阅读说明：本技术 一种中药组合物在制备治疗或预防感染性心内膜炎药物中的应用 (Application of traditional Chinese medicine composition in preparation of medicine for treating or preventing infectious endocarditis ) 是由 肖伟 王永香 李芳� 吴云 王振中 于 2019-08-14 设计创作，主要内容包括：本发明提供了一种治疗感染性心内膜炎的组合物。本发明所述的中药组合物能显著降低感染性心内膜炎大鼠的血培养阳性率,减少大鼠动脉瓣及导管周围赘生物的生成；明显降低急性细菌性心内膜炎家兔的血培养阳性率,减少家兔心脏主动脉瓣赘生物的重量。而且通过临床实验表明,本发明提供的中药组合物对于感染性心内膜炎具有较好的疗效。(The invention provides a composition for treating infectious endocarditis. The traditional Chinese medicine composition can obviously reduce the blood culture positive rate of infectious endocarditis rats and reduce the generation of neoplasms around the artery valve and the catheter of the rats; obviously reduces the blood culture positive rate of the rabbits with the acute bacterial endocarditis and reduces the weight of the aortic valve neoplasm of the hearts of the rabbits. Clinical experiments show that the traditional Chinese medicine composition provided by the invention has a good curative effect on infective endocarditis.)

1. An application of a traditional Chinese medicine composition in preparing a medicine for treating or preventing infective endocarditis is characterized in that the traditional Chinese medicine composition comprises: 5-30 parts of sweet wormwood, 3-20 parts of honeysuckle and 2-15 parts of gardenia.

2. The use of claim 1, wherein the Chinese medicinal composition comprises: 5-25 parts of sweet wormwood, 3-15 parts of honeysuckle and 2-12 parts of gardenia.

3. The use of claim 1, wherein the Chinese medicinal composition comprises: 10-25 parts of sweet wormwood, 6-15 parts of honeysuckle and 4-12 parts of gardenia.

4. The use of claim 1, wherein the Chinese medicinal composition comprises: 11 parts of sweet wormwood, 8 parts of honeysuckle and 7 parts of gardenia.

5. The use of claim 1, wherein the Chinese medicinal composition comprises: 25 parts of sweet wormwood, 15 parts of honeysuckle and 12 parts of cape jasmine.

6. the use according to any one of claims 1 to 5, wherein the medicament for the treatment or prevention of infectious endocarditis is selected from the group consisting of an oral administration form, an injection administration form and an external administration form.

7. The use according to claim 6, wherein the medicament for the treatment or prevention of infective endocarditis is selected from the group consisting of decoctions, granules, capsules, tablets, oral liquids, pills, tinctures, syrups, suppositories, gels, sprays, and injections.

8. the use of any one of claims 1-5, wherein the preparation method of the Chinese medicinal composition comprises the following steps:

Step A, soaking honeysuckle and sweet wormwood in water, heating, decocting and distilling, and collecting volatile oil for later use; concentrating and drying the decoction to obtain honeysuckle and sweet wormwood dry extract powder;

Heating and refluxing fructus Gardeniae with ethanol water solution, filtering, recovering ethanol from filtrate, concentrating, adjusting to acidity with hydrochloric acid, heating for 0.5-1.5 hr, refrigerating for 10-14 hr, filtering, concentrating the filtrate, and drying to obtain fructus Gardeniae dry extract powder;

And step C, coating the volatile oil by using auxiliary materials conventionally, and then uniformly mixing the volatile oil with the dry paste powder.

