别嘌醇过量致超敏综合征合并肾功能不全急性加重死亡

1例49岁男性患者因痛风给予别嘌醇0.1 g,3次/d,但患者误服为0.3 g、3次/d,5 d后改为0.1 g、3次/d。服药25 d后患者出现发热伴皮肤瘙痒、斑丘疹。7 d后四肢、面部、腹部呈红皮病样改变,口腔可见溃疡,双侧扁桃体有大片白色渗出物,遂入院。实验室检查：白细胞计数14.1×10^9/L,嗜酸粒细胞计数1100×10^6/L;丙氨酸转氨酶130 U/L,天冬氨酸转氨酶93 U/L,总胆红素160.5μmol/L,直接胆红素144.3μmol/L;尿素氮39.2 mmol/L,肌酐628μmol/L,尿酸508μmol/L;凝血酶原活动度61%。诊断为别嘌醇致超敏综合征,药物性肝损伤,慢性肾功能不全急性加重。停用别嘌醇,静脉滴注复方甘草酸苷、谷胱甘肽、维生素C、维生素B6、亚胺培南西司他丁钠和人血白蛋白。入院第5天,患者出现高热、咳嗽、消化道出血,转入ICU,给予甲泼尼龙冲击治疗。随后2周,患者相继出现肺部感染、Ⅰ型呼吸衰竭、尿少和肾衰竭。入院第31天,患者因肝、肾衰竭和感染性休克死亡。     

别嘌醇致重症药疹和迟发型过敏性休克

1例74岁男性因尿酸增高口服别嘌醇0．1g,2次／d。用药第16天出现全身瘙瘁,第21天胸部及背部皮肤出现针尖样红色皮疹,停药并给予对症处理2d无效,皮疹加重,且出现头昏、胸闷,遂入院。入院后检查心率73次／min,血压70／46mmHg（1mm Hg=0．133kPa）,血清丙氨酸转氨酶124U／L,天冬氨酸转氨酶80U／L,尿素氮22．6mmol／L,肌酐151μmol／L,尿酸738tzmol／L。入院后心率一度降至42次／min。给予对症、支持治疗21d后,患者皮疹基本消退,血压、心率及肾功能正常,肝功能仍异常。     

别嘌醇与秋水仙碱联用致血尿

1例31岁女性因痛风急性发作,口服别嘌醇0.1 g,2次/d,秋水仙碱1 mg,1次/d。服药15 d后出现肉眼血尿,尿常规检查示潜血(+++),蛋白(+),白细胞(+),红细胞4439个/μl,白细胞921个/μl。立即停用别嘌醇和秋水仙碱,给予抗感染、止血等治疗。停药后第10天尿常规:潜血(++),白细胞(-),红细胞2～4个/μl,白细胞0个/μl;第16天尿常规:潜血(-),白细胞(-),红细胞1个/μl,白细胞0个/μl。     

别嘌醇致剥脱性皮炎2例

例1男,63岁。因“关节痛6个月,伴发热、全身皮疹7d”,于2006年3月19日入我院。患者于6个月前,因关节痛在我院诊治,并诊断为痛风,同时给予口服别嘌醇0.1g,3次/d治疗。7d前,患者出现全身皮疹伴瘙痒,畏寒、发热,经当地医院用地塞地米松30mg/d治疗3d,因疗效差,诊断为“药疹”,并将患者转入我院。入院查体:T39.7℃,颜面红肿,口腔粘膜充血,舌尖及双侧颊粘膜处可见多个2cm×1cm至3cm×3cm大小溃疡。全身皮肤散在较密集的红斑,高出皮肤压之不退色。躯干部呈叶状大片脱屑,手足部呈破手套、破袜套样脱落,头发,指甲无脱落。肛门及会阴部未见溃烂。实验…     

酚氨咖敏片致药物超敏反应综合征

1例43岁女性患者,因感冒口服酚氨咖敏片(1片,tid),第2天停药。用药第5天出现四肢发疹,红斑伴瘙痒明显,用药第7天发展至面部,用药第9天出现高热,实验室检查示白细胞 22.82 × 10_-9?L_-1,中性粒细胞百分率89.3%, 嗜酸性粒细胞百分率2.7%,丙氨酸氨基转移酶95 U?L_-1,门冬氨酸氨基转移酶55 U?L_-1,乳酸脱氢酶228 U?L_-1,磷酸肌酸激酶27 U_?L_-1,总胆红素10.2 μmol?L_-1,直接胆红素3.4 μmol?L_-1,1-3-β-D葡聚糖7.00 pg?ml_-1,内毒素5.00 pg?ml_-1。考虑为酚氨咖敏片致药物超敏反应综合征。给予注射用甲泼尼龙琥珀酸钠(80 mg,qd)、复方甘草酸苷注射液(100 ml,qd)静脉滴注,依巴斯汀片(10 mg,qd)、盐酸赛庚啶片(2 mg,qd)口服。停药第14天面部、躯干、四肢见暗红斑及色素沉着斑片,皮疹明显消退,白细胞14.95 × 10_-9?L_-1,中性粒细胞百分率72.0%, 嗜酸性粒细胞百分率1.2%,丙氨酸氨基转移酶44 U?L_-1,门冬氨酸氨基转移酶14 U?L_-1,乳酸脱氢酶165 U?L_-1,磷酸肌酸激酶14 U?L_-1,总胆红素9.0 μmol?L_-1,直接胆红素1.9 μmol?L_-1。停药后6周,皮疹全部消退,皮肤颜色基本正常。     

Pathophysiological characterization of drug hypersensitivity to tribenoside

Background

Tribenoside is a semisynthetic sugar derivative that is mainly indicated for treatment of chronic venous insufficiency. Up to 10% of patients treated by tribenoside can suffer from skin side effects. The adverse effects usually present as angioedema, urticaria, or maculopapular exanthema. The pathophysiology of the reaction has not as yet been elucidated.

