伏立康唑角膜基质内注射联合纳他霉素滴眼治疗真菌性角膜炎的疗效评估

目的:探讨伏立康唑角膜基质内注射联合纳他霉素滴眼治疗真菌性角膜炎(FK)的临床疗效.方法:选择2014年3月~2016年9月我院眼科收治的FK患者84例(84眼),按随机数字表法分为对照组与观察组,各42例(42眼).对照组采用纳他霉素及伏立康唑滴局部滴眼,观察组在对照组基础上加用伏立康唑角膜基质内注射,比较两组的疗效.结果:观察组的治疗总有效率为92.86%,显著高于对照组的76.19%;观察组眼部异物感、前房积脓、角膜溃疡、畏光流泪消退时间均较对照组明显缩短;治疗后第3d、7d、14d及28d,观察组的角膜病变严重程度评分、角膜溃疡面积均显著低于对照组,视力显著高于对照组;观察组的不良反应率为7.14%,与对照组的2.38%比较差异无统计学意义;观察组3个月复发率为3.45%,显著低于对照组的26.32%.结论:伏立康唑角膜基质内注射联合纳他霉素滴眼治疗FK疗效确切、安全可靠,能促进临床症状体征消退,改善患者的视力状态并降低复发率,值得推广应用.     

成人伏立康唑个体化用药监测分析

目的 基于《伏立康唑个体化用药指南》中伏立康唑的谷浓度与抗感染的疗效、肝脏毒性相关性仅以一个中等质量的证据来评判,不能很好满足临床需求。本论文将建立动态监测成人住院患者的伏立康唑谷浓度变化,力求探究谷浓度与疗效、不良反应的相关性。方法 收集使用伏立康唑治疗的成人患者63例,共107份血液标本,采用酶免方法动态监测伏立康唑的药物谷浓度,观察患者的用药疗效、有无不良反应,剖析伏立康唑谷浓度与临床指标的相关性。结果 ①使用常规剂量伏立康唑治疗后,62/107（57.9%）血液标本的伏立康唑谷浓度在0.5~5.0 μg/mL,均数为2.7 μg/mL;4/107（3.7%）血液标本的谷浓度<0.5 μg/mL,均数为0.3 μg/mL;41/107（38.4%）血液标本的谷浓度>5.0 μg/mL,中位数为8.7 μg/mL。②谷浓度<0.5 μg/mL组、谷浓度≥0.5 μg/mL组治疗有效的比率分别为50.0%、74.5%,但2组差异无统计学意义（P=0.624）。提高1例谷浓度<0.5 μg/mL且治疗无效的患者剂量,使谷浓度达到有效浓度,感染症状获得改善。③10例（15.8%）发生不良反应,谷浓度>5.0 μg/mL的患者与谷浓度≤5.0 μg/mL的患者不良反应发生率分别为18.2%、14.6%,主要体现为肝功能异常。④伏立康唑谷浓度≤5.0 μg/mL的患者组与谷浓度>5.0 μg/mL的患者组碱性磷酸酶（alkaline phosphatase,ALP）、谷氨酰转肽酶（glutamyl transpeptidase,GGT）差异有统计学意义（P<0.05）,当谷浓度>5.0 μg/mL时,抗感染治疗后,降钙素原（procalcitonin,PCT）明显降低（P<0.05）。结论 伏立康唑血药浓度个体间差异较大,必须规律监测谷浓度。伏立康唑谷浓度与肝功能、感染指标相关,可能要加大人群数或者在CYP2C19基因检测支持下来观察谷浓度与疗效、不良反应的相关性。     

Interaction between caspofungin or voriconazole and cefoperazone–sulbactam or piperacillin–tazobactam by in vitro and in vivo methods

Immunosuppressive patients are at risk of fungal and bacterial infections. Therefore, these patients receive prophylactic, preemptive, empirical or target antifungal and concomitant antibiotic therapy. To this end, caspofungin (CAS) or voriconazole (VRC) antifungals and cefoperazone–sulbactam (CPZ/SAM) or piperacillin–tazobactam (PIP/TAZ) antibiotics may be used. Here, we aimed to investigate the interaction between these antifungals and antibiotics by in vitro and in vivo methods. The interaction was tested by chequerboard analysis and fractional inhibitory concentration index (FICI). It was also tested in a neutropenic mice‐invasive candidiasis model and evaluated by fungal burden in kidney tissue of infected animals from the first day to the fifth day of treatment with 24 h intervals. A synergism was detected between CAS and CPZ/SAM (FICI = 0.1) and PIP/TAZ (FICI = 0.3). Fungal burden in tissues of drug‐treated mice was reduced compared with controls in a time‐dependent manner. In comparison with CAS‐alone treated group, there were 1.32 log₁₀ reductions of fungal burden in CAS + CPZ/SAM (p = 0.002) and in CAS + PIP/TAZ group (p = 0.14). The same interactions were not found with VRC and antibiotics. CPZ/SAM had stronger synergistic interaction with CAS than PIP/TAZ. The mechanism of synergism is not well understood. This is most likely due to an increase in the anticandidal effect of CAS plus antibiotics.     

Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes

1.?Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VIC_min) in haematological patients, but the effects were not clear.

2.?Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VIC_min was adjusted on daily dose (VIC_min/D) for overcoming effect of dose.

3.?A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VIC_min/D in Group 1 (R^2?=^?.255, p?<?.001). Only age was confirmed as a factor of VIC_min/D in Group 2 (R^2?=^?0.144, p?=?.021).

4.?Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3.     

129例伏立康唑致精神症状不良反应分析

目的:探讨伏立康唑引起精神症状的表现及转归,为合理安全用药提供参考。方法:对1996年6月至2016年6月国内使用伏立康唑引起精神症状的129例病例进行回顾性及描述性分析。结果:在129例伏立康唑引起的精神症状不良反应的病例中,其中56例性别已知,男性病例多于女性,无年龄显著差异。其发生时间多在用药2~3d之后,停药或者用药干预后大部分能完全缓解。结论:患者用药过程中,临床药师要做好用药监护,做好疾病治疗前精神疾患危险性评估,加强医师、护士对精神症状不良反应的认识,加强患者的用教育,预防不良反应发生。     

RP-HPLC法测定人血浆中伏立康唑的浓度

目的 建立反相高效液相色谱法(RP-HPLC)测定人血浆中伏立康唑的浓度。方法 Syncronis C18柱(5μm,4.6mm ×250mm);流动相：0.025M磷酸二氢钾缓冲溶液pH=5.25(加三乙胺62.5μL)：乙腈：甲醇=35：45：20;流速：1.0mL.min-1;紫外检测波长260nm;柱温：30℃,以酮康唑为内标,血浆样品经乙腈沉淀蛋白,20μL进样检测。结果 伏立康唑血浆浓度在0.2～10μg.mL-1范围内线性关系良好,LLOQ为0.2μg.mL-1,标准曲线为As=0.4609C 0.0301(r2=0.9996,n=5),低浓度、中浓度、高浓度的日内和日间变异RSD均小于7％,准确度范围为98%~103%,提取回收率在86%~95%。稳定性考察RSD<8%。结论 本方法操作简便,灵敏度和准确度均较高,稳定性好,适用于伏立康唑血药浓度检测,为临床实施伏立康唑的个体化药物治疗提供依据。