9. The use according to any one of claims 1 to 5, wherein the medicament for the treatment or prevention of infectious endocarditis is prepared by a method comprising:

Soaking flos Lonicerae and herba Artemisiae Annuae in 13-18 times of water for 3 hr, heating, decocting, distilling for 2 times, each for 2 hr, and collecting volatile oil; mixing decoctions, concentrating under reduced pressure to relative density of 1.03-1.08, centrifuging at 20000 rpm, collecting supernatant, performing fractional ultrafiltration, concentrating ultrafiltrate under reduced pressure to relative density of 1.10-1.12 at 50 deg.C, and vacuum drying to obtain flos Lonicerae and herba Artemisiae Annuae dry extract powder; pulverizing fructus Gardeniae, reflux-extracting with 6 times of 80% ethanol under heating for 1-3 times, each for 1 hr, mixing the medicinal liquids, filtering, recovering ethanol from the filtrate, concentrating to 1: 1, adjusting pH to 4.0 with hydrochloric acid, heating at 100 deg.C for 1 hr, refrigerating for 12 hr, filtering, concentrating the filtrate to relative density of 1.10-1.12 at 50 deg.C, and vacuum drying to obtain fructus Gardeniae dry extract powder; adding 6g poloxamer 108 into the volatile oil, grinding, mixing, adding 900ml water for injection, stirring to clarify, adding the above dried extract powder, stirring to dissolve, adjusting pH to 7.5-8.0 with sodium hydroxide solution, and adding water for injection to 1000 ml; filtered through a G4 sintered funnel, filled in a 10ml ampoule and sterilized by flowing steam at 100 ℃.

Technical Field

The invention belongs to the field of traditional Chinese medicine application, and particularly relates to application of a traditional Chinese medicine composition in preparation of a medicine for treating or preventing infectious endocarditis.

Background

Infectious Endocarditis (IE) is a pathological condition in which pathogenic microorganisms migrate to the endocardium and heart valves by the blood-circulating route, causing infection of the endocardium surface with microorganisms. It is mainly manifested as a large and diverse-sized neoplasm, usually platelets and cellulose mass containing a large number of microorganisms and a small number of inflammatory cells, adhering to the endocardial surface. Detachment of the neoplasm may cause metastasis of the embolic infection or sepsis, and may die if the patient is not treated in time. IE has various clinical signs and many complications, and can cause the function of a plurality of visceral organs to be affected, so that IE is still a relatively serious disease clinically at present.

The application of antibiotics is the most important measure for treating infectious endocarditis, but the antibiotics have large side effect and high price, and the traditional Chinese medicine has the advantages of strong effect, lasting drug effect, no drug resistance, small toxic and side effect and the like as the traditional Chinese medicine in China, so that the development of a traditional Chinese medicine preparation for treating the infectious endocarditis has very important clinical significance.

Disclosure of Invention

the invention aims to provide a traditional Chinese medicine composition for treating or preventing infective endocarditis.

Specifically, the invention provides application of a traditional Chinese medicine composition in preparation of a medicine for treating or preventing infectious endocarditis, which is characterized by comprising the following components in parts by weight: 5-30 parts of sweet wormwood, 3-20 parts of honeysuckle and 2-15 parts of gardenia.

Preferably, the traditional Chinese medicine composition comprises: 5-25 parts of sweet wormwood, 3-15 parts of honeysuckle and 2-12 parts of gardenia.

More preferably, the Chinese medicinal composition comprises: 10-25 parts of sweet wormwood, 6-15 parts of honeysuckle and 4-12 parts of gardenia.

More preferably, the Chinese medicinal composition comprises: 11 parts of sweet wormwood, 8 parts of honeysuckle and 7 parts of gardenia.

More preferably, the Chinese medicinal composition comprises: 25 parts of sweet wormwood, 15 parts of honeysuckle and 12 parts of cape jasmine.

The Chinese medicinal composition can be added with pharmaceutically acceptable adjuvants to make into various pharmaceutically acceptable dosage forms, such as decoction, granule, capsule, tablet, oral liquid, pill, tincture, syrup, suppository, gel, spray, injection, etc. The raw material medicines can be directly ground into powder, or can be extracts or other forms prepared by conventional means. The composition of the present invention may also be directly ground into powder, or an extract prepared by a conventional method in the art, etc.

Specifically, the medicament for treating or preventing the infective endocarditis is selected from an oral administration dosage form, an injection administration dosage form or an external administration preparation.

