头孢菌素类药物致史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的文献分析

目的： 分析头孢菌素类药物致史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）不良反应发生情况及其临床特点,为临床安全用药提供参考。方法： 检索Web of Science、PubMed、中国知网数据库、维普数据库和万方数据库关于头孢菌素类药物致SJS/TEN的文献报道并进行分析。结果： 共纳入文献25篇,26例不良反应,其中,男性15例（57.69%）,女性11例（42.31%）;年龄最小5岁,最大85岁,中位年龄61.5岁;SJS 9例（34.62%）,TEN 17例（65.38%）;发生时间集中在用药后3 d内的13例（50.01%）;临床表现以皮肤伴有或不伴渗出多型红斑、斑丘疹为主的皮疹伴发热、口腔、生殖器和或眼黏膜破溃,随着病程进展进而出现皮肤水疱破裂及脱落,常伴有继发性感染及多脏器损害,以肝肾损害较常见。结论： 临床应用头孢菌素类药物存在SJS/TEN的风险,医务人员应了解其发病特点及早期鉴别SJS/TEN症状,一旦发生应根据患者严重程度尽早给予对症治疗,降低SJS/TEN的病死率,加强后期随访及患者用药教育。     

奥马珠单抗不良反应文献分析

目的:分析奥马珠单抗致不良反应(adverse drug reaction,ADR)的临床表现和特点,为临床安全用药提供参考。方法:检索中国知网、万方、维普、Web of Science、PubMed、Embase等数据库关于奥马珠单抗致ADR的个案报道并进行分析。结果:收集奥马珠单抗致ADR的个案报道26篇,共35例,其中男性9例(25.71%)、女性26例(74.29%),年龄分布以30~69岁居多(82.86%),发生时间大多在用药后1年内(87.27%),过敏反应主要集中在用药3个月内(66.67%),ADR以皮肤及其附件损害(48.78%)、呼吸系统损害(14.63%)和循环系统损害(12.19%)为主。多数患者对症处理后均好转,仅1例死亡,4例发生过敏反应的患者接受脱敏治疗并成功脱敏。结论:临床应用奥马珠单抗应加强ADR监测,防范严重ADR的发生,确保用药安全。     

帕博利珠单抗致原发性肾上腺功能减退1例及文献分析

目的探讨帕博利珠单抗致原发性肾上腺功能减退的发病机制及管理措施。方法分析1例帕博利珠单抗致原发性肾上腺功能减退的诊疗经过,结合文献分析,阐述帕博利珠单抗与原发性肾上腺功能减退不良反应的因果关系、发生率、发病机制和处理措施。结果患者静脉使用帕博利珠单抗6个月后出现明显乏力、体力差、食欲差、皮肤变黑症状。入院行实验室检查8AM血清促肾上腺皮质激素(ACTH)16.7 pmol·L^-1,8AM血清皮质醇<25.7 nmol·L^-1,考虑为帕博利珠单抗致原发性肾上腺功能减退。建议暂停帕博利珠单抗治疗,口服醋酸泼尼松片每日2次,每次5 mg用于类固醇激素替代治疗,1周后患者症状好转出院。院外逐渐减少醋酸泼尼松片至5 mg·d^-1维持剂量。结论对帕博利珠单抗致原发性肾上腺功能减退,应根据不良反应分级标准采取相应的分级处理措施。     

