二代酪氨酸激酶抑制剂治疗慢性粒细胞性白血病继发T315I突变1例报道及分析

正慢性粒细胞白血病(chronic myeloid leukemia,CML)为血液系统恶性肿瘤性疾病。近年来,随着伊马替尼等酪氨酸激酶抑制剂(TKIs)的问世,CML的治疗取得极大进展,多数病人通过TKIs治疗已能获得长期生存,并取得较好生活质量。尽管如此,仍有少部分患者接受TKIs治疗疗效欠佳甚至治疗失败,疾病很快进展至加速急变期乃至死亡。     

某院非小细胞肺癌患者小分子靶向药物使用合理性评价

目的 促进小分子靶向药物的临床合理应用。方法 回顾性分析某院2020年使用酪氨酸激酶抑制剂类（TKIs）小分子靶向药物的非小细胞肺癌（NSCLC）患者的病历信息，制订《非小细胞肺癌小分子靶向药物专项评价表》，统计其中TKIs的使用情况，包括适应证、用法用量、抗肿瘤治疗联合用药等，并依据国家药品监督管理局（NMPA）和美国食品和药物管理局（FDA）药品说明书、相关指南、循证医学证据等级高的临床研究等评价其用药合理性。结果 共纳入患者1 436例，用药不合理率为18.73%(269/1 436)，其中适应证不适宜106例次（7.38%）、遴选药品不适宜6例次（0.42%）、抗肿瘤治疗联合用药不适宜157例次（10.93%）,105例次（7.31%）合并使用具有潜在不良相互作用的非抗肿瘤药物；非肿瘤专科患者TKIs类小分子靶向药物使用合理率为74.06%(177/239)，低于肿瘤专科的82.71%(990/1 197)。结论 该院NSCLC患者TKIs类小分子靶向药物的使用整体较规范，但也存在不合理用药现象，需临床药师持续干预与反馈，以促进其合理、规范使用。     

二代表皮生长因子受体酪氨酸激酶抑制剂在非小细胞肺癌中的应用

抑制表皮生长因子受体(EGFR)的信号传导通路是治疗非小细胞肺癌(NSCLC)的有效策略。现在临床上应用的主要是酪氨酸激酶抑制剂(TKIs)的第一代产品-吉非替尼(Gefitinib)和埃罗替尼(erlotinib)。临床前和早期临床试验已经证明第二代TKIs可以提高患者的生存率。因此,本文重点讨论治疗NSCLC最具发展前途的四种第二代TKIs:EKB-569、HKI-272、CI-1033和ZD-6474。     

酪氨酸激酶抑制剂心血管毒性研究进展

目的 综述酪氨酸激酶抑制(TKIs)心血管毒性研究进展.方法 以查阅文献为主要依据,对心血管毒性及酪氨酸激酶抑制剂的研究发展变化进行分析、整理和总结.结果 呈现出TKIs广泛应用于肿瘤患者时心血管毒性问题日益突出的发展变化趋势,以及不同TKIs作用靶点不同,其心血管毒性的病理机制及临床表现存在差异.结论 本文分别对BCR-ABL、VEGFR、EGFR及BTK/ITK靶点TKIs的心血管毒性可能分子机制进行介绍,对TKIs心血管毒性的临床预测和药学监护有一定的指导价值.     

酪氨酸激酶抑制剂的药物相互作用研究进展

口服酪氨酸激酶抑制剂(TKIs)高效、低毒因而使用广泛,药物相互作用风险也随之增加。本文总结了截止至2015年12月31日,美国食品和药物管理局和我国国家食品药品监督管理总局批准用于非小细胞肺癌的TKIs与其他药物和食物的相互作用研究进展,并给出用药建议,为临床使用提供参考。     

