Bibliometric Analysis of Adverse Drug Reactions of Shuxuening Injection

[Abstract] Shuxuening injection has made great contributions to the treatment of ischemic cardiovascular and cerebrovascular diseases since it was marketed as 1995. With the widespread use in clinic in recent years, the safety of its drugs has gradually attracted people's attention. In this paper, the published reports of ADR cases of Shuxuening injection in China were retrieved, and the data of gender, age, allergic history, primary disease, dosage, course of treatment, solvent and occurrence time of ADR in the literature were quantitatively analyzed, so as to study the regularity and influencing factors of ADR of Shuxuening injection and provide reference for rational clinical medication. The results showed that the main clinical manifestations of adverse reactions of Shuxuening injection were systemic damage, skin and mucous membrane damage and respiratory system damage. ADR first appeared after infusion 1 min, and at the latest after continuous infusion 1 1 days. According to the specific distribution of ADR occurrence time, 70% of ADR occurred within 65438±0h hours, indicating that ADR occurred rapidly. In the clinical application of Shuxuening injection, the ratio of ADR/ADE caused by over-standard medication is not high, and the degree of ADR has not been found to be related to allergic history and combined medication. The occurrence of ADR is not entirely a drug problem, but the solvent may be an important factor.

[Keywords] Shuxuening injection; Adverse reactions; solvent

Adverse drug reaction reports can be divided into group case reports and case reports. Group case reports mainly come from the retrospective case analysis of a hospital information system and the report of an adverse drug reaction center in a province. The number of reported cases is relatively large, but the personal information of patients and the description of drugs used are lacking. The case report is a single case or several cases from different regions and hospitals. The personal information of patients and the description of drugs used are more detailed. Both of them reflect the characteristics of adverse reactions caused by drugs from different levels, which can provide reference for clinical safe drug use. In recent years, the literature analysis of adverse drug reaction reports of Shuxuening injection has been published one after another, with 32 cases publishing the most [1] and 27 cases publishing 1 recently [2]. However, by searching many domestic databases, the author found that the number of cases should be no less than 50, indicating that the retrieval of previously published research documents is not comprehensive enough. Collect the full text of the retrieved cases, use bibliometrics to extract information, analyze the frequency of case literature, and find out the characteristics and distribution of Shuxuening's adverse reactions.

1 materials and methods

1. 1 Literature Retrieval Search China Biomedical Literature Service System (Chinese database), Wan Fang data resource database group, CNKI China periodical full-text database and VIP medical resource information system. The retrieval time is 2013-01-1. The retrieval strategy gives priority to the recall rate, and the retrieval formula is: Full-text inclusion? Shu xuening? What does the title or keyword or abstract contain? ADR？ Or? Allergy? Or? ADR？ Or? Infusion? And does not contain. Shuxuening tablets? , get a bibliography. Import the document management software Note Express to check duplicates, filter documents according to abstracts, and eliminate irrelevant documents. Download the full text through China HowNet, VIP and Wanfang databases, and filter the documents according to the full text to eliminate irrelevant documents.

1.2 ADR case report of standard Shuxuening injection, which should include basic information of patients with adverse events, medication information and clinical manifestations.

1.3 standard safety monitoring research or summary analysis excluding several ADR cases; The adverse reactions of Shuxuening injection were mentioned in the clinical trial of effectiveness; Literature review of adverse reactions of Shuxuening injection: no adverse events were reported; Published many documents.

1.4 document information extraction and analysis In this study, 37 case reports were included, including 50 cases. According to the designed ADR case information extraction table, fill in the information item by item. The extraction items include literature title, published journal name, reporter unit, publication year, sex, age, allergic history, primary disease, ADR clinical manifestations, ADR occurrence time and solvent.

Two results

2. 1 year and periodical of publication: ADR cases of Shuxuening have appeared since 2006, and have been reported every year since then, with the most reported year being 20 10 and 14 articles. From 2006 to 20 12, the number of articles published in each year was 2, 4, 2, 7, 14, 3, 5 and 37 respectively, which were counted as * * *. These literatures were published in 33 domestic journals, including 3 articles in Pharmacovigilance of China, 2 articles in Practical Medicine of China, 2 articles in Shandong Medicine, and the rest were 1 article.