国产程序性死亡受体-1抑制剂致严重免疫相关皮肤不良反应文献分析

目的：分析国产程序性死亡受体-1(PD-1)抑制剂致Stevens-Johnson综合征（SJS）、中毒性表皮坏死松解症（TEN）严重免疫相关皮肤不良反应的规律和特点,为临床合理用药提供参考。方法：检索自建库至2022年12月31日以来中国知网、万方、维普、PubMed、Springer、Elsevier等中外文数据库中关于国产PD-1抑制剂致SJS/TEN的相关病例报告,并进行分析和讨论。结果：共涉及23例患者,其中TEN17例（73.91%）,SJS5例（21.74%）,SJS/TEN1例（4.35%）。发生TEN的中位时间为首次用药后28.5 d;发生SJS的中位时间为首次用药后90 d。23例患者中19例（82.61%）患者出现黏膜受累情况,23例患者前期均出现不同程度的皮疹。23例患者均采用全身糖皮质激素治疗,14例（60.87%）患者联合使用免疫球蛋白,2例（8.70%）患者联合使用TNF-α抑制剂,1例患者联合使用环孢素（4.35%）。23例患者18例（78.26%）好转或痊愈,3例（13.04%）死亡,1例（4.35%）失明,1例（4.35%）转院治疗。结论：临床使用P...     

帕博利珠单抗致免疫相关性不良反应文献回顾性分析

目的：分析帕博利珠单抗药品不良反应(Adverse Drug Reactions,ADR)的发生情况和临床特点,为临床合理用药提供参考。方法：检索中国知网、万方、维普、PubMed、Springer及Wiley中关于帕博利珠单抗的ADR个案报道,对其进行统计和分析。结果：帕博利珠单抗致ADR个案报道共41篇53例。 患者的年龄主要为51~70岁(54.71%)。ADR多发生在用药3个月后(47.37%),以皮肤系统(47.37%) 损害多见。ADR主要表现为大疱性类天疱疮(8例次)和视力下降(5例次)等。结论：在临床使用帕博利珠单抗时应注意监测和防治其ADR,避免严重的ADR发生。     

基于分区生存模型的帕博利珠单抗单药与化疗一线治疗PD-L1肿瘤比例分数不同的非小细胞肺癌的成本-效果分析

目的：从卫生体系角度出发,评价帕博利珠单抗单药与化疗一线治疗PD-L1肿瘤比例分数≥1%的局部晚期或转移性非小细胞肺癌的经济性,为相关卫生决策提供参考。方法：根据疾病发展进程建立无进展、进展和死亡三状态分区生存模型,以质量调整生命年（QALY）作为产出指标计算增量成本-效果比。生存分析数据来自于一项多中心随机对照非盲的Ⅲ期临床试验KEYNOTE-042,成本数据来自于米内网和8个省市的医疗卫生服务项目价格中位数,效用数据源于已发表文献,并对关键参数进行敏感性分析和情景分析。结果：基础分析结果表明,相较于标准化疗组,帕博利珠单抗单药治疗相对于化疗的增量成本效果比在PD-L1肿瘤比例分数不同的人群中分别为228 254.12元/QALY（TPS≥50%）、351 267.03元/QALY（TPS≥20%）和256 990.96元/QALY（TPS≥1%）。单因素敏感性分析显示帕博利珠单抗价格和PFS状态效用等对ICER的变化有较大影响。概率敏感度分析结果表明模型结构稳定,稳健性较好。结论：在中国3倍人均GDP（193 932.00元）的意愿支付阈值下,帕博利珠单抗单药治疗与化疗相比不具有成本-效果,其经济性未来可通过降低价格来实现。     

重症多形红斑型药疹25例和中毒性表皮坏死松解症17例回顾性分析

对1990年12月~2013年4月本院收治的25例重症多形红斑（SJS）和17例中毒性表皮坏死松解症（TEN）患者的临床资料进行回顾性分析。探讨SJS和TEN的致敏因素、发生规律、临床特征和治疗措施。药物是引起SJS和TEN的最主要病因。致敏药物以抗菌药物为主（52.38%）,其次是抗癫痫药（28.57%）。黏膜损害和肝功能损害是最常见的并发症。 SJS和TEN均系统应用糖皮质激素治疗,SJS组8例和TEN组4例给予激素联合人免疫球蛋白治疗。系统应用糖皮质激素尤其是联合人免疫球蛋白治疗SJS和TEN有效。     

