Case Reporting Academic Papers (2)

Bibliometric Analysis of ADR Case Reporting for Shu Xuning Injection

[Abstract] Since its introduction to the market in 1995, Shu Xuning Injection has made an important contribution to the treatment of ischemic cardiovascular and cerebrovascular diseases. With its extensive clinical use in recent years, its drug safety has been gradually attracting attention. This article searched for ADR case reports of Shuxuaining injection published in China, and measured and analyzed the data of gender, age, allergy history, primary disease, dose, course of treatment, dissolution, and time of ADR occurrence in the literature, aiming to study the pattern and influencing factors of the occurrence of ADR of Shuxuaining injection, and to provide references for the rational use of medication in the clinic. The results showed that the clinical manifestations of ADR of Shu Xuning Injection were mainly systemic damage, skin, mucous membrane damage and respiratory system damage, and the earliest ADR occurred after 1 min of infusion, and the latest one occurred on the 11th day of continuous infusion, and from the distribution of the ADR occurrence time, 70% of the ADRs occurred within 1 h, which showed that the ADRs were mainly rapid-acting allergic reactions. In the clinical application of Shu Xuning injection, the proportion of ADR/ADE caused by overdosing is not high, and the degree of ADR occurrence has not been found to be associated with the history of allergy and coadministration of drugs, and the occurrence of ADR is not entirely a problem of the drug, and the solvent may be an important factor.

[Keywords] Shu Xuning injection; adverse drug reaction; solvent

ADR (adverse drug reaction) reports are divided into group case reports and individual case reports. Group case reports mainly come from the retrospective case analysis of the information system of a certain hospital and the report of the ADR center in a certain province, which have a relatively large number of reported cases but lack the personal information of the patients and the description of the drugs they used. The number of cases reported is relatively large, but the personal information of the patients and the description of the drugs they used are missing. Case reports, on the other hand, come from single or several cases in different regions and hospitals, with more detailed descriptions of the patients' personal information and the drugs they used. Both of them reflect the ADR characteristics caused by drugs from different levels, which can provide reference for the safe use of drugs in clinical practice. In recent years, literature analyses of ADR case reports on Shu Xuning injection have been published, with the largest number of published cases being 32 [1], and the most recently published one being 27 [2]. However, by searching several domestic databases, the author found that the number of cases should be no less than 50, indicating that the literature search of the previously published studies was not comprehensive enough. The author collected the full text of the retrieved cases, and used bibliometric methods to extract information and frequency analysis of the case literature, in order to find the characteristics of ADR of Shu Xuning and its distribution pattern.

1 Materials and methods

1.1 Literature search Search China Biomedical Literature Service System (Chinese Library), Wanfang Data Resource Base Group, CNKI Chinese Journal Full Text Database and VIP Medicine Resource Information System. The search period was from the time of library construction to 2013-01-11.The search strategy prioritized the search rate, and the search formula was: full text contains ? Shu Xuning?AND title OR keywords OR abstract containing ?ADR?OR ? Allergy?or ?ADR?or ?Infusion?and does not contain ? Sulforaphane tablets? , to obtain the bibliography. We imported the literature management software Note Express to check the weight, and screened the literature according to the abstract to eliminate non-relevant literature, and downloaded the full text through CNKI, VIP, and Wanfang databases, and screened the literature according to the full text to eliminate non-relevant literature.

1.2 Inclusion criteria ADR case reports of Shu Xuning Injection should include the basic information of the patient who had an adverse event, medication information and clinical manifestations.

1.3 Exclusion criteria: safety monitoring studies or summary analysis of several cases of ADR; validity clinical trials mentioning the ADR of Shu Xuning Injection; literature review of the ADR of Shu Xuning Injection; cases with no reported adverse events; duplicated published literature.