Specifically, the medicament for treating or preventing the infectious endocarditis is selected from decoction, granules, capsules, tablets, oral liquid, pills, tinctures, syrups, suppositories, gels, sprays and injections.

further, the composition preparation method may comprise the steps of:

Step A, soaking honeysuckle and sweet wormwood in water, heating, decocting and distilling, and collecting volatile oil for later use; concentrating and drying the decoction to obtain honeysuckle and sweet wormwood dry extract powder;

Heating and refluxing fructus Gardeniae with ethanol water solution, filtering, recovering ethanol from filtrate, concentrating, adjusting to acidity with hydrochloric acid, heating for 0.5-1.5 hr, refrigerating for 10-14 hr, filtering, concentrating the filtrate, and drying to obtain fructus Gardeniae dry extract powder;

And step C, coating the volatile oil by using auxiliary materials conventionally, and then uniformly mixing the volatile oil with the dry paste powder.

Preferably, the preparation method of the medicament for treating or preventing the infective endocarditis comprises the following steps:

Soaking flos Lonicerae and herba Artemisiae Annuae in 13-18 times of water for 3 hr, heating, decocting, distilling for 2 times, each for 2 hr, and collecting volatile oil; mixing decoctions, concentrating under reduced pressure to relative density of 1.03-1.08, centrifuging at 20000 rpm, collecting supernatant, performing fractional ultrafiltration, concentrating ultrafiltrate under reduced pressure to relative density of 1.10-1.12 at 50 deg.C, and vacuum drying to obtain flos Lonicerae and herba Artemisiae Annuae dry extract powder; pulverizing fructus Gardeniae, reflux-extracting with 6 times of 80% ethanol under heating for 1-3 times, each for 1 hr, mixing the medicinal liquids, filtering, recovering ethanol from the filtrate, concentrating to 1: 1, adjusting pH to 4.0 with hydrochloric acid, heating at 100 deg.C for 1 hr, refrigerating for 12 hr, filtering, concentrating the filtrate to relative density of 1.10-1.12 at 50 deg.C, and vacuum drying to obtain fructus Gardeniae dry extract powder; adding 6g poloxamer 108 into the volatile oil, grinding, mixing, adding 900ml water for injection, stirring to clarify, adding the above dried extract powder, stirring to dissolve, adjusting pH to 7.5-8.0 with sodium hydroxide solution, and adding water for injection to 1000 ml; filtered through a G4 sintered funnel, filled in a 10ml ampoule and sterilized by flowing steam at 100 ℃.

The traditional Chinese medicine composition can obviously reduce the blood culture positive rate of infectious endocarditis rats and reduce the generation of neoplasms around the artery valve and the catheter of the rats; obviously reduces the blood culture positive rate of the rabbits with the acute bacterial endocarditis and reduces the weight of the aortic valve neoplasm of the hearts of the rabbits. In addition, clinical experiment results also show that the traditional Chinese medicine composition provided by the invention has a better curative effect on infective endocarditis.

Detailed Description

As described above, the present invention is directed to a composition or a medicament for treating or preventing infective endocarditis. The following will specifically describe the contents of the experimental examples.

The sweet wormwood (Artemisia annua Herba) in the medicine is the dry overground part of Artemisia annua L of Compositae, and is mainly produced in Jiangsu, Jiangxi, Zhejiang and Hunan places. Flos Lonicerae (Lonicera Japonica Flos) is dried bud or flower with initial bloom of Lonicera Japonica (Lonicera Japonica Thunb.) belonging to Caprifoliaceae, and is mainly produced in Shandong, Henan, and Jiangsu; gardenia jasminoides Ellis (Gardenia Fructus) is dried mature fruit of Gardenia jasminoides Ellis (Gardenia jasminoides Ellis) belonging to Gardenia of Rubiaceae, and is mainly produced in Zhejiang, Jiangxi, Hubei and Hunan provinces.

