临床药师参与1例别嘌醇致重症药疹治疗的病例分析

目的:探讨临床药师在识别和处理别嘌醇致重症药疹中的作用。方法:临床药师参与1例高尿酸血症患者的药物治疗,通过筛查患者住院前后所用药物、建议进行人类白细胞抗原(HLA)-B~*5801相关基因检测,并根据检测结果最终确定导致重症药疹的药物为别嘌醇。同时,根据患者临床症状、基因型、实验室检查指标、药敏试验结果等先后建议加用依巴斯汀片、复方吲哚美辛酊、曲安奈德益康唑乳膏等对症治疗;停用别嘌醇片,改用激素+免疫球蛋白冲击疗法(注射用甲泼尼龙琥珀酸钠80 mg,ivgtt,qd+静注人免疫球蛋白20 g,ivgtt,qd)控制过敏症状;加用百令胶囊、复方α-酮酸片改善肾功能;改用注射用美罗培南、伏立康唑片抗感染;并行疗效评价、电解质水平监测、用药教育、转科随访等药学监护。结果:医师采纳临床药师建议;患者药疹逐渐消退,肺部感染好转。结论:别嘌醇引起的重症药疹病情重、病程长,甚至可危及患者的生命。因此,建议在使用别嘌醇前进行HLA-B~*5801等相关基因筛查,并加强用药宣教,确保患者用药的安全、有效。     

药疹168例临床分析

药疹是药物不良反应最常见的表现形式,病情危重者可危及生命。近年来,随着新药不断研发和上市,引起药疹的药物不断增加,致敏药物也发生了变化。为研究引起药疹的药物种类、临床特点及防治方法,笔者对2000～2009年我院收治168例药疹患者的临床资料进行回顾性分析,现将结果报道如下。     

别嘌醇致严重不良反应1例并文献分析

目的：研究别嘌醇致不良反应的规律,指导临床安全使用。方法回顾性分析别嘌醇致不良反应的病例及文献。结果别嘌醇导致的不良反应前4位分别为药疹,发热、肝、肾功能损害;重症药疹的发生率、死亡率高;中老年男性、合并多种基础疾病、肝肾功能受损人群使用时应注意;与有些药物,如氢氧化铝、阿糖腺苷等不宜合用;重症药疹的发生可能与人白细胞抗原（HLA）基因相关。结论别嘌醇在临床使用时应注意中老年男性、合并用药,严格按照说明书用法用量。     

抗结核药物致药疹63 例临床分析

目的 探讨抗结核药物引起药疹的临床表现及治疗.方法 对63例应用抗结核药物所致药疹肺结核患者的临床资料进行回顾性分析.结果 抗结核药物所致药疹的类型以麻疹样药疹及猩红热样药疹多见.致敏药物中以利福平最多见,乙胺丁醇、左氧氟沙星最少见.药疹在诊疗后3～13d消退,平均7d.结论 抗结核药物引起的药疹是肺结核患者在治疗过程中常见的不良反应,一旦发生应立即停药,并积极治疗,如不及时救治可危及生命,应引起临床医生高度重视.     

药物与小儿药疹

药疹是指药物引起的皮肤粘膜炎症性反应。导致药疹发生的药物达数千种,有报道每20个治疗疗程就有1例药疹发生。药疹轻者仅有一过性皮疹,重症可伴有内脏损害直至危及生命。临床上以抗生素、解热镇痛类、磺胺类及巴比妥类药物最易引发皮肤损害。现就引起小儿药疹的药物、药疹的临床表现及治疗作一综述。     

药疹的临床观察

药疹是药物不良反应(adverse drug reactions)最常见的表现形式,病情危重者可危及生命.近年来,随着新药的不断研发和上市,引起药疹的药物亦不断增加,致敏药物也发生了变化.为了研究引起药疹的药物种类、临床特点及防治,笔者对1998 ～ 2007年我院收治的168例药疹患者临床资料进行回顾性分析,现将结果报告如下.     

五年住院药疹病例回顾性分析

目的探讨药疹的临床特点、诊断治疗方法及药物种类与药疹类型的关系。方法对我院2009年1月至2014年2月收治的住院药疹患者的临床资料进行回顾性分析。结果 510例药疹中Naranjo评分≥5分者共461例,其中男133例,女328例。244例(52.93%)为单一致敏药物,以抗菌药物、中成药、非甾体抗炎药为主;重症药疹61例(13.23%),非重症药疹400例(86.77%),两组在年龄、潜伏期、临床特征及实验室检查方面差异有统计学意义(P<0.05)。结论发疹型及荨麻疹型最为常见,抗菌药物较易导致发疹型药疹,而生物制剂较易引发荨麻疹型药疹,抗痛风药及抗癫疒间药较易引起重症药疹。对药疹的病因学诊断及预防应提出更高要求。     

