伏立康唑致环孢素血药浓度升高相关癫痫样发作

1例18岁异基因外周造血干细胞移植术后女性患者服用环孢素100mg、1次/12h,吗替麦考酚酯1.0g、1次/12h,甲泼尼龙8mg、1次/12h,环孢素血药浓度维持在177～283ng/L。2个月后因肺部真菌感染加用伏立康唑200mg,1次/12h口服。用药第8天,患者出现头痛、头晕、视物模糊等症状,急诊入院。对症治疗无效且继续加重,出现牙关紧闭、四肢抽搐等癫痫样发作症状,急查环孢素血药浓度为378ng/L,考虑其癫痫样发作与环孢素血药浓度过高有关。停用环孢素和伏立康唑,对症治疗10d后症状好转,但肺部真菌感染未控制,重新给予伏立康唑200mg,1次/12h,将环孢素减量为75mg,1次/12h,血药浓度维持在250ng/L左右。入院治疗12d患者带药出院。随访1个月,上述症状未再出现。     

Update on antifungal agents for paediatric patients

Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.     

人血浆中伏立康唑的LC-MS-MS法测定方法学研究

目的:建立测定人血浆中伏立康唑浓度的液相色谱-串联质谱联用法。方法:待测血浆0.5 mL经乙醚-二氯甲烷萃取,以甲醇-10 mmo.lL-1醋酸铵水溶液(80∶20)为流动相,流速为1.0 mL.min-1,液相色谱-串联质谱联用法多反应离子检测,正离子模式,用于定量分析的离子分别是伏立康唑m/z351.0→127.0[M H ]和地西泮m/z285.8→193.3[M H ]。结果:血浆中无干扰测定的内源性物质,每个样品分析时间小于5 min,线性范围为20.0~4 000 ng.mL-1,定量下限为20.0 ng.mL-1,批内、批间精密度均小于10%,提取回收率大于85%。结论:该法操作快速、简单、准确、灵敏度高,适用于临床药动学研究。     

Influence of voriconazole and fluconazole on Candida albicans in long-time continuous flow culture

We investigated the influence of voriconazole and fluconazole in a long term trial of continuous flow culture (cfc) up to 9 days. The effects of these azoles were different in dependence on the growth circumstances. Under anaerobic conditions a fungicidal effect of voriconazole was detectable, defined by an inhibition of 99.9%. This also applied to fluconazole for the majority of tested strains of C. albicans. Under aerobic conditions with an otherwise similar situation we found only a fungistatic reaction (inhibition of 90%). Fluorescence microscopy comparing fungal morphology in biofilms on glass surfaces in the cfc revealed a differentiation into blastospores, germ tubes, pseudomycelia and mycelia in the control trial after a cultivation of 8 days. Under anaerobic conditions with azoles only some single cells could be found, sometimes in cell detritus. The adhesion was clearly reduced. Under aerobic conditions more blastospores but no differentiated mycelia were to be seen.     

注射用伏立康唑无菌检查法的建立

目的：确定新药伏立康唑注射用无菌粉末的无菌检查法。方法：无菌检查法的验证试验——抑细菌和抑真菌试验及冲洗量试验。通过菌悬液的制备、培养基的检查、冲洗量的选择、阳性对照菌的选择及加入顺序等全过程，说明无菌检查法的建立，必须有验证试验的保证。结果：该药的无菌检查选用薄膜过滤法，以黑曲霉为阳性对照菌，冲洗总量1500ml。结论：通过验证试验保证的无菌检查条件检查该药，方法可行，结果可靠。应在药品检验工作中，逐步完善微生物检验方法学的内容，从而提高我国药品微生物检验工作的总体水平。     

Changes in Candida albicans colonization and morphology under influence of voriconazole

The aim was the investigation of fungal colonization and morphological alterations under the influence of voriconazole in an in vitro system. Voriconazole stopped growth and colonization of Candida albicans (wild type SC5314) on cover slips in microtiter plates dependent on drug concentration, the time of Candida growth before the input of voriconazole and oxygen concentration. The direct microscopy by fluorescence staining with the optical brightener Blancophor showed short bizarrely deformed mycelia looking swollen. The colonization on cover glass was diminished. Microcolonies or starting of biofilm formation as in the control was not observed. The metabolic activity was demonstrated by vital staining with FUN 1 resulting in red fluorescent structures in the yeast forms and mycelia in the controls. Under voriconazole influence the remaining cells only showed a green or pale yellow fluorescence. Most of the cells lost their metabolic activity.     

