Application of stroke refreshing formula in preparation of medicine for preventing stroke-related pneumonia

Abstract

The invention belongs to the field of traditional Chinese medicine, and particularly relates to application of a stroke consciousness restoring prescription in preparation of medicine for preventing stroke-related pneumonia, and the stroke consciousness restoring prescription is composed of ligusticum wallichii, ginseng, pseudo-ginseng and rheum officinale according to the mass ratio of (1-10): (1-10): (1-10): (1-10). Clinical tests show that after the stroke refreshing oral liquid is used for treatment during hospitalization, the pneumonia incidence rate of patients in a stroke refreshing group during hospitalization is remarkably lower than that of a placebo group (OR 0.69, 95% CI 0.48-0.99 and P = 0.0436), and meanwhile, the pneumonia incidence rate of the patients in the stroke refreshing group within 7 days is remarkably lower than that of the placebo group (OR 0.68, 95% CI 0.49-0.94 and P = 0.0215). The result shows that the stroke refreshing formula can effectively reduce the pneumonia infection risk and prevent the occurrence of stroke-related pneumonia. Therefore, the stroke refreshing formula can be used as a medicine for preventing the stroke-related pneumonia.

Description

Technical Field

[0001] The invention belongs to the field of traditional Chinese medicine, and particularly relates to use of a stroke-awakening prescription in preparing medicines for preventing stroke-related pneumonia. Background Art

[0002] Stroke-associated pneumonia (SAP) is the most common complication of acute cerebral hemorrhage and one of the main causes of aggravated illness, prolonged hospital stay, and death. After cerebral hemorrhage, the body's yin and yang are out of balance, and the lung's ability to clear and purge is reduced, resulting in a lack of phlegm, which can cause multifunctional organ disorders including SAP. SAP is usually treated with conventional Western medicine, such as controlling blood sugar, lowering blood pressure, dehydration, anti-infection, and maintaining water, electrolyte, and acid-base balance. However, the use of broad-spectrum antibiotics increases the resistance of pathogens, making it more difficult to treat infected patients. Traditional Chinese medicine has few side effects and good efficacy, and has good application prospects in the prevention and treatment of SAP. Therefore, it is of great significance to find effective Chinese medicine prescriptions to prevent and treat SAP.

[0003] The oral solution for awakening the brain after apoplexy (composed of chuanxiong, ginseng, notoginseng and rhubarb, with the mass ratio of the four being 1-10:1-10:1-10:1-10) is clinically used to treat cerebrovascular diseases, including stroke, cerebral hemorrhage, cerebral infarction and vascular dementia (see the Chinese patent application document with publication number CN 1507352A for details). The oral solution for awakening the brain after apoplexy has been clinically used for more than 20 years. The diseases it is clinically used to treat are currently limited to cerebrovascular diseases such as stroke, cerebral hemorrhage, cerebral infarction and vascular dementia, and other diseases have not yet been involved. Therefore, the clinical application value of the oral solution for awakening the brain after apoplexy needs to be further explored. Summary of the invention

[0004] The purpose of the present invention is to provide a new use of the stroke-awakening prescription, namely, use of the stroke-awakening prescription in preparing a medicine for preventing stroke-related pneumonia.

[0005] According to the first aspect of the present invention, there is provided the use of a stroke-awakening prescription in the preparation of a drug for preventing stroke-related pneumonia, wherein the stroke-awakening prescription consists of chuanxiong, ginseng, notoginseng and rhubarb, and the mass ratio of the four is 1-10:1-10:1-10:1-10.

[0006] The present invention believes that in the stroke awakening prescription, ginseng is the main medicine, which greatly replenishes the vital energy. After a stroke, the patient's vital energy is greatly damaged, and the body's resistance drops sharply. The qi-replenishing effect of ginseng can quickly replenish the vital energy and enhance the body's ability to resist exogenous pathogens. The lung governs qi and controls breathing, and relies on the promotion of vital energy. With sufficient vital energy, the function of the lung is stabilized, and the function of defending the outside is sound, which can more effectively resist the invasion of external pathogens, fundamentally prevent the occurrence of stroke-related pneumonia, and also provide positive support for the subsequent body to resist the inflammation that has occurred. Panax notoginseng and Chuanxiong are ministerial medicines. Panax notoginseng has the effects of promoting blood circulation and stopping bleeding, reducing swelling and relieving pain. Panax notoginseng and ginseng can promote the smooth flow of qi and blood. Chuanxiong is a blood qi medicine, which has the effects of promoting blood circulation, promoting qi and relieving pain. Chuanxiong lactone can also play a role in protecting nerve function by regulating the expression of anti-apoptosis and pro-apoptosis proteins. Rhubarb is a guiding drug, which has the effects of purging heat and clearing the intestines, cooling blood and detoxifying, and removing blood stasis and dredges the menstruation. The purging heat and detoxifying effect of rhubarb can help to remove heat and toxins in the body and alleviate the symptoms of lung infection. At the same time, the blood stasis and dredges effect of rhubarb also helps to improve blood circulation, which complements Chuanxiong and Panax notoginseng.

