浅析牛黄解毒片中砷含量及对其安全性的影响

牛黄解毒片是临床用清热解毒药,但牛黄解毒片在使用中常出现一些不良反应,国外对该品种的安全性评价也较为片面。本文对造成牛黄解毒片不良反应的常见原因及砷含量对其安全性的影响进行总结,针对牛黄解毒片目前存在的问题提出一些建议与思考,以期为牛黄解毒片及其他含砷中药复方制剂合理化标准的制定提供参考,推进中药国际化进程。     

牛黄解毒片(丸)引起不良反应38例分析

本文汇总了近年来牛黄解毒片（丸）所致38例不良反应的一般资料及不良反应症状表现，分析了不良反应产生的原因，认为该药的不良反应可能多由雄黄引起。由于雄黄在体内可被部分吸收并蓄积，因而提醒人们注意牛黄解毒片（丸）及其它含雄黄的药物在使用时应不要过量，务必不要长期服用，不要滥用，以减少砷在体内的蓄积，避免由不合理应用造成对人体的伤害。     

牛黄解毒片致不良反应5例分析

牛黄解毒片临床常用于清热、降火解毒、通便.近年来,关于牛黄解毒片的不良反应时有发生,现将我院不良反应监测中心有关牛黄解毒片引起的不良反应报告如下:     

牛黄解毒片中砷元素分析

目的对牛黄解毒片中总砷、可溶性砷、可溶性砷（Ⅲ）和砷（Ⅴ）进行分析,为评价牛黄解毒片的安全性提供依据。方法采用微波消解-原子荧光法测定牛黄解毒片中的总砷含量,50%甲醇浸提-原子荧光法测定可溶性砷,717阴离子交换树脂分离-原子荧光法测定可溶性砷（Ⅲ）和砷（Ⅴ）。结果3种牛黄解毒片制剂中总砷含量为65.72～75.79g/kg,可溶性砷占总砷百分比为0.43%～1.23%,其中可溶性砷（Ⅲ）含量0.19～0.55g/kg,可溶性砷（Ⅴ）含量范围在0.09～0.44g/kg。结论不同的牛黄解毒片中可溶性砷及其中两种价态砷的含量差异较大,因此有必要对牛黄解毒片中砷的含量进行质量控制。     

牛黄解毒片(丸)40例不良反应分析

目的 分析牛黄解毒片(丸)所致的不良反应的一般规律及其特点,为临床合理用药提供参考.方法 对1994年1月-2006年6月国内公开发表的药学杂志刊登的有关牛黄解毒片(丸)所致40例不良反应进行分类统计与分析.结果 牛黄解毒片(丸)可致免疫系统、消化系统、泌尿系统等不良反应,最常见为过敏反应.结论 牛黄解毒片(丸)可引起一定的不良反应,临床需注意其合理使用.     

浅谈哪些中成药与西药不宜合用

近些年来,中西医结合在临床治疗中,取得了显著疗效,但在药物使用上不能合理用药,造成疗效减低和一些不良反应,为防止不合理用药,及用药中出现不良反应,现将如下几种中成药与西药合用所产生的反应及副作用介绍如下。1 牛黄解毒片与四环素四环素内含酰氨基和多个羟基,牛黄解毒片内含石     

原子荧光光谱法测定牛黄解毒片中的可溶性砷含量

目的：测定牛黄解毒片的总砷含量以及在人工胃液、人工肠液和水中可溶性砷的含量,了解该复方制剂的砷含量情况,为牛黄解毒片在临床上的合理用药和安全性提供实验依据。方法样品经硝酸、高氯酸、硫酸和盐酸消化后,用硫脲抗坏血酸使五价砷还原为三价砷,再与硼氢化钾反应生成砷化氢气体,载入原子荧光光谱仪测定总砷;样品分别浸泡到人工胃液、人工肠液和水中,经不同时段分别取出上清液进行加酸定容处理,载入原子荧光光谱仪测定可溶性砷。结果可溶性砷在人工胃液及人工肠液中比在水中更早达到溶出平衡。在人工胃液中可溶性砷占总砷含量的2.86%,在人工肠液中可溶性砷占总砷含量的3.13%,在水中可溶性砷占总砷含量的0.11%。结论人工胃液中成人每天可溶性砷最大摄入量为31.38μg,人工肠液中为27.10μg,水中则为15.69μg,未超出世界卫生组织的标准,说明牛黄解毒片可安全服用。     

如何解决牛黄解毒片薄膜衣片生产中存在的问题

目的:探讨牛黄解毒片处方中的冰片,在生产过程中造成薄膜包衣不好包衣、片面粗糙、不光滑、容易产生麻片的原因,采用三种不同的方案来解决.     