对乙酰氨基酚致婴儿肝损伤1 例药学监护并文献复习

[摘要] 目的:探讨对乙酰氨基酚( APAP)致婴儿肝损伤的药学监护及有效治疗方法,初步分析 APAP 引起的肝损伤与相关药物 基因的关系。 方法:临床药师进行药学监护,分析 1 例婴儿使用 APAP 混悬滴剂(泰诺林)治疗后出现急性肝损伤的临床资料, 并结合相关文献进行讨论。 结果:该患儿出现肝损伤后,使用还原型谷胱甘肽保肝、血浆置换解毒,最终患儿的肝损伤症状明显 好转。 经过检测药物相关的 HLA 基因,发现 APAP 导致的肝损伤可能与 HLA鄄B*1502 基因阳性有关。 结论:APAP 导致的肝损 伤是临床常见不良反应,患儿用药后应监测肝功能,必要时给予对症治疗。 同时,对出现肝损伤的婴儿应加强检测药物相关基 因,避免不良发应再次发生。     

145例药疹临床分析

目的探讨临床应用药物与药疹发生的关系以及药疹的防治。方法对我院2000年1月至2007年12月间因药疹住院的患者临床资料进行分析。结果145例患者中有62．8％（91／145）可明确为一种致敏药物。由抗生素类引起的药疹共有58例,其中青霉素类27例,其次是解热镇痛类药9例。重症药疹16例,卡马西平和别嘌呤醇引起的药疹中重症药疹分别占66％（2／3）及80％（4／5）,治疗所需的糖皮质激素控制剂量多为泼尼松80～120mg／d。病程较长。结论抗生素类是引起药疹最常见的药物,其次为解热镇痛药。引起重症药疹的药物主要为卡马西平和别嘌呤醇。     

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。     

Drug patch testing in systemic cutaneous drug allergy

Patch testing with the suspected compound has been reported to be helpful in determining the cause of a cutaneous adverse drug reaction (CADR) and in studying the pathophysiological mechanisms involved. The main advantages of drug patch tests are that they can be done with no hospital surveillance because they induce only rarely adverse reactions and that any commercialized form of a drug can be used. In contrast, intradermal tests can be performed only with injectable forms or with a pure and sterile form of the drug. It is advised to perform drug patch tests during the 6 months following the CADR as we do not know whether positive results will persist. Due to the possibility that a low concentration might yield false negative results, drug patch tests have to be performed with rather high concentrations of the commercialized form of the drug, mostly diluted at 30% in petrolatum and/or in water. For some drugs and severe CADR, it is necessary to tests with lower concentrations or in other vehicles. Drug patch tests are positive in ca. 32-50% of patients who have developed a CADR. The clinical relevance of drug patch tests depends on the clinical features of the CADR (valuable in testing generalized eczema, systemic contact dermatitis, maculopapular rash, acute generalized exanthematous pustulosis, fixed drug eruption) and on the involved drug. As false positive results can be observed, it is always necessary to consider the relevance of any positive drug patch test. Their specificity and their negative predictive value have not been yet determined.     

HLA and pharmacogenetics of drug hypersensitivity

Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development.     

人类白细胞抗原基因多态性与药物不良反应研究进展

药物不良反应已成为危害人类健康的重要公共卫生问题.人类白细胞抗原基因(HLA)是目前已知的人类最复杂基因系统.近年来研究发现,人类白细胞抗原基因多态性与药物不良反应之间有着很强的遗传相关性,且部分研究成果在临床已得到很好地应用.本文就人类白细胞抗原基因多态性与药物不良反应之间的研究及其临床应用进行阐述.     

Cutaneous adverse drug reaction profile in a tertiary care out patient setting in Eastern India

Background:

Cutaneous adverse drug reactions (CADR) are the most frequent of all manifestations of drug sensitivity and manifest with varied and diverse morphology.

Aims:

To study the prevalence and clinical spectrum of CADR among patients attending outpatient department (OPD) in a tertiary care hospital.

Materials and Methods:

An observational study was undertaken over a 1-year period in dermatology OPD of a tertiary care teaching hospital in Eastern India. Patients presenting with suspected drug-related cutaneous lesions were included if drug identity could be ascertained. Clinical profiling was done. Drug history was recorded in a format specified in Indian National Pharmacovigilance Programme and causality assessment carried out as per World Health Organization-Uppsala Monitoring Centre (WHO-UMC) criteria.

Results:

Commonest CADR in our study was morbilliform eruption (30.18%), followed by fixed drug eruption (24.52%), Stevens–Johnson syndrome (SJS)-Toxic epidermal necrolysis (TEN) and overlap of two (24.50%), exfoliative dermatitis (7.54%), urticaria (5.6%), phototoxic drug reaction (3.8%), pityriasis rosea-like eruptions (1.89%), and severe mucositis (1.80%). Drugs implicated were sulfonamides (17%), fixed-dose combinations of fluoroquinolones with nitroimidazoles (11.30%), analgesics (11.30%), antiepileptics (11.30%), beta-lactam antibiotics (9.40%), fluoroquinolones alone (7.50%), allopurinol (7.50%), and azithromycin (5.70%). Reaction latency varied from 1 to 43 days. Causality assessment was certain and probable for 18.9% and 41.5% of the reactions, respectively, and reactions were serious in 33.96% (95% confidence interval 21.21-46.71%).

