New application of gastrodin in preventing and / or treating delirium disease

Abstract

The invention provides a new application of gastrodin in preparation of a medicine for preventing and / or treating postoperative delirium of a patient, and a result shows that the occurrence rate of postoperative delirium can be remarkably reduced by applying gastrodin to the patient in a perioperative period for the patient receiving different operations. The gastrodin has a relatively good prevention or treatment effect on postoperative delirium, and particularly has a relatively high selective effect on postoperative delirium subtypes, such as excessive delirium and / or mixed delirium, and middle-aged and elderly postoperative delirium patients. When being used for preventing or treating postoperative delirium, the gastrodin also has the advantages of lower occurrence rate of adverse events and higher safety.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and particularly relates to a new use of gastrodin in preparing a drug for preventing and / or treating postoperative delirium in patients. Background Art

[0002] Delirium is an acute deterioration of mental function caused mainly by disease, surgery, trauma, drugs, environmental factors, social factors, etc., which lasts from a few hours to a few days. Delirium was also called "acute confusion" in the past. According to the definition of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V): Delirium is an acute onset of confusion, accompanied by inattention, confusion, incoherent thinking and abnormal perceptual function; some patients with delirium may experience psychotic symptoms such as hallucinations and delusions.

[0003] The pathogenesis of delirium is complex, and there is still a lack of understanding of it. The research on its neuropathology and physiological mechanism is still in its infancy. The mechanism of occurrence may be the result of the combined action of multiple pathways, mainly including the theory of cerebral blood supply / metabolism disorder, neurotransmitter theory, neuroinflammatory theory, blood-brain barrier destruction theory, abnormal nerve cell metabolism theory, neuroendocrine / stress theory, etc. Therefore, the current prevention or treatment of delirium will seek different treatment plans or drug treatments based on the judgment of different causes or mechanisms of the disease, among which haloperidol is the only drug recommended in the guidelines.

[0004] Postoperative delirium (POD) is a type of delirium, that is, delirium that occurs after surgery. It is a common central nervous system complication after surgery and is more common 1-3 days after surgery. Postoperative delirium is very harmful. Postoperative delirium will prolong the patient's mechanical ventilation time, ICU stay time and hospitalization time, increase the incidence of perioperative complications, mortality and medical expenses; studies have shown that every 48 hours of delirium will increase the mortality rate by at least 10% to 20%. Similarly, delirium can be further divided into three subtypes based on clinical manifestations, including hyperactivity type (restlessness, constant activity, agitation, high alert state), activity inhibition type (sleepiness, reduced activity, reduced language), and mixed type. Several different clinical classifications show completely different clinical characteristics. (1) Hyperactive patients are highly alert, restless, and may have hallucinations or delusions, and aggressive mental disorders. This is the most easily detected type of delirium. (2) Inactive patients are characterized by nighttime drowsiness, dull expression, delayed recovery from anesthesia, and abnormally slow speech or movements. Because they are difficult to detect, they are often missed and have a poor overall prognosis. (3) Mixed patients show alternating and repeated fluctuations of the above two types.

[0005] The incidence of postoperative delirium is high, among which the incidence of postoperative delirium in non-cardiac surgery patients aged 65 and above is 11.1%; due to the influence of extracorporeal circulation, the incidence of postoperative delirium in cardiac surgery patients is as high as 26% to 52%; foreign reports show that the incidence of delirium after coronary artery bypass grafting is 36.3%, and my country reports that the incidence of delirium after cardiac surgery is 25.7%.

[0006] There is currently no "specific drug" for the prevention or treatment of intraoperative delirium. Literature reports that drugs that can reduce the incidence of postoperative delirium include dexmedetomidine and ketamine, but the efficacy of these drugs in preventing postoperative delirium is not sufficient, because some studies have shown that they cannot reduce the incidence of postoperative delirium. In the treatment of postoperative delirium, haloperidol has been proven to be the most commonly used and effective drug for the treatment of delirium. Haloperidol is a highly effective antipsychotic drug that can improve various types of delirium attacks, alleviate mental symptoms, and normalize sleep cycles.

[0007] Gastrodin, 4-hydroxymethylphenyl-beta-D-pyranoglucoside, CAS No. 62499-27-8, has a chemical structure as shown in Formula I. This compound is an organic compound extracted from the dried root of Gastrodia elata, an orchidaceous plant, and the raw material is produced in Yunnan. Gastrodin or its hydrate form has the function of dilating cerebral blood vessels, improving cerebral circulation, improving neurotransmitter dysfunction, and improving neuroinflammation. It can be used clinically to treat vertebral-basilar artery insufficiency, vestibular neuronitis and vertigo.

