ZA200601412B - Treatment of aspirin resistance with radix salviae miltiorrhizae, its extract and composition - Google Patents

Description

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Treatment of Aspirin Resistance with

Radix Salviae Miltiorrhizae, Its Extract and Composition

Technical Field

The present invention relates to medicine. In particular, the present invention relates tothe treatment of aspirin resistant cardiv-corehroy ascuiar discuss using Rewdix

Safviae Milnorrhizac (RSM). its extract and composition comprising any or both of them. especiaily the tormulation Danshen Drop Piiis (Drop Pills of RSM).

Background

Aspirin belongs to a class of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs). It is an effective anti-inflammatory drug with both analgesic and antipyretic effects. It works by blocking the production of prostaglandin. The most commonly known side effects of aspirin include: ® Gastrointestinal reactions, such as poor appetite, peptic ulcers, and in some cases, even perforation ® Allergic reaction ® Acute renal failure and chronic interstitial nephritis, etc.

As researches become more and more extensive, aspirin’s indications have been enlarged from the treatment of fever, relieving mild to moderate pain of various kinds such as headache, toothache, neuralgia, arthralgia, myalgia and dysmenorrhea, and the treatment of rheumatism to the trcatment and secondary prevention of cerebral arteriosclerosis, coronary heart disease, and myocardial infarction.

At present, aspirin is widely used in the treatment of cardiovascular disease. The mechanism is that aspirin can block the production of thromboxane A2 (TXA2) in vivo.

As TXA2 can promote platelet conglutination and coagulation, aspirin can reduce the incidences of arteriosclerosis and myocardial infarction by inhibiting platelet aggregation,

But researches have found that the biosynthesis of thromboxane A2 is not effectively prevented in some patients after they take the drug. That is, aspirin looses its protective cffects on cerebrovascular and cardiovascular systems. This is called aspirin resistance (AR). For most patients, aspirin can reduce the risk of cardiovascular discase by 25%, but for patients with aspirin resistance, administration of aspirin, instead of protecting from ]

: MEN . 1040028 -_ cardiovascular cvents, can increase the incidence of myocardial infarction and stroke.

These findings have limited the application of aspirin.

At present, there are not so many reports on the treatment of aspirin resistance.

Yusuf S ctc. reported that, in patients with acute coronary syndrome receiving aspirin, including those undergoing percutaneous coronary intervention, administration of clopidogrel in addition to treatment with aspirin is beneticial in reducing the incidence of early and Jong-term major cardiovascular events, {Ub ffects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study”. Lancet, 2001].

At present, for researches on aspirin resistance, immunoenzyme assay is commonly used for the measurement of the level of urinary 11-dehydrothromboxane B, (TXB,) in the urine sample of patients before taking drug. 11-dehydrothromboxane B, is a metabolite of thromboxane A,. High urinary 11-dehydrothromboxane B, level can identify patients with aspirin resistance and drugs having effects on easing aspirin

I5 resistance. It is based on this foundation that this invention is completed.

The Chinese traditional medicine for treating blood disorders, especially for activating blood circulation to dissipate blood stasis, is the commonly used medicine by doctors of all ages. This kind of medicine has many effects, such as promoting blood flow to regulate menstruation, removing blood stasis to eliminate disease, and promoting the subsidence of swelling and the regeneration of tissue. Modern pharmacological studies have confirmed that drugs used to treat blood disorders have many actions such as dilating coronary artery, increasing the coronary blood flow, reducing the oxygen consumption of cardiac muscle, reducing peripheral vascular resistance, inhibiting platelet aggregation, improving microcirculation, inhibiting thrombosis, increasing the activities of fibrinolysis, regulating anticoagulative system, lowering blood pressure, and relieving smooth muscle spasm, etc. Rhizoma Chuanxiong, RSM, Herba Leonuri, Semen

Persicae, Flos Carthami, and Hirudo are among drugs used to treat blood disorders.

Their clinical applications are developing continuously, and particularly the studies of

RSM and its preparations are outstanding.

