新型棘白菌素类抗真菌药阿尼芬净

阿尼芬净(anidulafungin,VER-002;LY303366),是第三代棘白菌素类的半合成抗真菌药,是两性霉素B的衍生物,由美国Vicuron制药公司研制,同其他棘白菌素类抗真菌药比较,分布容积更大,抗菌谱更广,目前在美国处于Ⅲ期临床试验阶段.介绍阿尼芬净的作用机制、药效学、药动学和临床评价.     

Anidulafungin: a drug evaluation of a new echinocandin

Background: Over the past two decades, the frequency and type of invasive fungal infections have increased greatly and thus have driven the need for new antifungal agents. Anidulafungin is the newest addition to the echinocandin armamentarium. Objective: The intention of this review is to provide a drug evaluation of anidulafungin, including its spectrum of activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse event profile, and its role in the treatment of invasive candidiasis. Methods: A PubMed search was performed to gather the most current and pertinent articles. Conclusions: Clinical trials have demonstrated anidulafungin's efficacy and tolerability in invasive candidiasis. Anidulafungin is not associated with any drug–drug interactions and does not require dosage adjustment in patients with renal and/or hepatic impairment.     

Anidulafungin: an echinocandin antifungal

Anidulafungin (LY-303366, V-echinocandin trade mark, Vicuron Pharmaceuticals, Inc.) is a new echinocandin antifungal agent with broad spectrum activity against Candida and Aspergillus spp. Anidulafungin exhibits low toxicity, concentration-dependent fungicidal activity for Candida, and a prolonged post antifungal effect (> 12h). In vitro activity demonstrates excellent potency and spectrum versus azole-susceptible and -resistant Candida spp. and a low minimum effective concentration for Aspergillus spp. In vivo anidulafungin is fungicidal against Candida in neutropenic animal models of disseminated candidiasis. Against Candida anidulafungin exhibits concentration-dependent killing and clearance of residual fungal burden in target organs (liver, lung, spleen, kidney) and plasma/tissue concentrations exceed the minimum inhibitory and minimum fungicidal concentrations of the infecting organism throughout the dosing interval. Although the activity of anidulafungin in animal models of pulmonary or disseminated aspergillosis shows increased survival and improvement in the pulmonary infarct score, the effect on residual fungal burden and Aspergillus antigenemia determination does not indicate in vivo fungicidal activity. It seems that the major effect of anidulafungin and other echinocandins in vivo against Aspergillus spp. is the decrease in the angioinvasive potential of the organisms. Clinically, anidulafungin has been shown to be safe and effective in the treatment of oesophageal candidiasis and candidemia. Further clinical application of this new antifungal agent is warranted.     

Anidulafungin: an echinocandin antifungal

Anidulafungin (LY-303366, V-echinocandin?, Vicuron Pharmaceuticals, Inc.) is a new echinocandin antifungal agent with broad spectrum activity against Candida and Aspergillus spp. Anidulafungin exhibits low toxicity, concentration-dependent fungicidal activity for Candida, and a prolonged post antifungal effect (> 12h). In vitro activity demonstrates excellent potency and spectrum versus azole-susceptible and -resistant Candida spp. and a low minimum effective concentration for Aspergillus spp. In vivo anidulafungin is fungicidal against Candida in neutropenic animal models of disseminated candidiasis. Against Candida anidulafungin exhibits concentration-dependent killing and clearance of residual fungal burden in target organs (liver, lung, spleen, kidney) and plasma/tissue concentrations exceed the minimum inhibitory and minimum fungicidal concentrations of the infecting organism throughout the dosing interval. Although the activity of anidulafungin in animal models of pulmonary or disseminated aspergillosis shows increased survival and improvement in the pulmonary infarct score, the effect on residual fungal burden and Aspergillus antigenemia determination does not indicate in vivo fungicidal activity. It seems that the major effect of anidulafungin and other echinocandins in vivo against Aspergillus spp. is the decrease in the angioinvasive potential of the organisms. Clinically, anidulafungin has been shown to be safe and effective in the treatment of oesophageal candidiasis and candidemia. Further clinical application of this new antifungal agent is warranted.     

新一代三唑类抗真菌药物伏立康唑

通过文献检索综述了伏立康唑的抗菌作用，药代动力学及临床评价，伏立康唑是一种新型的抗真菌，抗菌谱广，抗菌作用强，不良反应少，耐受良好。     

Synerazol, a new antifungal antibiotic

Synerazol, a new antifungal antibiotic, was isolated from cultured broth of Aspergillus fumigatus SANK 10588. The structure was determined based on NMR and mass spectral evidences. Synerazol was found to be a related substance to pseurotin A. Synerazol was active against Candida albicans and other fungi, and showed marked synergistic activity with azole-type antifungal agents.     

