Gefitinib: an adverse effects profile

Gefitinib, an epidermal growth factor receptor inhibitor, is currently approved for use in patients with advanced non-small cell lung cancer who have failed previous chemotherapy or who are not suitable for chemotherapy in > 30 countries. The approved dose in patients with non-small cell lung cancer is 250 mg/day. The most common adverse effects are rash, diarrhoea, acne, dry skin, nausea and vomiting. Most of the effects are mild-to-moderate in nature and do not require discontinuation of therapy. The severity of many of these effects is dose-related with grade 3-4 effects more likely at a dose > 250 mg/day. The most severe adverse effect is interstitial lung disease (ILD), which occurs in approximately 1% of patients worldwide except for Japan where the incidence of ILD is 2%. ILD is fatal in approximately one out of three of the cases. The most common adverse effects associated with chemotherapy, myelosuppression and alopecia, are not commonly seen with gefitinib monotherapy.     

416例吉非替尼不良反应病例回顾分析

目的:对接受表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂吉非替尼治疗的癌症患者发生药物不良反应(adverse drug reactions,ADR)的病例报告进行系统回顾,分析死亡危险因素及对策.方法:对PubMed、Embase、Cochrane图书馆、CIN...     

降血压药物的潜在不良反应及其预防

了解抗高血压药物的不良反应对高血压的长期治疗具有重要临床意义。本文回顾抗高血压药物的潜在不良反应如心脏抑制、肾损害及血钾异常等,其目的为有助于预防严重不良反应的发生和改善高血压患者的用药依从性。     

吉非替尼片溶出度测定方法的考察

目的 建立吉非替尼片的溶出度试验方法。方法 应用桨法测定溶出度,并以HPLC测定样品中药物浓度,通过对溶出介质,转速和时间进行筛选,拟定吉非替尼片的溶出度试验方法,并以该方法测定不同制剂的溶出度。结果 采用桨法,转速50 r·min^-1,选取pH 1.0盐酸液、pH 4.5醋酸盐缓冲液、5%聚山梨酯80水溶液和含5%聚山梨酯80的pH 6.8磷酸盐缓冲液作为溶出介质,溶出截止时间为60 min。应用HPLC测定样品中药物浓度,溶出介质,辅料和滤膜吸附对测定无干扰,药物在10~300 μg·mL^-1内线性相关良好,回收率在98%~100%内,精密度及稳定性的RSD值均<2%。结论 建立的溶出度测定方法具有较强区分度,能为制剂处方工艺筛选提供评价依据。     

Decreased Biosynthesis of Lung Surfactant Constituent Phosphatidylcholine Due to Inhibition of Choline Transporter by Gefitinib in Lung Alveolar Cells

Purpose We investigated whether gefitinib, an anticancer agent, inhibits phosphatidylcholine (PC) biosynthesis and choline uptake by alveolar epithelial type II cells. Materials and Methods Uptake of choline and PC biosynthesis were examined in vitro, using human alveolar epithelia-derived cell line A549 and rat alveolar type (AT) II cells as models. Results Gefitinib reduced the incorporation of [³H]choline into PC in A549 and rat ATII cells. The uptake of [³H]choline by A549 and rat ATII cells was concentration-dependent, and the Km values were 15.0 and 10–100 μM, respectively. The uptake of [³H]choline by A549 and rat ATII cells was weakly Na⁺-dependent, and inhibited by hemicholinium-3. RT-PCR revealed expression of choline transporter-like protein (CTL)1 and organic cation transporter (OCT)3 mRNAs in both cells. The choline uptake by A549 and rat ATII cells was strongly inhibited by gefitinib with the IC₅₀ value of 6.77 μM and 10.5 μM, respectively. Conclusions Our results demonstrate that gefitinib reduces PC biosynthesis via inhibition of cellular choline uptake by A549 and rat ATII cells, which is mainly mediated by CTL1, resulting in abnormality of lung surfactant that can be one of mechanisms of the interstitial lung disease associated with gefitinib.     

表皮生长因子受体酪氨酸激酶抑制剂吉非替尼

吉非替尼(ZD1839,Iressa)是一种表皮生长因子受体酪氨酸激酶抑制剂,通过阻断酪氨酸激酶信号传导通路抑制肿瘤生长.2个大型的Ⅱ期临床试验(IDEAL)证实了其对于晚期非小细胞肺癌具有应用前景,可以改善症状,延长患者的生存期.此外,在对多种恶性实体瘤的Ⅰ期和Ⅱ期临床研究中也初步证实了该药具有抗肿瘤活性.     