If the specific conditions are not indicated, the method is carried out according to the conventional conditions or the conditions suggested by manufacturers, and the used raw material medicines or auxiliary materials and the used reagents or instruments are the conventional products which can be obtained commercially.

It is particularly pointed out that the present invention is described in more detail below by means of specific embodiments in order to be able to better understand the solution of the invention and the advantages of its various aspects. The present invention is not limited by the following examples, and specific embodiments may be determined according to the technical solutions and practical situations of the present invention.

Effect of Chinese medicinal composition on infective endocarditis rats

1. Experimental Material

1.1 drugs and reagents

Ampicillin capsule, Wuhan Jianmin group anywhere pharmaceutical industry Co., Ltd, 0.25 g/granule; the traditional Chinese medicine composition prepared according to the second embodiment is 5.2g crude drug/g by Jiangsu Kangyuan pharmaceutical industry GmbH; chloral hydrate, Shanghai national drug group, 250 g/bottle; grass green streptococcus, china type culture collection; heparin sodium injection, Anhufeng technical industry, Inc., standard: 2 ml: 1000U; 0.9% sodium chloride injection, Shandong Kelun pharmaceutical Co., Ltd, Specification: 250mL of: 2.25 g.

1.2 animals

50 healthy SD rats, SPF level, male, weight 230 ~ 270g, provided by Beijing Witonglihua laboratory animal technology Limited, license number: SCXK (Kyoto) 2016-.

1.3 instruments

Surgical microscope, Olympus; electronic balance, sidoris scientific instruments (beijing) ltd; centrifuge5804R high speed refrigerated Centrifuge, Eppendorf; 8453 ultraviolet and visible spectrophotometer, Agilent.

2. Experimental methods

2.1 Molding

SD male rats are anesthetized with 10% chloral hydrate after fasting without water supply, fixed on an operating table, separated from the right common carotid artery, ligated at the distal end of the common carotid artery, and the cervical artery is clamped by a hemostatic clamp at the proximal end. A beveled incision was cut with an ophthalmic scissors between the two ligations, the PE-50 catheter was inserted into the vessel, the hemostatic clip was removed, and the catheter was carefully inserted slowly into the left ventricle of the rat. When resistance is felt in the pushing process, the catheter reaches the atrioventricular junction, the inserting direction of the catheter is adjusted at the moment, the blood flow beating condition in the catheter is observed, the catheter is pushed forwards rapidly when the blood flow in the catheter beats outwards, and the hand feeling of the inserting tube is strong in heart beating effect at the moment, so that the catheter enters the left ventricle. During the period, 1mL of heparin sodium solution with the concentration of 500U/mL is injected into blood vessel through a three-way pipe in order to avoid blood coagulation. And finally, fixing the tail end of the catheter inserted into the ventricle of the rat under the skin after heat sealing by using a lighter, suturing the incision, and breeding in a single cage after disinfection.

2.2 grouping

The blank control group 10 was subjected to intubation only, and the remaining rats were treated with s.viridans in the tail vein after intubation: the Streptococcus viridis cells were cultured and the cells were resuspended in sterile physiological saline, and the concentration of the cells was adjusted to 1X 106 CFU/mL. After the catheter of the rat is left for 24 hours after intubation, 1mL of the prepared bacterial solution is taken and inoculated into the rat body by tail vein injection.

30 rats positive to streptococcus viridis cultured with menstrual blood were randomly divided into: a model group, an ampicillin capsule group and a traditional Chinese medicine composition group.

2.3 administration of drugs

The traditional Chinese medicine composition group rats are administrated with 4.68g crude drugs/kg by stomach filling, the ampicillin capsule group is administrated with 135mg/kg, the administration volumes are 10ml/kg, and the blank control group and the model group are administrated with the same volume of sodium chloride injection for 1 time/day and are continuously administrated for 4 weeks.

2.4 sampling and index detection

2.4.1 blood culture Positive detection 1 hour after last administration, tail vein blood homogenate was diluted and inoculated on sterile Streptococcus culture medium, and colony was observed overnight at 37 deg.C, and blood culture positive was observed if there was colony growth.