[0008]

[0009] Formula I However, the prior art has not reported the clinical application of gastrodin in postoperative delirium, especially its application performance in different clinical subtypes. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a use of gastrodin in preparing a drug for preventing or treating postoperative delirium in patients.

[0011] The gastrodin described in the present invention is conventional gastrodin in the art, wherein the gastrodin described in the present invention can be prepared by conventional methods in the art.

[0012] The gastrodin described in the present invention is a conventional pharmaceutically acceptable compound form in the art, preferably including: hydrates, hemihydrates, drug precursors, metabolites and other compound forms of gastrodin, preferably gastrodin hemihydrate.

[0013] Preferably, the gastrodin of the present invention is gastrodin hemihydrate, the compound name is: 4-hydroxymethylbenzene-β-D-pyranoglucoside hemihydrate, the molecular formula is C 13H 18 O7·1 / 2 H2O, CAS No.: 62499-27-8, the compound structure is shown in Formula II. The compound can be extracted from the dried root of Gastrodia elata, an orchidaceae plant, or prepared by artificial synthesis, and the raw material is produced in Yunnan.

[0014]

[0015] In the present invention, the delirium is the delirium conventionally described in the art. According to the 11th edition of the International Classification of Diseases (ICD-11) released by the World Health Organization in 2018, delirium is defined as: delirium is an acute or subacute onset of attention disorder (i.e., weakened ability to point, focus, maintain and shift attention) and consciousness disorder (i.e., weakened orientation to the environment), symptoms often fluctuate within 1 day, and are accompanied by other cognitive disorders (such as memory, language, visual-spatial function or sensory perception disorders, etc.), which can affect the sleep-wake cycle, and its cause is often non-psychiatric behavioral disorder diseases, substance or drug poisoning or withdrawal. The delirium is postoperative delirium, and the subtypes included in the postoperative delirium are preferably: hyperactive delirium or mixed delirium, preferably mixed delirium.

[0016] In the present invention, the surgery for preventing or treating postoperative delirium is a conventional surgery in the field, preferably including: major orthopedic surgery, major thoracic surgery, major abdominal surgery, cardiac surgery or neurosurgery, more preferably: upper abdominal surgery, spine and joint surgery, hip surgery, gastrointestinal surgery, prostate surgery, coronary artery bypass surgery, craniotomy.

[0017] In the present invention, the patient is a conventional patient in the field, preferably a patient who has received the above-mentioned surgical treatment of the present invention, more preferably a patient who has received upper abdominal surgery, spine and joint surgery, hip surgery, gastrointestinal surgery, prostate surgery, coronary artery bypass surgery, craniotomy, craniotomy. The patient is preferably a middle-aged or elderly patient, and the age of the middle-aged or elderly patient is more preferably ≥50 years old, and preferably, the age of the middle-aged or elderly patient is ≥60 years old.

[0018] In the present invention, the drug dosage form for preventing or treating postoperative delirium is a conventional dosage form in the art, preferably including: tablets, capsules, oral liquids, injections, powder injections or pills, etc. The drug dosage form is preferably an injection. The preparation method of the above-mentioned drug preparation is a conventional preparation method in the art. Preferably, the gastrodin used in this application is gastrodin injection, which comes from Kunming Pharmaceutical Group Co., Ltd.

[0019] The use of gastrodin in the present invention in preparing a drug for preventing or treating postoperative delirium in patients is a conventional pharmaceutical use in the field. The use is preferably: the use of gastrodin in preparing a drug for preventing postoperative delirium in patients, and more preferably: the use of gastrodin in preparing a drug for treating postoperative delirium in patients.

[0020] In the present invention, the use of the gastrodin in the preparation of a drug for preventing or treating postoperative delirium, the daily dosage is the conventional dosage in the art, and the dosage is preferably: 10 mg / kg to 40 mg / kg.

[0021] The gastrodin provided by the present invention shows positive technical effects in preventing or treating postoperative delirium, which are mainly manifested in the following aspects: 1. Gastrodia elata extract can significantly reduce the incidence of postoperative delirium and has a good preventive or therapeutic effect on postoperative delirium.

[0022] 2. Gastrodia elata extract is highly selective for preventing or treating delirium, especially in reducing the incidence of mixed delirium.

[0023] 3. Gastrodia elata extract has a better therapeutic effect on middle-aged and elderly patients with postoperative delirium, especially those aged ≥50 or ≥60 years.

[0024] 4. Gastrodia elata extract has the advantages of low incidence of adverse events and high safety in the treatment of postoperative delirium.

