Cartledge J D, Denning D W, Dupont B, Clumeck N, De Wit S, Midgley J, Hawkins D A, Gazzard B G
Chelsea and Westminster Hospital, London, UK.
AIDS. 1998 Mar 5;12(4):411-6. doi: 10.1097/00002030-199804000-00010.
To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis.
Multicentre open study.
HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more.
Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7.
Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall.
D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.
评估D0870治疗HIV相关的氟康唑耐药性口腔食管念珠菌病的疗效和耐受性。
多中心开放性研究。
尽管每天接受至少7天剂量为100毫克或更高的氟康唑治疗，但仍患有口腔食管念珠菌病的HIV血清阳性患者。
患者先接受一剂D0870（150毫克），然后每天25毫克，持续6天。比较念珠菌病的症状和体征在入组时以及治疗第3天和第7天的情况。每次就诊时，采集样本用于安全监测和念珠菌分离株的体外药敏试验。在第1天和第7天采集有限的药代动力学样本。
在26例可评估患者中，16例有部分改善，9例无改善，只有1例在第7天时鹅口疮完全清除。对清除患者的分离株进行体外试验表明，其对氟康唑敏感。在入组时推测有食管受累的22例患者中，14例吞咽困难症状消失，5例有所改善。药代动力学测量显示，第1天记录的D0870最高水平差异很大（范围为0.07 - 0.34毫克/升），分离株的药敏试验也显示对D0870的最低抑菌浓度值范围较广（范围为<0.06 - 8毫克/升；中位数为0.25毫克/升）。当将这些数据与临床反应相结合时，强烈提示症状无改善与血浆D0870水平低或存在对D0870敏感性较低的分离株有关。有6例患者血红蛋白下降，其中3例正在接受已知会抑制骨髓的联合治疗。3例患者报告头痛为不良事件，归因于研究用药，但总体而言D0870耐受性良好。
D0870在治疗氟康唑耐药性口腔食管念珠菌病方面显示出前景，且耐受性良好，尽管在这个难以治疗的患者群体中，由于在这项初步研究中给予低剂量D0870所达到的血浆水平不足，其疗效可能有限。