1.4 Literature information extraction and analysis Thirty-seven case reports were included in this study***, ***counting 50 cases, and the information was filled in item by item according to the designed ADR case information extraction form, and the items extracted included the title of the literature, the name of the journal in which it was published, the unit of the reporter, the year of the publication of the literature, the gender, the age, the history of allergy, the primary pathology, the clinical manifestations of the ADR, and the time of occurrence of the ADR, solvent, route of administration, dosage, drip rate, co-medication, drug batch number, and the treatment and prognosis received by the patient after the occurrence of ADR, and then analyzed the data by frequency analysis.

2 Results

2.1 Literature publication Years and journals: since 2006, there have been case reports of ADR of Sulforaphane, and then every year after that, with the most reported year being 2010, with 14 articles.The number of articles published in each year, from 2006 to 2012, was 2, 4, 2, 7, 14, 3, 5 articles, *** counting 37 articles. They were published in 33 domestic journals, including 3 in China Pharmacovigilance, 2 each in China Practical Medicine and Shandong Medicine, and the rest were 1 each.

Author units and geographic regions: the authors of the 37 documents were from 33 hospitals in China, including 17 tertiary hospitals and 16 secondary hospitals. The data on the number of publications show that there are 3 articles in Yanbian University Hospital, 2 articles each in Guangxi Yulin Second People's Hospital and PLA No. 253 Hospital, and the rest are all 1 article. The location of the authors spread across 17 provinces and cities, and the three regions with the highest number of articles were Jilin (5 articles), Heilongjiang (4 articles), and Shaanxi (4 articles). The northern region *** published 32 articles, while the southern region only 5 articles.

2.2 Sex and age 49 of the 50 cases indicated their sex and age, of which 24 were male and 25 were female. The oldest was 85 years old, and the youngest was 31 years old, as shown in Table 1.The data showed that the proportion of men and women who had ADRs with Shu Xuning Injection was comparable, and the highest ADR incidence was found in patients aged 51 to 60 years old.

2.3 Allergy history Of the 50 cases, 6 cases were labeled as having a history of drug allergy, of which 4 were allergic to penicillin, 1 was allergic to Yansuning injection, and 1 had a history of drug allergy, but the specific allergic medication was unknown. Twenty-five cases were labeled as having no history of allergy, and another 19 cases were not labeled as having a history of allergy.

2.4 Pathogenesis The function of Shuxuning injection is to dilate blood vessels and improve microcirculation. It is used for ischemic cardiovascular and cerebrovascular diseases, coronary heart disease, angina pectoris, cerebral embolism, cerebral vasospasm and so on. All 50 cases in this study were labeled with the original disease, and 60% (30/50) fell within the above indications. As some patients suffered from multiple diseases, the results of combined measurement analysis showed that the primary diseases of 50 patients*** counted 29 kinds, and ischemic cardiovascular and cerebrovascular diseases constituted 48.61%, which was still the main disease, and the specific distribution is shown in Table 2.

2.5 Mode of administration, dosage, solvent, and titration rate In the instruction manual of Shuxuning injection, there is a clear description of the one-day dosage of intravenous drip and solvent: 20 mL per day, 20 mL per day, 20 mL per day, 20 mL per day. There are clear instructions: 20 mL per day, diluted 250 mL or 500 mL with 5% glucose injection, or as directed by a physician. Of the 50 cases in this study, 49 were administered intravenously and 1 intravenously; most of the doses dispensed in one dose were 20 mL in 32 cases, and the rest were less than 20 mL; 70% (35/50) of the solvents used were 250 mL of 5% dextrose, and 24% (12/50) of the solvents used were 250 mL of 0.9% saline, while 6% (3/50) did not specify the solvent used; the rate of titration was recorded in detail in only 34 reports, and the rate of titration was reported in only 34 reports. Detailed recording of the drip rate was reported in only 34% (17/50), with a drip rate of roughly 40-50 drops/min.