[0025] In summary: the present invention provides a new use of gastrodin in the preparation of a drug for preventing or treating postoperative delirium in patients, and achieves the positive effects of significantly lowering the incidence of postoperative delirium, better selectivity, and better safety. DETAILED DESCRIPTION

[0026] A randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy and safety of gastrodin injection in preventing perioperative neurocognitive impairment after coronary artery bypass grafting.

[0027] Example 1: A randomized, double-blind, placebo-controlled clinical trial of the effectiveness and safety of gastrodin injection in preventing perioperative neurocognitive disorders after coronary artery bypass grafting.

[0028] Purpose of the study: To evaluate the efficacy and safety of gastrodin injection in preventing cognitive impairment and postoperative delirium after coronary artery bypass grafting by comparing with placebo.

[0029] Trial population: Chinese patients scheduled for coronary artery bypass grafting.

[0030] Experimental design: Randomized, double-blind, placebo-controlled parallel design.

[0031] Sample size: 160 patients who were scheduled for coronary artery bypass grafting were randomly divided into an experimental group and a control group, with 80 patients in each group.

[0032] Research center: Department of Anesthesiology, Wuhan Union Hospital.

[0033] Dosage regimen: Experimental Group: Gastrodia elata injection (Kunming Pharmaceutical Group, Kunming, Yunnan, China) (2 ml: 0.2 g, intravenous pump, 600 mg each time (3 vials), twice a day, diluted with 44-250 ml of 5% glucose injection or 0.9% sodium chloride injection, pump injection time not less than 1 h), was administered on the day of surgery and on days 1-6 after surgery.

[0034] Control group: Placebo (intravenous injection, 3 vials each time, twice a day, diluted with 44-250 ml of 5% glucose injection or 0.9% sodium chloride injection, and the injection time is not less than 1 hour) was administered on the day of surgery and on the 1st to 6th day after surgery.

[0035] Main outcome measures: The incidence of perioperative neurocognitive disorders was evaluated by CAM-ICU scale 1-7 days after surgery for postoperative delirium. Cognitive function was evaluated by telephone follow-up using Mini-Mental State Examination (MMSE) 7 days, 1 month, and 3 months after surgery, and by telephone using Telephone Questionnaire for Cognitive Function-Revised (TICS-m) 12 months after surgery.

[0036] The number of effective samples was 78 cases in the gastrodin treatment group and 77 cases in the normal saline control group.

[0037] The inclusion criteria are: 1) The patient or his / her legal representative signs the informed consent form, 2) 18-75 years old, 3) planned elective coronary artery bypass grafting / coronary artery bypass grafting, 4) New York Heart Association (NYHA) II-III cardiac function classification, 5) American Society of Anesthesiologists (ASA) level II-III, 6) Preoperative Mini-Mental State Examination (MMSE) score>24 points, 7) ≥ 6 years of education, 8) Ability to complete the Cantab core cognitive testing system (MOT, PAL, RTI, RVP and SWM).

[0038] Main statistical methods: FAS set (full analysis set): refers to the set of qualified cases and dropped cases, but does not include excluded cases. PPS set (per protocol set): refers to the set of cases that meet the inclusion criteria, do not meet the exclusion criteria, and complete the treatment plan, that is, the cases that meet the trial protocol, have good compliance, complete the content specified in the research medical record, and the cases that withdraw from the trial due to poor efficacy are analyzed. SS set (safety set): actual data of at least one treatment and safety indicators. Missing values ​​in the safety set shall not be carried forward; some excluded cases that can be evaluated are included, such as cases whose age exceeds the inclusion criteria, but cases that cannot be judged for safety due to the use of prohibited drugs are not included. The incidence of adverse reactions uses the number of cases in the safety set as the denominator. When the primary efficacy index is missing, the LOCF (last observation carry forward) method is used for estimation according to the principle of intention-to-treat analysis. The missing values ​​of comparability analysis and secondary efficacy indicators are not carried forward, and the analysis is based on the actual data obtained.

[0039] SAS9.4 and SPSS25.0 statistical analysis software were used for analysis. The data of continuous variables were analyzed by Kolmogorov–Smirnov test. The data that conformed to the normal distribution were presented as mean and SD, and the data that did not conform to the normal distribution were presented as median (range). The data of categorical variables were presented as n (%).

[0040] Main outcome measures: The incidence of delirium 7 days after surgery and the incidence of cognitive impairment 7 days and 1 month after surgery were compared using the 𝜒2 test or Fisher's exact probability. The 95 CI of the difference between the two groups (experimental group - control group) was calculated at the same time. If the upper limit was not greater than 0, it was considered that there was a statistical difference between the two groups.

