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加入doxycycline这种安全便宜的抗生素到标准的干扰素beta-1a治疗中，对复发缓和多发性硬化症(relapsing remitting multiple sclerosis，RRMS)病患有效。
一个小型、开放标签的15位RRMS病患研究的四个月初步结果显示，合并使用肌肉注射干扰素beta-1a和口服doxycycline可以明显降低临床复发、脑部病灶以及失能。
主要研究者、路易斯安那州立大学健康科学中心的Alireza Minagar医师向Medscape神经学及神经外科学表示，这是首次使用这类型治疗于MS，而令我们惊讶的是，这种治疗是有效的。
该研究线上发表于12月10日的神经学档案(Archives of Neurology)期刊。
【显著的抗发炎效果】
根据Minagar所述，之前的研究显示，四环素类抗生素，特别是minocycline和 doxycycline，有显著的抗发炎效果。
特别的是，它们抑制基质金属蛋白酶(Matrix metalloproteinases，MMPs)，这种酵素在MS的病理上扮演重要角色；MMPs会降低干扰素beta，并且使这种标准的MS治疗无效。
作者指出，因此，抑制MMP活性或者降低MMP数值，将可以有潜力控制MS的发炎状态。
为了进行该研究，15位RRMS病患每周使用30μg的干扰素beta-1a、至少6个月，而在每个月肌肉注射干扰素beta-1a 30μg加上每天口服100mg doxycycline、4个月之后，疾病活性有了突破性的进步。
这些病患的扩展残疾状况评分(Expanded Disability Status Scale，EDSS)分数介于1.5 和4，开始时的脑部核磁共振造影(MRI)有至少1个钆加强病灶(gadolinium-enhancing lesions)。
【脑部病灶减少】
研究的初步结果是钆加强脑部病灶数量改变，次级结果包括复发率、安全性、对合并治疗的耐受性，以及EDSS分数改变。
此外，于研究开始和结束时测量血清MMP-9 值和单核球经内皮移动到血清值。
以神经学检查纪录副作用，逐月搜集EDSS分数和安全资料，为期3个月。
研究结论中，研究者发现60%病患的脑病灶比开始时减少25%以上；再者，研究结果显示EDSS分数平均减少2.3，治疗前的平均分数是3.8，只有1位病患出现复发。
研究者也发现脑部病灶减少时，MMP-9值也降低了。
【审慎乐观】
这15位病患对合并治疗都耐受良好，只有轻微副作用，但是自发性地解决了；doxycycline的一般常见副作用是胃肠道症状，如恶心、呕吐、腹泻；干扰素beta-1a常见的副作用，包括类流感症状、疲劳、头痛和肌肉痛。
Minagar表示，最重要的是，合并治疗并无意料之外的影响或者协同效应。
虽然此研究结果是令人鼓舞的，目前尚无法提出具体的临床建议。
这些MS病患是我们医院中最严重的病患，尽管他们对治疗相当配合，仍面临失败，不过他们现在可望因为这个新的合并治疗有更佳的反应。
Minagar表示，不过，研究结果虽人令人感到鼓舞，仍需小心诠释；在我们提出具体临床建议之前，仍需有更大型的研究来确认这些结果。
他表示，另一方面，如果这些发现被确认，合并doxycycline治疗可以提供一些严重MS病患一种经济安全有效的治疗方式，可以减缓甚至逆转疾病病程。
该研究接受Biogen Idec制药独家赞助，Minagar医师和同校的共同研究者Steven Alexander博士接受拜耳制药和EMD Serono的独家赞助。
Arch Neurol.线上发表于2007年12月10日。摘要。
Combination Therapy With Antibiotics Shows Promise in Severe MS
By Caroline Cassels
Medscape Medical News
The addition of doxycycline — an inexpensive and safe antibiotic — to standard therapy with interferon beta-1a is showing promise in patients with relapsing remitting multiple sclerosis (RRMS).
Preliminary 4-month results from a small, open-label study of 15 RRMS patients taking a combination of intramuscular interferon beta-1a and oral doxycycline show significant reductions in clinical relapses, brain lesions, and disability scores.
"This is the first time anyone has used this form of therapy in a clinical trial for the treatment of MS, and to our great surprise it worked," principal investigator Alireza Minagar, MD, from Louisiana State University Health Sciences Center, in Shreveport, told Medscape Neurology & Neurosurgery.
The study is published online December 10 in Archives of Neurology.
Significant Anti-Inflammatory Effect
According to Dr. Minagar, previous research has shown that members of the tetracycline family of antibiotics, specifically minocycline and doxycycline, have significant anti-inflammatory effects.
Specifically, they inhibit matrix metalloproteinases (MMPs), enzymes that play a critical role in the pathogenesis of MS. It has also been shown that MMPs can degrade interferon beta and render this standard MS treatment ineffective.
"Therefore, inhibition of MMP activity or decreasing MMP levels may be a potential mechanism to control the inflammatory cascade in MS," the authors write.
For the study, 15 patients with RRMS who had been taking 30 μg of interferon beta-1a weekly for a minimum of 6 months and who had breakthrough disease activity received ongoing therapy with intramuscular interferon beta-1a 30 μg monthly plus oral doxycycline 100 mg/day for 4 months.
Eligible patients also had an Expanded Disability Status Scale (EDSS) score of between 1.5 and 4, and 1 or more gadolinium-enhancing lesions on baseline brain magnetic resonance imaging (MRI).
Reduction in Brain Lesions
The study's primary outcome was a change in the number of gadolinium-enhancing brain lesions. Secondary outcomes included relapse rate, safety, tolerability of the combination therapy, and changes in EDSS score.
In addition, serum MMP-9 levels and transendothelial migration of monocytes exposed to serum were measured at the beginning and end of the study.
Neurologic examinations, recording of adverse effects, and determination of EDSS scores and safety data were gathered and assessed monthly for 3 months.
At the study conclusion, investigators found that 60% of patients had more than a 25% reduction in the number of brain lesions compared with baseline. Furthermore, the study results revealed a median decrease in EDSS score of 2.3, compared with an average pretreatment score of 3.8. Only 1 patient experienced a relapse.
The investigators also found that reduced MMP-9 levels were associated with a change in the number of brain lesions.
Cautious Optimism
All 15 subjects tolerated the combination therapy well, with only mild adverse effects that resolved spontaneously. Commonly associated effects of doxycycline include gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. Those commonly associated with interferon beta-1a therapy include influenzalike syndromes, fatigue, headache, and muscle pain.
Most important, said Dr. Minagar, there were no unexpected or synergistic effects of the combination therapy.
Although the study results are encouraging, no clinical recommendations can be made at this time.
"These [MS] patients were some of the sickest we've ever had at our center. Despite the fact that they were compliant with their therapy, they were still failing, and yet they responded well to this treatment.
"Nevertheless, the study's results, however encouraging, need to be interpreted with caution. Before we can make any clinical recommendations, these results need to be replicated in much larger numbers of patients," said Dr. Minagar.
On the other hand, he said, if the findings are confirmed, combination therapy with doxycycline could offer some of the most severely affected MS patients an economical, safe, and effective treatment that has the potential to slow and possibly reverse disease progression.
The study was supported by an independent medical grant from Biogen Idec. Dr. Minagar and coinvestigator Steven Alexander, PhD, also from Louisiana State University Health Sciences Center, have received independent medical grants from Bayer Pharmaceuticals and EMD Serono.
Arch Neurol. Published online December 10, 2007. Abstract