CN109091667B - Application of human urinary kallidinogenase in preparing medicine for treating migraine and composition thereof - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of human urinary kallidinogenase in preparing a medicine for treating migraine and a pharmaceutical composition for treating the migraine. The present invention provides the use of human urinary kallidinogenase for the treatment of migraine. The invention also provides a pharmaceutical composition for treating migraine, which comprises human urinary kallidinogenase and panax notoginseng saponins, and the pharmaceutical composition has a synergistic effect in treating migraine and has the advantages of obvious treatment effect, simple preparation process, low adverse reaction incidence rate and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of human urinary kallidinogenase in preparing a medicine for treating migraine and a composition thereof.
Background
Human urinary kallidinogenase is a glycoprotein extracted from urine of healthy men, has a molecular weight of about 54000Da, and is a single chain consisting of 238 amino acids. The human urinary kallidinogenase has the functions of activating human plasma kininogen to be converted into kinins, expanding capillary vessels, resisting thrombus, improving blood circulation, increasing blood flow, resisting coagulation, dissolving thrombus, reducing blood viscosity, increasing deformability of red blood cells, inhibiting platelet aggregation and the like, and is protease with high application value.
Headache is one of the most common clinical symptoms, and migraine is the most common primary headache. With the development of socio-economic and the increase of living pressure, the prevalence rate of migraine is on the rise. Migraine is a chronic, recurrent and disabling neurovascular dysfunctional disease, most scholars consider migraine as a multifactorial disease caused by interaction of environmental factors and genetic factors, and the theories of pathogenesis of migraine are numerous, including the theories of vascularity, neuroreflexia, trigeminal neurovascular reflexia and the like, wherein the trigeminal neurovascular reflexia dominates, and neurogenic inflammation as a key link of the trigeminal neurovascular reflexia is recognized as one of main mechanisms in the migraine occurrence process. The neurogenic inflammation theory considers that the nociceptive stimulation generated at the periphery generates aseptic inflammatory reaction when being conducted to the tail nucleus of trigeminal nerve and higher brain center along the trigeminal nerve, and trigeminal nerve endings release inflammatory reaction transmitters such as calcitonin gene-related peptide (CGRP) and the like to cause the changes of vasodilation, mast cell degranulation and the like, release histamine and generate pain. The migraine is actually angioneurotic headache, and has a certain relation with some intracranial vascular diseases, and researches show that the probability of cerebral infarction of migraine patients is higher than that of common people. At present, the drugs for treating migraine are mainly nonspecific drugs and specific drugs, and the nonspecific drugs mainly comprise non-steroidal anti-inflammatory drugs, barbiturate sedatives and opioids, and although the drugs can be used for treating migraine, some drugs have serious addiction and induce drug resistance to other drugs; specific drugs include triptans, ergotamines and calcitonin gene-related peptide receptors, but the incidence of adverse drug reactions is high.
Panax notoginsenosides are the main active ingredients of Panax notoginseng (Burk.) F.H.Chen of Panax of Araliaceae, and contain various monomeric saponins. The panax notoginseng saponins have the pharmacological effects of expanding blood vessels, reducing myocardial oxygen consumption, removing free radicals, resisting inflammation, resisting oxidation and the like, and are a cardiovascular disease medicament with remarkable treatment effect and small side effect. Chinese patent document CN 1864701A discloses a traditional Chinese medicine film agent which is quickly dissolved in oral cavity, the film agent is composed of traditional Chinese medicine active ingredients, film forming materials and pharmaceutic adjuvants, wherein the traditional Chinese medicine active ingredients comprise coronary heart salvia miltiorrhiza extract, panax notoginseng saponins, breviscapine, gastrodin, acegastrodin and the like, and the traditional Chinese medicine film agent can be used as an emergency medicine for treating cardiovascular and cerebrovascular diseases and migraine. Chinese patent document CN 101024073A discloses the application of human urinary kallidinogenase in preparing medicine for treating and/or preventing hypertension complicated with cerebral infarction. At present, no report related to the combined application of human urinary kallidinogenase and panax notoginseng saponins for treating migraine exists, so that a novel and effective pharmaceutical composition for treating migraine is very necessary to provide people based on the problems of adverse reactions and the like caused by the medicines for treating migraine in the prior art.
Disclosure of Invention
The first purpose of the invention is to provide the application of human urinary kallidinogenase in preparing medicines for treating migraine.