RSM comes from salvia, a perennial herb of salvia family. It is bitter in taste, and slightly cold in nature. It has efficacies of activating blood circulation to dissipate blood stasis, enriching blood and easing mind, cooling blood and expelling carbuncle, and g « “" -_ expelling toxin and promoting tissue regeneration. It is a drug commonly used in traditional Chinese medicine for activating blood circulation to dissipate blood stasis.

The main ingredients of RSM are liposoluble diterpenes, and water-soluble phenolic acids. In addition it contains flavonoids, triterpenes and sterols, etc. Among its diterpenes ingredients, tanshinone I, [I A, Il, V and VI, cryptotanshinone, isotanshinone I, 11 and [IB. dihydrotanshinone | and so on have a quinoid or Ketotorm structure. Water soluble ingredients of phenolic acids include danshensu. protecatechualdehy de. protocatechuic acid. caffeic acid. and derivatives of danshonsu und caffeic adid, or depsides that arc formed by esterification of dimers, such as salvianolic acid A, B, C, D, E and G, alkannic acid B, rosemary acid, methyl ester of rosemary acid, etc. Tanshinone IIA is one of the active ingredients cf diterpenes for activating blood circulation to dissipate biood stasis.

RSM is currently an important Chinese herbal medicine in the treatment of cardiovascular disease.

Modern researches have confirmed that RSM has pharmacological actions on: ® coronary artery ® myocardium repair and regeneration ® microcirculation ® hemorheology ® blood lipids.

These are manifested in dilating the coronary artery, anti-myocardial ischemia, anti-clotting, anti-thrombosis, sedation, alleviating pain, anti-atherosclerosis, and reducing blood lipids, etc.

The major effect of RSM on blood is the inhibition of platelet aggregation induced by adenosine diphosphate (ADP) . For patients with blood stasis, the dense and sticky blood condition causes slow blood flow and the platelets tend to adhere to the endangium that has been damaged. Drugs used for activating blood circulation and dissipating blood stasis can improve hemorheology and reduce the adhesion and aggregation of platelets.

Furthermore, these drugs can reduce the surface activity of platelets.

The mechanism of action of inhibition of platelet aggregation by drugs used in activating blood circulation to dissipate blood stasis is as follows: platelet aggregation is closely related to thc metabolism and activity of prostaglandin and cyclic nucleotide system. Platelet thromboxane (TXA;) is biosynthesized from phospholipids through many

‘ ' steps and using arachidonic acid as its intermediate. This process is essentially catalyzed by phosphatidase A and cyclooxygenase. The activities of these enzymes are regulated by cAMP which inhibits the activities of these enzymes and therefore the biosynthesis of

TXA,. If cAMP is reduced, the biosynthesis of TXA, increases. TXA; can promote the release of Ca from sarcoplasmic reticulum which is a reservoir of calcium in platelets. Ca acts on the dense granules causing adenosine diphosphate (ADP) and 5-hydroxytryptamine (3-H) to release trom them As ADP und S-HiD are the potent promoters for plateiet aggregation, the concentration ot ¢ AMP is the key factor in platelet aggregation. Increased cAMP reduces platelet aggregation. Furthermore, RSM has the activity of increasing fibrinolysis through activating the profibrinolysin-fibrinolysin system. Also, RSM can shorten the time of serum prothrombin formation.

Radix Notoginseng belongs to a class of traditional Chinese medicine used for hemostasia. In traditional Chinese medicine, it is regarded as having actions of dissipating blood stasis and arresting bleeding, and eliminating swelling and alleviating pain. It has the action of arresting bleeding as well as activating blood. Modern pharmacological researches have confirmed that Radix Notoginseng has both the hemostasis action and anti-clotting action. The hemostatic action includes slowing the bleeding and the hemoglutination progress, increasing platelets quantity and promoting the occurrence of pseudopod stretching, aggregation, and degranulation, etc. It can also reduce the permeability of blood capillary. Ingredients contained in Radix Notoginseng that have anti-clotting action include Radix Notoginseng sponin, Notoginsenoside diol and triol. They all inhibit platelet aggregation in human and rabbit. Radix Notoginseng sponin also promotes the secretion of tissue type profibrinolysin from the blood endothelial cells, and prevents the formation of thrombus.