牛黄解毒片中不同单味组分对雄黄可溶性砷含量影响的比较研究

目的研究牛黄解毒片中各单味组分对雄黄可溶性砷含量的影响。方法采用雄黄与牛黄解毒片中的7种单味药按牛黄解毒片处方比例分别组方分为9组供试品并经人工胃液处理后,用分光光度法分别测定可溶性砷的含量。结果与雄黄组相比,雄黄与处方中各组分单独组方后测得的可溶性砷含量均有不同程度降低。其中大黄+雄黄组和甘草+雄黄组使可溶性砷含量减少为84.9%和81.1%,而冰片+雄黄组等影响不显著。结论牛黄解毒片中的大黄、甘草等与雄黄配伍能较显著地抑制雄黄中可溶性砷的溶出,为进一步探讨雄黄复方中影响可溶性砷盐的主要物质提供参考依据。     

牛黄解毒片的不良反应及其安全性综述

目的 了解牛黄解毒片在使用中所发生的不良反应、配伍禁忌，促进合理用药。方法 对1994。2005年有关牛黄解毒片的不良反应和药品联用情况的相关文献进行整合分析。结果 牛黄解毒片中雄黄的日服用剂量标准已超出了《中华人民共和国药典》规定的最大服用量的3倍。结论 严格药品配伍，并按照药品说明书的规定合理用药，以减少药品不良反应的发生。建议进行处方基础研究，减少雄黄的处方量或降低牛黄解毒片的日服用剂量。     

小儿氨酚黄那敏片质量标准的完善

目的:完善小儿氨酚黄那敏片质量标准.方法:采用薄层色谱法对人工牛黄中的胆红素、贝斯素、胆酸、猪去氧胆酸进行鉴别;采用高效液相色谱法对小儿氨酚黄那敏片中对乙酰胺基酚和马来酸氯苯那敏进行含量测定.结果:薄层色谱鉴别方法专属性强;含量测定方法简便,重复性好.结论:建立的方法可准确、快速地进行定性、定量测定,可用于该制剂的质量控制.     

Identification of structure–activity relationships for adverse effects of pharmaceuticals in humans. Part A: Use of FDA post-market reports to create a database of hepatobiliary and urinary tract toxicities

The Informatics and Computational Safety Analysis Staff at the US FDA’s Center for Drug Evaluation and Research has created a database of pharmaceutical adverse effects (AEs) linked to pharmaceutical chemical structures and estimated population exposures. The database is being used to develop quantitative structure–activity relationship (QSAR) models for the prediction of drug-induced liver and renal injury, as well as to identify relationships among AEs. The post-market observations contained in the database were obtained from FDA’s Spontaneous Reporting System (SRS) and the Adverse Event Reporting System (AERS) accessed through Elsevier PharmaPendium™ software. The database contains approximately 3100 unique pharmaceutical compounds and 9685 AE endpoints. To account for variations in AE reports due to different patient populations and exposures for each drug, a proportional reporting ratio (PRR) was used. The PRR was applied to all AEs to identify chemicals that could be scored as positive in the training data sets of QSAR models. Additionally, toxicologically similar AEs were grouped into clusters based upon both biological effects and statistical correlation. This clustering created a weight of evidence paradigm for the identification of compounds most likely to cause human harm based upon findings in multiple related AE endpoints.     

Assessment of adverse drug events among patients in a tertiary care medical center.

PURPOSE: Specific patient and clinical characteristics associated with an increased risk of sustaining an adverse event (AE) were identified. METHODS: AE reports for patients in a 658-bed tertiary care medical center between January 1, 2000, and June 30, 2002, were analyzed. The data collected from each report included medical record number, patient sex, patient age, clinical service, date of occurrence, diagnoses, type of error, suspected medication, and severity of the AE. A three-stage logistic regression model with high-risk indicators was used to evaluate key indicators of the most vulnerable patient populations. RESULTS: The number of control patients and those with AEs totaled 60,206. This population was then randomly split into two equal groups of patients: the training data set (n = 30,103) and the validation data set (n = 30,103). AEs occurred in a higher percentage of patients who were age <1 year, 1-15, 47-59, and > or =60 years than in other groups. A higher percentage of AEs were reported in men than women, but the groups were not significantly different when comparing those with an AE and those without an AE. Asian Indian patients demonstrated a high rate of AEs, but this may be a statistical artifact, reflecting their very small percentage in the study. Evaluation of admission sources revealed that doctors' offices, clinic referrals, and local hospital transfers accounted for higher rates of AEs than other sources. CONCLUSION: Certain age groups, diagnoses, admission sources, types of insurance, and the use of specific medications or medication classes were associated with increased AE rates at a tertiary care medical center.     

Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study

BACKGROUND: It has been proposed that objective cognitive testing provides additional information to that collected via adverse event (AE) recordings. However, in clinical trials of compounds with potentially negative effects on cognition, the results of cognitive testing may overlap with AE recordings. AIMS: To examine cognitive function in subjects who do and do not report sedation-related AEs in a Phase I clinical trial. METHODS: Five computerized cognitive tasks were administered to 28 healthy male volunteers enrolled in a simulated Phase I study using midazolam to induce sedation-related AEs and cognitive dysfunction. For each subject, the magnitude of cognitive change between pre-dose and 1 hr post-dose assessments was calculated. Group and individual level cognitive outcome was compared between subjects who did and did not report sedation-related AEs following administration of 1.75 and 5.25 mg midazolam. RESULTS: At both doses of midazolam, cognitive dysfunction was observed in both subject groups (i.e., those who did and did not report AEs). Analysis of individual outcomes identified consistent cognitive dysfunction among subjects who reported sedation-related AEs. Further, in the 5.25 mg condition a subset of individuals (66.7%) who did not report sedation-related AEs nevertheless displayed substantial cognitive dysfunction. CONCLUSIONS: Following administration of oral midazolam, there is a dissociation between sedation-related AE recordings and performance on computerized cognitive tests of motor function, attention, strategy use and problem solving, learning and delayed recall. Inclusion of computerized cognitive tests in early phase trials may allow identification of subtle cognitive change, beyond that which is possible by self-report and clinical observation.     

Safety and tolerability of antipsychotic-mood stabilizer co-treatment in the management of acute bipolar disorder: results from a systematic review and exploratory meta-analysis

Introduction: Mood stabilizer (MS) plus antipsychotic (AP) co-treatment is common in patients with acute bipolar disorder (BD), but adverse effects (AEs) of this strategy have not been systematically reviewed.

Areas covered: We conducted a systematic review searching PubMed/MEDLINE and PsycINFO on April 1, 2015 for randomized trials in ≥ 20 adults with acute manic/mixed or depressed BD comparing MS or AP monotherapy with their combination that reported quantitative AE data. Pooled together, MS+AP versus MS monotherapy (studies = 18, n = 4419) was associated with significantly higher burden regarding 21/53 (39.6%) individual AEs, particularly weight gain-related (5/5 = 100%), extrapyramidal (5/12 = 41.7%) and glucose/lipid-related AEs (3/8 = 37.5%). AP+MS versus AP monotherapy (studies = 3, n = 397) was associated with significantly higher burden regarding 4/21 (19.0%) individual AEs (≥ 1 AE, tremor, sedation/somnolence, vomiting).

Expert opinion: Efficacy advantages of AP+MS co-treatment versus monotherapy should be balanced with its greater AE burden. AE risk is higher for adding AP to MS (17 additional AEs) than adding MS to an AP, including the particularly concerning cardiometabolic AEs. More data are needed, as only one or two studies provided data for 21/21 (100%) AEs of MS augmentation of AP, and 13/53 (24.5%) AEs of AP augmentation of MS, and as sparse data suggest clinically relevant AE differences across individual AP+MS combinations.     

Consumer opinions on adverse events associated with medical devices

IntroductionPost-market surveillance of medical devices relies on compulsory and voluntary reports. Although direct consumer reporting of medical device-related adverse events (AEs) is available in Australia, the proportion of consumer reports has remained low. Limited qualitative research has previously explored consumer insights on AEs associated with medical devices and in particular, AE reporting.ObjectiveTo explore consumer opinions on AEs related to medical devices, and their knowledge of, experiences with, and views on, the reporting of medical device-related AEs.MethodsFocus groups (n = 4; total of 29 participants) were conducted in metropolitan Sydney, Australia. Focus group discussions of approximately 1.5 h in length centred on consumers' understanding of AEs, opinions on AEs and their previous experiences, views on medical device benefits and harms, and actions taken (or potential actions) in response to AEs. With participant consent, discussions were audio-recorded, transcribed verbatim, and thematically analysed.ResultsParticipants regarded medical device-related side effects to be unexpected AEs associated with their use. Where there was a clear need for the medical device itself, potential improvement in quality of life took precedence over potential harms. Most participants had not experienced negative issues with their medical device(s). There was poor awareness among participants of an existing direct consumer AE reporting system for medical devices. Despite this, the value of reporting was acknowledged. Severity of the AE was a key motivator for potential AE reporting.ConclusionsFurther efforts are necessary to improve consumer awareness of available AE reporting systems to better support post-market surveillance and safe medical device use.     