[0007] The onset of stroke-related pneumonia is closely related to a series of pathological changes in the body caused by stroke. Whether it is a stroke event such as cerebral hemorrhage or cerebral infarction, it will cause a sudden change in brain blood circulation and cause a stress response in the systemic neuro-endocrine-immune network. The stroke awakening prescription acts on cerebrovascular diseases, can regulate brain blood circulation, repair nerve damage, improve this abnormal stress state, and prevent lung immune defense loopholes caused by excessive stress, providing a theoretical possibility for its use in preventing pneumonia. After cerebrovascular lesions, patients often experience complications such as dysphagia and impaired consciousness, which greatly increases the risk of aspiration and is an important cause of stroke-related pneumonia. The stroke awakening prescription has a positive effect on improving brain nerve function, and is expected to indirectly regulate swallowing and consciousness-related nerve reflexes, reduce the possibility of aspiration, and block the pathogenesis of pneumonia.

[0008] The sources of the raw materials for the stroke-refreshing prescription are as follows:

[0009] Chuanxiong: The dried rhizome of Ligusticum chuanxiong Hort., a plant of the Apiaceae family.

[0010] Ginseng: The root of Panax ginseng CAMey., a plant of the Araliaceae family.

[0011] Panax notoginseng: The dried root of Panax notoginseng (Burk.) FHChen, a plant of the genus Panax in the Araliaceae family.

[0012] Rhubarb: the roots and rhizomes of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. of the Polygonaceae family.

[0013] In some embodiments, the stroke-refreshing prescription consists of Chuanxiong, ginseng, Panax notoginseng and rhubarb, and the mass ratio of the four is 2:2:2:1.

[0014] In some embodiments, ginseng is red ginseng. After processing, the medicinal properties of red ginseng become warmer. After a stroke, the yang energy of patients is often damaged and the qi and blood are weak. The warm nature of red ginseng can quickly invigorate the yang energy and dispel the cold evil. Sufficient yang energy can accelerate the circulation of qi and blood, providing a stronger driving force for the body to resist evil and recover. The drug effect has a long retention time, continuously helps to improve the body's functions, stabilize the positive energy, and reduce the chance of external evil attacking the lungs. At the same time, the dryness of red ginseng is reduced, and the safety is higher. When formulating and using the drug, the dosage can be controlled more flexibly, and it can be accurately adapted to stroke patients with different conditions and constitutions, maximizing its positive regulatory role in preventing and treating stroke-related pneumonia, and reducing the interference of adverse reactions.

[0015] In some embodiments, the dosage form of the stroke-refreshing prescription is an oral solution, capsule, granule, tablet, powder, granule or decoction.

[0016] In some embodiments, the stroke brain-refreshing prescription may further include pharmaceutically acceptable excipients.

[0017] In some embodiments, the auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.

[0018] The stroke-refreshing prescription of the present invention can be prepared by using the corresponding existing preparation method according to the specification requirements of the specific preparation, and can also be prepared by using the method disclosed in the Chinese patent application document with publication number CN 1507352A.