Borneolum is a crystal product obtained by processing dammar, a resin obtained from plants of the dipteroarpaceae family. The crystal obtained from leaves of Blumea balsamifera Dc, a plant of the Composite family, by steam distillation, is called

Praeparatio Blumeae Folii. Products synthesized and processed from camphor, terebenthene and so on through chemical methods are called Borneolum Syntheticum.

Borneolum is pungent and bitter in nature. As it is aromatic, it can have a strong stimulating action on the scnse organs, and dispel the stagnated fire. Its effects of inducing and promoting resuscitation are similar to Pingxiang (a Chinese medicine). The

1010028 - Soe oen

ZU C4 12 main ingredient of Borneolum is d-borneol. Praeparatio Blumeac Folii’s main ingredient is l-borneol. Modern pharmacological researches have confirmed that Borncolum has effects against myocardial ischemia, and can significantly increase coronary blood flow.

Furthermore, as Borneolum can increase the permeability of blood-brain barrier, it can allow more drugs to cross the barrier.

In recent vears. through clinical observations and experimental studies. the application of RS\I preparations. particulary Compound Danshen Drop Pills 1CDDPs. compound RSM drop piils), has rurther been oreadencd. Now it has been continmed that it has effects against angina pectoris, and the effects of improving myocardial ischemia, reducing blood viscosity and platelet aggregation and so on. As a preparation for treatment and prevention of coronary heart disease and angina pectoris, the effect of

CDDPs on the hemorheology has been confirmed. Huang Weilan etc. have carried out a comparison study on normal mice and stress stimulated mice, and found that the hemorheological indexes of the mice of both groups were improved significantly after they were given CDDPs. For example, platelet aggregation rate in 1 min and maximum aggregation rate were reduced (P<0.05), and content of plasmatic fibrin was reduced (P<0.01). These indicated a weakening of the thrombosis characteristics. In stress stimulated mice the shear rate was reduced significantly from blood viscosity under the condition of n1~100 (P<0.05), indicating a process of reducing of blood circulation resistance and strengthening of circulation. Furthermore, there were observed reduction in filtration rate and enhancement in deformability of erythrocyte, but the packed cell volume was unchanged. These indicate that it is upon improving the quality of red blood cell that CDDPs achieve reduction of blood viscosity and improvement of circulation. In mice that did not undergo stimulation, although the whole blood viscosity was reduced, the reduction was insignificant (P>0.05). This means that the improvement of hemorheology by CDDPs in the abnormal hemorheological condition is more significant than in the normal hemorheological condition. Recent researches have found that CDDPs have effects of anti-atherosclerosis, lowering blood lipid, anti-fibrosis of chronic hepatopathy and so on. But up till now, there is not any reliable report about the actions of RSM preparations, particularly CDDPs, on aspirin resistance.

Summary of the Invention

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One aspect of the present invention relates to the use of RSM and its extract in the treatment of aspirin resistant cardiovascular and cerebrovascular diseases.

Or the purpose of the present invention is to provide the use of RSM and its extract in the preparation of a medicament for treating aspirin resistance.

Said aspirin resistance refers to an inability to effectively inhibit the biosynthesis of thromboxane A; after taking aspirin. That is. aspirin loses its protective effect on cardiovascular and cerebrovascular system. In ine major of patients. aspirin can reduce the risk of cardiovascuiar and ceredprovascular diseases by 23%. But for patients With aspirin resistance, treatment of cardiovascular and cerebrovascular diseases with aspirin can not prevent them from the cardiovascular and cerebrovascular events, but instead, can increase the risk of myocardial infarction and stroke. These findings have restricted the application of aspirin. In the present invention these cardiovascular and cerebrovascular diseases are called aspirin resistant cardiovascular and cerebrovascular diseases, particularly coronary heart discase and angina pectoris in which aspirin treatment is ineffective. In this invention, drugs that are effective in the treatment of aspirin resistant cardiovascular and cerebrovascular diseases are called drugs of anti-aspirin resistance; this action is called effect of anti-aspirin resistance.