2.4.2 rat neoplasms generation examination after dosing was complete groups of SD rats were sacrificed, rat hearts were dissected and observed, neoplasms around the arterial valve and catheter were carefully dissected and weighed.

3. Results

3.1 antibacterial efficacy

Table 1 influence of the Chinese medicinal composition on the blood culture positivity (n ═ 10)

P <0.01 in comparison to model groups

The blood culture positive rate of the model group is 90% (9/10), and after the traditional Chinese medicine composition is continuously administered for 4 weeks, the blood culture positive rate of the traditional Chinese medicine composition group is 30% (3/10), namely, compared with the model group, the blood culture positive rate of the traditional Chinese medicine composition group is remarkably reduced (P is less than 0.01), thereby showing that the traditional Chinese medicine composition can effectively resist the infectious endocarditis of rats.

3.2 Effect on rat cardiac neoplasm weight

TABLE 2 Effect of Chinese medicinal composition on rat cardiac neoplasm weight (n ═ 10)

P <0.01, p <0.05 compared to model groups

According to the experiment, a rat infectious endocarditis model is constructed by means of cardiac intubation and tail vein injection of grass green streptococcus, and the model shows that the weight of the rat cardiac neoplasm in the model group is obviously increased. As can be seen from the data in Table 2, compared with the model group, the Chinese medicinal composition group can obviously reduce the generation of neoplasms around the heart valve and catheter of the rat (p is less than 0.05), i.e. the Chinese medicinal composition has better therapeutic effect on the animal model of infectious endocarditis of the rat.

Effect of traditional Chinese medicine composition on acute bacterial endocarditis of rabbits

1. Experimental Material

1.1 drugs and reagents

Ampicillin capsule, Wuhan Jianmin group anywhere pharmaceutical industry Co., Ltd, 0.25 g/granule; the traditional Chinese medicine composition prepared according to the second embodiment is 5.2g crude drug/g by Jiangsu Kangyuan pharmaceutical industry GmbH; sodium pentobarbital, national drug group chemical reagents ltd, 250 g/bottle; hemolytic streptococcus type A, provided by the bacterial preservation center of the institute of Chinese medicinal and biological product assay; 0.9% sodium chloride injection, Shandong Kelun pharmaceutical Co., Ltd, Specification: 250mL of: 2.25 g.

1.2 animals

40 New Zealand white rabbits are of a common grade, half male and female, 2.0-2.5 kg in weight, provided by eastern culture Co., Ltd, of the State of Metaplexis, with license numbers: SCXK (Su) 2014-.

1.3 instruments

Surgical microscope, Olympus; electronic balance, sidoris scientific instruments (beijing) ltd; centrifuge5804R high speed refrigerated Centrifuge, Eppendorf; 8453 ultraviolet and visible spectrophotometer, Agilent.

2. Experimental methods

2.1 Molding

Healthy rabbits were anesthetized by injecting a 3% sodium pentobarbital solution into the ear vein at a dose of 0.5ml/kg, fixed on an operating table, exposing the middle of the neck, preparing skin, sterilizing, incising the skin at the middle, and isolating the subcutaneous tissue, muscle and right common carotid artery. The proximal end was closed with an artery clamp and the distal end was ligated with surgical suture. The right common carotid artery was trimmed to a small incision with an ophthalmic scissors, the sterile catheter was inserted, the arterial clamp was removed, and the catheter was slowly advanced. When the front end of the catheter enters the left ventricle through the aortic valve, a sudden drop in blood pressure is seen, the mean arterial pressure is about 70mmHg, and the fluctuation amplitude is obviously increased. Meanwhile, the hand carrying out intubation can feel stronger heart pulsation, which proves that the front end of the catheter enters the left ventricle cavity. At this time, the vessel is slightly pushed forward, the end of the vessel is fixed under the skin after ligation, the operation incision is sutured, and the vessel is raised in a single cage after disinfection.