Author's unit and region: The authors of 37 articles come from 33 hospitals in China, including tertiary hospitals 17 and secondary hospitals 16. According to the published data, there are 3 articles in the Affiliated Hospital of Yanbian University, 2 articles in the Second People's Hospital of Yulin City, Guangxi, 2 articles in the 253rd Hospital of the People's Liberation Army, and the rest are 1 article. The author is located in 17 provinces and cities, and the three regions with the largest number of articles are Jilin (5 articles), Heilongjiang (4 articles) and Shaanxi (4 articles). Thirty-two articles were published in the northern region, while only five were published in the southern region.

2.2 Among 50 cases of gender and age, 49 cases were marked with gender and age, including 24 males and 25 females. The oldest is 85 years old and the youngest is 3 1 year old. See table 1 for details. The data showed that the proportion of male and female patients with Shuxuening injection was equal, and the incidence of ADR was the highest in patients aged 5 1 ~ 60 years.

2.3 Of the 50 cases with allergic history, 6 cases have drug allergic history, including 4 cases with penicillin allergic history, 1 case with Yanhuning injection allergic history 1 case and 1 case with drug allergic history 1 case, but the specific allergic drugs are unknown. 25 cases were marked as having no allergic history, and 19 cases were unmarked with allergic history.

2.4 Primary disease Shuxuening injection drug instructions are mainly used to dilate blood vessels and improve microcirculation. Used for ischemic cardiovascular and cerebrovascular diseases, coronary heart disease, angina pectoris, cerebral embolism, cerebral vasospasm, etc. All the 50 patients in this study had primary diseases, of which 60%(30/50) met the above indications. Because some patients suffer from various diseases, combined with econometric analysis, there are 29 primary diseases in 50 patients, and the proportion of ischemic cardiovascular and cerebrovascular diseases is 48.6 1%, which is still the main disease. See Table 2 for the specific distribution.

2.5 The mode of administration, dosage, solvent, daily dosage and solvent for intravenous drip of Shuxuening injection are clearly stated in the drug instructions: 20 mL per day, diluted with 5% glucose injection for 250 mL or 500 mL, or as directed by the doctor. Among the 50 cases in this study, 49 cases were intravenous drip, with intravenous injection 1 case; The dosage of a prescription is mostly 20 mL, 32 cases, and the rest are below 20 mL; 70%(35/50) of the solvent used is 250 ml of 5% glucose, 24%( 12/50) is 250 ml of 0.9% physiological saline, and 6%(3/50) is unspecified. Only 34%( 17/50) reported that the dropping speed was recorded in detail, and the dropping speed was about 40 ~ 50 drops/minute.

2.6 Among 50 cases of combined medication, 10 cases were marked with combined medication. No combination medication? There are 3 cases and 37 cases are unknown. 10 patients did not use other injections at the same time and did not use mixed drugs during the drip of Shuxuening injection. However, there are also combined drugs, such as using other injections or taking other drugs orally before and after Dishuxuening injection. Most of the combined drugs are commonly used drugs for ischemic cardiovascular and cerebrovascular diseases such as lowering blood sugar, lowering blood pressure, antiplatelet and dilating coronary artery, and there are also a few antibacterial and antiviral drugs. 10 The degree of adverse reactions of patients with combined medication was average, and no correlation between combined medication and the degree of adverse reactions was found. 2.7 ADR features There were no deaths among the 50 cases, but there were serious adverse reactions 10 cases, 7 cases of anaphylactic shock and 3 cases of severe anaphylactoid reaction. The adverse reactions of Shuxuening injection involve 49 clinical manifestations of 7 systems/organs, as shown in Table 3. The main clinical manifestations are systemic damage, skin and mucous membrane damage and respiratory system damage.

2.8 ADR occurrence time: All 50 cases indicated the time when ADR started to take medicine, which occurred at the earliest after infusion 1 min and at the latest after continuous infusion 1 1 day. There are both immediate allergic reactions and delayed allergic reactions. From the specific distribution of ADR occurrence time, as shown in Table 4, 70%(35/50) of ADR occurred within 65438±0h hours, indicating that the ADR of Shuxuening injection is mainly an immediate allergic reaction.

