伏立康唑与奥美拉唑可能的不良相互作用致肌病及肝功能恶化

1例35岁男性患者,因慢性重型乙型肝炎并自发性腹膜炎入院,给予保肝、退黄、利尿、抑酸(奥美拉唑)和抗病毒(阿德福韦酯+拉米夫定)药物治疗,其间发生肺部侵袭性真菌感染。给予卡泊芬净抗真菌治疗10 d,实验室检查结果及临床症状好转。后因经济原因改为口服伏立康唑(首剂量0.4 g,之后0.2 g2,次/d),治疗第3天患者开始出现频繁的恶心、呕吐,对症治疗效果不佳;第10天改为伏立康唑0.2 g、2次/d静脉滴注,仍频繁呕吐;治疗第14天出现四肢肌肉酸痛症状,实验室检查示:AST880 U/L,ALT 166 U/L,CK 22 855 U/L and CK-MB 442 U/L。停用伏立康唑4,d后患者CK和CK-MB水平分别降至5625 U/L和73 U/L,但AST和ALT水平分别升至1226 U/L和396 U/L。该肌病和肝功能恶化考虑可能与伏立康唑和奥美拉唑不良相互作用有关。患者最终肝衰竭,家属主动要求出院。     

高效液相色谱法测定血浆中伏立康唑的浓度

目的建立测定人血浆中伏立康唑浓度的高效液相色谱法。方法色谱柱为Hedera ODS-2(4.6 mm×250mm,5μm),流动相为:0.1 mol·L-1磷酸二氢钠-水-乙腈(20∶35∶45),流速为1.0 mL·min-1,血浆样品经乙酸乙酯-二氯甲烷(75∶25)提取后,在255 nm波长下进行检测。结果伏立康唑在0.101~12.16μg·mL-1与峰面积呈现良好的线性关系(Y=0.5345X+0.00254,r2=0.9995),相对回收率均在95%~110%,日内和日间RSD均<6%。结论该方法专属性强、灵敏度高,适合伏立康唑的血浆浓度测定及药动学研究。     

Subcutaneous infection caused by Blastoschizomyces capitatus post allogeneic hematopoietic transplant and its successful treatment with voriconazole

We describe a 33‐year‐old man with relapsed acute myelogenous leukemia who developed subcutaneous nodules >6 months after allogeneic hematopoietic stem cell transplant. These nodules were caused by Blastoschizomyces capitatus. The lesions progressed after treatment with a posaconazole suspension. The lesions resolved after switching to voriconazole, which was given for 21 weeks. B. capitatus is a rare infection affecting immunocompromised patients, which responds to azoles.     

Persistent poor long-term prognosis of allogeneic hematopoietic stem cell transplant recipients surviving invasive aspergillosis

Background Voriconazole treatment increases early survival of allogeneic hematopoietic stem cell transplant recipients with invasive aspergillosis. We investigated whether this survival advantage translates into an increased long-term survival. DESIGN AND METHODS: This retrospective study involved all patients with an invasive aspergillosis diagnosis transplanted between September 1997 and December 2008, at the Saint-Louis Hospital, Paris, France. The primary end point was survival up to 36 months. Survival analysis before and after 12 weeks, as well as cumulative incidence analysis in a competing risk framework, were used to assess the effect of voriconazole treatment and other factors on mortality. RESULTS: Among 87 patients, 42 received first-line voriconazole and 45 received another antifungal agent. Median survival time was 2.6 months and survival rate at 36 months was 18%. Overall, there was a significant difference in the survival rates of the two groups. Specifically, there was a dramatic difference in survival rates up to ten months post-aspergillosis diagnosis but no significant difference after this time. Over the first 36 months as a whole, no significant difference in survival rate was observed between the two groups. First-line voriconazole significantly reduced aspergillosis-attributable mortality. However, first-line voriconazole patients experienced a significantly higher probability of death from a non-aspergillosis-attributable cause. Conclusions Although the prognosis for invasive aspergillosis after stem cell transplantation has dramatically improved with the use of voriconazole, this major advance in care does not translate into increased long-term survival for these severely immunocompromised patients.     

Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.     

49例慢性阻塞性肺疾病合并肺部真菌感染的临床分析

目的 观察慢性阻塞性肺疾病合并肺部真菌感染的病原菌分布、临床特点及治疗情况.方法 结合文献及临床病例回顾分析49例我院收治的慢性阻塞性肺疾病合并肺部真菌感染的深部痰液进行培养鉴定情况、临床资料及治疗效果.结果 49例慢性阻塞性肺疾病合并真菌感染的患者检出白色念珠菌23例,热带念珠菌7例,光滑念珠菌4例,近平滑念珠菌3例,克柔念珠菌2例,曲霉菌10例.经氟康唑和伏立康唑早期治疗后痊愈9例(18.4％),有效27例(55.1％).结论 早期诊断、早期治疗可减少慢性阻塞性肺疾病继发肺部真菌感染的死亡率、提高临床疗效.     

伏立康唑磺丁基醚-β-环糊精包合物体内药动学的对比研究

目的：自制伏立康唑磺丁基醚-β-环糊精包合物与注射用伏立康唑（VFEND^®）大鼠体内药动学对比研究。方法：以VFEND^®为对照,Wistar大鼠为受试动物,采用超高效液相-飞行时间质谱（U-HPLC/Q-TOF-MS）监测伏立康唑的血药浓度,计算药动学参数,对自制药与对照药的各药动参数进行独立样本双侧t检验。结果：自制药和对照药大鼠体内伏立康唑的消除半衰期（t_1/2）分别为（2.099±0.202）h和（2.142±0.163）h,药物浓度-时间曲线下面积（AUC_0-12）分别为（23.247±1.264）μg·h·mL^-1和（22.748±1.568）μg·h·mL^-1。结论：自制药与对照药的大鼠体内药动学行为相似,各药动学参数相近。