According to the invention, the influence of human urinary kininogenase on the regulation and control research ethological score of the peroxisome proliferator receptor (PPARs) expression of migraine rats and the influence of human urinary kininogenase on the concentration of calcitonin gene-related peptide (CGRP) released by trigeminal nerve endings in the plasma of the migraine rats are researched, so that the human urinary kininogenase can effectively reduce the regulation and control research ethological score of the PPARs expression of the migraine rats and can remarkably reduce the concentration of CGRP released by the trigeminal nerve endings in the plasma of the migraine rats. Therefore, the invention provides a new application of human urinary kallidinogenase in the field of medicine, namely the human urinary kallidinogenase can be used as a medicine for treating migraine.
Further, the dosage of human urinary kallidinogenase for adults is 1.2 multiplied by 10-3～3.3×10-3PNA/kg。
Further, the human urinary kallidinogenase is used for adults at a dosage of 2.5X 10-3PNA/kg。
The invention also aims to provide a pharmaceutical composition for treating migraine, which comprises human urinary kininogenase and panax notoginseng saponins, has a remarkable effect on reducing the regulation and control research behavioral scores of the PPARs in migraine rats and the concentration of CGRP in plasma, and has a synergistic effect compared with the pharmaceutical composition prepared by singly administering the human urinary kininogenase or the panax notoginseng saponins.
Further, the pharmaceutical composition is an injection, and can be prepared according to a conventional preparation.
Further, the injection comprises the following components per milliliter: 0.072-0.198 PNA of human urinary kallidinogenase and 3-6 mg of panax notoginseng saponins.
Still further, the injection comprises the following components per milliliter: human urinary kallidinogenase 0.15PNA and notoginseng total saponin 4.5 mg.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention provides a new application of human urinary kallidinogenase in the field of medicine, namely the human urinary kallidinogenase can be used as a medicine for treating migraine, the application direction of the human urinary kallidinogenase is developed, and a new medicine is provided for a large number of migraine patients.
(2) The invention provides a pharmaceutical composition for treating migraine, which comprises human urinary kallidinogenase and panax notoginseng saponins. Meanwhile, compared with the single use of human urinary kallidinogenase or panax notoginseng saponins, the pharmaceutical composition provided by the invention has a remarkable synergistic effect in the aspect of treating migraine.
(3) The invention provides a pharmaceutical composition for treating migraine, which is in the form of injection, has good stability and obviously reduces the incidence rate of adverse reactions.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
The invention discloses human urokininogenase, namely injection uliriline, which is purchased from Guangzhou Tianpu biochemical medicine GmbH (national standard H20052064, specification 0.15PNA unit/bottle); panax notoginsenosides, i.e., injectable thrombolytic drug (lyophilized), were purchased from Guangxi Sterculia procumbens pharmaceutical (group) GmbH (national Standard Z20025652, 100mg × 10 bottles).
Example 1 human urinary kallidinogenase injection of the invention
Dissolving filtered and sterilized 150PNA units of human urinary kallidinogenase in proper amount of water for injection, regulating pH value to neutral, adding water for injection to 1000mL, adding sodium chloride to regulate isotonicity, sterile filtering, and packaging into 1000 ampoules.
Example 2 injection for treating migraine according to the invention
Dissolving filtered and sterilized human urinary kallidinogenase 72PNA unit in appropriate amount of water for injection, adding 3g of Panax notoginsenosides, dissolving, adjusting pH to neutral, adding water for injection to 1000mL, adding sodium chloride to adjust isotonic, sterile filtering, and packaging into 1000 ampoules.
EXAMPLE 3 injection for treating migraine according to the invention
Dissolving filtered and sterilized human urinary kallidinogenase 150PNA unit in appropriate amount of water for injection, adding 4.5g of Panax notoginsenosides, dissolving, adjusting pH to neutral, adding water for injection to 1000mL, adding sodium chloride to adjust isotonic, sterile filtering, and packaging into 1000 ampoules.
EXAMPLE 4 injection for treating migraine according to the invention
Dissolving filtered and sterilized human urinary kallidinogenase 198PNA unit in appropriate amount of water for injection, adding 6g of Panax notoginsenosides, dissolving, adjusting pH to neutral, adding water for injection to 1000mL, adding sodium chloride to adjust isotonic, sterile filtering, and packaging into 1000 ampoules.
Example 5 injection for treating migraine according to the invention
Dissolving filtered and sterilized human urinary kallidinogenase 72PNA unit in appropriate amount of water for injection, adding 3.5g of Panax notoginsenosides, dissolving, adjusting pH to neutral, adding water for injection to 1000mL, adding sodium chloride to adjust isotonic, sterile filtering, and packaging into 1000 ampoules.