Pharmacogenomics and adverse drug reactions: the case of statins

Introduction: The use of genomics to predict adverse drug reactions (ADRs) has been the subject of much research over the last decade. Concerns about the muscular safety of statins, a highly prescribed group of drugs, are partially related to their high exposure. Many studies have identified a variety of genetic markers related to statin-induced myopathy. However, only polymorphisms in the SLCO1B1 gene (which encodes the carrier responsible for the hepatic uptake of statins, which, in turn, contributes to the regulation of plasma levels of SLCO1B1) were strongly associated with statin-induced muscular adverse effects. These was found to be most prominent for simvastatin. The strength of these findings relies on the use of modern genetic approaches, such as well-designed, case-controlled and genome-wide association studies. Nevertheless, the clinical use of this information is far from known at present and needs to be evaluated.

Areas covered: The links between genetic polymorphisms (i.e., SLCO1B1 gene) and statin-induced muscle ADRs and the methodological issues involved in the establishment of such an association are explored.

Expert opinion: Despite there being a statin–gene association for myopathy, in the case of some statins the usefulness of this information still needs to be proven.     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

毒性试验组织病理学结果有害作用判断概述

药物非临床安全性评价毒性试验有害作用的判断非常重要,因其可为保护临床试验暴露于新化学实体或药物的受试者提供重要信息。毒性试验组织病理学检查可提供受试物毒性作用的形态学数据,帮助分析和确定有害作用和非有害作用及其剂量水平。参照美国毒性病理学会（STP）和欧洲毒性病理学会（ESTP）的推荐最佳实践或建议及其他相关文献,对有害作用的定义、区分有害作用与非有害作用的要素、有害作用数据沟通和使用来评估人类潜在风险等建议等进行简要概述分析,以期为我国非临床药物安全性评价毒性试验中有害作用判定提供参考。     

平阳霉素治疗血管瘤与脉管畸形严重不良反应的防治

目的：探讨平阳霉素（PYM）治疗血管瘤与脉管畸形的严重不良反应的防治措施。方法：用PYM治疗血管瘤与脉管畸形346例，在治疗前后作血常规及X线胸片检查，治疗期间观察并防治局部及全身反应。结果：发生不良反应25例。其中发热14例，局部溃疡7例，呕吐1例，过敏性休克3例。结论：PYM治疗血管瘤与脉管畸形可发生过敏性休克及肺纤维化等严重不良反应。注射PYM前应做好充分的抢救准备；治疗过程中控制好PYM的使用总量，注意随访胸部X线片，一旦出现肺纤维化，应立即停药。     

吉非替尼治疗难治性非小细胞肺癌的疗效

目的:探讨吉非替尼治疗难治性非小细胞肺癌的疗效和不良反应。方法:共入组难治性非小细胞肺癌47例,给吉非替尼250 mg每日1次口服,直至肿瘤进展或病人不能耐受治疗的毒性而中止治疗。至少服药16 wk后评价疗效。结果:全组总有效率34％[(16／47);完全缓解(CR)1例,部分缓解(PR)15例],疾病控制率为83％(39／47;CR 1例,PR 15例,稳定23例)。男性组和女性组的有效率分别为50％和20％(P<0．05), 中位生存期为297 d(118～868 d)。中位疾病进展时间(TTP)173 d(59～693 d)。1 a和6 mo生存率分别为 36％和79％。全组病人症状改善率为89％(42／47)。主要的不良反应是痤疮样皮疹(32％)、腹泻(11％)、恶心呕吐(23％),未发生明显骨髓抑制及间质性肺炎。结论:吉非替尼治疗难治性非小细胞肺癌有一定疗效, 不良反应轻微,可提高病人的生活质量。     

