Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

Production of Sanguinarine by Chelidonium majus Callus Cultures

Tissue callus cultures originating from CHELIDONIUM MAJUS L. seeds were established on Gamborg B5, Murashige-Skoog (MS), and Schenk-Hildebrandt (SH) media. In all experimental conditions, calli accumulated a complex pattern of isoquinoline derivatives. The highest values, both in growth and in sanguinarine production, were obtained using SH medium.     

Causality assessment in hepatotoxicity by drugs and dietary supplements

Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.     

高效液相色谱法测定白屈菜注射液中白屈菜碱的含量

目的:建立用高效液相色谱法(HPLC)测定白屈菜注射液中白屈菜碱的含量.方法:采用Diamonsil G18柱(4.6 mm×250 mm,5 μm);流动相为乙腈-0.01mol·L-1磷酸二氢钾梯度洗脱,柱温:35℃;流速:1 mL·min-1;检测波长290 nm.结果:白屈菜碱的线性范围为:0.106 8～1.068 μg,r=0.999 6(n=6),平均回收率为99.12%,RSD为1.09%.结论:该方法稳定、结果准确,可作为白屈菜注射液的质量控制方法.     

Telithromycin use and spontaneous reports of hepatotoxicity.

BACKGROUND AND OBJECTIVE: Recent reports have described cases of telithromycin-related hepatotoxicity. The objective of this study is to quantify the effect of telithromycin use on the risk of hepatotoxicity. METHODS: We conducted a spontaneous-report case-control study of hepatotoxicity in telithromycin recipients using reports from the US FDA Adverse Event Reporting System. Reports from between 1 January 2005 and 30 June 2005 were examined. Cases included reports of patients with abnormal liver function tests, hepatocellular damage and hepatic impairment, while patients with reported conditions with similar reporting probabilities were considered as controls. The primary outcome measure of the analysis was the reporting odds ratio (ROR) evaluating the a priori hypothesis that telithromycin use confers an elevated risk of hepatotoxicity relative to other agents. RESULTS: A total of 2219 cases and 20,667 controls were identified. We estimated an ROR for hepatotoxicity associated with telithromycin compared with other agents of 1.82 (95% CI 1.12, 2.96) after controlling for age and gender, approximating an 82% excess risk in users of telithromycin relative to users of other agents. CONCLUSIONS: This analysis is the first to specifically quantify the effect of telithromycin on the risk of hepatotoxicity. Telithromycin use may increase the risk of hepatotoxicity by >80%. Biases inherent in spontaneous reports include under-reporting of events and differential or time-varying reporting due to enhanced clinician awareness. Future studies should employ alternative data sources because of the inherent limitations of passive surveillance systems.     

Inhibition of mouse liver respiration by Chelidonium majus isoquinoline alkaloids

The alkaloids from Chelidonium majus L. which had a significant inhibitory effect in mitochondrial respiration were those which contain a positive charge due to a quaternary nitrogen atom, i.e., chelerythrine, sanguinarine, berberine and coptisine, both with malate+glutamate or with succinate as substrates. When malate+glutamate was used as substrate, chelerythrine and berberine, which contain methoxy groups, were particularly more active, since they had a strong effect even at low concentrations. In submitochondrial particles, berberine and coptisine had a marked inhibitory effect on NADH dehydrogenase activity but practically no effect on succinate dehydrogenase activity, whereas chelerythrine and sanguinarine inhibited more strongly succinate dehydrogenase than NADH dehydrogenase, which is in agreement with the results found for mitochondrial respiration. Protopine and allocryptopine, which did not inhibit mitochondrial respiration, strongly inhibited NADH dehydrogenase in submitochondrial particles, but had no effect on succinate dehydrogenase activity.     

