Efficacy of different antifungal drugs as initial treatment for patients with talaromycosis: A systematic review and meta-analysis

There are no standard choices on antifungal drugs for talaromycosis due to various factors, and related studies are also limited. This study summarizes and analyzes efficacy of different antifungal drugs for patients with talaromycosis, which can provide more reference evidence for drugs’ choices in practice. We conducted a meta-analysis on prognostic impacts of different antifungal drugs against talaromycosis, and primary outcome was all-cause mortality. A total of 975 patients from 8 studies were included. One of the 8 studies was a randomized controlled trial and the others were retrospective studies. Among these patients, 582 cases were initiated with amphotericin B, 31 cases died (9.28%). The other 393 cases were initiated with itraconazole, and 54 cases died (14.00%). The initial use of amphotericin B for talaromycosis significantly reduced mortality compared with itraconazole (risk ratio (RR): 0.61; 95% confidence interval (CI): 0.41–0.90; P = 0.01; I² = 4%). Initial treatment with amphotericin B for talaromycosis in different regions (internal and external) and studies (sample size < 100) had no obvious prognostic advantages over itraconazole (RR: 0.60, 95% CI: 0.32–1.13; P = 0.11; I² = 44%; RR: 0.61, 95% CI: 0.37– 1.00; P = 0.05; I² = 0%; RR: 0.71, 95% CI: 0.39–1.29; P = 0.26; I² = 0%, respectively). However, when study's sample size was ≥ 100, the mortality of amphotericin B group was significantly reduced (RR: 0.54, 95% CI: 0.32– 0.92; P = 0.02; I² = 46%). In conclusion, amphotericin B is a better choice as initial therapeutic drug for talaromycosis.     

Fungal colonization in neutropenic patients: a randomized study comparing itraconazole solution and amphotericin B solution

We assessed the impact of prophylaxis with the oral itraconazole solution and amphotericin B solution on fungal colonization and infection in a randomized study among patients with hematological malignancies and neutropenia. Infecting and colonizing Candida strains of patients suffering from candidiasis were genotyped by random amplification of polymorphic DNA (RAPD) analysis. A total of 106 patients were evaluated in this study: 52 patients in the itraconazole and 54 in the amphotericin B arm. During neutropenia fungal colonization in the oropharynx occurred in 11 (19.6%) and 24 (40.6%) and in the rectum in 11 (19.6%) and 23 (38.9%) courses in the itraconazole and amphotericin B groups (P<0.05), respectively. Candida albicans was the most prevalent species in both study groups. Mixed fungal colonization with Candida krusei and Candida glabrata was increased in the amphotericin B group, yet without clinical importance since infections were due to C. albicans. The occurrence of invasive candidiasis was significantly increased in multicolonized compared to monocolonized patients. In the amphotericin B group 20 and in the itraconazole group 2 neutropenic patients showed multicolonization with Candida spp. (P<0.05). Overall fungal infections were 3.8% in the itraconazole and 14.8% in the amphotericin B group (P<0.05). RAPD typing showed oropharynx strains involved in superficial infections in four of five patients. In all four patients with deep fungal infections, it appears that the colonizing rectum strains were identical to infecting strains of Candida spp. Itraconazole solution significantly reduced Candida colonization and infection compared to amphotericin B solution. Most patients remained infected with the colonized strains for the entire study period, irrespective of antifungal prophylaxis.     

伊曲康唑序贯治疗恶性血液病患者侵袭性肺部真菌感染的疗效及安全性评价

目的评价伊曲康唑注射液与口服液序贯治疗恶性血液病患者合并侵袭性肺部真菌感染的临床疗效及安全性。方法回顾性分析自2009年1月至2011年12月本院收治的54例恶性血液病合并肺部真菌感染的患者,均给予伊曲康唑联合重组人粒细胞集落刺激因子（rhG-CSF）治疗。结果54例患者中确诊组6例、临床诊断组26例、拟诊组22例;三组患者治疗有效率分别为16.67%（1/6）、69.23%（18/26）和72.73%（16/22）,确诊组有效率低于临床诊断组（P=0.029）与拟诊组（P=0.022）;有效组疗程为（29.97±4.71）d,无效组疗程为（15.42±3.24）d,差异具有统计学意义（t=13.36,P=0.000）。根据治疗时机的选择,将患者分为抢先/经验性治疗组和目标/挽救组。抢先/经验治疗组有效率为74.42%（32/43）,高于目标/挽救治疗组的27.27%（3/11）,差异具有统计学意义（χ2=6.595,P=0.010）。中性粒细胞缺乏为恶性血液病患者侵袭性肺部真菌感染的独立危险因素。结论伊曲康唑是治疗恶性血液病患者肺部真菌感染的有效安全药物;rhG-CSF能够协同其抗真菌疗效。     

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized,three-period,reference-replicated,crossover study

Background: The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations.