2.9 Drug Batch Number Of the 50 Shuxuening injections, 32 were marked with drug batch numbers, involving 9 domestic manufacturers, 1 foreign product. Among them, Shenwei Pharmaceutical Group Co., Ltd. 1 1 case, Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd. 7 cases, Beijing Shuanghe Pharmaceutical Co., Ltd. 4 cases, Zhejiang Tianrui Pharmaceutical Co., Ltd. 4 cases, Hainan Tongyong Pharmaceutical Co., Ltd. 1 case, Wanrong Sanjiu Pharmaceutical Co., Ltd. 1 case, Shi Yao Baiyin Co., Ltd.

2. 10 Treatment Measures and Prognosis of Shuxuening Injection After ADR, 50 patients stopped infusion immediately after ADR, and were given symptomatic treatment such as anti-allergy and anti-shock, and the symptoms were relieved/disappeared. The shortest time is 10 min and the longest time is15 d.

3 discussion

3. 1 Allergy history and ADR incidence The measured data of 50 cases of Shuxuening injection showed that 10 patients with severe ADR had no allergic history or allergic history, and the ADR incidence of 6 patients with drug allergy history was average. No correlation was found between allergic history and ADR incidence. For the evaluation of serious adverse drug reactions, refer to the Technical Specifications and Evaluation Criteria for Common Serious Adverse Drug Reactions issued by the National Adverse Drug Reactions Monitoring Center (comprehensive number of monitoring and evaluation: 2006/2007)20 1026), and the rest are the same.

Many clinical studies believe that the history of drug and food allergy is the most important factor affecting ADR. In recent years, there have been similar reports [3], and people with allergic history have an increased chance of drug ADR. For example, in people with positive allergic history, the incidence of allergic reaction and total ADR of cephalosporins are 14 and 10 times that of people with negative allergic history, respectively [4]. However, it has also been reported that there is no significant statistical difference in the incidence of adverse drug reactions between patients with previous allergic history and patients without allergic history [5]. Studies have found that many patients with a history of penicillin allergy are not allergic to cephalosporins [6]. It can be considered that the past allergic history does not necessarily increase the incidence of ADR. At present, there is no large sample study on the relationship between ADR occurrence and allergic history of Shuxuening injection, and the influence of allergic history on ADR occurrence cannot be determined. In addition, in this study, the quantitative analysis of the literature shows that all patients with severe ADR have no allergic history or no allergic history, while all patients with allergic history have ordinary ADR. The case information analysis of Shuxuening injection without indicating the manufacturer also shows the same result. After consulting the ADR reports of Shuxuening injection from other manufacturers, the analysis results are consistent with the above. At present, all ADR case reports of Shuxuening injection (37 literatures, 50 cases) show that the occurrence of ADR has nothing to do with allergic history, so the past allergic history does not necessarily aggravate the occurrence of ADR. It is suggested that patients with or without allergic history may have serious adverse reactions when using Shuxuening injection, so all patients who use Shuxuening injection should be closely observed during medication. In addition, patients with previous allergic history (non-Ginkgo biloba preparation allergy) can also do skin test first. If the skin test results are negative, they can take medicine as appropriate.

3.2 Drug use and adverse reactions/events Recent experimental studies have shown that Shuxuening injection can protect ischemic myocardium, damaged liver and brain tissue from reperfusion, improve vascular endothelial injury, increase cerebral blood flow, scavenge free radicals, inhibit thrombosis, reduce platelet adhesion rate and enhance cellular immune activity [7]. Clinically, it is mainly used for ischemic cardiovascular and cerebrovascular diseases, coronary heart disease, angina pectoris, cerebral embolism, cerebral vasospasm and so on. By analyzing the use of Shuxuening injection in 50 cases, it is found that most patients can take drugs according to the dosage, indications or doctor's advice specified in the drug instructions, and the proportion of ADR events caused by over-instruction drugs is not high.