帕博利珠单抗致重症肌无力文献分析及思考

目的 分析帕博利珠单抗致重症肌无力(MG)的发生规律和特点,为临床合理用药提供依据。方法 以“帕博利珠单抗”、“重症肌无力”、“不良反应”、“致”、“pembrolizumab”、“adverse reaction”、“myasthenia gravis”、“induced”或“related”为检索词,检索2014年9月至2021年1月,CNKI、万方、维普、PubMed、Medline、Elsevier和Springer等数据库中帕博利珠单抗致MG相关个案报道并分析。结果 共计16篇文献,涉及17例患者,男11例(64.7%),女6例(35.3%),60岁以上患者14例(82.4%),有MG病史2例(11.8%),8周内发生不良反应的患者占88.2%。临床表现主要为眼部症状和延髓反应,6例(35.3%)患者出现了呼吸困难,进行了气管插管或无创正压机械通气,4例(23.5%)伴有心脏症状。12例(70.6%)经治疗后好转或痊愈,5例(29.4%)死亡。结论 帕博利珠单抗致MG反应多发生在8周内,约1/3患者死亡,需要临床高度警惕。     

历年广东省药学会超药品说明书用药目录概况与分析:以抗肿瘤药品为例

目的:为抗肿瘤药物临床超说明书使用提供参考。方法:系统检索2015至2021年广东省药学会官网发布的超药品说明书用药目录(以下简称"目录"),检索时限截至2021年7月20日,重点对比历年目录中抗肿瘤药品数量、分类、Micromedex证据分级变化情况。结果:迄今纳入目录的药品共125个(以通用名计),总条目数242条,其中抗肿瘤药品28种,总条目数81条,抗肿瘤药品占目录总条目数平均30%及以上;单靶点抑制剂的品种逐渐增加:2015年版仅贝伐珠单抗和利妥昔单抗2个品种,涉及5条超说明书用药;2021年版增加至9个品种,含培唑帕尼、厄洛替尼、依维莫司、帕博利珠单抗等,涉及32条超说明书用药;历年目录同一个药品同一适应证的Micromedex分级基本不变,仅部分品种依照相关指南做了调整。结论:目录纳入药品数量持续增长,尤其是抗肿瘤药品,迫切需要规范与完善超说明书用药体系,加快药品说明书更新审核程序。     

帕博利珠单抗致免疫性心肌炎1例报告及文献回顾分析

1例老年女性黑色素瘤患者接受帕博利珠单抗200 mg治疗,21 d后发生免疫性心肌炎伴横纹肌溶解,考虑与帕博利珠单抗治疗有关。经给予糖皮质激素冲击治疗和对症支持治疗,患者病情逐渐好转并出院。     

喹诺酮类药物致Stevens-Johnson综合征和中毒性表皮坏死松解症文献分析

目的:分析喹诺酮类药物致Stevens-Johnson综合征(SJS)和中毒性表皮坏死松解症(TEN)不良反应的发生情况,为临床合理用药提供参考.方法:通过PubMed、Web of Science、Springer、Embase、Scopus、万方期刊论文数据库、维普期刊数据库、中国知网(CNKI)、中国生物医学文献...     

Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, Lyell's disease, syndrome) are considered to be part of a spectrum of adverse cutaneous drug reactions with increasing severity and extent of skin detachment, ranging from SJS (less than 10% body surface area skin detachment, 1-5% mortality) to TEN (greater than 30% skin detachment, 25-35% mortality). Both SJS and TEN are characterized morphologically by ongoing apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis. Recent evidence is supportive of a role for the death receptor Fas and its ligand FasL, in the pathogenesis of keratinocyte apoptosis during TEN. This Fas-mediated keratinocyte apoptosis that causes epidermal detachment in TEN can be inhibited in vitro by antagonistic monoclonal antibodies to Fas and by intravenous immunoglobulins (IVIG) which have been shown to contain natural anti-Fas antibodies. Over the last 6 years, numerous case reports and 8 non-controlled clinical studies containing 9 or more patients have analyzed the therapeutic effect of IVIG in TEN. Taken together, although each study has its potential biases, 6 of the 8 studies point towards a benefit of IVIG used at doses greater than 2 g/kg on the mortality associated with TEN. Hopefully, these studies will serve as the basis for designing a prospective controlled trial in the near future; as such, an approach appears the only way to definitively determine the therapeutic potential of IVIG in TEN.     