[0019] Compared with the prior art, the beneficial effects of the present invention include:

[0020] The clinical trial of the present invention shows that after the use of the stroke awakening oral liquid for treatment during hospitalization, the incidence of pneumonia during hospitalization in the stroke awakening oral liquid group was significantly lower than that in the placebo group (OR 0.69, 95% CI 0.48 to 0.99, P = 0.0436), and at the same time, the incidence of pneumonia within 7 days in the stroke awakening oral liquid group was significantly lower than that in the placebo group (OR 0.68, 95% CI 0.49 to 0.94, P = 0.0215). This result suggests that the stroke awakening oral liquid can effectively reduce the risk of pneumonia infection and prevent the occurrence of stroke-related pneumonia. At the same time, the stroke awakening oral liquid has certain clinical advantages in reducing hospitalization costs, shortening hospitalization time and reducing dependence on intensive care. Therefore, the stroke awakening oral liquid can be used as a drug for preventing stroke-related pneumonia. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below in conjunction with specific embodiments. It is worth noting that the following embodiments are only for better explanation of the present invention and are not intended to limit the scope of protection of the present invention. The undisclosed process steps in the embodiments are prior art. Unless otherwise specified, the following raw materials are commercially available.

[0022] Example 1

[0023] The drug composition of the stroke-awakening decoction of the present embodiment is chuanxiong, ginseng, notoginseng and rhubarb, and the mass ratio of the four is 2:2:2:1.

[0024] The stroke refreshing soup of this embodiment can be prepared by the existing preparation method according to the specification requirements of the decoction.

[0025] Exemplarily, the preparation method thereof comprises the following steps:

[0026] Weigh about 175.5 kg of ginseng, about 175.5 kg of Panax notoginseng, about 175.5 kg of Chuanxiong, and about 87.8 kg of rhubarb, chop the herbs, mix them in a stainless steel sandwich pot, add 4265 liters of water and boil for about 2 hours. After cooling, filter, and sterilize the filtrate at high temperature and put it into a brown bottle for clinical use.

[0027] Example 2

[0028] The drug composition of the oral solution for awakening the brain after apoplexy in this embodiment is chuanxiong, ginseng, notoginseng and rhubarb, and the mass ratio of the four is 2:2:2:1.

[0029] The stroke refreshing oral solution of this embodiment can be prepared by an existing preparation method according to the specification requirements of oral solution, and auxiliary materials such as sorbic acid and polysorbate 80 can be added during the preparation.

[0030] For example, the preparation method can be carried out according to the method disclosed in Example 2 of the Chinese patent application document with publication number CN 1507352A. The obtained solution is divided into 100 mL vials, and when taken, 33 mL each time, orally, once every 8 hours.

[0031] Next, in order to explore the preventive effect of the stroke-awakening prescription on stroke-related pneumonia, the stroke-awakening oral liquid prepared in Example 2 was used to conduct the following clinical trials.

[0032] 1. Relevant standards

[0033] 1. TCM syndrome diagnosis: refer to the TCM syndrome scale for stroke. The standard of TCM syndrome scale for stroke refers to the “Standards for TCM Diagnosis and Therapeutic Effect Evaluation of Stroke” issued by the Internal Medicine Society of the Chinese Association of Traditional Chinese Medicine in 1986.

[0034] 2. Inclusion criteria

[0035] (1) Aged ≥ 18 years;

[0036] (2) Patients with cerebral hemorrhage admitted to the hospital within 72 hours of onset;

[0037] (3) Meet the Western medical diagnostic criteria for intracerebral hemorrhage (ICH) and the TCM syndrome differentiation criteria for stroke with phlegm-heat and visceral excess;

[0038] (4) patients with gastric intubation within one day of admission;

[0039] (5) Sign the informed consent form.

[0040] 3. Diagnosis of stroke-related pneumonia: refer to the modified CDC criteria and meet at least one of the following criteria:

[0041] (1) Fever (body temperature > 38°C) without other clear causes;

[0042] (2) Leukopenia (<4000 cells / mm 3 ) or increase (>12000 / mm 3 );

[0043] (3) Elderly persons aged ≥70 years with altered consciousness without other clear causes.

[0044] And meet at least 2 of the following criteria:

[0045] (1) New onset of purulent sputum, or changes in sputum properties or increased respiratory secretions or increased frequency of sputum suction within 24 hours;

[0046] (2) new or worsening cough or dyspnea or shortness of breath (respiratory rate > 25 times / min);

[0047] (3) rales, crackles, or bronchial breath sounds detected by lung auscultation;

[0048] (4) Gas exchange disorders (such as hypoxemia (PaO2 / FiO2≤240), increased oxygen requirement), and at least one of the following manifestations on ≥2 consecutive chest X-rays: new or progressive persistent infiltrative lesions, consolidation, or cavitation (Note: for patients without underlying cardiopulmonary disease, a single chest X-ray with any one of the above manifestations is sufficient).

