CN110755440B - Application of ligustrazine and mannuronic acid composition in preparing medicine for treating thrombotic diseases and nervous system diseases - Google Patents
Application of ligustrazine and mannuronic acid composition in preparing medicine for treating thrombotic diseases and nervous system diseases Download PDFInfo
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- CN110755440B CN110755440B CN201911140294.7A CN201911140294A CN110755440B CN 110755440 B CN110755440 B CN 110755440B CN 201911140294 A CN201911140294 A CN 201911140294A CN 110755440 B CN110755440 B CN 110755440B
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Abstract
The invention provides an application of a composition of ligustrazine and mannuronic acid in preparing a medicament for treating thrombotic diseases and nervous system diseases, and test results prove that: compared with the single administration of the ligustrazine and the mannuronic acid, the combined administration of the ligustrazine and the mannuronic acid produces the synergistic effect of obviously better than the single administration and the effect of resisting platelet aggregation. The invention proves that the ligustrazine and the mannuronic acid can be combined and compounded to be applied to the preparation of medicines for treating thrombotic diseases and central nervous system disorder and circulatory disturbance caused by thrombus, and the invention has good market application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a composition of ligustrazine and mannuronic acid in preparation of medicines for treating thrombotic diseases and nervous and circulatory system diseases.
Background
Cardiovascular and cerebrovascular diseases are diseases which seriously threaten human life and health in the modern society, and are clinically manifested as cardiovascular and cerebrovascular ischemia or hemorrhage. According to the WHO estimation, 400 million people die of cardiovascular and cerebrovascular diseases every year in China by 2020. Stroke is also called cerebral stroke or cerebrovascular accident, the main clinical manifestations are cerebral ischemia and hemorrhagic injury, one thousand five million people suffer from stroke every year in the world, and in China, stroke is the first leading cause of human death and the third leading cause of disability. Most strokes are sudden death caused by oxidative stress of certain brain cells due to occlusion or rupture of cerebral arteries caused by blood clots. Ischemic stroke is a complex systemic disease with significant morbidity and mortality worldwide and requires significant medical and health expenditures, a serious problem in the medical world and even the society. Although many drugs have different curative effects on ischemic stroke, the effect is not ideal, and no certain drug is effective for all patients with ischemic stroke at present, namely no specific drug in the true sense is provided for the stroke. Therefore, the development of a novel efficient medicament for treating the cerebral arterial thrombosis has great practical significance. Currently, there are two main treatments for ischemic stroke: firstly, the blood oxygen supply of an ischemic area is increased by dissolving thrombus, and the clinical application of the blood oxygen supply mainly comprises vasodilators, anti-platelet aggregation drugs, anticoagulant drugs and thrombolytic drugs; and secondly, protecting neurons of ischemic tissues and preventing cells from being excitable and toxic.
The natural product is one of the important sources of the lead compounds of the innovative medicaments. Ligustrazine (ligustrazine) is separated from rhizoma Ligustici Chuanxiong, and is one of effective components of rhizoma Ligustici Chuanxiong. Ligustrazine has effects of inhibiting platelet aggregation, relieving angiospasm of smooth muscle, improving myocardial ischemia, and improving blood rheological property. However, pharmacokinetic studies find that ligustrazine has the disadvantages of fast metabolism, short half-life, low bioavailability and the like in animal bodies; clinical continuous administration is often performed to ensure that the concentration of ligustrazine in blood plasma can be kept at a certain level, but the toxicity of the medicine is increased. Therefore, the research on the ligustrazine derivative and the compound preparation thereof attracts the wide attention of scientists, so that the application problems of improving the drug effect of the drug by combined medication and the like are expected. Xujuan et al, CN201910378502, discloses pharmaceutical cocrystals of ethinylestradiol and ligustrazine and their application; zhengjiangyong et al disclose ligustrazine phosphate compounds and pharmaceutical compositions containing the same and effective components of ginkgo leaves in 201410092322; chuanjun in CN 200610153342 discloses a pharmaceutical composition of ligustrazine and rhodiola; however, there is no report that ligustrazine and mannuronic acid are combined for use in related diseases.
Disclosure of Invention
The invention aims to provide the application of the composition of ligustrazine and mannuronic acid in preparing medicaments for treating thrombotic diseases and nervous system diseases.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the invention provides a composition of ligustrazine and mannuronic acid, wherein the weight ratio of the ligustrazine to the mannuronic acid in the composition is 1: 20-1: 1.5.