第三代BCR-ABL酪氨酸激酶抑制剂普纳替尼

普纳替尼作为新一代酪氨酸激酶抑制剂(TKIs),对BCR-ABL阳性白血病,如慢性髓细胞白血病(CML)、费城染色体阳性急性淋巴细胞性白血病(Ph+ALL)有显著的治疗效果,甚至在对当前市场上供应的第一、二代TKIs出现耐药(如T315I突变)的情况下仍有效。目前普纳替尼已获美国FDA批准用于对其他TKIs耐药的CML与Ph+ALL患者的治疗,并在尼洛替尼与达沙替尼耐药或不耐受的T315I突变患者中进行了Ⅱ期临床研究。     

酪氨酸激酶抑制剂相关治疗药物监测的研究进展

目的:了解酪氨酸激酶抑制剂(TKIs)在治疗药物监测(TDM)方面的研究进展,为促进其临床合理用药提供参考。方法:以"酪氨酸激酶抑制剂""治疗药物监测""血药浓度""Tyrosine kinase inhibitors""Therapeutic drug monitoring""Concentrations"等为关键词,在中国知网、万方数据库、维普网、Pub Med等数据库中组合检索2000年7月-2020年7月发表的相关文献,从药动学/药效学、药物相互作用、暴露与疗效/毒性和常用检测方法等方面对主要TKIs相关TDM的现有证据进行总结。结果与结论:TKIs主要包括伊马替尼、厄洛替尼、吉非替尼、索拉非尼、达沙替尼、舒尼替尼、尼洛替尼、拉帕替尼、阿帕替尼等药物。TKIs的药动学在个体间差异较大,且饮食、吸烟、性别等因素均会影响其药动学参数;药物之间的相互作用可能会引起TKIs药物暴露量的变化,导致患者出现TKIs血药浓度过高或过低的情况。多数TKIs药物将谷浓度(cmin)值作为其监测浓度,权衡疗效与毒性反应。虽然TKIs的暴露量与疗效/毒性之间具有相关性,但确切关系尚不清楚。TKIs常用的定量分析方法为高效液相色谱结合紫外检测、液相色谱串联质谱和酶联免疫吸附测定法等。目前,对TKIs的TDM研究仍处于探索阶段,仍需要进一步研究以确定其治疗窗口,以实现TKIs的常规监测并制订相关共识指南,从而促进其临床合理用药。     

上海地区非甾体抗炎药不良反应回顾与分析

目的 调查上海市长期使用非甾体抗炎药(NSAIDs)人群药物不良反应发生情况及相关参数。方法 用整群抽样,回顾性询问填表法,获取了1002例患者的基本情况、NSAID s使用情况、合并用药情况和药物不良反应(发生、治疗、预后)等情况。结果 调查显示,患者使用NSAIDs均在1年以上,药物不良反应发生率较高(66％),症状主要集中在胃肠道、皮疹、中枢症状,严重药物不良反应约7％,药物不良反应预后较好。结论 NSAID s药物不良反应受多种因素影响。     

非小细胞肺癌58例表皮生长因子受体突变状态

目的 探讨非小细胞肺癌(NSCLC)表皮生长因子受体(EGFR)突变状态及其对预测酪氨酸激酶抑制剂(TKIs)疗效的价值.方法 提取58例NSCLC患者肿瘤组织和正常肺组织的DNA,用巢式PCR扩增,直接测序法检测EGFR外显子19和21基因突变.结果 正常肺组织中EGFR基因均为野生型.肿瘤组织EGFR基因突变率为32.8％(19/58),外显子19和21突变率分别为73.7％(14/19)和26.3％00(5/19).腺癌、女性、不吸烟患者突变率要高于鳞癌、男性、吸烟患者(P＜0.05).随访3.0-29.3个月;58例患者的中位生存时间为23.5个月.19例EGFR基因突变者中,3例应用TKIs治疗,均健在.结论 NSCLC患者中,19外显子是EGFR基因突变的主要类型,女性、腺癌、不吸烟患者突变率较高.检测EGFR基因突变状态可用于预测NSCLC患者对TKIs治疗的敏感性.     