The present invention adopts a now commonly used method for research of aspirin resistance. It uses immunoenzyme assay to test the urinary sample of the patients and analyze the change in the level of urinary 11-dehydrothromboxane B, (TXB,) to determine if there is any reduction of aspirin resistance in the patients after taking RSM preparation. From clinical investigations, the present invention confirms that RSM and its extract have effects of reducing aspirin resistance, and can be used as drugs of anti-aspirin resistance and for the preparation of drugs of anti-aspirin resistance.

Another aspect of the present invention relates to the use of a composition that contains RSM as its active ingredient in the treatment of aspirin resistant cardiovascular and cerebrovascular diseases. The compositions of the present invention include compound RSM preparations, particularly CDDPs and compound Danshen tablets (CDT, compound RSM tablets).

The following RSM compositions of this invention have preferable anti-aspirin resistance effect: RSM 30-180 parts, Radix Notoginseng 5-40 parts, Borneolum 0.3-2.5 parts, and adjuvants 10-40 parts. A preferred composition comprises RSM 75-115 parts,

. \

Radix Notoginseng 14-20 parts, Borneolum 0.8-1.2 parts, and adjuvants 15-30 parts. The most preferred composition comprises RSM 90 parts, Radix Notoginseng 17.6 parts,

Borneolum 1 parts, and adjuvants 20 parts.

The adjuvants used in the compositions of the present invention can be any adjuvants commonly used in the art of pharmaceutics. preferably polyethylene glycol, and most preferably polyethylene glycol 6000.

RS\IL its extract and compositions containing them as the active ingredients can be formulated into any pharmaceutical preparation. The preferred preparations are drop pills. spray solution, pellets, pills, granules, capsules, tablets. powder and oral liquid, etc.

For the preparation of active ingredients of the present invention, the following methods can be adopted: water extraction, water extraction combined with ethanol precipitation, extraction, impregnation, percolation, refluxing extraction, consecutive refluxing extraction, and macroporous resin adsorption. For example, these medicinal materials can be ground into powder and are mixed uniformly to form a powder preparation that can be infused orally. These medicinal materials can also be decocted with water, and then concentrated to form an oral liquid. But in order to exert the best effect of every active ingredient of the medicinal materials, it is preferable to use the following process for extraction.

RSM, 90g; Radix Notoginseng, 17.6g; Borneolum, 1g; polyethylene glycol 6000, 20g are provided. RSM and Radix Notoginseng are decocted with water for three times.

The decoctions are pooled and filtrated. The filtrate is condensed. 2 volumes of 95% ethanol are added and the solution is allowed to stand still for 24 hours before filtrating.

After the ethanol is recovered from the solution, the solution is condensed to reach a relative density of 1.33~1.35 (55~60°C) . Borncolum is dissolved in ethanol of appropriate volume. The above-mentioned solutions of extraction and of borneolum are added into polyethylene glycol that is melted in a water bath and stirred thoroughly. The resulted solution is kept at a temperature of 70+2°C. The solution is dropped by using a dropper of appropriate diameter at a speed of 60-80 drops per minute into liquid paraffin that is cooled in an ice bath. After being shaped, the pills are taken out and mopped out the liquid paraffin from its surface with absorbent paper. 1000 pills are prepared.

Amounts of the above components can be increased or reduced proportionally when in production factory use. If it is in a large scale production, the amounts in kilograms or tons as the measure unit may be used. 1f it is in a small-scale production, the amounts in grams may be used. The weights of every component may be increased or reduced, but the proportions of the medicinal materials are unchanged.

The said RSM, its extract and compositions comprising them include simple recipe or compound preparations that contain RSM or its extract. These compound preparations can contain other traditional Chinese medicine or chemical drug component.

Detailed Description of the Invention

The present invention is elaborated in details hereinafter. The specific examples or embodiments should not be construed to limit the scope of the application in any way.

Preparation Examples

Example 1: Method for Preparing Danhong Injection (Injection of RSM and Flos

Carthami)

I. RSM 750g, Flos Carthami 250g and sodium chloride for injection 7g were prepared for ready use. 2. The RSM was immersed in a diluted warm ethanol for one hour before filtrating.