Fatal Toxic Epidermal Necrolysis Associated with Minoxidil

Minoxidil is a direct-acting peripheral vasodilator for the treatment of symptomatic hypertension, or refractory hypertension associated with target organ damage, that is not manageable with a diuretic and two other antihypertensive drugs. The most frequent adverse events associated with minoxidil include hypertrichosis and cardiovascular events related to its powerful antihypertensive effect, and less frequently, rashes, bullous eruptions, and Stevens-Johnson syndrome (SJS). Evidence suggests that SJS and toxic epidermal necrolysis (TEN) are variants of a single disease with common causes and mechanisms, but differing severities. Epidermal detachment is mild in SJS, moderate in overlap SJS-TEN, and severe (> 30% of body surface area) in TEN. We describe a case of minoxidil-associated SJS that evolved into fatal TEN. A 69-year-old African-American woman with a history of chronic kidney disease was admitted to the hospital for a cerebrovascular accident and uncontrolled hypertension. On hospital day 12, oral minoxidil was added to her drug regimen. On day 23, she developed a maculopapular rash on her face that gradually diffused to her chest and back. Vesicles and papular lesions extended to her extremities and mucosal membranes; results of a skin biopsy revealed SJS. A positive Nikolsky's sign (blisters spread on application of pressure) was detected. On days 27–31, diffuse bullae developed with rash exacerbation. Skin detachment exceeded 30% and was consistent with TEN. The patient died on day 39. An evaluation of the causality and time course suggested that minoxidil was the most likely culpable drug, with a Naranjo adverse drug reaction probability scale score indicating that the likelihood of the association was possible (score of 3). The mechanism of this reaction has not been well elucidated. It may be related to an impaired clearance of the minoxidil metabolite, or an immune stimulation resulting in apoptosis and epidermis destruction. To our knowledge, this is the first case report of fatal TEN associated with minoxidil. This case report emphasizes the importance of monitoring for serious dermatologic reactions in patients receiving minoxidil therapy.     

Association between HLA and Stevens–Johnson Syndrome Induced by Carbamazepine in Southern Han Chinese: Genetic Markers besides B*1502?

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia. Negative correlations between CBZ-induced SJS/TEN and B*0702 or B*4001 have also been reported, suggesting a possible protective role. Here, we genotyped HLA-B and HLA-A in 18 cases with CBZ-induced SJS/TEN, in comparison with CBZ-tolerant and normal controls in Southern Han Chinese. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN was found, with 72.2% sensitivity and 87.1% specificity. However, we also found five patients with SJS (5/18, 27.78%) who were negative for HLA-B*1502. HLA-A*2402 was present in nine of 16 cases with SJS (56.25%, including three of five cases negative for HLA-B*1502), which was significantly more frequent than that of CBZ-tolerant controls or the general southern population. Only one case with SJS carried HLA-A*3101. No statistical difference in the mean age, sex ratio and CBZ usage was found between the CBZ-induced SJS/TEN group and the CBZ-tolerant group. In search for possible protective genetic markers in HLA-B*1502-positive but CBZ-tolerant patients, we failed to find any significant factors in the HLA alleles observed. Given the association between HLA-B*1502 and CBZ-induced SJS/TEN, genetic testing before initiating CBZ therapy is suggested in Han Chinese population. However, physicians should also be vigilant about SJS/TEN in those negative for HLA-B*1502. Other factors for the development of CBZ-induced SJS/TEN in HLA-B*1502-negative patients and protective factors in CBZ-tolerant patients should be investigated further.     

