抽象
伏立康唑单药治疗是有效,更安全,比糖皮质激素治疗ABPA的治疗http://ow.ly/jCix30l2Lb9
致编辑:
糖皮质激素是最广泛使用的药物过敏性支气管肺曲霉病(ABPA)的治疗中,病症的特征在于免疫反应针对安装烟曲霉定植患者呼吸道哮喘和囊性纤维化[1,2]。不幸的是,使用糖皮质激素与一些不良反应有关[3]。在ABPA一种新的治疗策略将是使用抗真菌三唑作为单一疗法的。最近,我们已经表明,伊曲康唑是有效的急性阶段ABPA单药治疗[4]。无论伏立康唑单药治疗也是急性阶段有效ABPA仍然不明。
我们在医学教育的研究生院和研究的胸科门诊(PGIMER)进行了单中心,非盲法,随机对照试验,2014年1月和2015年7月之间。该研究所伦理委员会批准了研究方案,并从所有受试者获得书面同意。我们ABPA包括连续的科目,如果他们符合所有的标准如下:1)哮喘;2)直接皮肤高反应性,以黑抗原;3) elevated total IgE >1000 IU·mL-1;4)烟曲霉-specific IgE >0.35 kUA·L-1以下标准和两种:1)血清沉淀素存在针对烟曲霉;2)固定的或短暂的放射线肺不透光;3) peripheral blood eosinophil count >1000 cells·µL-1;4)支气管扩张上计算机断层扫描(CT)扫描胸部[五]。我们排除了以下标准科目:1)未能提供同意书;2) intake of systemic glucocorticoids or azoles for >3 weeks in the preceding 6 months; 3) omalizumab therapy; 4) immunosuppressive therapy and immunosuppressive states; 5) enrolment in another trial of ABPA; and 6) pregnancy.
受试者被顺序1随机:1至任一伏立康唑基或使用计算机生成的随机化序列糖皮质激素组(分配置于不透明密封信封)(图1)。Patients in the glucocorticoid arm received oral prednisolone (Omnacortil tablets, Macleod's Pharmaceuticals, India) at 0.5 mg·kg-1·天-1for 4 weeks; 0.25 mg·kg-1·天-1for 4 weeks; 0.125 mg·kg-1·天-1for 4 weeks; then tapered by 5 mg·(2 weeks)-1and discontinued (total duration: 4 months). In the voriconazole arm, subjects received oral voriconazole (Voritek capsules, Cipla Pharmaceuticals, India) at 200 mg twice daily, 1 h before or after a meal, for 4 months. Adherence to therapy was ensured by instructing patients to bring the empty pill covers. We also measured voriconazole levels at 6 weeks and 3 months. For the control of asthma, treatment with inhaled corticosteroids (ICS), long-acting β2-agonists (formoterol) and montelukast was allowed in both groups. We recorded demographic, clinical, immunological, spirometric and radiological details at the baseline visit. The subjects were followed with clinical examination, chest radiograph and serum total IgE every 6 weeks for 6 months. At the first follow-up visit, we also performed spirometry and assessed health status using the St. George's Respiratory Questionnaire (SGRQ) score. Subsequently, the patients were followed-up every 6 months, or earlier if there was worsening in symptoms. We clinically evaluated all the subjects for adverse reactions and also monitored fasting plasma glucose, blood pressure and liver function every 6 weeks.
治疗效果被分类为:1)复合物反应:改善基线的咳嗽和呼吸困难(> 75%)伴随胸片混浊的至少50%的间隙(如果存在之前开始治疗)与血清中总IgE下降沿by ≥25%, after 6 weeks of treatment [4,6]。2)ABPA加重:临床和/或放射性随着血清总IgE比前基线值的加倍恶化;和3)哮喘恶化:临床在咳嗽和呼吸困难恶化,无放射性恶化或血清总IgE的加倍。The first ABPA exacerbation in both arms was treated with oral prednisolone at a dose of 0.5 mg·kg-1·天-1for 4 weeks; 0.25 mg·kg-1·天-1for 4 weeks; 0.125 mg·kg-1·天-1for 4 weeks; then decreased by 5 mg·(2 weeks)-1(total: 4 months). All subsequent exacerbations were treated with prednisolone at the dose above along with itraconazole at 400 mg·day-1for 6 months. Asthma exacerbations were treated with oral prednisolone at 0.5 mg·kg-1·天-1for 5–7 days [7]。The primary outcomes were: 1) composite response rates in the two groups after initiation of treatment (6 weeks and 3 months); and 2) ABPA exacerbation rates in the two groups after completion of treatment (12 and 24 months). The secondary outcome was treatment-related adverse effects in the two groups.