EXAMPLE 6 injection for treating migraine according to the invention
Dissolving filtered and sterilized 150PNA units of human urinary kallidinogenase in appropriate amount of water for injection, adding 3g of Panax notoginsenosides, dissolving, adjusting pH to neutral, adding water for injection to 1000mL, adding sodium chloride to adjust isotonic, sterile filtering, and packaging into 1000 ampoules.
Test example I, Effect of the pharmaceutical composition for treating migraine of the present invention on the modulation of the expression of PPARs in migraine rats to study the behavioral scores
Male SD rats of cleaning grade, provided by the experimental animals center of university of zhongshan; glycerol nitrate injection (1 mL/5mg specification, approved reference: H11020289) was purchased from Beijing Yimin pharmaceutical Co., Ltd; sumatriptan succinate tablets (specification: 100mg, approved article: H20040700) were purchased from Tianjin Huajin pharmaceutical Co., Ltd.
The specific experimental steps are as follows:
s1, grouping: 80 male SD rats are grouped by a random number table method according to the weight balance principle, the grouping condition is specifically shown in table 1, then molding treatment is carried out, wherein a model group, a sumatriptan succinate group, a human urinary kallidinogenase group, a panax notoginseng saponins group and a human urinary kallidinogenase and panax notoginseng saponins drug composition group are subjected to abdominal subcutaneous injection by a nitroglycerin method of 10mg/kg, and blank groups are subjected to abdominal subcutaneous injection by normal saline with equal dosage. And (3) evaluation standard of molding success: 5min scratch after incubation: 1 point for 10 times, beating: and (3) climbing a cage for 2 times which is 1 minute: 1 point for 3 times, dysphoria: 1 minute of reciprocating motion, tail biting: 1 time to 1 point, ear red: if the mold is divided into 1 minute, the mold is supplemented if the mold is not successfully manufactured;
s2, administration: all animals were started one week after acclimatization and given a dosing treatment two hours after molding, wherein the dosing for each group was as follows:
blank group: feeding normally without any treatment;
model group: continuously injecting normal saline with the same volume as human urinary kallidinogenase into vein for one week;
sumatriptan succinate tablet set: perfusing the stomach with 9mg/kg sumatriptan succinate tablets continuously for one week;
human urinary kininogenase group: at 16X 10-3PNA/kg human urinary kallidinogenase was continuously injected intravenously for one week;
panax notoginsenosides group: continuously performing intravenous injection with 0.47mg/kg of Panax notoginsenosides for one week;
human urinary kallidinogenase + panax notoginseng saponins group A: at 7.5X 10-3PNA/kg human urinary kallidinogenase +0.3mg/kg panax notoginseng saponins for one week by continuous intravenous injection;
human urinary kallidinogenase + panax notoginseng saponins group B: at 16X 10-3PNA/kg human urinary kallidinogenase +0.47mg/kg panax notoginseng saponins for one week by continuous intravenous injection;
human urinary kallidinogenase + panax notoginseng saponins group C: at 21X 10-3PNA/kg human urinary kallidinogenase +0.625mg/kg panax notoginseng saponins for one week by continuous intravenous injection;
human urinary kallidinogenase + panax notoginseng saponins group D: at 7.5X 10-3PNA/kg human urinary kallidinogenase +0.625mg/kg panax notoginseng saponins for one week by continuous intravenous injection;
human urinary kallidinogenase + panax notoginseng saponins E group: at 21X 10-3PNA/kg human urinary kallidinogenase +0.3mg/kg panax notoginseng saponins for one week by continuous intravenous injection;
s3, observation of behavioral changes: by observing the video recording for two hours, each group of molding conditions is observed and the calculation of the behavioral score is carried out according to the scoring standard.
TABLE 1 grouping of experimental rats
| Group of | Number of animals (only) |
| Blank group | 8 |
| Model set | 8 |
| Sumatriptan succinate tablet set | 8 |
| Human urinary kallidinogenase group | 8 |
| Notoginseng radix total saponin group | 8 |
| Human urinary kallidinogenase and panax notoginseng saponins A group | 8 |
| Human urinary kallidinogenase and panax notoginseng saponins B group | 8 |
| Human urinary kallidinogenase + panax notoginseng saponins C group | 8 |
| Human urinary kallidinogenase + panax notoginseng saponins D group | 8 |
| Human urinary kallidinogenase and panax notoginseng saponins E group | 8 |
TABLE 2 comparison of behavioral scores of the human urokininogenase and Panax notoginsenosides pharmaceutical composition for the regulation and control of migraine rat PPARs expression
From table 2 above, it can be seen that:
(1) and (3) observing the video for 2 hours, calculating the ethological score according to the score standard, successfully molding all experimental animals, wherein the difference between each group of the ethological score has statistical significance, and comparing the ethological score with a blank group, the model group score is obviously higher than that of the blank group, so that the successful molding is indicated.