Dietary supplement-related adverse events reported to the California Poison Control System.

PURPOSE: Dietary supplement (DS)-related adverse events (AEs) reported to the California Poison Control System (CPCS) were studied. METHODS: The CPCS database was used to search for all telephone calls from consumers concerning DS-related AEs received during the six-month period between April and September 2002. The calls were characterized according to the substance involved, the caller's age (adult or pediatric), and the type of ingestion (accidental or intentional). Each exposure in which symptoms were reported was categorized as involving an AE. Each AE was assessed for severity and causality. RESULTS: Data on a total of 1183 telephone calls were retrieved, of which 828 calls (70%) met the study's inclusion criteria. DS exposure occurred in 389 adults (47%) and 438 children (53%). DS ingestion was accidental in 360 patients (43%) and intentional in 467 patients (56%). Exposure resulted in an AE in 480 patients (58%). AEs were reported in 353 patients (74%) who ingested products containing ephedra; other exposures frequently involved zinc, kava, creatine, and valerian. AEs were classified as moderate in 198 patients (41%) who ingested a DS and as severe in 40 patients (8%). One patient had a fatal reaction. Among the 480 AEs in DS-exposed consumers, the DS was classified as the definite cause of 1 AE (<1%) and a probable cause of 237 (49.4%). The most frequently reported AE symptoms were increased heart rate (45%), agitation (30%), vomiting (30%), and nausea (15%). CONCLUSION: A majority of DS-related AEs reported by consumers to CPCS involved ephedra-containing products.     

Adverse events regional feasibility study: indicative findings.

AIMS: To identify substantive findings of potential clinical and managerial significance from a regional feasibility study of adverse events (AEs). METHODS: A standardised protocol using structured implicit review was applied to 142 AEs generated in an audit study of three public hospitals in the Auckland region for admissions in 1995. Areas of potential significance addressed were: timing, location and impact of AEs; preventability; and clinical context and predictability. RESULTS: 142 cases were identified as AEs (10.7% of 1,326 screened records). In 102 cases, 7.7% of all screened records, it was considered to be more likely than not that health care management contributed to the AE. About half the reported AEs occurred before the index admission, the majority outside hospital. Over half of all events resulted in disability that was resolved within a month. An average 6.7 extra days stay in hospital were attributable to AEs. For 60% of AEs the evidence for preventability was either low or nonexistent. Areas of potential prevention were predominantly educational. Over half of all AEs occurred in a surgical context. Medical AEs were more likely to have occurred outside hospital, to be drug-related, to be associated with an acute admission, to be classified as highly preventable, and to have a greater impact on hospital stay. CONCLUSIONS: Although the data generated by a feasibility study must be treated with caution, the pattern of results is consistent with comparable Australian findings and is of potential clinical and managerial significance.     

Topical bovine thrombin and adverse events: a review of the literature

ABSTRACT

Objective: To review published evidence suggesting a link between topical bovine thrombin (TBT) and important adverse events (AEs).

Research design and methods: English language articles and abstracts were obtained from MEDLINE using combinations of text and MeSH terms for thrombin, bovine thrombin and their trade names. References from summary articles were also retrieved. Published case reports, review articles, and retrospective, prospective or observational studies involving either immunogenicity or AEs were selected for further assessment. Retrieved articles were evaluated separately as AE case reports, quantitative studies of antibodies, or quantitative studies of AEs.

Main outcome measures: Presence of case causal information, temporal pattern of case report publication, reproducibility of aggregate data findings, and study design features.

Results: The major limitations of reviewed publications were insufficient information regarding TBT and other exposures, and designs in which linkage between laboratory immune phenomena and AEs could not be evaluated. While immunogenicity studies did support an increased risk for post-TBT antibodies, there was no consistent evidence that this led to an increased AE risk or severity. Common evidentiary deficiencies included case reports from high incidence environments, studies of combination or mixture products, biased study designs, lack of patient-level exposure data, inadequate control groups and insufficient sample sizes. The best designed study (a randomized, controlled comparison of TBT to a recombinant bovine product) documented post-TBT antibody production, but no important efficacy or AE differences. An examination of publication dates for case reports showed a peak between 1992 and 1994 followed by a substantial drop. Since 1997 the number of published AE case reports has continued to decline.

Conclusions: TBT increases the risk for antibody elevations in patients. A careful review of published evidence does not show that either TBT itself or any associated elevations in anti-bovine antibodies are risk factors for clinically important AEs.