2.6 Combination of medications Of the 50 cases, 10 were labeled as combination of medications, and 10 were labeled as ? No combination of drugs? 3 cases, the other 37 cases were not indicated. 10 patients who combined medications did not use other injections at the same time during the titration of Shuxianin injection, and there was no mixing of medications. However, there were some combined medications, such as the use of other injections before and after the drip of Shuxu Xuning Injection, or the oral administration of other medications. Most of the drugs used in combination were common drugs for ischemic cardiovascular and cerebrovascular diseases, such as hypoglycemic, antihypertensive, antiplatelet, coronary expansion, etc., and a few antibacterial and antiviral drugs were also used.The degree of ADRs occurred in 10 cases of patients who used drugs in combination was average, and no correlation between the use of drugs in combination and the degree of occurrence of ADRs was found.　2.7 ADR characteristics There were no deaths among the 50 cases, but there were 10 cases of serious ADRs, 7 cases of anaphylaxis, and 3 cases of severe allergic-like reactions. ADR of Shu Xuning Injection involved 49 clinical manifestations in 7 systems/organs, as shown in Table 3, with systemic damage, skin and mucous membrane damage and respiratory damage as the main clinical manifestations.

2.8 Time of ADR occurrence All of the 50 cases were labeled with the time of ADR occurrence from the start of the medication, with the earliest occurring after 1 min of infusion and the latest occurring on the 11th day of consecutive infusion, with both rapid-onset and delayed-onset metabolic reactions. From the specific distribution of ADR occurrence time, see Table 4, 70% (35/50) cases of ADR occurred within 1 h, showing that the ADR of Shu Xuning injection is mainly rapid-type allergic reactions.

2.9 Drug batch number The drug batch number was indicated in 32 of the 50 cases of Shu Xuning Injection, involving 9 domestic manufacturers and one foreign product. Among them, there were 11 cases of China Shineway Pharmaceutical Group Co., Ltd, 7 cases of Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd, 4 cases of Beijing Shuanghe Pharmaceutical Co., Ltd, 4 cases of Zhejiang Tianrui Pharmaceutical Co., Ltd, 1 case of Hainan General Sanyang Pharmaceutical Co., Ltd, 1 case of Wanrong Sanjiu Pharmaceutical Co., Ltd, 1 case of Shanghai Xinxin Pioneer Pharmaceutical Co., Ltd, 1 case of Shijiazhuangyinhuhu Pharmaceutical Co., Ltd, 1 case of Shanxi Taiyuan Pharmaceutical Co. Ltd., 1 case in Shanxi Taiyuan Pharmaceutical Co.

2.10 Treatment and prognosis of patients after the occurrence of ADR Shuxuning injection 50 cases after the occurrence of ADR were immediately stopped infusion, anti-allergy, anti-shock and other symptomatic treatment, the symptoms were relieved / disappeared, the shortest time for 10 min, the longest time for 15 d.

3 Discussion

3.1 Allergy history and ADR occurrence The data of 50 case measures of Shu Xuning Injection showed that 10 patients with severe ADR were those with no history of allergy or no record of whether they had a history of allergy, and 6 patients with a history of drug allergy had an average degree of ADR, and a correlation between the history of allergy and the degree of occurrence of ADR was not found. Among the evaluation of serious drug ADR, refer to the National Drug ADR Monitoring Center issued the "common serious drug ADR technical specifications and evaluation standards" (Monitoring and Evaluation Synthesis No. 201026) to determine the serious drug ADR, the rest of the same.