Methods

In this study, we examined 22 patients with drug eruptions caused by tribenoside. Patch tests were performed to investigate in vivo cellular reactions. Laboratory investigations were carried out by lymphocyte transformation tests and basophil activation tests.

Results

We found a positive patch test reaction to tribenoside in one patient. The lymphocyte transformation test elicited a borderline positive reaction in one patient, and the basophil activation test gave a clearly positive reaction in another patient.

Conclusion

The diagnosis of drug hypersensitivity reactions is a challenge. Both delayed and immediate immunologic response may play a role in the etiology of tribenoside-induced exanthemas. Our investigation and results indicate that benzoic acid could be the antigenic determinant in drug hypersensitivity to tribenoside.     

Pancytopenia due to the interaction of allopurinol with azathioprine or mercaptopurine

(1) Allopurinol increases the haematological toxicity of azathioprine and mercaptopurine, with a risk of pancytopenia. (2) Combination of allopurinol with azathioprine or mercaptopurine should be avoided.     

Use of transgenic animals to investigate drug hypersensitivity

Hypersensitivity reactions to drugs and environmental agents are often due to exaggerated humoral (Th(2)) or cell mediated (Th(1)) immune responses with typical cytokine profiles. Overexpression of Th(2) cytokines, such as IL-4, IL-5 or IL-13 in mice, enhances an IgE antibody mediated response, while deletion of these cytokines attenuates and/or prevents allergic responses. Conversely, modulation of Th(1) cytokine gene expression may affect cell-mediated immune responses. Therefore, cytokine transgenic mice are used as investigative tools to study potential chemicals and/or drug allergies. In addition to cytokines and chemokines, other factors are important for the development of allergic responses, such as IgE, Fc receptors, vasopressin and several other factors, which can be tested in transgenic mice.     

拉莫三嗪致迟发性的可疑药物超敏综合征病例分析

1例16岁男性患者因诊断为症状性癫痫(2017年7月)口服丙戊酸钠缓释片0.5 g,2次/d;因出现发愣症状,于2018年7月18日加用拉莫三嗪片,经过2个月后加量至100 mg 2次/d。约第155天,患者双侧足踝、面部出现针尖大小红色斑点。停用拉莫三嗪,继续服用丙戊酸钠缓释片,1周后面部大面积出现丘疹、红斑及渗出,伴有肿胀,躯干及四肢近端出现大量红色斑疹,诊断为药源性皮疹入院,给予静脉注射人免疫球蛋白和糖皮质激素等对症治疗后,皮疹消退好转出院。     

卡马西平超敏综合征

1例59岁男性患者因耳鸣服用卡马西平0.1 g,1～2次/d,服药7 d后出现双下肢一过性皮疹。停用卡马西平后皮疹消失,但随后耳鸣症状加重,遂入院,给予卡马西平0.1 g,2次/d口服;甲钴胺1 mg,3次/d口服。入院第2天患者体温39.2℃;第3天面颊部、躯干及双侧膝关节处出现红色斑丘疹。血生化检查示丙氨酸转氨酶359 U/L,天冬氨酸转氨酶137 U/L,γ-谷氨酰转移酶506 U/L,乳酸脱氢酶273 U/L。停用卡马西平及甲钴胺,给予甲泼尼龙及抗过敏治疗。2 d后体温恢复正常,5 d后皮疹、肝功能逐渐好转。入院第9天患者再度发热,体温38.1℃,随后皮疹再次出现,且逐渐增多,遍布全身。实验室检查:白细胞13.78×10~9/L,嗜酸粒细胞0.113;丙氨酸转氨酶187 U/L,天冬氨酸转氨酶45 U/L,γ-谷氨酰转移酶374 U/L,乳酸脱氢酶239 U/L。诊断为卡马西平所致药物超敏综合征,给予甲泼尼龙加用人免疫球蛋白治疗,皮疹症状及肝功能逐渐好转。入院第16天患者双下肢再次出现皮疹,经甲泼尼龙及对症治疗后缓解。     

Influence of allopurinol on drug metabolism in man

1. Elimination rates of phenylbutazone and warfarin after single oral doses in human volunteers, and steady-state plasma concentrations of these drugs in patients have been measured before, during and after administration of allopurinol.2. Allopurinol, in usual clinical doses, had no significant influence on the elimination rate of either drug in the group of volunteers as a whole although in a few individuals an apparent inhibitory effect was observed.3. No significant changes in the steady-state plasma concentrations of either phenylbutazone or warfarin were observed in patients during the administration of allopurinol.4. It is concluded that although allopurinol may have an apparent inhibitory effect on drug elimination in a few individuals, its administration to most patients on anticoagulant therapy is unlikely to alter dose requirements.     

Clinical heterogeneity of drug hypersensitivity

Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually tailored, unexpected effect mediated by a drug specific activation of the immune response. The clinical presentation of "drug eruptions" is highly variable, from the most common transient and benign erythema that occurs 6-9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users. Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for "hypersensitivity syndrome"/DRESS and 25% for SJS or TEN. In addition if some medications are "usual suspects" for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis). The "phenotypic" diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.