2.2 grouping

The blank control group 8 was subjected to intubation only, and the remaining rabbits were subjected to intravenous injection of streptococcus hemolyticus a at the ear margin after intubation: the Streptococcus hemolyticus A culture solution was resuspended in sterile physiological saline, and the concentration of the culture solution was adjusted to 1X 109 CFU/mL.

24 rabbits positive for streptococcus hemolyticus a cultured by menstrual blood were randomly divided into: a model group, an ampicillin capsule group and a traditional Chinese medicine composition group.

2.3 administration of drugs

The composition of the invention is administrated by 2.53g crude drug/kg in the traditional Chinese medicine composition group through stomach irrigation of rabbits, the ampicillin capsule group is administrated at 73mg/kg, the administration volumes are 5ml/kg, and the blank control group and the model group are administrated with the sodium chloride injection with the same volume for 1 time/day and are administrated continuously for 4 weeks.

2.4 sampling and index detection

2.4.1 blood culture Positive detection 1 hour after last administration, auricular edge vein blood homogenate is inoculated on a sterile streptococcus culture medium after dilution, and the culture is carried out overnight at 37 ℃ to observe bacterial colony, and the growth of the bacterial colony is blood culture positive.

2.4.2 Rabbit neoplasm development examination after completion of dosing groups of rabbits were sacrificed, rabbit hearts were dissected and observed, aortic valve neoplasms were carefully dissected and weighed.

3. Results

3.1 antibacterial efficacy

Table 3 influence of the Chinese medicinal composition on the positive rate of blood culture (n ═ 8)

P <0.01 in comparison to model groups

The blood culture positive rate of the model group is 100% (8/8), and after the traditional Chinese medicine composition is continuously administered for 4 weeks, the blood culture positive rate of the traditional Chinese medicine composition group is 25% (2/8), namely, compared with the model group, the blood culture positive rate of the traditional Chinese medicine composition group is remarkably reduced (P is less than 0.01), thereby showing that the traditional Chinese medicine composition can effectively resist the acute bacterial endocarditis of the rabbits.

3.2 Effect on Rabbit Heart neoplasm weight

TABLE 4 influence of Chinese medicinal composition on the weight of the cardiac neoplasm in rabbits (n ═ 8)

P <0.01, p <0.05 compared to model groups

The experiment creates a rabbit acute bacterial endocarditis model by means of cardiac intubation and intravenous injection of type A hemolytic streptococcus at ear margin, and the model shows that the weight of the cardiac neoplasms of the rabbits in the model group is obviously increased. As can be seen from the data in Table 4, compared with the model group, the Chinese medicinal composition group can obviously reduce the generation of the aortic arch valve neoplasm of the rabbit (p is less than 0.05), namely the Chinese medicinal composition has better treatment effect on the animal model of the acute bacterial endocarditis of the rabbit.

Clinical therapeutic effect of the Chinese medicinal composition

1. general data

The number of patients with infectious endocarditis is 80, the age is 20-66, the average age is 41, and the course is 6-1 months from 2018 to 2018 and 9 months from 2018.

2. Method of treatment

The treatment group patients take the traditional Chinese medicine composition prepared according to the second embodiment, and the traditional Chinese medicine composition is orally taken 3 times a day, 28 days are 1 treatment course, usually 1-3 treatment courses are cured, and 4-5 treatment courses are needed for patients with severe symptoms.

3. Judgment of therapeutic effect

3.1 therapeutic criteria

And (3) curing: the symptoms such as general malaise, heart failure, visceral embolism and the like disappear, and the face is ruddy.

The method has the following advantages: the symptoms of general malaise, heart failure, visceral embolism and the like are obviously relieved or relieved, and the complexion is ruddy.

And (4) invalidation: no change in symptoms.

3.2 therapeutic results

Among 80 patients, 46 patients are cured, accounting for 57.5%; 25 cases are improved, accounting for 31.25 percent; 9 cases of invalidity account for 11.25%; the total effective rate is 88.75 percent.