceutically acceptable salt of the compound represented by the general formula (1) include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, and propion Acids, tartaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid and the like are used. Further, a solvate or hydrate of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof can also be used. Of these, particularly preferred is (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl represented by the following formula (4). Hydrogen succinate hydrochloride (hereinafter, this substance may be referred to as “sarpogrelate hydrochloride” in the present specification).

Aminoalkoxybibenzyls represented by the general formula (1), and pharmaceutically acceptable salts and esters thereof are known, and can be prepared by the method described in JP-A-58-32847 or a method analogous thereto. Can be easily synthesized. The sarpogrelate hydrochloride represented by the above formula (4) is commercially available from Mitsubishi Pharma Corporation as "Amplag (registered trademark)", and in the present invention, commercially available "Amplag" can be used as it is. is there.

The inhibitor of the present invention can inhibit the formation of large aggregates during platelet aggregation. In the process of platelet aggregation, the formation of small aggregates (comprising several to about 10 platelets) that occurs at the beginning of the aggregation process and the formation of large aggregates (comprising 100 or more platelets) that occur thereafter It is known to proceed by steps. The inhibitor of the present invention has an effect of inhibiting the formation of large aggregates. These two steps can be clearly distinguished by a particle measurement method using laser scattered light, and those skilled in the art can easily confirm the action of the inhibitor of the present invention.

Accordingly, the inhibitor of the present invention is useful as a medicament for preventing and / or treating various diseases associated with large aggregation of platelets. It is also useful as a medicament for preventing and / or treating various diseases caused by large aggregation of platelets. Such diseases include, for example, chronic arterial occlusion, intermittent claudication, ischemic cerebrovascular disease (transient cerebral ischemic attack and cerebral infarction), angina pectoris (chronic stable angina and unstable angina). Heart disease), myocardial infarction, pain and the like. Preferably, a transient cerebral ischemic attack or cerebral infarction is included.

The medicament of the present invention can be co-administered to a patient who has already been administered a drug selected from the group consisting of a platelet aggregation inhibitor and an anticoagulant, simultaneously or at an interval. Further, it is also possible to administer the medicament of the present invention after discontinuing administration of the platelet aggregation inhibitor, anticoagulant, and fibrinolytic agent.

Examples of platelet aggregation inhibitors include aspirin preparations (bufferin, biaspirin, etc.), ticlopidine hydrochloride (panaldine, etc.), cilostazol (pretal, etc.), dipyridamole (persantin, anginal, etc.), ozagrel sodium (cataclot, xambon, etc.), ozagrel hydrochloride (Vega, domenan), ethyl icosapentate (epadel, etc.), beraprost sodium (dorner, procylin), limaprost alfadex (opalmon, prorenal), alprostadil preparations (ripple, parx, prostandin, etc.) and the like. Examples of anticoagulants include warfarin potassium (such as warfarin), argatroban (such as Novastan and Slonnon), and heparin preparations (such as fragmin and sodium heparin). Examples of peptizers include urokinase (urokinase, etc.), nasalplase (thrombolyse, etc.), alteplase (glutopa, etc.), tisokinase (plus beta, etc.), nateplase (milizer), pamiteplase (solinase), monteplase (clearer) and the like. .

The method of administration when the inhibitor is used as a medicine in the present invention can be appropriately selected by those skilled in the art. For example, any route of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or the like, or oral administration can be selected. The dose can be determined as appropriate depending on conditions such as the age, health condition, and weight of the patient, the type and frequency of administration of a drug to be administered simultaneously, if any, or the nature of the desired effect. Generally, the daily dose of the active ingredient is 0.5 to 50 mg / kg body weight, usually 1 to 30 mg / kg body weight, and it can be administered once or more per day.

When the inhibitor of the present invention is used as a medicine, it is preferable to prepare and administer a pharmaceutical composition containing the above-mentioned active ingredient and one or more kinds of pharmaceutical additives. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, solutions, and elixirs. Pharmaceutical compositions suitable for parenteral administration include, for example, solutions and suspensions. Pharmaceutical compositions in a sterilized liquid form such as an agent can be exemplified.

The type of the pharmaceutical additive used for the preparation of the pharmaceutical composition is not particularly limited, and it is possible to select an appropriate pharmaceutical additive according to the form of various pharmaceutical compositions. The pharmaceutical additive may be either solid or liquid, and for example, a solid carrier or a liquid carrier may be used. As an example of the solid carrier, a usual gelatin type capsule can be used. In addition, for example, the active ingredient can be tableted with or without one or more pharmaceutical additives, or can be prepared as a powder and packaged. These capsules, tablets and powders may generally contain from 5 to 95% by weight, preferably from 5 to 90% by weight, of the active ingredient, based on the total weight of the formulation, the dosage unit form being from 5 to 500 mg, Preferably, it contains 25 to 250 mg of the active ingredient. As the liquid carrier, water or an oil of animal or plant origin such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil or synthetic oil is used. In general, physiological saline, dextrole or a similar sucrose solution, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as the liquid carrier. It can be prepared to contain from 5 to 20%, preferably 1 to 10% by weight of the active ingredient.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. As the sarpogrelate hydrochloride used below, "Amprag (registered trademark)" marketed by Mitsubishi Pharma Corporation was used.
Example 1
A single oral administration of sarpogrelate hydrochloride 50 mg tablets x 2 tablets (administration of 100 mg) or 50 mg tablets x 1 tablet (administration of 50 mg) at 8:00 am to 6 healthy adult males according to the following dosage schedule (9 courses) did. Each subject had at least 5 days off on each study day, and on the test day smoking was prohibited until the final blood draw was completed. In the table, “100 mg” indicates the administration of 100 mg, “50 mg” indicates the administration of 50 mg, and “None” indicates the non-administration.

