Hepatic adverse drug reactions: a case/non-case study in Italy

OBJECTIVE: Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. METHODS: Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). CONCLUSION: Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.     

Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase

AIM

To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents.

METHODS

Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding.

RESULTS

Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12–17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known.

CONCLUSIONS

Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.     

Signal detection for Thai traditional medicine: Examination of national pharmacovigilance data using reporting odds ratio and reported population attributable risk

Herbal containing medicine consumption has increased while the awareness of adverse drug reaction (ADR) was less than conventional medicine. Early detection of unexpected numbers of ADRs from herbal medicines’ reports which are abnormal from the whole database needs quantification. Disproportionality analysis has been performed for signal detection by using reporting odds ratio (ROR) as measurement. The impact of having medicine as exposures in each ADR should be measured by using reported population attributable risks (RPAR). This study aimed to quantify the contribution of Thai traditional medicine (TTM) to ADR reports and to assess the association between TTMs and serious adverse drug reactions. Data were retrieved from the adverse drug reaction surveillance database, Thai-Food and Drug Administration from 2002 to 2013. Crude and adjusted RORs for each drug–ADR pair and RPARs were computed. TTM contributed only 0.001% of all serious ADRs reported. Out of 4208 TTM-ADR pairs were examined, three had the statistically significant RORs, namely Andrographis paniculata and anaphylactic shock (ROR 2.32, 95% CI 1.03, 5.21); green traditional medicine and Stevens-Johnson syndrome (ROR 13.04, 95% CI 5.4–31.51) and Derris scandens Benth and angioedema (ROR 2.71, 95% CI 1.05–6.95). Their RPARs ranged from 0.05% to 0.16%. We conclude that TTMs need more intensive surveillance.     

Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy.

BACKGROUND: Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population. OBJECTIVE: In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature. METHODS: The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'. RESULTS: At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage. CONCLUSION: In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.     

Musculoskeletal adverse drug reactions: a review of literature and data from ADR spontaneous reporting databases

The musculoskeletal system can be a target organ for adverse drug reactions (ADRs). Drug-induced muscle, bone or connective tissue injuries may be due to, i), primary direct drug action, or, ii), undirected consequence of generalized drug-induced disease. Musculoskeletal ADRs may be only temporarily disabling, such as muscle cramps, as well as in other cases may be serious and life-threatening, such as rhabdomyolysis. In the last few years there has been an increasing awareness of musculoskeletal ADRs. Some recent drug safety issues dealt with serious or uncommon musculoskeletal reactions like rhabdomyolysis associated to statins and tendon rupture associated to fluoroquinolones. In this review, we firstly selected those drug classes having a significantly high percentage of musculoskeletal disorder reports in the WHO adverse drug reaction database, maintained by the Uppsala Monitoring Centre. Secondly, the different musculoskeletal ADRs were closely analyzed through the data obtained from an Italian interregional ADRs spontaneous reporting database. The findings on drugs associated to different musculoskeletal disorders, have been integrated with a review of the epidemiological data available in the literature. For the most involved drugs (HMG-CoA reductase inhibitors, fluoroquinolones, corticosteroids, bisphosphonates, retinoids) the underlying musculoskeletal ADR mechanisms were also reviewed and discussed.     

Ticlopidine Safety Profile: A Case/Non-Case Study on the Basis of the Spontaneous ADRs Reporting in Italy