五十科目(图1)被随机接受泼尼松龙(N = 25)或伏立康唑(N = 25)。基线特征,包括免疫学指标,分别在两组相似。平均±SD研究对象(72%为男性)的年龄为37.4±14.1年。哮喘在诊断时的平均时间为8.7年。The severity of airflow obstruction was similar in the two groups (forced expiratory volume in 1 s (FEV1)为在受试者的58%小于80%)。所有受试者对高分辨率的计算机断层扫描(HRCT)胸部扫描支气管扩张,而29%的也有高密度黏液。基线免疫学参数,包括血清IgE(总的和烟曲霉特异性)和嗜酸性粒细胞计数均在两组相似。所有受试者均接受ICS(平均值±SD剂量:397±187毫克·天-1)和长效β2激动剂(平均值±SD剂量:14±6.3毫克·天-1),而44%的孟鲁司特接收。参与者被随访平均±SD的77±32个月期间;however, all analyses were performed until 2 years of follow-up. The proportion of subjects demonstrating a composite response after 6 weeks and 3 months was similar in the two groups (prednisolone (n=25 (100%))与伏立康唑(N = 24(96%));p值= 0.31)(表格1)。The trough levels of voriconazole were >1 mg·L-1,>0.5 mg·L-1and <0.5 mg·L-1在分别为19,三和三名受试者。一世n the only subject who failed initial treatment with voriconazole, the drug levels were in the therapeutic range (>1 mg·L-1)。The numbers of subjects with exacerbations after 1 year and 2 years were similar in the two groups (表格1)。两组不良事件的发生率在所示表格1。cushingoid习性和体重增加的发生是在糖皮质激素组显著高。在肝功能紊乱的瞬态发生在8名受试者(32%)的伏立康唑组中使用。三名受试者每个接收伏立康唑开发瞬时视觉干扰和感光皮疹(其避免日光暴露后消失)。The percentage decline in IgE and the change in lung function were similar in the two groups after 6 weeks of treatment (表格1)。There was a considerable decline in SGRQ score at 6 weeks (mean: 23.9), which was not different in the two groups (表格1)。The time to first exacerbation (prednisolone (mean: 339 days)与voriconazole (mean: 248 days)) was similar in the two groups (表格1)。哮喘和ABPA加重的总数也是在2年两组类似的后续。
只有少数的随机临床试验的患者中的ABPA评价三唑。Two small placebo-controlled trials have previously demonstrated the usefulness of itraconazole (400 mg·day-1for 4 months) in glucocorticoid-dependent ABPA [8,9]。最近,我们已经发表伊曲康唑单药治疗的急性阶段ABPA复杂哮喘[结果4]。一世n that study, 131 patients with ABPA were randomised to receive either itraconazole (400 mg·day-1) or prednisolone (at the same dose as used in the current study) for 4 months [4]。虽然泼尼松龙诱导的复合响应优于伊曲康唑,伊曲康唑也是有效的在相当多的情况下(88%)。The exacerbation rate at 2 years was also similar in the two groups [4]。伏立康唑的单一疗法在目前的研究药效为96%,这是比itraconazole的功效[更高4]。伏立康唑的更好的结果(与伊曲康唑),可能是由于其对更好的固有活性烟曲霉,较小阻力的发生率,或更好的生物利用率[10]。
最后,我们的研究有一些限制。这是一个单中心,具有小的样本大小非盲法研究(被要求156名受试者当前研究具有检测在5%的显着性水平90%的功率)。因此,我们的结论是假设产生。举例来说,有向较低时先恶化和更多的ABPA和哮喘发作的伏立康唑手臂,这可能证明统计学显著了我们包括一个更大的研究人群的趋势。最后,我们用伏立康唑的固定剂量并没有调整基于水平的剂量。
总之,伏立康唑似乎是一样有效的急性阶段ABPA糖皮质激素。大规模的试验都必须确认我们的研究结果。
脚注
这项研究被注册在clinicaltrials.gov具有标识符数NCT01621321。
作者投稿:R.阿加瓦尔构思的学习观念,参与病人的管理和起草和修订的知识内容的手稿;S. Dhooria参与病人的管理和数据收集,并修订了知识内容的稿件;I.S.Sehgal的参与病人的管理和修订的稿件;一个。AGGARWAL参与病人的管理,统计分析和修订的知识内容的手稿;M.加尔格参与患者管理和修订的手稿;B. Saikia参与病人的管理和修订的稿件;A.查克拉巴蒂参与病人管理和修订的知识内容的手稿。
利益冲突:R.阿加瓦尔在研究进行期间已收到顾问费从Pulmatrix公司,美国。
支持声明:西普拉制药公司(印度孟买)支持这项工作,并提供研究药物,但曾在研究设计,数据收集,数据分析或准备手稿没有作用。本文资金的信息已交存交叉引用出资者注册。
- 收到2017年4月28日。
- 公认2018年7月7日。
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