[0049] 4. Exclusion criteria

[0050] (1) Patients with diseases such as pulmonary tuberculosis, pulmonary edema, pulmonary embolism, non-infectious interstitial lung disease and respiratory and circulatory failure;

[0051] (2) A clear history of digestive tract diseases such as digestive tract tumors, inflammatory bowel disease, active digestive tract bleeding, etc. in the past three months;

[0052] (3) Patients with immune-related diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren's syndrome, etc., or those who are receiving immunotherapy for other diseases and those who have received any antibiotic treatment within four weeks before inclusion in the study.

[0053] 5. Elimination criteria

[0054] After entering the clinical trial observation, patients who were mistakenly included because they did not meet the inclusion criteria and patients who met the inclusion criteria but did not take the medicine after inclusion can be regarded as excluded patients.

[0055] 6. Criteria for determination of dropout or loss to follow-up

[0056] (1) Those who were lost to follow-up during the treatment period;

[0057] (2) Those who actively requested to withdraw from treatment during the treatment period;

[0058] (3) Failure to take the study drug as required, taking less than 2 / 3 of the dose;

[0059] (4) Failure to complete the inspection and assessment within the required time;

[0060] (5) Patients who met the inclusion criteria specified in the clinical trial protocol but failed to complete the trial for some reason.

[0061] All of the above can be regarded as patients who dropped out or were lost to follow-up, including patients who dropped out voluntarily and patients who were identified as dropped out by doctors.

[0062] 7. Termination criteria

[0063] (1) Severe adverse reactions occurred during treatment;

[0064] (2) Patients who develop other serious illnesses or die during treatment.

[0065] 2. Grouping and Sample Size

[0066] According to the random block method, the subjects who met the inclusion criteria and did not meet the exclusion criteria were randomly divided into a stroke awakening group and a placebo group in a 1:1 ratio. The final number of patients included was 396 in the stroke awakening group and 418 in the placebo group.

[0067] 3. Trial Drugs and Treatments

[0068] Both groups of subjects received treatment for underlying diseases except hyperlipidemia according to the 2014 Chinese Guidelines for Secondary Prevention of Ischemic Stroke / Transient Ischemic Attack.

[0069] Stroke brain-awakening group: basic treatment + stroke brain-awakening oral solution prepared in Example 2 (33 ml each time, orally, once every 8 hours).

[0070] Placebo group: basic treatment + placebo (33 ml each time, orally, once every 8 hours, the placebo is composed of soy peptide, black sugar syrup, flavor, maltodextrin, salt, MSG and water (all food grade), without any pharmacological activity, and has good consistency with the above-mentioned stroke awakening oral solution in appearance, smell, taste, etc.).

[0071] Both groups of subjects were treated for 14 days and followed up for 90 days.

[0072] 4. Observation indicators

[0073] Pneumonia-related mortality rate, lung infection-related indicators (chest X-ray, rales, peripheral blood leukocytes and classification, C-reactive protein, clinical pulmonary infection score (CPIS) etc.), etc.

[0074] 5. Outcome indicators

[0075] 1. Main outcome measures

[0076] During the hospitalization period, the lung infection-related indicators (chest X-ray, rales, peripheral blood leukocytes and classification, C-reactive protein, CPIS score, etc.) and the incidence of pneumonia were analyzed.

[0077] 2. Secondary outcome indicators

[0078] Follow-up was conducted for 90 days to observe the changes in efficacy before and after treatment. The efficacy evaluation indicators were based on the international gold standard: 90-day uw-mRS, mRS, mortality, disability rate (percentage of mRS 3-5), independent living ability (percentage of BI>90), and quality of life (SSQOL). Safety evaluation was also conducted.

[0079] 6. Statistical Methods

[0080] The experimental results were entered into a data entry database using Epidata3.1 and then imported into R software for statistical analysis.

[0081] VII. Experimental Results

[0082] 1. Comparison of patient baseline

[0083] The baseline comparison results of the two groups of patients are shown in Table 1:

[0084] Table 1 Baseline comparison results between the two groups of patients

[0085]

[0086]

[0087]

[0088]

[0089] As can be seen from Table 1, there was no statistical difference in the baseline indicators before treatment between the two groups of patients (P>0.05), and they were comparable.