3.3 Characteristics and mechanism of adverse reactions The serious adverse reactions of Shuxuening injection are mainly systemic damage and respiratory system damage. Moderate and mild ADR is mainly caused by skin and its accessories, central and peripheral nervous system, cardiovascular and cerebrovascular system and gastrointestinal system. The specific clinical manifestations are shown in Table 3. It is suggested that clinical medical staff should consider the adverse reactions/events of Shuxuening injection when discovering the above symptoms, and take corresponding measures in time. Patients with ADR should stop taking drugs immediately, and receive anti-allergic and anti-shock treatment. Almost all ADR can be controlled. By analyzing the clinical manifestations and occurrence time of ADR, the main ADR types are type ⅰ immediate allergic reaction and type ⅳ delayed allergic reaction. Type I allergic reaction may be related to the high content of ginkgolic acid in Ginkgo biloba injection. These biomacromolecules enter the body as antigens or haptens to stimulate the immune system, that is, the antigens quickly combine with the corresponding pre-allergic antibody IgE stored in the body, so that mast cells and basophils thresh and release histamine or histamine-like substances, which cause a series of negative reactions of various organs and tissues in a very short time, including vasodilation and congestion, enhanced permeability and greater damage to the respiratory system. Type Ⅳ delayed allergic reaction is due to lymphatic factor produced by sensitized lymphocytes after being attacked by antigens, which causes tissue damage, so allergic dermatitis is more common. It is suggested that patients should be monitored during clinical use, especially during intravenous drip1h.

3.4 There have been many experimental studies and clinical reports on serious adverse reactions and solvents. Shuxuening injection is prone to salting-out reaction with normal saline, which may be the main reason why the solvent for Shuxuening injection in China is 5% glucose. However, it is also common to use physiological saline as a solvent in clinical practice. It has also been reported that the adverse reaction rate of Shuxuening combined with glucose is high, but it is obviously reduced when it is combined with normal saline. There is not enough evidence-based medical evidence at present. The data of this study show that the occurrence of serious adverse reactions of Shuxuening injection is closely related to the solvent 5% glucose. Shuxuening injection used 5% glucose in 10 cases of serious adverse reactions. According to other related literature reports, it was found that there were many serious adverse reactions when glucose injection was combined with drugs, but the incidence was low when it was combined with sodium chloride [8]. Whether there is a positive correlation between the occurrence of serious adverse reactions of Shuxuening injection and the use of glucose injection, and whether 5% glucose is reasonable as the solvent of Shuxuening injection needs further study. Another experimental result shows that the number of insoluble particles in the same batch of Chinese medicine injections and infusion mixtures produced by different manufacturers is quite different, and the same batch of Chinese medicine injections and infusion mixtures produced by different manufacturers contains 2? The quantity difference of M insoluble particles is even as high as 40 times [9]. Due to different manufacturers, regardless of the quality, the pH value and solubility are different in a certain range. These factors can lead to different solution quality after the same batch of traditional Chinese medicine injections are compatible with solvents of the same composition produced by different manufacturers. If there are many insoluble particles after compatibility, these insoluble particles can cause local blood vessel blockage and insufficient blood supply, further lead to tissue hypoxia, edema, phlebitis and granuloma, thus causing allergic reactions and pyrogen reactions. It can be considered that some ADR is not necessarily a problem of traditional Chinese medicine injection, but a factor of solvent. Therefore, it is suggested that the report of clinical adverse events should indicate not only the manufacturer and batch number of traditional Chinese medicine injections, but also the manufacturer and batch number of solvents.

Infusion granules are non-metabolic granular impurities that enter the human body during infusion, and most of them are 1 ~ 15? M, how many can be between 50 and 300? M[ 1 1]. Ordinary infusion sets can only intercept > 10? M particles, and the diameter of human capillaries is only 4 ~ 7? M. Large particles can cause vascular embolism, and small particles enter the pulmonary circulation to cause granuloma. As for how to reduce the insoluble particles in the solution, some studies show that a large number of insoluble particles can be intercepted by infusion of traditional Chinese medicine injections with precision infusion devices, so as to reduce the incidence of ADR caused by drugs such as phlebitis and allergic reactions [12]. It is suggested that manufacturers should equip special solvents or use precise infusion sets during intravenous drip, which can effectively reduce the incidence of ADR.

3.5 Importance of recording ADR/ event related information There are many factors that cause adverse drug events, and each factor may lead to the occurrence of adverse drug events, sometimes it is not necessarily a drug problem, but it is necessary to consider whether to standardize drug use. For example, the operating environment of drug injection, the storage time of prepared liquid medicine, whether to flush the tube before and after using other injections continuously, etc. Therefore, a comprehensive, timely and detailed record of the relevant information of adverse drug reactions is conducive to accurately judging adverse drug reactions and finding out the main influencing factors. This study found that some important information in some case reports was missing and wrong, such as concomitant medication, allergic history, drip rate, drug batch number and so on. It is suggested that clinical medical staff should record all relevant information in time, accurately and in detail when discovering ADR/ADE.