酪氨酸激酶抑制剂治疗慢性粒细胞白血病的不良反应及处理的研究进展

酪氨酸激酶抑制剂(TKI)抑制BCR-ABL基因,改善慢性粒细胞白血病(CML)患者长期生存,与正常人寿命无差异.CML患者使用TKI早期出现不良反应较轻,可对症处理或自行恢复,较严重时可考虑更换TKI.国内报道TKI长期使用的安全性问题多表现在血液学不良反应,其他不良反应文献报道少见,本文通过查询国内外文献,对TKI...     

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for 3 months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.     

Current concerns of undertreatment and overtreatment in chronic myeloid leukemia based on European LeukemiaNet 2013 recommendations

Introduction: The aim of this paper is to indicate optimal tyrosine kinase inhibitor (TKI) administration practices based on European LeukemiaNet (ELN) 2013 recommendations for chronic myeloid leukemia (CML). Likewise, current concerns of undertreatment and overtreatment with TKIs during the long-term clinical course of CML will be outlined.

Areas covered: Currently available TKIs for the management of CML are reviewed. The survival benefit of TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) for the CML is excellent. The CML and TKI literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as the ELN CML 2013 recommendations.

Expert opinion: Initial TKI treatment for low-risk chronic phase CML is imatinib 400 mg; high-Sokal risk and/or CML patients with complex karyotypic abnormalities would require more powerful second-generation TKIs (dasatinib 100 mg or nilotinib 600 mg). Absence of early molecular response after 6 months, complete cytogenetic response after 12 months and major molecular response after 18 months may require a more powerful TKI switch. If one of the two second-generation TKIs (nilotinib or dasatinib) was used as first-line therapy and failed, the other (dasatinib or nilotinib) could be administered.     

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib

Introduction: In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment.

Areas covered: Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported. Limited attention to long-term events or more in general, to the impact of AEs on patient quality of life (QoL), remains a problem. Ponatinib is active against all BCR-ABL1 mutants, including T315I, and is widely used to treat patients who developed resistance to other TKIs in any CML phase; however, only limited data is available on the possible role of ponatinib for intolerant patients.

Expert opinion: We review the different definitions of intolerance used in sponsored trials and in clinical practice, and we discuss how such definitions impact on the management of AEs. We summarize how to evaluate QoL during treatment with TKIs and how to include ponatinib among possible option for intolerant patients.     

Safety Issues in the Pharmacologic Management of Chronic Pain in the Elderly

Chronic pain is commonly encountered in elderly patients. About 20–50% of community-dwelling elderly experience it, and 45–80% of nursing home residents may be affected. Selection of pharmacologic therapy for the management of chronic pain must take into consideration the increased potential for adverse effects in this population. Major classes of drugs used to treat chronic pain (nonsteroidal antiinflammatory drugs, opioids, antidepressants) have adverse effects that occur more frequently in elderly than in younger patients. Given the often prolonged duration of therapy, optimal management requires minimizing the risk of adverse reactions.     

Omacetaxine as an anticancer therapeutic: what is old is new again

Omacetaxine mepesuccinate was originally identified more than 35 years ago and initial studies in chronic myeloid leukemia (CML) showed promising activity. It has also been studied in other hematologic and solid tumors as both a single agent and in combination with other treatments. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) abated the clinical development of omacetaxine as a treatment for CML. The advent of resistance to imatinib and other TKIs in CML patients (often due to the presence of an ABL mutation at position 315) has led to a revived clinical interest in omacetaxine in CML patients who failed TKIs. Here we review omacetaxine's mechanism of action (MOA) as a protein translation inhibitor, how its MOA may translate into activity in treatment of cancers, its potential to eradicate leukemia initiating cells and other cancer stem cells and the potential significance of this activity in clinical practice.     

Asthma medications and their potential adverse effects in the elderly: recommendations for prescribing.