The extraction by immersing was repeated. The filtrates were pooled for use. The residue of RSM was combined with Flos Carthami before immersing in warm water for one hour followed by filtrating. The extraction by immersing was repeated. All the filtrates were pooled and condensed to a clear paste with a relative density of 1.10~1.20 (65°C) .

Sodium chloride for injection was added into the paste to an isatonic concentration. After the pH was adjusted to 6-7, the paste was filtrated followed by refrigerating for 24 hours.

A sufficient quantity of water was added to produce the desired volume. The resulted slurry was filtrated, vialed and sterilized to produce danhong injection.

Example 2: Method for Preparing Qianglinaoxinkang Capsules 1. RSM 1500g, Armillaria Mellea extract 1500g and royal jelly 125g were prepared for ready use. 2. The RSM 75g was crushed into fine powder and the rest RSM was crushed to coarse powder. Water was added into the resulted powder to decoct three times, with the first time and the second time 2 hours and the third time 3 hours. The decoctions were

-— combined and filtrated. The filtrate was condensed under decompression condition to a thick paste with a relative density of 1.30~1.32 (70°C) . The paste was evaporated under decompression condition and crushed into fine powder. Armillaria Mellea extract was condensed under decompression condition to a thick paste having a relative density of 1.30~1.32(70°C). The pastc was evaporated under decompression condition and crushed into fine powder. The fine powder was combined with the abo e-mentioned fine ponder and mixed thoroughly. The minture was granulated and desiceated The roval jeiiy was freeze-dried to obtain fine powuer. The powder was combined with the above granules and mixed thoroughly before encapsulating to produce the titled capsules.

Example 3: Method for Preparing Tongxinshu Capsules

I. Seabuckthorn flavone 250g, RSM extract 20g, Rhizoma Chuanxiong 10g and talcum powder 20g were prepared for ready use. 2. The Rhizoma Chuanxiong was crushed into fine powder and admixed with seabuckthorn flavone and RSM extract. The talcum powder was added followed by encapsulation to produce the tongxinshu capsules.

Example 4: Method for Preparing Compound Dangshen Tablets 1. Radix Codonopsis 704g, RSM 192g, Radix Angelicae Sinensis 192g, Radix

Glehniae 128g, Radix Tinosporae 64g, starch 4.7g, dextrin 9.4g, talcum powder 4.3g and magnesium stearate 1.6g were prepared for ready use. 2. The Radix Tinosporae was immersed in water for 2 hours. The rest four medicinal materials including RSM were immersed in water for 1 hour. The extract thus obtained was pooled and decocted three times, each for one hour. The decoctions for three times were pooled and filtrated, followed by condensing and drying under decompression condition at a temperature less than 85°C. The dry extract resulted was crushed to coarse powder before adding starch and dextrin. The mixture was mixed up thoroughly and granulated before drying at 85°C. The granules were trimmed and the talcum powder and magnesium stearate were added before mixing thoroughly. The mixture obtained was tableted and sugar-coated to produce the desired tablets.

Example 5: Method for Preparing Danxiangguanxin Injection

— 1. RSM 1000g and Lignum Dalbergiae Odoriferae 100g were prepared for ready use. 2. The Lignum Dalbergiae Odoriferae was soaked with water and a sufficient quantity of water was added before distilling. About 700 m! distillate was collected and refrigerated for 24 hours. The oil layer was removed and filtrated. The aqueous layer was collected in another container. The RSM was decocted with water for three times. 2 hours for each time. The decoctions were pooled and filtrated before condensing to Soil. The ethanol was added to obtain an cthanc! content of 7370 und the resailed solution was refrigerated for 48 hours before filtrating. The filtrate was condensed to 200ml by recovering the ethanol. Ethanol was added again to obtain an ethanol content of 85%. The resulted solution was refrigerated for 48 hours before fiitrating. The filtrate was condensed to 120m! by recovering the ethanol. A sufficient quantity of water for injection was added to the desired volume of 1000ml and refrigerated for 16 hours before filtrating. The filtrate was condensed to a volume of 250 ml and refrigerated for 72 hours.