Conclusions:

Cutaneous adverse drug reaction profile in this study is similar in many ways to studies conducted earlier in India. Incidence of life-threatening reactions like SJS-TEN was higher compared with studies conducted abroad. Reaction time and lesion patterns are helpful in identifying an offending drug in the setting of multiple drug therapy.KEY WORDS: Causality assessment, cutaneous adverse drug reaction, dermatologic pharmacology, pharmacovigilance     

Pharmacogenetic determinants of immediate and delayed reactions of drug hypersensitivity

Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.     

鱼腥草注射液安全性的计量学评价

目的 观察鱼腥草注射液临床引用的不良反应发生率、发生类型及相关风险因素,为临床安全用药提供依据.方法 检索中国知网《中国期刊全文数据库》、《CHKD期刊全文数据库》、维普医药信息资源系统(1979～2010年),以“鱼腥草注射液”and“不良反应”or“治疗”or“病例报道”为检索式,下载全文.收录中国期刊文献全文97篇,包含54篇不良反应发生类型和43篇不良反应发生率的文献.结果 鱼腥草注射液不良反应可累及多个器官、系统,以皮肤损害、过敏反应、胃肠道损害最为常见,以速发型(30min)为主兼具迟发型,严重者可致过敏性休克.结论 加强鱼腥草注射液的不良反应监测,完善药品说明书及规范临床的合理用药,防止严重不良反应的发生.     

A recent update of pharmacogenomics in drug-induced severe skin reactions

In some adverse drug reactions (ADRs), genetic predisposition plays a significant role in pathogenesis, and the skin is the most frequently reported target. These severe cutaneous ADRs include bullous fixed drug eruptions (FDE), acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The putative contribution of individual effector cells in drug hypersensitivity is briefly mentioned. To trigger these drug hypersensitivities, certain class I HLA alleles (e.g., HLA-A and HLA-B alleles) and certain class II HLA alleles (e.g., HLA-DR alleles) have been recently found to be the genetic determinants. One of the best characterized examples mentioned in this article is HLA-B*1502 to determine the incidence of carbamazepine-induced SJS. How drugs are processed and presented by these HLA alleles to activate immune responses has been explained by several hypotheses. Further implication of pharmagenomic findings to prevent drug-induced severe skin reactions can be achieved by pre-screening putative risk HLA alleles before using drugs.     

Overview of the pharmacoeconomics of pharmacogenetics

Pharmacoeconomics and pharmacogenetics are two fields converging together as it is increasingly recognized that genetic markers predicting efficacy and toxicity to drugs can cost-effectively improve patient care. While pharmacogenetics aims at identifying genetic markers underlying the response to drugs, pharmacoeconomics aims at delivering healthcare cost-effectively. Several studies have investigated the potential cost-effectiveness of pharmacogenetic-based approaches. Recent evidences include screening for thiopurine methyltransferase gene polymorphisms to prevent azathioprine-induced myelosuppression, or screening for human leukocyte antigen (HLA)B5701 to prevent hypersensitivity reactions to abacavir therapy. Furthermore, examples suggesting a cost-effectiveness of markers predicting drug efficacy include screening the angiotensin-converting enzyme gene polymorphisms for statins therapy, the alpha-adducin gene variant for diuretic therapy and the assessment of human epidermal growth factor receptor (HER2) expression for trastuzumab therapy. However, thus far, all these pharmacoeconomic analyses are exploratory and validations in prospective randomized clinical trials are warranted.     

253例莲必治注射液不良反应/事件文献分析

目的探讨莲必治注射液致不良反应/事件(ADR/AE)发生的发生类型、特点及相关风险因素,为临床安全用药提供参考。方法检索中国期刊全文数据库、万方数据、维普医药信息资源系统等期刊数据库(1978年1月~2012年3月),以"莲必治注射液"、"不良反应"、"治疗"、"病例报道"等为检索词,检索文献全文136篇,纳入分析的文献36篇,进行统计学分析。结果该药不良反应可累积多个系统-器官,以皮肤损害、过敏反应、胃肠道损害最为常见,严重者可致过敏性休克,急性肾功能衰竭;男女比例各占53.23%、41.94%,19～60岁占比为43.48%,不良反应发生在30分钟以内的占45.05%,1小时内占51.37%,联合用药时占70.36%,结论莲必治注射液的不良反应以速发型为主兼具迟发型,多发于青壮年,并且联合用药时不良反应发生率较高。