基于HPLC-Q-TOF/MS的白屈菜生物碱化学组成快速辨识研究

利用HPLC-Q-TOF/MS技术快速准确、系统全面的定性鉴定白屈菜中生物碱。采用XCharge C18色谱柱(5μm, 4.6 mm×250 mm);以乙腈-0.1%甲酸为流动相梯度洗脱;流速0.7 mL·min-1。根据一级质谱分子离子和二级质谱碎片离子,归纳白屈菜生物碱的质谱裂解规律,结合相关文献,对白屈菜中生物碱进行系统的结构鉴定。为验证结果的准确性,纯化制备其中3个生物碱并通过核磁技术鉴定化学结构。从白屈菜中鉴定出21个生物碱,包含1个阿朴菲类生物碱、3个普罗托品类生物碱、11个苯并菲啶类生物碱以及6个原小檗碱类生物碱。其中N-甲基金罂粟碱(8)为白屈菜中首次报道,二氢黄连碱(11)和去甲基白屈菜碱(12)为白屈菜中首次用该技术鉴定。制备化合物的化学结构鉴定结果与质谱定性结果一致。经验证,该方法快速准确,可为白屈菜化学成分的分析鉴定和提取分离提供依据。     

Antimicrobial-induced mania (antibiomania): a review of spontaneous reports.

The authors reviewed reported cases of antibiotic-induced manic episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced mania. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced mania were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported manic episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of mania. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing mania while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced mania, the relative risk factors of developing an antimicrobial-induced manic episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "antibiomania."     

Herbal hepatotoxicity: a case of difficult interpretation

Herbal medicines are widely used in the world and are generally considered effective and safe, although many studies have demonstrated their potential toxic effects, particularly for the liver. We present a case of a woman, who developed a mixed cholestatic/hepatocellular liver injury due to herbal products. Firstly, she was admitted to Division of Surgery for right upper abdominal pain and jaundice and, for the suspect of biliary obstruction, she underwent to cholecystectomy. For persistence of liver enzymes elevation, she was admitted to our Gastroenterology Unit. We excluded every etiologies of hepatitis and, after an intensive dialogue with the patient, we obtained a history of herbal medicines use. Then, we performed a liver biopsy which was compatible with hepatotoxic injury. Therapy with ursodeoxycholic acid (UDCA) was started. Liver function tests returned to normal in two months. We describe this clinical case to encourage the communication doctor/patient in phytotherapy area and physician knowledge about efficacy and side effects of herbal medicine to avoid delayed diagnosis.     

Efficacy of a plant extract (Chelidonium majus L.) in combating induced hepatocarcinogenesis in mice.

Ethanolic whole plant extract of Chelidonium majus, extensively used in traditional systems of medicine against various liver ailments, has been tested for its possible anti-tumor, hepato-protective and anti-genotoxic effects in p-dimethylaminoazobenzene (p-DAB) induced hepatocarcinogenesis in mice through multiple assays: cytogenetical, biochemical, histological and electron microscopical. Different sets of mice, 5 (for 7, 15 and 30 days' treatment) or 10 (for 60, 90 and 120 days) each, were chronically fed a diet suitably mixed with p-DAB and phenobarbital to develop liver tumors. One sub-group of carcinogen fed mice was also fed C. majus extract; 0.1 ml daily (drug-treated) while the other equal amount of dilute ethyl alcohol ("vehicle" of plant extract) (positive control). A separate group of mice was maintained with normal diet without any carcinogen treatment (negative control). Data of several cytogenetical endpoints and biochemical assay of some toxicity marker enzymes at all fixation intervals and histology of liver sections through ordinary, scanning and transmission electron microscopy at 60 and 120 days and that of spleen and kidney at 90 days were critically analyzed in the treated lots vis-a-vis controls. The results suggest anti-tumor, anti-genotoxic and hepato-protective effects of the plant extract, showing potentials for use in cancer therapy.     