Further, the weight ratio of the ligustrazine to the mannuronic acid in the composition is 1: 15-1: 2.
Further, the weight ratio of the ligustrazine to the mannuronic acid is 1: 15-1: 3.
Further, the weight ratio of the ligustrazine to the mannuronic acid is 1: 12-1: 3.
Further, the weight ratio of the ligustrazine to the mannuronic acid is 1: 10-1: 4.
Furthermore, in the pharmaceutical composition of unit dose, the content of the ligustrazine is 10-400mg.
Furthermore, in the pharmaceutical composition of unit dose, the content of the ligustrazine is 15-375mg.
Further, the content of the ligustrazine is 20-300mg.
Further, the mannuronic acid is selected from brown algae degradation products and diacid products generated by further reduction end oxidation.
Further, the ligustrazine and the mannuronic acid respectively comprise pharmaceutically acceptable salts, selective sulfuric acid substitution, phosphoric acid substitution, nitric acid substitution, propyl ester substitution analogues thereof or a combination of one or more of the compounds, and also comprise pharmaceutically acceptable salts or solvates of derivatives of the ligustrazine and the mannuronic acid.
The invention also provides the application of the ligustrazine and the mannuronic acid in preparing the medicines for preventing or treating thrombotic diseases and nervous system diseases.
Further, the thrombotic diseases comprise apoplexy, cardiovascular and cerebrovascular diseases, peripheral vascular embolism, nephritis and renal failure related diseases
Further, the composition is a pharmaceutical composition for oral administration, and the pharmaceutical composition is selected from tablets, capsules, oral liquid, powder and granules.
Further, the neurological and circulatory diseases include senile dementia, memory deterioration, and diseases related to cardiac dysfunction.
The invention has the advantages and the technical effects that: the invention provides a ligustrazine and mannuronic acid pharmaceutical composition and application thereof, and test results prove that: compared with single administration of ligustrazine and mannuronic acid, the combination administration of ligustrazine and mannuronic acid produces a synergistic effect which is obviously superior to that of single administration and can resist platelet aggregation, and the indication shows that the ligustrazine and mannuronic acid can act from different ways after the combination and the combination can synergistically play stronger efficacies of preventing and treating thrombotic diseases. Can be used for preparing medicines for treating thrombotic diseases, nervous system disorder and circulatory disturbance after the ligustrazine and the mannuronic acid are combined and compounded, and has good market application prospect.
Detailed Description
The technical solutions in the embodiments of the present invention are described in detail below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: action of oral ligustrazine and mannuronic acid on platelet aggregation of experimental rat
SD rats, male, 3-4 weeks old, were selected and provided by the Experimental animals center, shandong province. The experimental animals are divided into 5 groups, each group comprises 6 animals, a control group and ligustrazine of 100mg/kg; mannuronic acid 200mg/kg; 100mg/kg and 200mg/kg of the combination of ligustrazine and mannuronic acid (1; intragastric administration; the preparation is administered once daily for one week, and is fixed on operating table after experiment, and used for puncturing heart and collecting blood, and using lemonAnticoagulating sodium citrate, centrifuging at 1000rpm for 10 minutes, and sucking supernatant fluid to obtain platelet-rich plasma PRP; the remaining blood was centrifuged again at 3000rpm for 20 minutes, and the supernatant was platelet poor plasma PPP. Regulation of PRP platelet count to 4X10 with PPP 8 And/ml. Adjusting to zero by PPP, adding PRP into a turbid pen, bathing at 37 ℃ for 10 minutes, respectively adding an inducer ADP, measuring the platelet aggregation property on a platelet apparatus, recording the maximum platelet aggregation rate within 15 minutes, and calculating the platelet aggregation inhibition rate. Platelet aggregation inhibition (%) = [ 1-percent sample tube aggregation/percent control tube aggregation]×100。
The experimental results in Table 1 show that ligustrazine can obviously inhibit platelet aggregation at 100mg/kg, mannuronic acid can inhibit but is not obvious at 200mg/kg, and ligustrazine can not inhibit obviously at 25 mg/kg. When the two drugs are jointly administered, the activity of inhibiting platelet aggregation is greatly improved, and the platelet aggregation can be more obviously inhibited by containing (25-50 mg/kg) ligustrazine, so that the combined drug group can greatly reduce the toxic and side effects of the ligustrazine, the mannuronic acid as an edible compound has no toxic and side effects, and the ligustrazine and the mannuronic acid have the function of synergy.