Clinical studies have mostly concluded that a history of drug and food allergy is the most important factor influencing the occurrence of their ADR. In recent years, it has been similarly reported [3] that people with a history of previous allergy have an increased chance of developing drug ADRs. For example, in people with a positive history of allergy, the incidence of cephalosporin allergic reactions and total ADRs was 14, 10 times higher than in those with a negative history of allergy [4]. However, it has also been reported that there is no statistically significant difference between patients with a previous history of allergy and those without a history of allergy regarding the occurrence of drug ADRs [5]. One study found that many patients with a history of penicillin allergy were not allergic to cephalosporin antimicrobials [6]. It can be assumed that a history of prior allergy does not necessarily increase the incidence of ADR. Currently, there are no large-sample studies on the relationship between the occurrence of ADR and history of allergy in Shu Xuning injection, and it is not possible to determine the effect of history of allergy on the incidence of ADR. Also in this study, econometric analyses of the literature showed that none of the patients who had severe ADRs had a history of allergy or had no documented history of allergy, whereas those who had a history of allergy had general ADRs. analysis of the case information for Shuxuning Injection from an unspecified manufacturer showed the same results. ADR case reports for other manufacturers of Shu Xuning Injection were later reviewed, and the results of the analysis were consistent with the above. The results of the analysis of all current case reports of ADR with Shu Xuning Injection (*** counting 37 articles and 50 cases) indicate that the degree of ADR is not associated with a history of allergy, and therefore a history of prior allergy does not necessarily exacerbate the degree of ADR. It suggests that when using Shu Xuning Injection, patients are at risk of developing severe ADR regardless of a history of allergy, so all patients on the drug should be closely observed during administration. Another previous history of allergy (non-ginkgo biloba preparation allergy) patients can also be done first skin test, if the skin test results are negative, can be used as appropriate.

3.2 Medication and ADR/events Recent experimental studies have shown that Shu Xuning Injection has a protective effect on ischemic myocardium, damaged liver reperfusion and brain tissue in ischemic area, which can improve vascular endothelial damage, increase cerebral blood flow, scavenge free radicals, inhibit thrombosis, reduce platelet adhesion and enhance the body's cellular immune activity, etc.[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 Shu Xuning injection in 50 cases, it was found that the vast majority of patients were able to use the drug in accordance with the dosage, indications, or doctor's orders stipulated in the drug manual, and the proportion of ADR events caused by the use of over-the-top medication was not high.

3.3 Characteristics and mechanism of ADR The serious ADR of Shu Xuning Injection is mainly characterized by systemic damage and respiratory damage. Mild and moderate ADRs are mainly characterized by damage to the skin and its accessories, central and peripheral nervous system, cardiovascular and cerebral vascular system and gastrointestinal system, and the specific clinical manifestations are shown in Table 3.It is suggested that clinical healthcare personnel should consider the ADRs/events of Shuxuaining Injection when the above symptoms are found, and take appropriate measures in time. Patients with ADR should be treated with symptomatic treatment such as stopping the drug immediately, anti-allergy, anti-shock, etc. Almost all ADRs can be controlled. By analyzing the clinical manifestations and the time of occurrence of ADRs, their ADRs were mainly type I rapid-onset allergic reactions and type IV delayed-onset allergic reactions. type I rapid-onset allergic reactions may be related to the high content of ginkgolides in Ginkgo biloba injection, which are biomolecule moieties that themselves act as antigens or semiantigens to enter the body and stimulate the immune system to produce them, i.e., antigenic substances that enter the body rapidly interact with the pre-existing After entering the body, the antigenic substance combines with the corresponding pro-cellular allergic antibody IgE, causing mast cells and basophils to degranulate and release histamine or histamine-like substances, which causes a series of negative reactions in a very short period of time in a variety of organs and tissues, including dilatation and congestion of small blood vessels and increased permeability, and damage to the respiratory system, which is common, and can lead to anaphylactic shock in severe cases.Type IV delayed-type allergic reactions are due to the production of lymphokines in sensitized lymphocytes after they have been attacked by the antigen, causing tissue damage. Lymphokines, resulting in tissue damage, so it is common to see allergic dermatitis. It is recommended to monitor the patient throughout the clinical use, especially in the drip 1 h should closely observe the patient's condition.