Histidinomycin, a new antifungal antibiotic

A new antifungal antibiotic named histidinomycin was isolated from the broth filtrate of a streptomycete, tentatively designated as isolate H 878-MY 1. Histidinomycin was purified as the monohydrochloride and the molecular formula was proposed to be C22H30N8O11.HCl. The antibiotic gave histidine by acid hydrolysis. Histidinomycin showed rather narrow antimicrobial spectrum for only few genera of phytophathogenic fungi.     

Anidulafungin: a new echinocandin for the treatment of fungal infections

Immunocompromised hosts are at increased risk for invasive fungal infections. Over the last five decades, the mainstay of therapy against systemic mycoses has revolved around amphotericin B deoxycholate. Unfortunately, this drug has substantial toxicities, and agents such as fluconazole were developed as an alternative to treat and prevent these invasive infections. Due to widespread use, fluconazole-resistant organisms have emerged; therefore, new agents with improved safety, efficacy and tolerability have now become desirable. The echinocandins are a new class of antifungal agents with novel activity against the fungal cell wall. In February 2006, the U.S. Food and Drug Administration approved the echinocandin anidulafungin for the treatment of patients with candidemia, peritonitis, intra-abdominal abscesses and esophageal candidiasis.     

Anidulafungin

Anidulafungin is a novel antifungal agent which, like other echinocandins, inhibits beta-(1,3)-D-glucan synthase and disrupts fungal cell-wall synthesis. It has marked antifungal activity against a broad spectrum of Candida spp. and Aspergillus spp., including amphotericin B- and triazole-resistant strains. In clinical trials, anidulafungin has primarily been evaluated in patients with oesophageal and invasive candidiasis. Preliminary data are emerging for other indications such as invasive aspergillosis. In a large, multicentre, double-blind, double-dummy, randomised trial in patients with oesophageal candidiasis, intravenous anidulafungin 50 mg/day was as effective as oral fluconazole 100 mg/day regarding end-of-treatment rates of endoscopic cure and clinical and microbiological success. Duration of treatment was approximately 2-3 weeks, and patients in both groups received a loading dose of study drug (twice the daily maintenance dose) on day 1. Anidulafungin is generally well tolerated. Across the dosage range 50-100 mg/day, adverse events appear not to be dose- or infusion-related. In the largest clinical trial to date, the most common treatment-related adverse events were phlebitis/thrombophlebitis, headache, nausea, vomiting and pyrexia.     

抗真菌新药伏立康唑的合成工艺优化

目的优化伏立康唑的合成工艺。方法以6-乙基-5-氟-4-羟基嘧啶为原料,通过氯代、溴代、缩合、氢化等反应及手性拆分方法制得了伏立康唑。结果伏立康唑的总收率为25．3％,远远高于文献报道的收率（4Z）,制得的伏立康唑经过重结晶得到色谱纯度〉99％的成品。结论本方法合成路线短,反应过程温和,产物收率较高,产品纯度好,适于工业化生产。     

抗真菌新药伏立康唑

近年来,由于细胞毒药物、免疫抑制剂、广谱抗生素的广泛应用,器官移植术、导管技术、静脉高营养等治疗手段的开展,以及临床严重疾病如肿瘤、血液病、艾滋病、糖尿病、老年疾病的发病率不断上升,使深部真菌感染呈增长趋势。三唑类抗真菌药较两性霉素B和氟胞嘧啶抗菌活性更强、毒性更低,因而被广泛地应用于临床,但第一代三唑类药物抗菌谱窄、生物利用度低并有药物相互作用和耐药性等问题,已不能满足临床的需要。伏立康唑(voriconazole,商品名Vfend)是由美国辉瑞公司开发研制的第二代三唑类广谱抗真菌药。本药于20世纪90年代初筛选得到,1995年…     

Fluconazole: a new antifungal agent

The chemistry, activity, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and administration of fluconazole are reviewed. Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esophageal candidiasis and cryptococcal meningitis. Like the imidazoles, fluconazole inhibits the C-14 demethylation of lanosterol, but it has little or no effect on mammalian cytochrome P-450 enzymes. Fluconazole's activity in vitro does not reflect its effectiveness in vivo. Pharmacokinetic characteristics include water solubility and excellent bioavailability, low protein binding, extensive tissue distribution, and penetration into the cerebrospinal fluid. Fluconazole is eliminated primarily by the kidneys; dosage adjustments are necessary in patients with renal insufficiency. Studies have shown fluconazole to be effective in patients with cryptococcal meningitis and candidiasis, but the superiority of fluconazole over such agents as amphotericin B, ketoconazole, clotrimazole, and itraconazole remains to be proved. Fluconazole has shown varying degrees of success in the treatment of other systemic mycoses. The adverse effects of fluconazole are relatively infrequent and are primarily gastrointestinal. Tolbutamide, warfarin, rifampin, cyclosporine, and phenytoin interact with fluconazole. The drug is available in both oral and intravenous formulations. Fluconazole is a broad-spectrum antifungal drug that appears to be similar in efficacy to other antifungals in the treatment of some systemic mycoses. More studies must be completed before fluconazole can be recommended as a first-line antifungal therapy.