(2) Compared with a model group, the individual administration group of the human urinary kallidinogenase and the individual administration group of the panax notoginseng saponins can reduce the regulation and study ethological score of migraine rats, which means that the rat migraine rats have treatment effect, wherein the effect of the individual administration group of the human urinary kallidinogenase on treating the rat migraine is obviously superior to that of the panax notoginseng saponins, and the individual administration of the human urinary kallidinogenase has better treatment effect on the migraine rats.
(3) Compared with a group for singly administering human urinary kallidinogenase and a group for singly administering panax notoginseng saponins, the treatment effect of the human urinary kallidinogenase and panax notoginseng saponins medicinal composition group on migraine rats is obviously better than that of the group for singly administering, wherein the group consisting of human urinary kallidinogenase and panax notoginseng saponins B has the most obvious effect on treating the migraine rats, and is the best embodiment of the invention, so that the human urinary kallidinogenase and panax notoginseng saponins medicinal composition has the obvious effect on treating the migraine of the rats and has the synergistic effect.
Test example II Effect of the pharmaceutical composition for treating migraine of the present invention on the concentration of CGRP in plasma of migraine rats
The Elisa method is adopted to determine the influence of human urinary kininogenase on the concentration of CGRP in the plasma of migraine rats, and the specific experimental steps are as follows:
s1, experimental material drawing: in the first test example, after 4 hours of model building, each group of rats injected with anesthetic, until the whole body becomes soft, the rats were stooped up and fixed on an operating table, after conventional disinfection, the abdominal cavity was cut off along the median line of the abdomen with surgical scissors, the peripheral fat of the blood vessel was gently opened with a small forceps, a disposable blood taking needle was inserted into the abdominal aorta, the blood was taken into a blood taking tube, the rat was reversely shaken for 5 times, and the rat was left to stand for 2 hours;
s2, placing the blood collection tube into a refrigerated centrifuge, centrifuging for 10min at 3000 r/min and 4 ℃, and taking the supernatant for storage. The Elisa kit was removed from the refrigerator and the concentration of CGRP in migraine rat plasma was determined strictly according to the Elisa kit instructions.
TABLE 3 Effect of pharmaceutical compositions of human urinary kallidinogenase and Panax notoginsenosides on the concentration of CGRP in plasma of migraine rats
From table 3 above, it can be seen that:
(1) compared with the blank group, the concentration of CGRP in the plasma of the migraine rat in the model group is obviously increased, and compared with the model group, the human urinary kininogenase group, the panax notoginseng saponins group and the pharmaceutical composition group of the human urinary kininogenase and the panax notoginseng saponins can obviously reduce the concentration of CGRP in the plasma of the migraine rat and have a therapeutic effect on the migraine of the rat.
(2) Compared with the panax notoginseng saponins, the human urinary kininogenase group can greatly reduce the concentration of CGRP in plasma of a rat with migraine, and has more obvious treatment effect on the migraine of the rat, so that the human urinary kininogenase has better treatment effect on the rat with the migraine when being singly administered; compared with a group for singly administering human urinary kallidinogenase and a group for singly administering panax notoginseng saponins, the pharmaceutical composition group of human urinary kallidinogenase and panax notoginseng saponins can greatly reduce the concentration of CGRP in plasma of migraine rats, and has obviously better treatment effect on the migraine rats than the group for singly administering, wherein the group of human urinary kallidinogenase and panax notoginseng saponins B has the most obvious effect of treating the migraine rats, and is the best embodiment of the invention, so that the pharmaceutical composition of human urinary kallidinogenase and panax notoginseng saponins has obvious effect of treating the migraine of the rats and has synergistic effect.
(3) The adverse reaction incidence rates of the human urinary kininogenase group and the human urinary kininogenase and panax notoginseng saponins pharmaceutical composition group B are considered at the same time, and indexes such as blood pressure change, listlessness, somnolence and the like of a tested rat are measured and observed, so that the adverse reaction incidence rates of the human urinary kininogenase group and the human urinary kininogenase and panax notoginseng saponins pharmaceutical composition group B are respectively reduced by about 5-8% and 15-20% compared with the sumatriptan succinate group, and the pharmaceutical composition for treating migraine has lower toxic and side effects.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (1)
1. A pharmaceutical composition for treating migraine, comprising human urinary kallidinogenase and panax notoginseng saponins; the pharmaceutical composition is an injection, and each milliliter of the injection comprises the following components: human urinary kallidinogenase 0.15PNA and notoginseng total saponin 4.5 mg.
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