[0090] 2. Primary and secondary outcome indicators and safety results of the two groups of patients

[0091] The primary outcome indicators, secondary outcome indicators and safety results of the two groups of patients are shown in Table 2:

[0092] Table 2 Primary and secondary outcome indicators and safety results of the two groups of patients

[0093]

[0094]

[0095]

[0096]

[0097] Note: ① In the table, OR / MD (95% CI) means OR, MD means mean difference, and 95% CI means 95% confidence interval.

[0098] ②The adjusted model was adjusted for factors such as center, baseline NIHSS, and pre-onset mRS.

[0099] ③This study adopted a multivariate logistic model for analysis. The samples included in the analysis of each indicator in the table were people with no missing variables. Therefore, under some indicators in the table, the number of people in the stroke awakening group was less than 396, and the number of people in the placebo group was less than 418.

[0100] As can be seen from Table 2, after the use of Zhongfeng Xingnao Oral Liquid during hospitalization, the incidence of pneumonia during hospitalization in the stroke Xingnao group was significantly lower than that in the placebo group (OR 0.69, 95% CI 0.48 to 0.99, P = 0.0436). At the same time, the incidence of pneumonia within 7 days of follow-up in the stroke Xingnao group was significantly lower than that in the placebo group (OR 0.68, 95% CI 0.49 to 0.94, P = 0.0215). This result suggests that Zhongfeng Xingnao Recipe can effectively reduce the risk of pneumonia infection and prevent the occurrence of stroke-related pneumonia.

[0101] The stroke awakening brain prescription may improve the patient's lung protection mechanism through multiple pharmacological actions, such as anti-inflammation, enhancing immune function, and promoting microcirculation, thereby preventing the occurrence of pneumonia, especially in high-risk groups with impaired immune function and long-term bedridden after stroke.

[0102] 3. Differences in other treatment conditions

[0103] The differences in other treatment conditions between the two groups are shown in Table 3:

[0104] Table 3 Differences in other treatment conditions between the two groups

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] As can be seen from Table 3, the hospitalization cost and length of stay in the stroke awakening group were significantly lower than those in the placebo group, which were 71,352 yuan and 12.6 days, respectively, which were statistically significant compared with 77,618 yuan and 13.8 days in the placebo group (P<0.001). This result reflects the positive role of the stroke awakening prescription in improving the recovery speed of patients, reducing the occurrence of complications, and shortening the length of hospital stay. It is worth noting that the mechanical ventilation requirement of the stroke awakening group at 28 days of follow-up was significantly lower than that of the placebo group (32% vs 63%, P=0.002), which further indicates that the stroke awakening prescription can effectively reduce the respiratory support requirements of stroke patients. In terms of cooling therapy, the frequency of use of the stroke awakening group at 7 and 14 days of follow-up was also significantly lower than that of the placebo group (P=0.032 and P=0.049), which reflects the positive role of the stroke awakening prescription in alleviating post-stroke inflammatory response and stabilizing the patient's condition. In addition, the frequency of intubation in the stroke awakening brain group at 7 and 14 days of follow-up was significantly lower than that in the placebo group (P=0.03 and P=0.048), which reflects the positive role of the stroke awakening brain recipe in reducing physical therapy for stroke patients.

[0113] In general, the stroke awakening prescription has certain clinical advantages in reducing hospitalization costs, shortening hospitalization time and reducing dependence on intensive care treatment, and is worthy of further promotion and application in clinical practice.

[0114] The above are only some specific embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. Use of the Zhongfeng Xingnao Recipe in the preparation of a drug for preventing stroke-related pneumonia, wherein: The stroke brain-awakening prescription is composed of chuanxiong, ginseng, notoginseng and rhubarb, and the mass ratio of the four is 1-10:1-10:1-10:1-10.

2. The use according to claim 1, characterized in that: The stroke brain-awakening prescription consists of chuanxiong, ginseng, notoginseng and rhubarb, and the mass ratio of the four is 2:2:2:

1.

3. The use according to claim 1 or 2, characterized in that: The ginseng is red ginseng.

4. The use according to claim 1 or 2, characterized in that: The dosage form of the stroke brain-awakening prescription is oral solution, capsule, granule, tablet, powder, granule or decoction.

5. The use according to claim 1 or 2, characterized in that: The stroke brain-refreshing prescription may also be added with pharmaceutically acceptable excipients.

6. The use according to claim 5, characterized in that: The auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant, and a lubricant.

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