Introducton: Ticlopidine is an antiplatelet agent available from several decades. Its most important adverse drug reactions (ADRs) involve haematological system. Our aim was to evaluate the safety profile of ticlopidine in the real life, on the basis of spontaneous ADR reporting. Materials and Methods: Spontaneous reports from 8 Italian Regions collected from 1990 to March 2007 were analysed. According to WHO Adverse Reaction Terminology for causality assessment only "certain", "probable" or "possible" ADRs were included. Association between drugs and any ADR was assessed by using the case/non-case methodoloy. Reporting odds ratio (ROR) was computed as a measure of disproportionality. Results: Overall, 478 reports concerning ticlopidine were analysed. The system organ classes with significant disproportionality for ticlopidine included White Cell Disorders (ROR=22.43, 95% CI 18.54-27.12), Red Cell Disorders (8.22; 6.03-11.18), Liver And Biliary System (6.67; 5.35-8.32), Platelet, Bleeding & Clotting (6.59; 5.16-8.40). Fifteen percent of the ADRs occurred beyond the first three months of ticlopidine therapy. In 386 reports (80.7%), ticlopidine was the only suspected drug. Conclusion: Safety profile of ticlopidine can be considered well-established in terms of ADRs type but their frequency and severity continue to be higher in its current use. Since this drug is still widely used in Italy, both healthcare providers and patients should be aware of its ADRs. More specifically, patients should be regularly monitored during the whole period of use and not only in the first months of treatment.     

培门冬酶治疗恶性血液系统疾病的药物不良反应及处置措施研究

目的了解培门冬酶(PEG-Asp)2009年以来的药物不良反应(ADRs)发生情况及其处置措施,为临床安全用药提供依据。方法回顾分析72例PEG-Asp的ADRs报告,统计ADRs的发生特点及处置措施。对不同性别、年龄、给药途径的患者ADRs发生时间、发生类型以及涉及器官系统、临床表现、转归数据进行分析。结果在72例患者中,18岁以下患者最多(24例,33.33%);严重ADRs 17例(23.61%)。典型ADRs包括过敏性休克11例,发生于5 min^3 h内,30 min时最高发,给药途径均为肌内注射;胰腺炎(7例,9.72%)发生于3~19 d;深静脉血栓(6例,8.33%)发生于2~23 d。对PEG-Asp的ADRs进行分析提示,静脉滴注比肌内注射更少报道引起不良事件常用术语标准(CTCAE)≥3级的过敏反应,儿童的ADRs上报比例较高。处置中经过对症治疗或停药后,大部分不良事件结局为好转或痊愈。结论从本ADRs发生时间来看,需要在用药后较长时间内对患者进行监测,静脉滴注引起严重过敏反应的报道更少。在给药前预处理方面,国内尚缺乏统一的标准,建立合理的预处理方法可以降低严重ADRs的发生。     

Drug-related deaths: an analysis of the Italian spontaneous reporting database.

BACKGROUND: Adverse drug reactions (ADRs) represent a major public health concern, with death as the ultimate adverse drug outcome. Despite the relevance of this, the frequency of fatal ADRs (FADRs) is to a large extent unknown. Although spontaneous reporting data cannot give an exact estimate of the magnitude of drug-related mortality, it may highlight the importance and large dimensions of this public health problem. OBJECTIVE: To describe the types and pattern of reported FADRs by analysing data from the national spontaneous reporting system in Italy. METHODS: The Italian Medicines Agency (AIFA) runs a pharmacovigilance database where all the individual case safety reports (since January 2001) are stored. We selected and then analysed in detail all the case reports (to the end of December 2006) in which death was reported as the outcome. We included in the study only FADR case reports with a probable or possible causality assessment, according to the criteria established by the WHO. In line with the Italian reporting form, we divided FADR reports into two groups: (i) suspected ADRs that caused death; and (ii) suspected ADRs that contributed to death. RESULTS: In the AIFA database 38 507 suspected ADR case reports were collected, of which 641 (1.66%) had a fatal outcome. We analysed 450 case reports (1.17% of total reports), 159 (35.33%) of them causing the patient's death and 291 (64.67%) contributing to death. The annual percentage of FADR reports followed a constant trend during the 6-year period. The majority of fatal reports (79%) were sent by hospital doctors. In total, 222 different drugs were suspected as causes of FADRs. 'Systemic anti-infective drugs' was the drug category associated with the highest percentage of FADRs (21.9%), followed by antineoplastic and immunomodulating agents (18.8%), and then by nervous system drugs (14.8%). Other drug categories involved in the fatal case reports were antithrombotic agents, NSAIDs and contrast media. CONCLUSIONS: The drugs most frequently involved in FADRs were drugs of wide usage with a narrow therapeutic range or those that caused serious skin or systemic allergic reactions. Ceftriaxone, ticlopidine and nimesulide were associated with the highest number of fatal case reports; the related FADRs were already known and recognized for each of these drugs. We highlight some cases reflecting probable inappropriate drug use by Italian physicians. This suggests a need for continued clinical pharmacology training and that many FADRs might be preventable through better medical and prescribing practice.     