Research design and methods: The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC_0-72h, AUC_0-∝, C_max, T_max, T_1/2 and K_el.

Results: The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC_0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for C_max, the 90% CI for this parameter for itraconazole was 93.49–133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15–138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events.

Conclusions: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.     

伊曲康唑不同治疗方案对比特比萘芬治疗甲真菌病疗效和安全性的Meta分析

目的:系统评价伊曲康唑不同治疗方案对比特比萘芬治疗甲真菌病的临床疗效与安全性,以为临床治疗提供循证参考。方法:计算机检索Pub Med、EMBase、Medline、The Cochrane Library、中国期刊全文数据库、维普中文科技期刊全文数据库、万方数字化期刊全文库,收集伊曲康唑对比特比萘芬治疗甲真菌病的随机对照试验(RCT),提取资料并评价质量后,采用Rev Man 5.2统计软件进行Meta分析。结果:共纳入11项RCT,合计1 886例患者。Meta分析结果显示,伊曲康唑连续治疗的临床治愈率[RR=0.94,95%CI(0.76,1.18),P=0.61]与特比萘芬比较差异无统计学意义,而真菌学治愈率[RR=0.80,95%CI(0.68,0.95),P=0.01]和总治愈率低于特比萘芬,两组比较差异有统计学意义;伊曲康唑冲击治疗的临床治愈率[RR=0.75,95%CI(0.65,0.87),P<0.000]和总治愈率[OR=0.39,95%CI(0.27,0.55),P<0.000]低于特比萘芬,而真菌学治愈率与特比萘芬比较差异无统计学意义[RR=0.82,95%CI(0.63,1.07),P=0.14];两组患者消化系统不良反应发生率比较,差异无统计学意义[OR=1.02,95%CI(0.83,1.25),P=0.86]。结论:伊曲康唑不同治疗方案治疗甲真菌病的疗效均低于特比萘芬,安全性相似。由于纳入研究数量较少、质量一般,该结论尚有待大样本、高质量的RCT进一步验证。     

斯皮仁诺联合联苯苄唑乳膏治疗足癣的临床疗效观察

目的：观察伊曲康唑胶囊联合外用联苯苄唑乳膏治疗足癣的临床疗效及安全性。方法将120例足癣患者随机分为两组,治疗组及对照组各60例,疗程均为4周,治疗组口服伊曲康唑胶囊200mg,每天1次,外用联苯苄唑乳膏外涂;对照组仅予外用联苯苄唑乳膏。结果用药2周后治疗组和对照组的痊愈率分别为25.00%和1.67%,总有效率分别为68.3%和33.3%,真菌清除率分别为68.3%和33.3%;用药4周后治疗组和对照组的痊愈率分别为70%和60%,总有效率分别为96.7%和85.0%,真菌清除率分别为96.7%和85.0%;两组临床疗效均有统计学差异（P＜0.05）。结论口服伊曲康唑联合外用联苯苄唑乳膏治疗足癣临床疗效较好,有效提高临床治愈率和真菌学清除率,是临床治疗足癣较好方法之一。     

伊曲康唑预防急性白血病患儿侵袭性真菌感染的临床研究

目的：评价伊曲康唑口服液在急性白血病（AL）患儿化疗后粒细胞缺乏伴感染时侵袭性真菌感染（IFI）预防性治疗的效果。方法回顾性分析2009年6月-2013年6月我院收集的AL化疗后伴粒细胞缺乏的213例患儿,将其分为伊曲康唑早期预防组和晚期预防组。伊曲康唑早期预防组（330例次）在粒细胞缺乏伴发热应用广谱抗生素同时服用伊曲康唑口服液;对照组（191例次）在粒细胞缺乏出现发热、经广谱抗生素应用72 h 后发热无改善者加用伊曲康唑口服液,比较两组患儿IFI发生率。结果伊曲康唑早期预防组和对照组各有7例和18例发生IFI,发生率分别为2.12％和9.42％,两组IFI发生率差异有显著性（P＜0．01）。结论 AL化疗后粒细胞缺乏患儿在发热早期进行预防性口服伊曲康唑可以有效降低IFI的发生率。