Therefore, the combined medicine not only has the synergistic effect, but also can obviously reduce the dosage of the ligustrazine and reduce the toxic and side effects.
TABLE 1 Effect of ligustrazine and mannuronic acid on platelet aggregation in rats of Home
| Sample (I) | Platelet aggregation inhibition rate | Platelet aggregation Rate |
| Control of | 55±1.2％ | |
| Ligustrazine group 100mg/kg | 32％ | 37±2.0％ |
| Ligustrazine 25mg/kg | 18％ | 45±1.7％ |
| Mannuronic acid group 200mg/kg | 10％ | 50±1.8％ |
| Combination group 100mg/kg | 42％ | 32±2.1％ |
| Combination group 200mg/kg | 55％ | 25±2.7％ |
Example 2: action of oral ligustrazine and mannuronic acid on rabbit platelet aggregation
New Zealand rabbits are selected as experimental animals, the weight of the experimental animals is 2-3kg, and the male animals are provided by the experimental animal center of Shandong province. The experimental animals are divided into 5 groups, each group comprises 6 animals, a control group and ligustrazine of 100mg/kg; mannuronic acid 200mg/kg; 100mg/kg and 200mg/kg of the combination of ligustrazine and mannuronic acid (1; intragastric administration; the preparation method comprises the steps of once a day, continuously administering for one week, fixing the rabbit on the back on an operating table after the experiment is finished, puncturing the heart with a needle to take blood, simultaneously using sodium citrate for anticoagulation, centrifuging at 1000rpm for 10 minutes, and absorbing supernatant fluid to obtain platelet-rich plasma PRP; the residual blood is centrifuged again at 3000rpm for 20 minutes, and the supernatant is the platelet poor plasma PPP. PRP platelet counts were adjusted to 4X108/ml using PPP. Adjusting to zero by PPP, adding PRP into a turbid pen, bathing at 37 ℃ for 10 minutes, respectively adding an inducer ADP, measuring the platelet aggregation property on a platelet apparatus, recording the maximum platelet aggregation rate within 15 minutes, and calculating the platelet aggregation inhibition rate.
Platelet aggregation inhibition (%) = [ 1-sample tube aggregation percentage/control tube aggregation percentage ] × 100.
The experimental results in table 2 show that ligustrazine can obviously inhibit platelet aggregation at 100mg/kg, mannuronic acid has an inhibiting effect but is not obvious at 200mg/kg, and ligustrazine with low dose (25 mg/kg) can obviously inhibit platelet aggregation when the ligustrazine and mannuronic acid are jointly administered, so that the clinical dose of the ligustrazine can be obviously reduced, the toxic and side effects of the ligustrazine are reduced as much as possible, and the ligustrazine and mannuronic acid have a synergistic function.
TABLE 2 Effect of ligustrazine and mannuronic acid on platelet aggregation in rabbits
The above examples are merely illustrative of the technical solutions of the present invention, and not limitative thereof; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or equivalents may be substituted for some of the features thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (6)
1. The composition of ligustrazine and mannuronic acid is characterized in that the weight ratio of the ligustrazine to the mannuronic acid in the composition is 1; the content of ligustrazine is 15-375mg.
2. The combination of ligustrazine and mannuronic acid as claimed in claim 1, wherein the mannuronic acid is selected from brown algae degradation products and diacid products generated by further reducing terminal oxidation.
3. The composition of ligustrazine and mannuronic acid as claimed in claim 1, wherein the ligustrazine and mannuronic acid comprise pharmaceutically acceptable salts thereof, respectively.
4. Use of the composition of any one of claims 1 to 3 for the preparation of a medicament for the prevention or treatment of thrombotic disorders.
5. The use according to claim 4, wherein the thrombotic disorders include stroke and peripheral vascular embolism.
6. The use according to claim 4, wherein the composition is a pharmaceutical composition for oral administration, and the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, oral liquids, powders, and granules.
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| CN1088937A (en) * | 1993-01-01 | 1994-07-06 | 青岛海洋大学 | A kind of propyl mannuronate sulfate as medicine |
| CN1230175C (en) * | 2002-12-27 | 2005-12-07 | 李晓祥 | Ligustrazine hydrochloride freeze-dried preparation for injection and its preparing method |
| CN1562050A (en) * | 2004-03-24 | 2005-01-12 | 中国海洋大学 | Use of oligose alginate in anti-dementia and anti-diabetes |
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