3.4 Serious ADR and solvent Previously, there were several experimental studies and clinical reports that Shu Xuning Injection is prone to saline salting out reaction with saline, which may be the main reason why the instruction manual of Shu Xuning Injection in China indicates that the solvent medium is 5% dextrose. However, in clinical practice, the use of saline as a solvent is also more common. And it has been reported that the incidence of ADR is high with glucose, while it is significantly lower with saline, and there is not enough evidence-based medical evidence. The data in the present study suggest that the occurrence of serious ADRs for Shuxuning injection is more associated with the solvent 5% glucose used. In all 10 cases of serious ADR with Shu Xuning Injection, the solvent used was 5% dextrose. It has also been reported in the literature that the combination of drugs found more serious ADRs with the use of dextrose injection dispensing solution and less with sodium chloride dispensing solution [8]. Whether there is a positive relationship between the occurrence of serious ADRs of Shu Xuning injection and the use of glucose injection, and whether 5% glucose sugar is reasonable as the solvent of Shu Xuning injection, need to be further studied.　The results of another experiment showed that there was a large difference in the number of insoluble particles in the mixed solution of the same batch number of traditional Chinese medicine injection and the infusion solution produced by different manufacturers after dispensing, and the difference in the number of 2 ?m insoluble particles contained in the mixed solution after the infusion solution of the same batch number of traditional Chinese medicine injection and the infusion solution produced by different manufacturers was even as large as 40 times [9]. The same component of the solvent, due to the different manufacturers, and regardless of the quality of its pH, solubility, etc., there is a certain range of values within the difference, these factors can lead to the same batch number of traditional Chinese medicine injections and different manufacturers of the same component of the solvent after the different quality of the solution after the matching, if the number of insoluble particles after the matching is higher, these insoluble particles can cause local vascular blockage and insufficient blood supply, and further These insoluble particles can cause local vascular blockage and insufficient blood supply, and further lead to tissue hypoxia, resulting in edema, phlebitis, granuloma, and thus allergic reactions and pyrogenic reactions [10]. It can be assumed that some ADRs are not necessarily a problem of TCM injections, but a factor of the solvent. Therefore, it is recommended that clinical adverse event reports should indicate not only the manufacturer and batch number of the Chinese medicine injection, but also the manufacturer and batch number of the solvent.

Infusion particles are non-metabolic particulate impurities that enter the body during infusion, mostly with a diameter of 1 to 15 ?m, and a few can be 50 to 300 ?m [11]. Ordinary infusion sets can only retain particles of >10 ?m, while the diameter of human capillaries is only 4-7 ?m. Large particles can cause vascular embolism, and small particles can enter the pulmonary circulation and cause granulomas. Regarding how to reduce the insoluble particles of the solution, some studies have shown that the use of precision infusers to infuse traditional Chinese medicine injections can retain a large number of insoluble particles, which can reduce the entry of insoluble particles into the bloodstream, and thus reduce the occurrence of phlebitis, allergic reactions, and other drug ADRs [12]. It is recommended that manufacturers equip with special solvents, or use precision infusion sets for intravenous drip, which can effectively reduce the incidence of its ADR.

3.5 Importance of ADR/event-related information records There are many factors that cause adverse drug events, and each of them may lead to the occurrence of adverse events, and sometimes it is not necessarily a problem of the drug, but should be considered whether to standardize the use of drugs. For example, the operating environment of injectable medication, the time of placing the medication, and whether to flush the tube before and after the continuous use of other injectable medication. Therefore, comprehensive, timely and detailed recording of information related to ADR events is beneficial to accurately assess ADR events and identify the main influencing factors. In this study, we found that some important information was missing and incorrect in some case reports, such as co-administration, allergy history, drip rate, drug lot number, etc. It is recommended that clinical healthcare professionals should record all relevant information in a timely, accurate and detailed manner when ADR/ADE is detected.

3.6 Limitations The study in this article is based on the analysis of a few ADR cases, which is not representative enough to reflect the whole picture of ADR/event occurrence of Shu Xuning Injection; the cases are from the literature, which may have publication bias; the quality of the literature varies, and some information is missing. However, the results of the above analysis can provide possible clues for the safety study of Shu Xuning injection.

[References]

[1] Wu Zhaoxuan. 32 cases of Shu Xuning injection adverse reaction variant analysis[J]. China Traditional Chinese Medicine Information, 2011, 3(20):16.