Exploratory study on biomarkers associated with severe cutaneous adverse reactions

Most of adverse drug reactions (ADRs) occur as an extension of pharmacological effects. They occur dependently on their blood concentrations and can be potentially reduced by controlling their dose. On the other hand, ADRs categorized as Type B usually occur irrelevantly to their pharmacological effects at different organs from their target, and are often life-threatening and unpredictable. The incidences of Type B ADRs are very low. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed allergic reactions in which T-cells are involved and categorized as Type B ADRs. Recent progress of pharmacogenomic studies has revealed that particular types of human leukocyte antigen (HLA) class I antigens have strong associations with severe cutaneous adverse reactions and that the associations are specific to causative drugs, phenotypes of adverse reactions and ethnic groups. We established a research group in 2006 with professionals of pharmacogenomics, dermatologists, ophthalmologists and psychiatrists to explore genetic biomarkers associated with Japanese SJS/TEN patients. To date, we have collected more than 100 Japanese SJS/TEN patients through participating institutes and a case-collecting system covering all over Japan constructed by us. No carriers of HLA-B*1502 which was reported to have extremely strong association with carbamazepine-induced SJS/TEN in Han Chinese and south Asians, although a moderate association between allopurinol-induced SJS/TEN and HLA-B*5801 detected in Han Chinese was observed.     

别嘌呤醇致Stevens-Johnson综合征及中毒性表皮坏死松解症的发病机制和治疗

别嘌呤醇是次黄嘌呤的同分异构体,在体内可抑制黄嘌呤氧化酶而抑制体内尿酸合成,是目前临床广泛使用的唯一一个抑制尿酸合成的抗痛风药,其可诱发Stevens-Johnson综合征和中毒性表皮坏死松解症。SJS/TEN虽较为少见,却是危及生命的严重皮肤不良反应。因此对于SJS/TEN发病机制的认识,可以有效预防SJS/TEN的发生,而正确治疗措施的采取将减少并发症的发生,降低病死率。本文就SJS/TEN的发病机制及治疗进行综述。     

抗癫痫药物等引发药疹与人类白细胞抗原基因的相关性研究

目的探讨抗癫痫药物等引发药疹与HLA基因多态性的相关性,以期为药疹的预防和治疗提供依据。方法收集48例药疹患者,采用PCR-SSP方法检测HLA-B*1502、HLA-A*0206、HLA-A*3101、HLA-A*1101、HLA-B*5901、HLA-Cw*0704、HLA-Cw*0801、HLA-DRB1*1202等8个等位基因。采用RT-PCR检测HLA-B*1502基因阳性者中mRNA表达水平。结果药物引发的药疹可能与HLA-B*1502、HLA-Cw*0801、HLA-A*0206和HLA-Cw*0704等位基因相关(P<0.05);其中抗癫痫药物引发的重症药疹与HLA-B*1502等位基因的相关性最强(P<0.01);且抗癫痫药物引发的重症药疹HLA-B*1502 mRNA的表达水平明显高于耐受组及对照组(P<0.01)。结论抗癫痫药物引发的重症药疹与HLA-B*1502等位基因密切相关。HLA-B*1502mRNA表达水平可以作为预测抗癫痫药物诱发重症药疹的重要指标。     

Immunohistochemical expression of apoptotic markers in drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease, which is almost always associated with drug intake. In contrast, erythema multiforme (EM) is a disorder regarded as only rarely caused by drugs. Keratinocyte apoptosis has been shown to play an important part in the pathogenesis of SJS and TEN, whilst its role in EM remains controversial. To determine the expression of apoptosis-associated molecules Fas, Fas ligand (FasL), Bcl-2 and Bax in the above disorders, an immunohistochemical analysis was performed. We studied both lesional skin from thirty patients having drug-induced EM and 5 cases classified within the SJS/TEN spec nottrum and normal skin samples. We found a keratinocyte overexpression of Fas antigen, an important molecule mediating apoptosis, not only in SJS and TEN but also in EM. Another noteworthy finding was the strong expression of Bcl-2, a protein known as blocking apoptosis, along the basal layer and in the dermal infiltrate both in SJS/TEN and in EM. Taken together, these findings suggest that Fas-dependent keratinocyte apoptosis may play a part in the pathogenesis of both SJS/TEN and EM. Fas-mediated cell death may be partially suppressed by the Bcl-2 protein.