局部进展期乳腺癌新辅助化疗3种方案的不良反应比较

目的:评价3种辅助化疗方案的不良反应,为局部进展期乳腺癌化疗方案的选择提供参考。方法:收集2000年1月至2005年12月应用3种不同新辅助化疗方案治疗的89例女性乳腺癌患者的临床资料,对各组不良反应和近期疗效进行回顾性分析。化疗方案为CEF(环磷酰胺+表阿霉素+氟尿嘧啶)、NEF(长春瑞滨+表阿霉素+氟尿嘧啶)和TAC(多西紫杉醇+表阿霉素+环磷酰胺),28d为1个周期,化疗2周期后手术,入组患者分别为36、32和21例。结果:①所有患者均完成2个周期化疗。CEF、NEF和TAC组肿瘤原发灶有效率分别为47.2%(7/36)、71.9%(23/32)和85.7%(18/21),CEF组与NEF组比较差异有统计学意义(x2=4.251,P=0.039),CEF组与TAC组比较有效率差异有统计学意义(x2=8.292,P=0.004),NEF与TAC组差异无显著性(x2=1.386,P=0.239)。②TAC组的不良反应为白细胞减少(21/21,100%)、脱发(21/21,100%)、关节肌肉痛(12/21,51.1%)、面色潮红(9/21,42.9%)及过敏反应(4/21,19%)。TAC组白细胞减少明显高于CEF组(77.1%)和NEF组(78.1%)。NEF组32例中有13例出现周围静脉炎(40.6%)。其他不良反应如血红蛋白减少、血小板减少及胃肠道反应,3组相似。结论:NEF治疗方案具有良好近期疗效,不良反应易耐受,适用于治疗局部进展期乳腺癌。     

Contribution of new technologies to characterization and prediction of adverse effects

Abstract

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.     

吉非替尼治疗16例晚期非小细胞肺癌的临床疗效

目的 观察吉非替尼单药治疗晚期非小细胞肺癌(NSCLC)的疗效和不良反应。方法 对16例化疗失败的晚期NSCLC患者给予吉非替尼口服250 mg·d^-1,至病情进展或出现不可耐受的不良反应。结果 16例晚期NSCLC患者中,无完全缓解者,部分缓解(PR)4例(25.0%),稳定(SD)6例(37.5%),临床获益率(PR+SD)为62.5%。临床获益率与性别、吸烟史及癌症分期无关。到随访截止日期,16例患者中,6例存活,10例死亡;中位肿瘤进展时间(TTP)为7个月,中位生存期(MST)为10个月。不良反应主要为Ⅰ～Ⅱ度皮疹和腹泻,对症处理后可缓解。结论 吉非替尼有明显抗肿瘤作用,能明显提高晚期NSCLC患者的生活质量,改善临床症状,不良反应可以耐受。     

New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors

Introduction: Tumor development results from a cancer-induced immunosuppression (immune-editing). Immunotherapy has revolutionized the treatment paradigm for many malignancies, putting clinicians before novel toxicities, of immune-mediated etiology (immune-related adverse events).

Areas covered: Immune-mediated toxicity depends on both innate and adaptive immunity mechanisms. Healthy tissue damage depends on an aspecific T-cell hyperactivation response causing cross-reaction with normal tissues, which leads to an overproduction of CD4 T-helper cell cytokines and an abnormal migration of cytolytic CD8 T-cells. By stimulating a diffuse T-cell repertoire expansion, immune-checkpoint inhibitors counteract tumor growth but reduce the self-tolerance, damaging healthy organs. In this review, we summarize the toxicity profile of the novel immune-checkpoint inhibitors and their clinical implications, we are convinced that a deep understanding and a prompt resolution of the paradigmatic toxicities of these drugs will result in clinical benefits to patients and an enhanced antitumor effect.

Expert opinion: A focus on immunotoxicity is important in the education of clinicians and will improve patient safety. There is a willingness to tailor specific immune-therapies to each cancer patient, and to stimulate researchers through understanding of the physiopathogenesis, using the hypothesis that immune-mediated toxicities can be used as predictors of response or a prognostic sign of survival, thereby guiding therapeutic decisions.     

高度关注TNF抑制剂引起严重不良反应的风险

肿瘤坏死因子(TNF)抑制剂在对常规治疗不敏感的炎症免疫性疾病的治疗中显示出较好疗效,但在使用过程中也出现了严重的、致命性的不良反应,包括增加恶性肿瘤、白血病、银屑病和其他免疫病的发病风险等。美国食品与药品管理局近日发布消息,要求在TNF抑制剂的处方信息中加入严重警示。医务人员需高度关注TNF抑制剂引起严重不良反应的风险,注意用药安全。     