[0041] Safety analysis: The incidence of adverse events was compared between groups using the χ2 test or Fisher's exact probability method.

[0042] A P value of less than or equal to 0.05 was considered to be statistically significant for the differences tested.

[0043] The primary outcome measure was the incidence of postoperative delirium 7 days after surgery. Postoperative delirium was assessed using the Confusion Assessment Method in the Intensive Care Unit (ICU) (CAM-ICU). First, the Richmond Agitation-Sedation Scale (RASS) was used to assess the level of consciousness of the participant. If the participant was deeply sedated or unresponsive (RASS of -4 or -5), the delirium assessment was suspended. If the score was ≥ -3, the second step was performed. CAM-ICU was used to assess whether the subject had POD. A positive diagnosis of feature 1, feature 2, and feature 3 or 4 on the CAM-ICU assessment scale was suggestive of postoperative delirium. The incidence of delirium 7 days after surgery was determined as 100 × (number of people positive for delirium 1-7 days after surgery / total number of cases in this group).

[0044] 3.1 There was no difference in the incidence of perioperative neurocognitive impairment between the two groups.

[0045] 3.2 The overall incidence of delirium 1-7 days after surgery: The experimental group was significantly lower than the control group, see Table 1 for details.

[0046] Table 1 Incidence of delirium after coronary artery bypass grafting Group Number of effective cases Number of postoperative delirium cases in the total sample (number of positive cases) Positive rate Normal saline control group 78 28 35.9% Gastrodin treatment group 77 15 19.5% As can be seen from Table 1, the incidence of delirium after coronary artery bypass grafting was 19.5% in the gastrodin treatment group and 35.9% in the saline control group (P=0.021). The difference between the two groups was -16.4 (95%CI: -30.3, -2.58), indicating that the treatment effect of the gastrodin group was significantly better than that of the control group. The use of gastrodin injection during the perioperative period of coronary artery bypass grafting can significantly reduce the incidence of delirium and has a good preventive or therapeutic effect on postoperative delirium.

[0047] 3.3 The incidence of delirium subtypes 1-7 days after surgery was statistically analyzed, as shown in Table 2.

[0048] Table 2 Statistical table of the incidence of delirium subtypes after coronary artery bypass grafting Group Total number of samples Number of delirium cases in the total sample Number of hypoactive delirium cases The proportion of remission delirium in the total sample The number of cases of hyperactivity type in delirium The proportion of excessive delirium in the total sample The number of mixed delirium cases The proportion of mixed delirium in the total sample Normal saline control group 78 28 6 7.7% 9 11.50% 12 15.38% Gastrodin treatment group 77 15 7 9.09% 4 5.2% 5 6.50% As can be seen from Table 2, there was no significant difference between the control group and the experimental group in the prevention or treatment of the incidence of hypoactive delirium; while in terms of the incidence of hyperactive and mixed delirium, the incidence of delirium in the experimental group was much lower than that in the control group, showing a high degree of selectivity in the prevention or treatment of delirium, especially in reducing the incidence of mixed and excessive postoperative delirium.

[0049] Table 3 Statistical table of the incidence of delirium after coronary artery bypass grafting in patients of different ages The results of age subgroup analysis (Table 3) showed that gastrodin was effective in subjects ≥50 years old (15.6% vs. 37.5%, P=0.005) or >60 years old (14.7% vs. 44.4%, P=0.007), but was ineffective in subjects <50 years old (30.0% vs. 12.5%, P=0.588).

[0050] Safety results: In this study, 14 subjects experienced adverse events. Specifically, 5 subjects (6.4%) in the gastrodin treatment group experienced adverse events, and 9 subjects (11.4%) in the control group experienced adverse events (P=0.270). No serious adverse events (including dry mouth and nose, dizziness, and stomach discomfort) occurred in this study. The above results show that gastrodin injection has a low incidence of adverse events and high safety in the treatment of postoperative delirium.

[0051] Example 2: Application of Gastrodin Injection in the Prevention and Treatment of Delirium after Hip Surgery A small-scale, randomized, double-blind, placebo-controlled trial was conducted on 37 patients who were admitted to the ICU after hip surgery and did not require mechanical ventilation.

[0052] Dosage regimen: Same as Example 1.

[0053] Main outcome measures: The incidence of perioperative neurocognitive disorder, postoperative delirium assessment using the CAM-ICU scale 1-7 days after surgery, cognitive function assessment using the Mini-Mental State Examination (MMSE) 7 days, 1 month, 3 months after surgery, and telephone follow-up using the Telephone Cognitive Function Questionnaire-Revised (TICS-m) 12 months after surgery.