The Effect of a Comprehensive Treatment Regimen for Deep Stromal Fungal Keratitis

Objective: To evaluate the efficacy and safety of a comprehensive treatment regimen based on intrastromal voriconazole injection in the treatment of deep stromal fungal keratitis in which the lesion has infiltrated more than half of the corneal stroma. Methods: This was a retrospective study. Sixty-two patients (62 eyes) with deep stromal fungal keratitis who underwent intrastromal voriconazole injection were selected at the Eye Hospital, Wenzhou Medical University from March 2013 to July 2017. Age, the diameter of the ulcer, cure rate, recurrence rate, complications, etc., were measured. All the patients were followed up for at least 6 months. Sixty-two patients were divided into an effective group (EGII) and an ineffectivegroup (IGII) based on the effect of the pure intrastromal voriconazole injection. The data were analyzed by an independent samples t-test and Chi-square test. Results: The 62 patients had ulcer diameters ranging from 2.8 to 11.0 (5.5±2.1)mm. The time from onset to treatment for the 62 patients ranged from 2 days to 2 years (44.2±98.6)days. Six patients sought treatment more than half a year after onset, and the remaining 56 patients had an onset time of 21.2±13.6 days. All patients were followed up for 6 to 36 (10.5±7.5)months. Forty-two patients (42 eyes) were cured by pure intrastromal voriconazole injection, 1 patient (1 eye) underwent a corneal transplant to improve vision after intrastromal voriconazole injection was effective; 19 patients (19 eyes) underwent conjunctival flap coverage after the injection failed. Combined with conjunctival flap coverage, 11 eyes were cured, 8 eyes required corneal transplants, and 2 patients relapsed after corneal transplants. The cure rate of the comprehensive treatment regimen was 85.5%, and the recurrence rate was 3.2%. The EGII group had a smaller ulcer diameter than the IGII group, and the difference between the two groups was statistically significant (t=-2.199, P=0.032). There were no complications during or after the operation. Conclusions: Intrastromal voriconazole injection has a safe and beneficial effect on deep stromal fungal keratitis that does not respond to conventional drugs. For eyes with a wide range of lesions, the effect of pure intrastromal voriconazole injection was not good, but the cure rate can be improved when treatment is combined with conjunctival flap coverage.     

伏立康唑治疗恶性血液病合并侵袭性真菌感染20例临床分析

目的:探讨伏立康唑治疗恶性血液病患者合并侵袭性真菌感染(IF I)的结果。方法:选择山西医科大学第二医院血液科2006年2月-2007年5月收治的恶性血液病合并IF I患者20例,采用常规剂量的伏立康唑序贯治疗。结果:20例IF I患者总治愈率和有效率分别为61.1%和83.3%。结论:恶性血液病合并侵袭性真菌感染者应用伏立康唑治疗有效,副作用小,安全性高。     

Risk of azole-enhanced vincristine neurotoxicity in pediatric patients with hematological malignancies: old problem - new dilemma

One of the most well-known drug interactions in pediatric oncology concerns the co-administration of itraconazole, an antifungal triazole, and vincristine, an antileukemic agent, which seems to enhance the risk of neurotoxicity of the latter, mediated through the cytochrome CYP450 enzyme system. The aim of this article is to review the metabolism of these two drugs, to analyze the published cases with severe triazole-enhanced vincristine neurotoxicity, to discuss the pathophysiological mechanisms of this adverse effect, and to contribute in understanding the differences in triazole-vincristine interaction severity.