Thirty minutes before administration, one and a half hours after administration, and three hours later, 18 mL of blood was collected into a syringe containing argatroban (0.1 mg / mL, final concentration) using a 19-gauge injection needle, and the collected blood was mixed by inversion. did. The remaining blood obtained by subdividing 3 ml as a blood concentration measurement sample was centrifuged at 100 × g for 15 minutes to separate platelet-rich plasma (PRP). The remainder was further centrifuged at 1500 xg for 15 minutes at room temperature to separate platelet poor plasma (PPP).

Platelet aggregation was measured by a particle counting method (PA-100 (Kowa Optimed)) using PRP with small aggregates, large aggregates, and changes in permeability as indices. The analysis of the small aggregates and the large aggregates was performed using the maximum value (volt / min) of the total scattering intensity obtained by the particle measurement as an index. 300 μL of PPP was placed in a glass cuvette (manufactured by Mevanix or equivalent), and calibration was performed. 300 μL of PRP was taken in another glass cuvette and incubated at 37 ° C. for 5 minutes. Thereafter, epinephrine and serotonin were added as platelet aggregation reagents, and measurement was performed for 5 minutes. The platelet aggregation induced by the platelet aggregation reagent was defined as the maximum value of the total scattering intensity, and the effect of sarpogrelate hydrochloride was compared using the value as an index.

The results are shown in FIG. From the results shown in the figure, in the blood one and a half hours after the administration of sarpogrelate hydrochloride, the formation of large platelet aggregates induced by the platelet aggregation reagent was significantly suppressed in a dose-dependent manner. In addition, it was confirmed by particle measurement that this aggregate formation induced by the platelet aggregation reagent was a large aggregate of platelets.

Example 2
Sarpogrelate hydrochloride was repeatedly administered to 6 healthy adult males according to the dosing schedule shown in the table below. Sarpogrelate hydrochloride was administered at a given time with about 100 ml of water.

A platelet function test for comparing the effect of sarpogrelate hydrochloride was performed in the same manner as in Example 1.

FIG. 2 shows the results. In the blood after repeated administration of sarpogrelate hydrochloride, the formation of large platelet aggregates induced by the platelet aggregation reagent was suppressed as in the blood after single administration.

The inhibitor of the present invention can inhibit the formation of large aggregates during the platelet aggregation process. Therefore, the inhibitor of the present invention is useful as a medicament for preventing and / or treating a disease associated with the formation of a large aggregate of platelets or a disease caused by the formation of a large aggregate of platelets.

FIG. 2 is a view showing the effect of the inhibitor of the present invention on the formation of large aggregates of platelets. FIG. 3 is a graph showing the effect of repeated administration of the inhibitor of the present invention on the formation of large aggregates of platelets.

Claims (16)

Contains, as an active ingredient, a substance selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. An inhibitor of the formation of large platelet aggregates.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₅ alkoxy group, or a C ₂ -C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom or a C ₁ -C ₅ R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH (where n represents an integer of 1 to 5), or O—CO— (CH ₂ ) ₁ -COOH (wherein, l represents. an integer of 1 to 3) represent, R ⁴ is ^{-N (R 5) (R 6} ) ( wherein, R ⁵ and R ⁶ are each independently hydrogen or Represents a C ₁ -C ₈ alkyl group) or

(In the formula, A represents a C ₃ -C ₅ alkylene group which may be substituted with a carboxyl group.), And m represents an integer of 0-5. ] The inhibitor according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following (2).

The inhibitor according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following (3).

The inhibitor according to claim 2 or 3 in the form of a hydrochloride. A substance selected from the group consisting of aminoalkoxybibenzyls represented by the general formula (1) according to claim 1, pharmaceutically acceptable salts or esters thereof, solvates and hydrates thereof. For treating and / or preventing a disease associated with the formation of large platelet aggregates or a disease caused by the formation of large platelet aggregates. The pharmaceutical according to claim 5, wherein the aminoalkoxybibenzyl is the compound represented by the formula (2) according to claim 2. The pharmaceutical according to claim 5, wherein the aminoalkoxybibenzyl is the compound represented by the formula (3) according to claim 3. The medicament according to claim 6 or 7, which is in the form of a hydrochloride. The medicament according to any one of claims 5 to 8, wherein the disease is selected from the group consisting of chronic arterial occlusion, intermittent claudication, ischemic cerebrovascular disease, angina, myocardial infarction, and pain. The medicament according to claim 9, wherein the ischemic cerebrovascular disorder is selected from the group consisting of transient cerebral ischemic attack and cerebral infarction. 10. The medicament according to claim 9, wherein the angina is selected from the group consisting of chronic stable angina and unstable angina. The medicament according to any one of claims 5 to 11, which is used in combination with a drug selected from the group consisting of a platelet aggregation inhibitor, an anticoagulant, and a fibrinolytic agent. The medicament according to any one of claims 5 to 11, which is administered after the discontinuation of administration of a drug selected from the group consisting of a platelet aggregation inhibitor, an anticoagulant, and a fibrinolytic agent. 14. The medicament according to claim 12, wherein the platelet aggregation inhibitor is an aspirin preparation, ticlopidine hydrochloride, or ozagrel sodium. 14. The medicament according to claim 12, wherein the anticoagulant is warfarin potassium or urokinase. 14. The medicament according to claim 12, wherein the fibrinolytic agent is urokinase, alteplase, or monteplase.

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