The incidence of drug-induced adverse effects is likely to increase as a result of advanced age and exposure of elderly patients to polypharmacy. Therefore, pharmacological therapy of asthma and chronic obstructive pulmonary disease (COPD) in the elderly patient can be potentially hazardous. beta(2)-agonists, administered as therapy for asthma and COPD, have recognised systemic sequelae, such as hypokalaemia and chronotropic effects, which may be life-threatening in susceptible patients. Adverse effects such as hypokalaemia can be aggravated by concomitant treatment with other drugs promoting potassium loss including diuretics, corticosteroids and theophyllines. In addition, relatively minor adverse events associated with the administration of beta(2)-agonists, such as tremor and blood pressure changes, may be of significance to the elderly patient leading to impairment in the quality of life. However, long-term treatment with beta(2)-agonists may reduce the incidence of drug-induced adverse effects as a result of beta-receptor subsensitivity. Oral and inhaled corticosteroids have been used for the treatment of acute asthma and COPD in the elderly patient. Long-term treatment with oral corticosteroids can result in serious systemic adverse effects such as suppressed adrenal function, bone loss, skin thinning and cataract formation. In contrast to beta(2)-agonists, oral corticosteroids can upregulate beta(2)-adrenoceptors and thereby potentiate the systemic sequelae of beta(2)-agonists. Hence, oral corticosteroids should be administered with caution for as short a duration as possible. Inhaled corticosteroids appear to be relatively well tolerated when administered at doses below approximately 1000 microg. However, larger doses of inhaled corticosteroids may affect hypothalamic-pituitary-adrenal function and bone turnover. In the case of inhaled corticosteroids, spacer devices, often used in older patients who cannot operate metered dose inhalers, can potentiate the systemic sequelae of both corticosteroids and beta(2)-agonists. The use of theophyllines in the treatment of COPD or chronic asthma is controversial. Theophyllines have a wide adverse effect profile and are prone to drug-drug interactions. The adverse effects may be mild or life threatening and include nausea and vomiting or sinus and supraventricular tachycardias. Therefore, theophyllines should be prescribed with extreme caution to elderly patients with asthma or COPD. In contrast, inhaled anticholinergic drugs such as ipratropium bromide and oxitropium bromide are generally safe in elderly patients and have useful bronchodilator function. Commonly reported adverse effects are an unpleasant taste and dryness of the mouth. When used as first-line therapy, anticholinergic drugs may optimise the bronchodilator effects of low-dose inhaled beta(2)-agonists in patients with chronic airflow obstruction, and hence obviate the need for higher doses.     

新型冠状病毒肺炎疫情下慢病长处方用药安全探讨

目的探讨新型冠状病毒肺炎(简称新冠肺炎)疫情期间长处方政策下慢病患者的用药安全。方法收集长期就诊医院近6个月的慢病患者用药方案500份,从不同慢病分类对用药方案中药物储存条件、服药时间及药物间潜在的相互作用等方面进行梳理,分析存在的用药安全风险,形成个体化用药指导单。结果制订慢病患者个体化用药指导单和用药时间轴,可有效降低慢病患者不正确的药品储存方式、服药时间及服药方式导致的药品不良事件发生风险。结论新冠肺炎疫情下,为慢病患者制订个体化用药指导单和用药时间轴,并提供合理的生活饮食建议,是慢病患者药学服务的一种延续,对于保障长处方政策下慢病患者的用药安全具有重要意义,值得推广。     