5种阿片受体激动剂不良反应信号的数据挖掘与分析

目的 基于美国食品药品管理局不良事件报告系统（FAERS）对5种阿片受体激动剂（吗啡、可待因、哌替啶、芬太尼、美沙酮）相关不良反应进行挖掘分析,为阿片受体激动剂的临床安全用药提供参考依据。方法 利用美国食品药品管理局公共数据开放项目（OpenFDA）平台,收集2004年第1季度至2021年第4季度FAERS数据库中5种阿片受体激动剂的不良反应报告数据,采用报告比值比（reporting odds ratio, ROR）法对5种阿片受体激动剂的药品不良反应（ADR）进行信号挖掘,分析ADR报告中的安全警告信号。结果 最终得到吗啡165 572份,可待因79 574份,哌替啶9 838份,芬太尼145 819份,美沙酮43 433份ADR报告。这些ADR报告中女性207 657份多于男性156 810份,主要集中于18～60岁年龄段病人,且美国地区的上报数最多为282 820份,严重ADR报告中以住院或住院时间延长的上报数最多为129 454份。在上报数前20位的ADR中,药物依赖、过量、新生儿戒断综合征、怀孕期间胎儿暴露相关ADR在5种药物的说明书中均有提及,各类神经系统疾病及精神病类相...     

258例药品不良反应报告分析

目的调查药物不良反应(ADR)的发生情况,促进临床合理用药。方法对本院258例药物不良反应(ADR)报告分别从患儿年龄、性别、给药途径、涉及药物种类及临床表现等方面进行分析和统计。结果收集的258例ADR报告中涉及药品13类,涉及的药品种类及例次中抗感染药物占首位(46.91%)。主要的ADR类型为皮肤及附件损害(48.04%),其次为消化系统损害(26.36%)。结论应重视ADR监测工作,促进临床合理用药。     

Non-sedating antihistamine drugs and cardiac arrhythmias -- biased risk estimates from spontaneous reporting systems?

AIMS: This study used spontaneous reports of adverse events to estimate the risk for developing cardiac arrhythmias due to the systemic use of non-sedating antihistamine drugs and compared the risk estimate before and after the regulatory action to recall the over-the-counter status of some of these drugs. METHODS: All suspected adverse drug reactions (ADRs) reported until July 1999 to the Netherlands Pharmacovigilance Foundation Lareb were used to calculate the ADR reporting odds ratio, defined as the ratio of exposure odds among reported arrhythmia cases, to the exposure odds of other ADRs (non-cases), adjusted for gender, age, reporter, year of reporting and comedication, stratified for the periods before and after the governmental decision in the Netherlands. RESULTS: Seven-hundred and thirty-seven cases of arrhythmia were reported, out of which there were 43 instances where the patients were using non-sedating antihistamines. In general non-sedating antihistamines are associated with cardiac arrhythmia to a higher extent in comparison with other drugs (ADR reporting odds ratio 2.05 [95% CI: 1.45, 2.89]). The association between arrhythmias and non-sedating antihistamine drugs calculated before 1998 was not significantly higher than 1 (OR 1.37 [95% CI: 0.85, 2.23]), whereas the risk estimate calculated after the governmental decision did significantly differ from 1 (OR 4.19 [95% CI: 2.49, 7.05]). CONCLUSIONS: Our data suggest that non-sedating antihistamines might have an increased risk for inducing arrhythmias. Our findings, however, strongly suggest that the increased risk identified can at least partly be explained by reporting bias as a result of publications about and mass media attention for antihistamine induced arrhythmias.     