苯那普利治疗老年原发性高血压22例

22例老年原发性高血压患者采用苯那普利口服5～20mg/日,平均疗程2～4周。结果显示血压控制总有效率达86.36％,对Ⅰ、Ⅱ期高血压疗效好,对Ⅲ期高血压配合小剂量利尿剂或钙离子拮抗剂联合用药亦可获得满意效果。该药每日只服1次即能24小时维持疗效,不良反应少,对心率无影响,对肾脏有保护作用,并且心电图提示心肌缺血的表现有改善。作者认为该药是治疗原发性高血压安全有效的药物。     

Unexpected severe hepatotoxicity of ciprofloxacine: two case reports

Ciprofloxacin is a fluoroquinolone antibiotic that has a relatively low rate of occurence of adverse side effects. However, increasing evidences suggest that ciprofloxacin may cause unexpected severe liver damage. Especially, the risk of hepatotoxicity is significantly higher in elderly men receiving drug for a long time. In this article, 2 cases of unexpected severe hepatoxicity of ciprofloxacin are presented.     

Studies on laticifers and milk of greater celandine (Chelidonium majus L.) with fluorescence imaging and fluorescence spectroscopic methods

Using fluorescence imaging and fluorescence spectroscopic methods, the localisation of the laticifers and the native spectral properties of the milk were studied in various organs of greater celandine (Chelidonium majus L.). Direct measurements on tissue pieces (without the extraction and the separation of the components) provided information about the complexity of the milk and the various ratios of the alkaloid contents in the tissues. Whole plant were studied in a gel documentation system using ultraviolet light source, while the localisation of the laticifers was observed along the leaf veins in fluorescence microscope, using blue excitation light. Measuring different tissue pieces, fluorescence spectroscopic studies showed that the greater celandine alkaloids have emission bands at 469, 530-531, 553, 572-575 and 592 nm and excitation bands at 365, 370, 386 is 400 nm. These results give a possibility for conclusions about the alkaloid contents and composition or ratios of the alkaloid components in various tissue pieces directly, via comparisons with alkaloid standards.     

老年性慢性阻塞性肺病并自发性气胸(附52例报告)

目的分析老年性慢性阻塞性肺病并自发性气胸特点.方法对我院,1999～2004年收治的老年性慢性阻塞性肺病并自发性气胸52例的临床资料进行回顾性分析.结果治愈45例,占86.5%;死亡5例,占9.6%;自动出院2例,占3.7%.结论老年性慢性阻塞性肺病并自发性气胸起病隐匿、进展快、常危及生命.及时诊断和治疗可以降低死亡率.     

Diclofenac (voltaren:Voltarol)-Associated hepatotoxicity

The television report on Cable News Network (CNN) on 9 August 1993 on the exceptionally large numbers of reports in the USA of hepatitis and jaundice associated with intake of diclofenac leading, in an appreciable number of cases, to death is indeed of much concern. All kinds of issues are raised, namely: (a) How many reports of adverse drug reactions (ADRs) are necessary before action should be taken? (b) What is the nature of action in this case? (c) What are the responsibilities, regarding proper conduct of enquiries and in taking preventive action, of the company marketing the drug, the government regulatory agencies (e.g. Food and Drug Administration (FDA)), and legal-political authorities. (d) Why is so little known about the causes of side-effects, such as hepatotoxicity from NSAIDs, which are not uncommon.     

无症状脑梗死临床特点及影像学诊断(附22例分析)

目的分析无症状脑梗死的临床特点及其影像诊断。方法回顾性研究22例无症状脑梗死患者的头颅影像学资料,分析病灶的临床表现以及影像学表现,包括信号或密度、大小、部位和范围,总结与类似病变的鉴别经验。结果22例患者中临床表现为头晕或眩晕12例,头痛5例,一过性肢体无力或麻木3例,2例表现为言语不清或表达不清等。CT表现为基底节12例（55％）,半卵圆区白质4例（18．2％）．,内囊3例（13．6％）,丘脑、脑干及小脑2例（共9％）,其它1例（4．2％）。其中单发病灶6例（27％）或多发病灶16例（73％）,表现为类圆形或不规划小片状低密度灶,MRI表现为T1W1上低信号,T2W1高信号。类似病灶较多,影像学有时难以鉴别。结论非梗死特异性症状脑梗死影像学表现与症状性脑梗死相同,临床表现也无特点。诊断应以影像学为依据并注意与多发性硬化、脑腔隙和白质疏松鉴别。