3.6 Limitations Based on the analysis of a few ADR cases, this study is not representative enough to reflect the whole picture of ADR/ events of Shuxuening injection; The case comes from literature, and there may be publication bias; The quality of literature is uneven and some information is missing. However, the above analysis results can provide possible clues for the safety study of Shuxuening injection.

[References]

[1] Wu. Analysis of 32 Cases of Adverse Drug Reactions Induced by Shuxuening Injection [J]. China Information of Traditional Chinese Medicine, 201,3 (20): 16.

Cai, Zhou Fuyong, Zhang Lingxi. Literature Analysis of 27 Cases of Adverse Drug Reactions of Shuxuening Injection [J]. China Medicine, 2013,22 (1): 29.

Zheng Miaoqiong, Zhuang, Sun. Clinical observation on the correlation between adverse reactions of iodine contrast media and allergic history [J]. china tropical medicine, 2006,6 (12): 2221.

Xu, Feng Xiying,. Investigation on the correlation between adverse reactions caused by cephalosporins and their allergic history [J]. Clinical Medicine, 2009,29 (4):119.

Cao Hong, Cao Fang, Sun. Relationship between adverse reactions of fluorescein fundus angiography and drug allergy history [J]. International Journal of Ophthalmology, 2009,9 (8):1624.

[6] Li Yong. Patients with a history of penicillin allergy can choose cephalosporin [N]. China medical journal, 20 10-3- 16.

Shi Yong, Chloe Wang. New progress in pharmacological action of Shuxuening injection [J]. Medical Review, 20 12,18 (10):1555.

Yang Deping. 154 cases of serious adverse reactions of Shuxuening injection [J]. China Pharmacovigilance, 20 10/0,7 (10): 620.

Huang Jia, Shi Weizhong, Xing Yihua. Changes of insoluble particles in injections and infusions of six commonly used traditional Chinese medicines from different manufacturers [J]. Jilin Traditional Chinese Medicine, 2009,29 (8): 715.

Xin Li, Li Lei. Effect of insoluble particles in infusion on human microcirculation [J]. Corps Medicine, 2006, 1 (1): 16.

Yang Lili, Liya, Kang Yubin. Particle changes of three kinds of traditional Chinese medicine injections at different temperatures and time [J]. Nursing and Rehabilitation, 201,1(1): 5.

[12] Han Hongmei, Zhi Yingjie. The role of precision infusion set in infusion of traditional Chinese medicine injections [J]. journal of traditional chinese medicine, China, 2012,37 (18): 2758.

Adverse Drug Reactions Caused by Parenteral Administration: A Case Report

Shu Xuening Based on Literature Analysis

Ai Qinghua 1, Wei Xu 2,-Ming 2*, Liao Xing 2,-Fei 2

(1. Postdoctoral Mobile Station of Chinese Academy of Traditional Chinese Medicine, Beijing100700;

2. Institute of Clinical Medicine, Chinese Academy of Traditional Chinese Medicine, Beijing 100700)

[Abstract] Shuxuening injection has made important contributions to the treatment of ischemic cardiovascular and cerebrovascular diseases since it was published in 1995. Shuxuening injection has been widely used in clinic, and its safety has gradually attracted attention. Based on the published case reports of adverse drug reactions (ADR), the characteristics of patients and other data were analyzed, including gender, age, allergic history, primary disease, dosage, course of treatment, solvent, ADR occurrence and time range. This will provide clinical reference for the adverse reactions of Shuxuening injection and its influencing factors. The analysis shows that the clinical symptoms of ADRs include systemic damage, with skin, mucosa and respiratory system damage being the most common. ADRs occurred at the earliest 1 min after infusion and at the latest 1 1 day after infusion. 70% of ADR occurs within 1 hour, so rapid occurrence is the main clinical feature. The use of drugs basically meets the requirements of drug instructions, and the correlation between adverse drug reactions and allergies or different drug combinations is not high. The occurrence of adverse reactions may not be entirely related to drugs, but the solvent used in the production process may be an important factor.

[Keywords] Shuxuening for injection; Adverse drug reactions/adverse drug events; solvent

doi: 10.4268/cjm cm 20 13 1847

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