[2] Cai Zhiqin, Zhou Fuyong, Zhang Lingxi.Literature Analysis of Adverse Reactions in 27 Cases of Shu Xuning Injection[J]. Chinese Pharmaceutical Industry, 2013, 22(1):29.

[3] Zheng Miaoqiong, Zhuang Huiling, Sun Jifang. Clinical observation on the correlation between iodine contrast ADR and allergy history[J]. Chinese Tropical Medicine, 2006, 6(12):2221.

[4] Xu RQ, Feng XY, Wang HY. Investigation on the correlation between ADR of cephalosporins applied by patients and their allergic history[J]. Clinical Medicine, 2009, 29(4):119.

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

[6] LI Yong. Cephalosporins may be an option for patients with a history of penicillin allergy[N]. China Medical News, 2010-3-16.

[7] Shi Y, Wang Lei. New progress in the study of pharmacological effects of Shu Xuning injection[J]. Medical Review, 2012, 18(10):1555.

[8] Yang Deping. Analysis of 154 cases of serious ADR of Shu Xuning Injection[J]. China Pharmacovigilance, 2010, 7(10):620.

[9] Huang J, Shi WZ, Xing YH. Changes of insoluble particles in six commonly used Chinese medicine injections paired with infusion solutions from different manufacturers[J]. Jilin Chinese Medicine, 2009, 29(8): 715.

[10] Li X, Lei L. Effects of insoluble particles in infusion agents on human microcirculation[J]. Corps Medicine, 2006, 1(1):16.

[11] YANG Li-Li, Li-Ya, Kang Y-Bin. Changes of particles at different temperatures and different times after the configuration of three traditional Chinese medicine injections[J]. Nursing and Rehabilitation, 2011, 10(1):5.

[12] HAN Hongmei, ZHI Yingjie. The role of using precision infusion set to infuse traditional Chinese medicine injection[J]. Chinese Journal of Traditional Chinese Medicine, 2012, 37(18):2758.

Adverse drug reactions case reports for parenterally administered

Shuxuening based on analysis of literature

AI Qing-hua1, WEI Xu2, XIE Yan-ming2* , LIAO Xing2, WANG Zhi-fei2

(1. Post-doctoral Station, China Academy of Chinese Medical Sciences, Beijing 100700, China;

2. Institute of Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China)

(2. 100700, China)

[Abstract] Parenterally administered Shuxuening had made important contributions in the treatment of ischemic Parenterally administered Shuxuening has made important contributions in the treatment of ischemic cardiovascular and cerebrovascular diseases since its use in 1995. Parenterally administered Shuxuening is widely used in clinical practice hence concern over its safety has gradually arisen. Based on published adverse drug reaction (ADR) case reports, this article analyzes cpatient characteristics and other data including: sex, age, gender, and age of the patient. Based on published adverse drug reaction (ADR) case reports, this article analyzes cpatient characteristics and other data including: gender, age, history of allergies, primary disease, dose, treatment course, solvent, ADR occurrence and time scales. This will provide a clinical reference regarding ADRs to parenterally administered Shuxuening and influencing factors on their occurrence. Analysis showed that ADRs clinical symptoms include systemic damage, with damage to the skin, mucous membranes and respiratory system most common. ADRs occurred earliest after 1 minute of infusion, and after the 11th day at the latest. 70% of cases of ADR occurred within 1 hour, therefore rapid occurrence is a primary clinical characteristic. The medication was largely used in accordance with the drug manual, and of the association of ADRs with allergies or different drug combinations was not a primary clinical characteristic. The medication was largely used in accordance with the drug manual, and of the association of ADRs with allergies or different drug combination was not high. The occurrence of ADRs may not be entirely associated with the drug but the solvent used in its manufacture may be an important factor. The occurrence of ADRs may not be entirely associated with the drug but the solvent used in its manufacture may be an important factor.

[Key words] parenterally administered Shuxuening; adverse drug reactions/adverse drug events; solvent

[Key words] parenterally administered Shuxuening; adverse drug reactions/adverse drug events; drug reactions/adverse drug events solvent