Signal detection of methylphenidate by comparing a spontaneous reporting database with a claims database

Data mining is critical for signal detection in pharmacovigilance systems. In this study, we compared signals between spontaneous reporting data and health insurance claims data for a socially issued drug, methylphenidate. We implemented data-mining tools for signal detection in both databases: Reporting Odds Ratios (ROR), Proportional Reporting Ratios (PRR), Chi-squared test, and Information Component (IC), in addition to a Relative Risk (RR) tool in the claims database. The claims database generated 15, 15, 36, 1, and 1 adverse drug reactions (ADRs) by ROR, PRR, chi-square, IC, and RR, respectively. The World Health Organization (WHO) spontaneous database generated 91, 91, 137, and 96 ADRs by ROR, PRR, chi-square, and IC, respectively. We found seven potential matching associations from the claims and WHO databases, but only one of them was present in the Korean spontaneous reporting database. In Korea, spontaneous reporting is still underreported and there is a small amount of data for Koreans. Signal comparison between the claims and WHO databases can provide additional regulatory insight.     

华蟾素注射液致不良反应252例文献分析

目的:探讨华蟾素注射液致不良反应(ADR)的一般规律及特点,促进临床合理用药。方法:检索1979-2010年中国知网中公开报道的有关华蟾素注射液致ADR的个案病例报道,并进行统计、分析。结果:共检索到17篇符合标准的文献,合计252例。华蟾素注射液引起的ADR,在本次统计的病例中男性多于女性,中青年发生人数较多。所致ADR以血管刺激性反应居多,有178例(70.63%);其次为变态反应,共53例(21.03%),其中过敏反应23例(9.13%)、过敏性休克3例(1.19%)、药物热27例(10.71%)。结论:华蟾素注射液引起ADR的原因较多,临床应加以重视,在用药时和用药后都应加强监测,坚持合理用药,以减少ADR的发生。     

Characteristics and quality of adverse drug reaction reports by pharmacists in Norway

PURPOSE: To evaluate the characteristics and quality of adverse drug reaction (ADR) reports submitted by pharmacists, and thereby assess the possible contribution of pharmacists to the spontaneous reporting system for ADRs in Norway. METHODS: An open, prospective study was conducted where dispensing pharmacists from 39 pharmacies were encouraged to report ADRs over a 3-month period. The submitted ADR reports were compared to reports by physicians from the same time period. All reports were evaluated for selected characteristics, that is distribution of Anatomical Therapeutic Chemical (ATC) classification codes of suspected drugs, distribution of ADRs according to system-organ classes and the quality of the reports. RESULTS: A total of 118 reports covering 274 ADRs received from the pharmacists were compared to 109 ADR reports with 304 ADRs submitted by physicians. Pharmacists more often reported ADRs related to cardiovascular drugs, alimentary tract and metabolism drugs and respiratory drugs, whereas physicians more frequently reported ADRs related to musculoskeletal drugs and antineoplastic and immunomodulating agents. ADRs reported by pharmacists more frequently described gastrointestinal reactions while physicians reported more ADRs in relation to the cardiovascular and blood system. Whereas 68% of the physicians' reports were classified as serious, only 5% of the pharmacists' reports were serious. More than 50% of the reports submitted by pharmacists concerned ADRs following a generic substitution, in contrast to only 2% of the physicians' reports. The pharmacists' reports were found to be of a lower documentation grade. However, there was no substantial difference in a subjective assessment of the quality of information in the reports submitted by the two categories of health professionals. CONCLUSIONS: Pharmacists submit valuable ADR reports which provide information complimentary to physicians' reports. This emphasises that pharmacist ADR reporting might constitute an important addition to the spontaneous reporting system.     