The pH was adjusted to 6.0-6.8 with 10% solution of sodium hydroxide. The active carbon was added in an amount of 0.1%-0.4% of the medicinal materials and boiled for 30 min before filtrating. The filtrate was adjusted to pH 4 with weak hydrochloric acid.

The active carbon was added again in an amount of 0.1%-0.4% of the medicinal materials before boiling 30 min. The resulted solution was refrigerated for at least 24 hours before filtrating. The filtrate was adjusted to pH 6.5-7.0 with 10% solution of sodium hydroxide.

After the above distillate of Lignum Dalbergiae Odoriferae was added, a sufficient quantity of water for injection was added to the desired volume. The solution was filtrated, vialed and sterilized to obtain the titled injection.

Example 6: Method for Preparing Danshen injection

I. RSM 64g and glucose 50g (67g) were prepared for ready use. 2. RSM was decocted with water for three times, 2 hours for each time. The decoctions were pooled and filtrated. The filtrate was condensed to a clear paste with a relative density of 1.16 (70°C) . Ethanol was added to obtain an ethanol content of 75%.

The solution was agitated thoroughly before refrigerating for 24 hours followed by filtrating. The filtrate was condensed to a clear paste with a relative density of 1.06~ 1.08 (78°C) by recovering the ethanol. The pH was adjusted to 9 with a solution of 40%

sodium hydroxide. The paste was boiled for one hour before adjusting the pH to 6 with hydrochloric acid followed by filtrating. After the filtrate was cooled to room temperature, the ethanol was added to obtain an ethanol content of 85%. The solution was agitated thoroughly before refrigerating for 24 hours followed by filtrating. The filtrate was condensed to a clear paste with a relative density of 1.11~1.13 (78°C) by recovering the cthanel. Water for injection was added to dilute the paste 4-1olds. After the pH was adjusted to 2 with hydrochloric acid. the dituted paste was refricerated ror 72 hours before filtrating. After voiling ne riitrate. acting carbon was added in an amount of 0.1%(g/ml). The filtrate was boiled for 15 min. before filtrating. The filtrate was held for future use. The glucose was added to the boiling water for injection to obtain a thick solution of 50%~ 60%. Hydrochloric acid q.s was added and active carbon was added in an amount of 0.1% (g/ml) at the same time. The solution was agitated thoroughly, and boiled for 15 min. The solution was filtrated when it was hot to remove the active carbon.

The filtrate was combined with the filtrate of RSM. The pH was adjusted to 3.8~4.2 with a solution of 10% sodium hydroxide. After boiling, active carbon was added in an amount of 0.05% (g/ml) followed by boiling for 30 min. After the solution was filtrated, a sufficient quantity of water for injection was added to the desired volume of 500ml.

Sodium bisulfite 0.5g was added and mixed thoroughly. The pH was adjusted to 5~6 with the solution of 10% sodium hydroxide. Water for injection was added to the desired volume before filtrating, fine filtrating and ultrafiltrating. The filtrate was vialed and sterilized to produce the titled injection.

Example 7: Mcthod for Preparing Jingzhi Guanxin Granules 1. RSM 350.8g, Radix Paeoniae Rubra 175.4g, Rhizoma Chuanxiong 175.4g, Flos

Carthami 175.4g, Lignum Dalbergiae Odoriferae 116.9g, sucrose 841g and dextrin 105g were prepared for use. 2. The four medicine materials except Flos Carthami were decocted with water for three times, with the first time 2 hours, the second time 1.5 hours, and the last 1 hour before filtrating. The filtrates were pooled and held for future use. Immerse Flos

Carthami was immersed in a suitable amount of warm water of 80°C for two times, with the first time 2 hours, and the second time 1 hour before filtrating. The filtrate was combined with the above filtrate and condensed to thick paste. The paste was dried at

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Claims (20)

1. M Ls 1040028 —- P) ER

   LOC. i612 -— CLAIMS:

   I. Use of RSM, its extract or compositions comprising any or both of them as active ingredients in the production of medicaments of anti-aspirin resistance.
2. 2. Usc oof claim 1 wherein the said aspirin resistance is aspirin resistant cardio-cerebrovascular diseases.
3. 3. Use of claim 2 wherein the said aspirin resistant cardio-cerebrovascular diseases include coronary heart disease and angina pectoris.
4. 4. Use of claim 1 wherein the said compositions include compound preparations comprising RSM or its extract.
5. 5. Use of claim 4 wherein the said compound preparations are selected from the group consisting of danhong injection, gianglinaoxinkang, tongxinshu capsules, compound dangshen tablets, danxiang guanxin injection, danshen injection, jingzhi guanxin granules, jingzhi guanxin tablets, shuxintong capsules, xinnaoning capsules, guanxindanshao tablets, xinxinshu capsules, xiongxiangtongmai pills, guanxindanshen tablets, guanxindanshen drop pills, compound danshen drop pills, and compound danshen tablets.
6. 6. Use of claim 4 wherein the said compositions comprise RSM 30-180 parts, Radix Notoginseng 5-40 parts, Borneolum 0.3-2.5 parts, and adjuvants 10-40 parts.
7. 7. Use of claim 6 wherein the said composition comprises RSM 75-115 parts, Radix Notoginseng 14-20 parts, Borneolum 0.8-1.2 parts, and adjuvants 15-30 parts.
8. 8. Use of claim 7 wherein the said composition comprises RSM 90 parts, Radix Notoginseng 17.6 parts, Borneolum 1 parts, and adjuvants 20 parts.
9. 9. Use of claim 6 wherein the adjuvants include polyethylene glycol.

   A SEERA PCT/CN2004/000989 WO 2005/049058 Al
10. 10. Use of claim 4 wherein the said compositions are selected from the group consisting of drop pills, spray solution, pellets, pills, granules, capsules, tablets, powder and oral liquid.
11. 11. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof comprising administering said RSM, its extract or compositions comprising any or both of them as active ingredients to said mammal.
12. 12. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 11 wherein the said aspirin resistance is aspirin resistant cardio-cerebrovascuiar diseases.
13. 13. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 12 wherein the said aspirin resistant cardio-cerebrovascular diseases include coronary heart disease and angina pectoris.
14. 14. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in any one of claims 11 to 13 wherein the RSM, its extract or compositions comprising any or both of them as active ingredients is in a dosage form which is selected from the group consisting of danhong injection, gianglinaoxinkang, tongxinshu capsules, compound dangshen tablets, danxiang guanxin injection, danshen injection, jingzhi guanxin granules, jingzhi guanxin tablets, shuxintong capsules, xinnaoning capsules, guanxindanshao tablets, xinxinshu capsules, xiongxiangtongmai pills, guanxindanshen tablets, guanxindanshen drop pills, compound danshen drop pills, and compound danshen tablets.
15. 15. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 11 or in claim 14 wherein the said compositions comprise RSM 30-180 parts, Radix Notoginseng 5-40 parts, Boneolum 0.3-2.5 parts, and adjuvants 10-40 parts. prt 1 AMENDED SHEET
16. PCT/CN2004/000989 WO 2005/049058 Al } 16. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 15 wherein the said composition comprises RSM 75-115 parts, Radix Notoginseng 14-20 parts, Borneolum 0.8-1.2 parts, and adjuvants 15-30 parts.
17. 17. RSM. its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 16 wherein the said composition comprises RSM YU parts, Radix Notoginseng 17.6 parts, Borneolum 1 parts, and adjuvants 20 parts.
18. 18. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in claim 15 wherein the adjuvants include polyethylene glycol.
19. 19. RSM, its extract or compositions comprising any or both of them as active ingredients for use in treating anti-aspirin resistance in a mammal in need thereof as described in any one of claims 11 to 13 wherein the RSM, its extract or compositions comprising any or both of them as active ingredients is in a dosage form which is selected from the group consisting of drop pills, spray solution, pellets, pills, granules, capsules, tablets, powder and oral liquid.
20. 20. A medicament substantially as herein described with reference to and as exemplified in any one of examples 1 to 40. a 40 AMENDED SHEET