Adding oral albuterol to glatiramer injections appears to enhance the clinical response of multiple sclerosis patients during the first year of therapy, according to a report in the September issue of the Archives of Neurology.

The combined treatment was superior to glatiramer plus placebo at 6 months and 12 months, but that benefit was no longer evident at 24 months, said Dr. Samia J. Khoury of Brigham and Women’s Hospital and Harvard Medical School, Boston, and her associates.

Albuterol is a beta-2 adrenergic agonist, and adrenergic mechanisms play a major role in modulating the immune response. Oral albuterol has been reported to decrease interleukin 12 and gamma-interferon levels in MS patients.

Dr. Khoury and her colleagues assessed albuterol as an add-on therapy in 44 patients with relapsing-remitting MS who were just beginning glatiramer treatment. The study subjects had never used immunomodulatory or immunosuppressive agents.

Twenty-three patients were randomly assigned to receive glatiramer injections plus oral albuterol and 21 to receive glatiramer injections plus oral placebo. All were followed at 6-month intervals for 2 years. Only 27 (61%) completed the full study period; however, 9 subjects in the combined-therapy group and 8 in the single-therapy group dropped out. A total of 39 subjects contributed to the analysis, and the mean duration of “time on study” was approximately 80 weeks for both groups.

The primary clinical end point was improvement on the Multiple Sclerosis Functional Composite (MSFC) score at 6, 12, 18, and 24 months.

Study subjects taking the combined therapy, compared with those taking glatiramer plus placebo, had significantly higher scores at 6 months (mean difference between groups 0.26) and 12 months (mean difference 0.21). Most of this difference was attributed to performance on a single measure, a timed 25-foot walk. These scores improved in subjects who took glatiramer plus albuterol but worsened in those taking glatiramer plus placebo.

It is unlikely that this difference would have resulted from albuterol’s known capacity to improve pulmonary function, the investigators noted (Arch. Neurol. 2010;67:1055-61).

The apparent benefit from add-on albuterol was accompanied by a decrease in interleukin-13 levels.

Albuterol’s additive benefit was no longer evident at 24 months (mean difference 0.09), as there was no significant difference between the two treatment groups on MSFC scores at that time.

Changes in scores on the Expanded Disability Status Scale and on an ambulation index were not significantly different between the two study groups at any assessment time.

More subjects taking glatiramer plus placebo (eight patients) than taking glatiramer plus albuterol (two patients) experienced relapses during the study. Moreover, the time to first relapse was longer in subjects taking the combined therapy. The annualized relapse rate was 0.09 relapses per year for combined therapy and 0.37 for glatiramer plus placebo.

Both study groups showed decreases in the number of brain lesions on MR imaging with treatment, and there were no significant differences between the two groups. Over time, subjects receiving combined therapy showed a smaller decrease in brain parenchymal fraction, but this study was not powered to detect a significant difference in this outcome.

“Many subjects experienced adverse events, but most were mild. One subject in each treatment group had a serious adverse event,” Dr. Khoury and her associates said.

Of the moderate or severe adverse events, only three were considered to be related to treatment: one reaction at the glatiramer injection site, one episode of leg weakness, and one episode of chest tightness.

“We conclude that treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis,” they wrote.

This study was supported in part by an Autoimmunity Center of Excellence study grant from the U.S. National Institute of Allergy and Infectious Diseases. Dr. Khoury and her associates reported ties to EpiVax, LifeCycle Pharmaceutical, PDL, BioPharma, Repligen, Wyeth, Allozyne, EISAI Research Institute, Xceed Molecular Corporation, Actelion, AutoImmune, Biogen Idec, EMD Serono, Enzo, Genentech, Teva Neuroscience, Vascular Biogenics, Millenium Pharmaceuticals, Bayer, and Pfizer.

 

 

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

一项发表在9月《神经病学档案》杂志上的研究报告表明，在使用格拉默注射液治疗多发性硬化症的同时使用沙丁胺醇似乎可以增强多发性硬化症患者第一年药物治疗的临床疗效。联合治疗优于格拉默与安慰剂在第6个月和第12个月的治疗效果，但是这一优势在第24个月时已经不再明显。该研究在波士顿布莱汉姆妇女医院和哈佛医学院的Samia J. Khoury博士领导下进行的。

 

沙丁胺醇是一种β-2肾上腺素能激动剂，而肾上腺素能机制在免疫反应的调节中扮演重要角色。已有报道证明口服沙丁胺醇能显著降低多发性硬化症患者白细胞介素-12和γ-干扰素水平。

 

研究者对44例复发-缓解型多发性硬化症患者评估了额外加入沙丁胺醇治疗多发性硬化症的效果，这些患者都刚刚开始使用格拉默进行治疗，且他们都从未使用过免疫调制或免疫抑制剂。23名患者随机接受格拉默注射剂与口服沙丁胺醇联合治疗，另外21例患者接受格拉默注射剂与口服安慰剂治疗。所有受试者在随后的2年期间里接受间隔6个月的随访。只有27例患者（61%）完成了全部的研究；联合治疗组有9名受试者、单一治疗组有8名患者信息遗失。对总共39名受试者的资料进行了统计分析，两个治疗组的“用于学习”的平均时间大约为80周。主要观察的临床终点是在第6、12、18、24个月时的多发性硬化症功能综合（MSFC）评分。

 

与采用格拉默和安慰剂相比，采取联合治疗的研究对象在第6个月和第12个月时评分更高，组间平均差分别为0.26和0.21。这一差别主要归因于在单一测量指标上的表现，如定时25英尺的步行路程。接受格拉默和沙丁醇胺联合治疗的受试者评分得到改善，而接受格拉默和安慰剂治疗的受试者出现明显恶化。这得益于额外加入沙丁醇胺引起的白细胞介素-13水平下降。不过，加用沙丁胺醇的好处在24个月时就不再明显（平均差为0.09），因为那时两组间的MSFC评分没有显著差别。此外，在任何测定时间里，这两个治疗组间的扩展残废量表（Expanded Disability Status Scale）评分的改变和行动指标没有显著差异。

 

在研究期间，使用格拉默与安慰剂（8例）的受试者比使用格拉默与沙丁胺醇（2例）更易复发，且其首次复发时间更久。联合治疗组的年复发率为0.09，而使用格拉默与安慰剂的患者为0.37。

 

两个试验组都在磁共振成像中表现出脑病变，且无明显组间差异。随着时间推移，接受综合治疗的受试者表现出脑实质级分（Brain Parenchymal Fraction）的轻微下降，但是这项研究并不足以检查这一后果的显著性差异。

 

一些受试者曾发生不良反应，但大多数是轻微的。各个治疗组中都有一位受试者发生一次严重的不良反应事件。在这些中重度不良反应事件中，仅有3人被认为是与治疗有关：一例是格拉默注射部位的反应，一例是腿无力，另外一例是胸闷。因此，他们认为，使用醋酸格拉默与沙丁胺醇联合治疗的多发性硬化症患者耐受性较好，临床预后也得到显著改善。

 

本研究部分得到来自美国国立过敏症与传染性疾病研究所的自身免疫疾病卓越研究中心的研究经费支持。Khoury博士和她的同事们称与下列单位有联系：EpiVax公司，LifeCycle制药公司，PDL公司，BioPharma公司，Repligen公司，惠氏公司，Allozyne公司，卫材研究所，Xceed分子公司，Actelion公司，AutoImmune公司，Biogen Idec公司，EMD Serono公司，Enzo公司，基因泰克公司，梯瓦神经科学公司，Vascular Biogenics公司，Millenium制药公司，拜耳公司和辉瑞公司。

 

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