3种磷酸二酯酶-5抑制剂不良反应比较与分析

目的：比较和探讨上市3种磷酸二酯酶与抑制剂西地那非、伐地那非、他达那非可疑不良反应发生的特点,旨在对临床规范用药提供有益借鉴。方法：查阅世界卫生组织药物不良反应数据库,检索并分析比较这3种药物的不良反应报告。结果：3种药物不良反应报告主要集中在心血管、神经、消化等系统。每种药物的不良反应各有特点,严重不良反应如异常勃起的报告率逐年下降。结论：应该继续规范3种药物的临床应用,以尽量减少死亡、异常勃起等严重不良反应的发生,对肺动脉高压、神经再生、女性性功能障碍等病症的应用研究更应该谨慎进行。     

2013-2015年重庆地区质子泵抑制剂不良反应报告分析

目的:调查分析2013-2015年重庆市质子泵抑制剂(PPIs)药品不良反应(ADR)上报信息,为临床合理、安全使用该类药品提供依据。方法:收集2013-2015年重庆市药品不良反应监测中心数据库中质子泵抑制剂不良反应报告,对1 063例重庆地区PPIs不良反应报告进行对比与合并统计分析。结果:质子泵抑制剂致不良反应女性的发生率较高,ADR发生区域较均衡,静脉给药导致ADR较口服多,约78%的ADR发生于首次输液,临床表现多样,涉及身体多个器官组织,严重的不良反应为过敏性休克、呼吸困难,胸闷等。主要的不良反应为皮疹和恶心等。结论:质子泵抑制剂临床使用广泛,ADR发生也较多,应监测并及时处理。     

Under-reporting of serious adverse drug reactions in Sweden

INTRODUCTION: Adverse drug reactions (ADR) constitute a major problem, both from a medical point of view and as an economical burden. Spontaneous reporting of ADRs is one of the methods for post marketing surveillance of drug safety. Under-reporting can also provide an important obstacle to rapid and relevant signal detection. AIM: To investigate the rate of under-reporting serious ADRs of selected ICD 10 diagnoses. METHOD: In order to investigate the under-reporting rate we investigated at five hospitals within the county of Norrbotten in Sweden the total number of diagnosed cases during a period of 5 years (1996-2000) with the following diagnoses: cerebral haemorrhage (I 61.0-I 61.9), pulmonary embolism (I 26.0 and I 26.9), embolism or thrombosis (I 74.0-I 74.9), phlebititis, thrombophlebitits or venous thrombosis (I 80.0-I 80.3, I 80.8 and I 80.9) and portal vein thrombosis and other thrombosis or emboli (I 82.0-I 82.3, I 82.8 and I 82.9). The identity of these patients was obtained through a database search. The patients' case records were then scrutinized by a specially trained nurse and the drugs used at the time of the event were noted. An assessment of the possibility of an ADR was performed using standard WHO causality criteria. Later, database search in the Swedish ADR registry was performed in order to investigate whether these suspected ADRs had been reported to the national authority in Sweden or not. RESULTS: In total 1349 case records were found and scrutinized. Of these, 107 patients had received drugs that could have been a probable or possible cause to the diagnoses. Of these 92 cases had not been reported and only 15 patients were found in the database, giving an overall under-reporting rate of all ADRs of 86%.The most commonly occurring diagnoses were cerebral haemorrhage followed by venous thrombosis, 545 and 468 respectively. Among those cases that should have been reported according to the existing rules for spontaneous reporting of suspected ADRs the most frequently occurring diagnosis was cerebral haemorrhage (I 61.0) in connection to treatment with anticoagulants. CONCLUSION: The rate of spontaneous ADR reporting is very low, also for serious and fatal reactions.     

Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring.

OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can explain symptoms of hypersensitivity. METHODS: Between January 1985 and January 2007, all adverse drug reactions (ADRs) reported to the Netherlands Pharmacovigilance Centre Lareb related to AEDs as suspected drugs were included in this study. ADRs were analysed using a case/non-case design. Cases were defined as those patients with ADRs involving symptoms of hypersensitivity. Non-cases were patients with all other ADR reports. Symptoms of hypersensitivity were classified according to the Gell and Coombs classification (type I-IV) and the organ involved (e.g. cutaneous, hepatic). AEDs were classified as aromatic anticonvulsant if their chemical structure contained at least one aromatic ring. All other AEDs were classified as non-aromatic. We assessed the strength of the association between aromatic AEDs versus non-aromatic AEDs and reported hypersensitivity reactions with logistic regression analysis and expressed these as reporting odds ratios (RORs). RESULTS: In total, 303 cases of hypersensitivity associated with the use of AEDs were reported. Aromatic AEDs were suspected in 64.4% of these reports versus 41.3% (574/1389) of the non-hypersensitivity reports. A significant ROR of 2.15 (95% CI 1.63, 2.82) was found for aromatic AEDs and all hypersensitivity reactions. Aromatic AEDs were significantly associated with immunoglobin E-mediated type I hypersensitivity reactions (ROR 2.15; 95% CI 1.23, 3.78) and T-cell-mediated type IV reactions (ROR 6.06; 95% CI 3.41, 10.75). Type II and III reactions did not show an association. Cutaneous symptoms represented 39.9% of the hypersensitivity-related ADRs. Aromatic AEDs were significantly associated with cutaneous hypersensitivity reactions (ROR 5.81; 95% CI 3.38, 9.99). CONCLUSION: This study confirms that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains apparent 'idiosyncratic' hypersensitivity reactions. Symptoms of hypersensitivity were reported twice as frequently with aromatic AEDs than with non-aromatic AEDs. Strong associations for aromatic AEDs versus non-aromatic AEDs were found for T-cell-mediated (type IV) reactions, as well as for cutaneous reactions.     

Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy.

Limited information is available on drug-induced neuropsychiatric disorders in general practice. The spontaneous reports of both neurological and psychiatric adverse drug reactions (ADRs) collected during a 2-year period in PharmaSearch database, an Italian database recording reports of ADRs from general practitioners (GPs), were examined. Between January 2002 and December 2003, 171 general practitioners sent to PharmaSearch a total of 1131 reports corresponding to 1892 ADRs. Of overall reports, 310 (27.4%) involved the central nervous system resulting in 440 neuropsychiatric reactions (specifically, 241 neurological and 199 psychiatric). In our survey, 40 reports were excluded because they were incomplete or contradictory and thus classified as 'unlikely' or 'unclassifiable'. Therefore, the present analysis was carried out on 270 reports with 391 neuropsychiatric reactions (213 neurological and 178 psychiatric, respectively). Vertigo (16.4%), confusion (10.7%) and headache (10.0%) were the reactions more commonly reported. Drugs indicated for the treatment of nervous system disorders (ATC 1 code=N) accounted only for 38.4% of neuropsychiatric reactions, while most of these reactions were related to drugs indicated for other than nervous system diseases. Non-steroidal anti-inflammatory drugs (NSAIDs), fluoroquinolones, antidepressant drugs, opioids, and drugs for peptic ulcer were the categories most frequently suspected for neuropsychiatric reactions. Of 391 neuropsychiatric reactions, 78 (19.9%) were unlabeled and 41 (10.5%) were serious. In conclusion, the present study carried out in general practice underlines the importance of neuropsychiatric ADRs and reminds GPs to pay attention to this kind of toxicity when they prescribe pharmacological agents to their patients.     

87例丹参及其制剂所致不良反应文献分析

目的：探讨丹参及其制剂不良反应发生的特点及规律。方法：采用《中国医院知识仓库》进行检索并查阅原始文献,对1994～2007年国内公开发行的医药期刊有关丹参所致不良反应进行统计、分析。结果：丹参及其制剂所致不良反应主要多发于用药30分钟以内,且多发于50～59岁年龄组,主要表现为皮肤过敏反应、过敏性休克、心血管系统反应、消化系统反应等,其中过敏性休克发生的比例最高。结论：临床医生、药师及护士应重视丹参及其制剂所致的不良反应,以确保用药合理、安全、有效。