[0054] Statistical method: Same as Example 1.

[0055] The test results are shown in Table 4: Table 4 Incidence of delirium after hip surgery Group Number of effective cases Number of postoperative delirium cases in the total sample (number of positive cases) Positive rate Normal saline control group 20 8 40.0% Gastrodin treatment group 17 4 23.5% As can be seen from Table 4, the incidence of delirium after hip surgery in the gastrodin treatment group and the saline control group was 23.5% (P<0.05) and 40.0% (P<0.05), respectively, indicating that the treatment effect of the gastrodin group was better than that of the control group. Therefore, the administration of gastrodin injection after hip surgery can reduce the incidence of postoperative delirium.

[0056] Example 3: Application of Gastrodin Injection in Preventing and Treating Postoperative Delirium after Craniotomy A small-scale randomized, double-blind, placebo-controlled trial was conducted on 45 patients who were admitted to the ICU after craniotomy and did not require mechanical ventilation.

[0057] Dosage regimen: Same as Example 1.

[0058] Main outcome measures: The incidence of perioperative neurocognitive disorder, postoperative delirium assessment using the CAM-ICU scale 1-7 days after surgery, cognitive function assessment using the Mini-Mental State Examination (MMSE) 7 days, 1 month, 3 months after surgery, and telephone follow-up using the Telephone Cognitive Function Questionnaire-Revised (TICS-m) 12 months after surgery.

[0059] Statistical method: Same as Example 1.

[0060] The test results are shown in Table 5: Table 5 Incidence of delirium after craniotomy Group Number of effective cases Number of postoperative delirium cases in the total sample (number of positive cases) Positive rate Normal saline control group 23 13 56.5% Gastrodin treatment group 22 7 31.8% As can be seen from Table 5, the positive rate of post-craniotomy delirium in the gastrodin treatment group was 31.8% (P<0.05), and the positive rate of post-craniotomy delirium in the normal saline control group was 56.5% (P<0.05), indicating that the treatment effect of the gastrodin group was better than that of the control group. The administration of gastrodin injection after craniotomy can reduce the incidence of postoperative delirium.

[0061] Example 4: Application of Gastrodin Injection in the Prevention and Treatment of Delirium after Gastrointestinal Surgery A small-scale, randomized, double-blind, placebo-controlled trial was conducted on 65 patients who were admitted to the ICU after gastrointestinal surgery and did not require mechanical ventilation.

[0062] Main dosage regimen: Same as Example 1.

[0063] Main outcome measures: Same as Example 1.

[0064] Statistical method: Same as Example 1.

[0065] The test results are shown in Table 6: Table 6 Incidence of delirium after gastrointestinal surgery Group Number of effective cases Number of postoperative delirium cases in the total sample (number of positive cases) Positive rate Normal saline control group 33 9 27.2% Gastrodin treatment group 32 5 15.6% As can be seen from Table 6, the positive rate of postoperative delirium in the gastrointestinal tract surgery group was 15.6% (P<0.05), and the positive rate of postoperative delirium in the normal saline control group was 27.2% (P<0.05), indicating that the treatment effect of the gastrodin group was better than that of the control group. The administration of gastrodin injection after gastrointestinal surgery can reduce the incidence of postoperative delirium.

[0066] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. Use of gastrodin in the preparation of a drug for preventing and / or treating postoperative delirium in patients.

2. The use according to claim 1, characterized in that The postoperative delirium is hyperactive delirium or mixed delirium.

3. The use according to claim 1, characterized in that The postoperative delirium was a mixed type of delirium.

4. The use according to claim 1, characterized in that The patients are those who underwent major orthopedic surgery, major thoracic surgery, major abdominal surgery, cardiac surgery, neurosurgery, upper abdominal surgery, spine and joint surgery, hip surgery, gastrointestinal surgery, prostate surgery, coronary artery bypass surgery, and craniotomy.

5. The use according to claim 4, characterized in that The patients were those who underwent coronary artery bypass surgery, hip surgery, craniotomy, and gastrointestinal surgery.

6. The use according to claim 4, characterized in that The patients are middle-aged and elderly patients.

7. The use according to claim 1, characterized in that The dosage form of the drug for preventing or treating postoperative delirium is tablets, capsules, oral liquid, injection, powder injection and dripping pills.

8. The use according to claim 7, characterized in that The dosage form of the drug is injection.

9. The use according to claim 1, characterized in that The gastrodin is a hemihydrate.

10. The use according to claim 1, characterized in that The use is for preparing a drug for treating postoperative delirium.

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