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孕激素是另一个令人失望的神经保护剂?
原作者: Wan-Tsu Wendy Chang, 文章来源: 《中华急诊医学杂志》编辑部 发布日期:2015-03-03

Title: Is progesterone yet another disappointing neuroprotectant?
题目:孕激素是另一个令人失望的神经保护剂?
Author 作者: Wan-Tsu Wendy Chang
翻译:郑辛甜 校对:肖锋

Is progesterone yet another disappointing neuroprotectant?
Traumatic brain injury (TBI) affects more than 1.7 million persons in the U.S. annually. The incidence of TBI is increasing globally, especially in developing countries. Despite improvement in trauma systems and critical care, the morbidity and mortality associated with severe TBI remain high.
Progesterone has been shown in preclinical and phase 2 randomized clinical trials to have pluripotent neuroprotective properties and improve mortality in TBI.
每年美国有超过170万人遭受创伤性脑损伤(TBI)。TBI的发病率在全球范围内不断增加,尤其是在发展中国家。尽管创伤系统和重症护理有所改善,重症脑外伤的发病率和病死率居高不下。孕激素已在临床前和II期随机临床试验中被证明具有不同程度的神经保护功能,用以改善TBI的病死率。
Two multicenter phase 3 trials were recently completed and published in the December 25th issue of the New England Journal of Medicine. However, their results were disappointing.
近期2项多中心III期临床试验已完成,发表在12月25日的NEJM上。然而,研究结果令人失望。
• The Progesterone for the Treatment of Traumatic Brain Injury (PROTECT III) trial, funded by the NIH, looked at progesterone administered within 4 hours after injury in patients with moderate to severe TBI.
• 由NIH资助的孕激素对创伤性脑损伤的治疗(PROTECT III)试验中,中度至重度颅脑损伤患者伤后4小时内给予孕激素。
• The Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) trial, funded by BHR Pharma, looked at progesterone administered within 8 hours after injury in patients with severe TBI.
• 由BHR制药公司资助的神经保护剂孕激素在重症创伤性脑损伤患者中的(SYNAPSE)试验,研究重症创伤性脑损伤患者伤后8小时内给予孕激素。
Both studies used the Glasgow Outcome Scale (GOS) or Extended
Glasgow Outcome Scale (GOS-E) at 6 months as their primary outcome. The GOS and GOS-E capture the degree of recovery from brain injury in terms of disability, stratified into levels by death, vegetative state, severe disability, moderate disability, and good recovery.
两项研究均采用伤后6个月GOS评分或扩展GOS评分(GOS-E)作为主要指标。GOS和GOS-E评分根据伤残情况评估脑损伤恢复程度,分为死亡、植物状态、严重残疾、中等残疾和恢复良好。

Progesterone was not found to have any benefit in functional outcome at 6 months.
研究均未发现孕激素对患者6个月的功能恢复有任何益处。
Both of these studies were well designed and conducted. However, they were based on small effect sizes of the phase 2 trials. In addition, they had very favorable outcome rates in the placebo group, thereby making it hard to demonstrate a benefit by their sample sizes.
两项研究都是精心设计和进行的。然而,它们都是基于小型的II期临床试验。此外,两项研究中的安慰剂组有非常好的结局,使得根据它们目前的样本量很难得出孕激素有益的结论。
There has been a long history of failed neuroprotectant trials likely due to the complex and variable injury mechanisms involved in TBI. The currently available outcome measures are also insensitive to the targeted mechanistic endpoints. More research is needed to understand not only potential therapies but also how to select appropriate patients for these therapies.
神经保护剂试验失败的历史已有很久,这可能是由于TBI复杂多变的损伤机制。目前可用的观测指标也对针对机制效果不敏感。需要更多的研究来了解不仅是潜在的治疗方法也是如何选择合适的患者进行这些治疗。

Take Home Point: Progesterone does not have any clear benefit in TBI at this time.
要点:孕激素目前未被证实对创伤性脑损伤有任何明确的益处。

References 参考文献:
Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371(26):2457-2466.
Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371(26):2467-2476.

文章来源:《中华急诊医学杂志》编辑部