Chronic arsenic poisoning

Symptomatic arsenic poisoning is not often seen in occupational exposure settings. Attempted homicide and deliberate long-term poisoning have resulted in chronic toxicity. Skin pigmentation changes, palmar and plantar hyperkeratoses, gastrointestinal symptoms, anemia, and liver disease are common. Noncirrhotic portal hypertension with bleeding esophageal varices, splenomegaly, and hypersplenism may occur. A metallic taste, gastrointestinal disturbances, and Mee's lines may be seen. Bone marrow depression is common. 'Blackfoot disease' has been associated with arsenic-contaminated drinking water in Taiwan; Raynaud's phenomenon and acrocyanosis also may occur. Large numbers of persons in areas of India, Pakistan, and several other countries have been chronically poisoned from naturally occurring arsenic in ground water. Toxic delirium and encephalopathy can be present. CCA-treated wood (chromated copper arsenate) is not a health risk unless burned in fireplaces or woodstoves. Peripheral neuropathy may also occur. Workplace exposure or chronic ingestion of arsenic-contaminated water or arsenical medications is associated with development of skin, lung, and other cancers. Treatment may incklude the use of chelating agents such as dimercaprol (BAL), dimercaptosuccinic acid (DMSA), and dimercaptopanesulfonic acid (DMPS).     

Imatinib: new preparation. For Chronic myeloid leukaemia: further assessment required

(1) Chronic myeloid leukaemia goes through three clinical phases: a chronic phase, an acceleration phase, and a terminal blast crisis. In the chronic phase, interferon alfa-2 is more effective than cytotoxic chemotherapies but it also has more adverse effects. (2) Imatinib inhibits tyrosine kinase, an enzyme encoded by the pathological gene BCR-ABL, which is created during a reverse translocation between chromosomes 9 and 22 (characteristic of chronic myeloid leukaemia). This translocation almost always creates the pathological chromosome Philadelphia in blood cell lines. (3) 1 027 patients were recruited to three non comparative trials of imatinib, each focusing on a different phase of chronic myeloid leukaemia. Efficacy was evaluated largely on the basis of blood cell count and clearance of cells harbouring the Philadelphia chromosome. (4) During the chronic phase, in patients in whom interferon alfa-2 had failed or been poorly tolerated, a major cytogenetic response, lasting at least one month, occurred in 35% of patients on imatinib, compared to 20% of patients on interferon alfa-2 + cytarabine (historical comparison). It is not known whether this translated into longer survival. (5) Preliminary results from a randomised but unblinded trial comparing imatinib with interferon + cytarabine seem to favour imatinib. Some patients developed relapses resistant to imatinib, owing to mutations in the BCR-ABL gene. (6) In patients going through the acceleration phase or blast crisis, imatinib did not improve survival compared with standard treatments. (7) The main adverse effects so far described with imatinib are gastrointestinal problems, oedema and fluid retention, and muscle and joint pain, which prompted patients to stop treatment in no more than 5% of cases. (8) Imatinib has a strong potential to interact with other drugs, including paracetamol, but few specific studies have been done. (9) In practice imatinib may be a useful option during the chronic phase, after interferon alfa-2 has failed or been stopped because of adverse effects, provided that its benefits, so far shown only in surrogate endpoints, translate into longer survival. During the acceleration phase and blast crisis imatinib may cause fewer side effects than existing treatments.     

Bosutinib for the treatment of chronic myeloid leukemia in chronic phase

The clinical outcome for patients with chronic myeloid leukemia in chronic phase (CML-CP) is currently very favorable due to the availability of tyrosine kinase inhibitors (TKIs) that are well tolerated and effectively suppress the constitutively activated BCR-ABL1 kinase that underlies the pathogenesis of this malignancy. Three TKIs -imatinib, nilotinib and dasatinib- have been approved as frontline therapy in CML-CP. Another TKI, bosutinib, inhibits with high potency numerous tyrosine kinases, including BCR-ABL1, Src family of kinases and MAPK, among others. Like nilotinib and dasatinib, bosutinib is a second-generation TKI that inhibits the majority of mutations associated with imatinib resistance, with the exception of T315I. In patients with CML-CP with prior intolerance or resistance to imatinib therapy, bosutinib rendered response rates similar to those observed in the same patient population treated with nilotinib or dasatinib. Preliminary results from the ongoing phase III BELA study in which bosutinib is compared in a randomized fashion to imatinib for patients with newly diagnosed CML-CP have been recently reported. We herein summarize the preclinical and clinical experience of bosutinib in CML.