Saxagliptin overview: special focus on safety and adverse effects

Adverse drug reactions (ADRs) have long been recognised as a significant cause of morbidity and mortality. They account for a substantial number of clinical consultations, hospital admissions and extended duration of in-patient stay as well as mortality. By far the most common ADRs are the concentration-dependent pharmacological reactions, the majority of which ought to be preventable. As a result of high concentrations of the parent drug and/or its metabolite(s), there is an augmentation of primary pharmacological activity and/or appearance of new and undesirable secondary pharmacological activity. Typically, these high concentrations result from administration of high doses in an attempt to maximise efficacy and/or modulation of the pharmacokinetics of a drug by either genetic or non-genetic factors. High plasma concentrations of parent drug may result from inherited impairment or drug-induced inhibition of its pharmacokinetic disposition. Conversely, inherited overcapacity or drug-induced induction of the metabolism of a drug may result in low concentrations of parent drug and frequently, rapid accumulation of its metabolites. Environmental, dietary and phytochemical factors may also influence the activity of drug metabolising enzymes. As with inherited polymorphisms of acetylation and cytochrome P450-based drug metabolising enzymes, polymorphisms of other conjugation reactions, such as glucuronidation, increasingly appear to be associated with drug toxicity. Diseases of organs involved in elimination of a drug also alter its pharmacokinetics, plasma concentration and, therefore, the profile of its concentration-dependent ADRs. Inherited mutations, concurrently administered drugs or presence of certain diseases may also alter the sensitivity of some pharmacological targets, accounting for a substantial number of ADRs and interactions. When there is enhanced pharmacodynamic sensitivity, plasma drug concentrations that are apparently within the normal ‘non-toxic’ range give rise to ADRs. Recent advances have also provided important insights into the wider scope of drug–drug interactions. Interactions that occur at P-glycoproteins, drug transporters and efflux pumps, at various transmembrane interfaces such as the gastrointestinal wall, renal tubules, hepatobiliary border and blood–brain barrier, are beginning to explain many non-metabolic interactions. These alter the systemic exposure to drugs and have so far, begun to explain unexpected neurotoxicity and hepatotoxicity. The function of these transporters is also genetically modulated. These advances, together with continued increased awareness and education of prescribers and pharmacists, offer great opportunities for substantially minimising concentration-related ADRs.     

360例小分子激酶抑制剂不良反应报告分析

目的 分析360例小分子激酶抑制剂不良反应（ADR）发生的一般规律和特点,为临床合理用药提供依据。方法 收集陕西省2016—2020年各级医疗卫生机构上报至陕西省食品药品研究院的360例小分子激酶抑制剂ADR报告,从性别、年龄、给药途径、药物种类、临床转归和ADR累及系统/器官进行统计分析。结果 在360例ADR患者中,男性多于女性,好发于40岁以上的中老年人。ADR累及系统/器官以消化系统为主,其次为皮肤及附件、血液系统、心血管系统。引起ADR最多的药品是伊布替尼。在临床转归方面,痊愈和好转占59.5%。1例“新的”ADR表现为全身皮肤变黑,其是否与该类药物有关有待进一步研究。结论 小分子激酶抑制剂ADR的发生与患者年龄、性别、药物种类等密切关联,并且涉及多个系统或器官,临床使用时应根据具体用药情况采取有效预防措施,以减少或避免ADR的发生,从而优化合理用药,确保患者用药安全。     

茵栀黄注射液不良反应临床分析

目的分析茵栀黄注射液使用的不良反应及其相关因素，为临床合理用药提供参考。方法通过文献检索获得菌栀黄注射液不良反应的报道资料和北京地坛医院使用菌栀黄注射液而发生不良反应的临床资料．对近年来茵栀黄注射液不良反应的病例共130例进行分析，资料采用描述性分析，总结不良反应发生患者的临床特征．茵栀黄注射液不良反应的类型、临床特点及其相关因索。结果茵栀黄注射液引起不良反应86．8％发生在首次用药过程中．有不良反应20种，以皮疹最为常见，占不良反应患者的67．69％（88／130），占不良反应的31．3％。重型不良反应以过敏性休克最为常见，占不良反应患者的10．77％（14／130），占不良反应的5．0％。年龄越大．不良反应发生率高．不良反应的程度越重。中、重型不良反应发生率在有过敏史者为42．46％。占总不良反应病例的34．62％（35／130）．结论茵栀黄注射液所致的不良反应与药物的应用方式、患者的个体因素相关．