3月1日,，《新英格蘭醫(yī)學(xué)雜志》(New England Journal of Medicine)發(fā)表的一項(xiàng)國際、隨機(jī),、雙盲,、安慰劑對照研究顯示，為期4周的金剛烷胺治療能夠加快創(chuàng)傷性腦損傷(TBI)后意識障礙患者的功能恢復(fù)速度,。
在這項(xiàng)研究中,，新澤西州JFK約翰遜康復(fù)研究所的JosephT.Giacino博士及其同事從3個國家的11家醫(yī)療中心納入184例入組前4~16周出現(xiàn)非穿透TBI并正在接受常規(guī)院內(nèi)康復(fù)的16~65歲患者?；颊弑辉\斷為植物狀態(tài),，即有覺醒但沒有自覺意識的行為證據(jù)，或處于最低限度的意識狀態(tài),，以及具有至少1個清晰可辨的意識行為跡象,。所有患者的殘疾等級量表(DRS)評分均高于11分，該量表的評分范圍為0分(最佳)至29分(最差),。采用修訂版昏迷恢復(fù)量表(CRS-R)評價發(fā)現(xiàn),，沒有1例患者能夠始終遵循命令或進(jìn)行功能性溝通。87例患者隨機(jī)接受金剛烷胺治療,，97例患者接受外形相同的安慰劑處置,，療程為4周。初始劑量為100mg(2次/d),，如果DRS評分相對基線未改善至少2分,，則在第3周將劑量增至150mg(2次/d)，第4周增至200mg(2次/d),。此后減停金剛烷胺或安慰劑,，并隨訪評價患者6周。主要預(yù)后終點(diǎn)是治療期間DRS評分的改善率。由不知曉治療分組情況的跨學(xué)科治療小組每周對DRS評分進(jìn)行1次評價,。研究者采用CRS-R來評價具有臨床相關(guān)性的行為指標(biāo),。
結(jié)果顯示，4周治療結(jié)束時,，2組的DRS評分均顯著改善,，但金剛烷胺組的改善速度明顯更快(–0.24分/周或更多)。此外,，在最終隨訪評價時,，金剛烷胺組DRS評分改善的患者比例較大，處于植物狀態(tài)的患者比例較小,，關(guān)鍵行為指標(biāo)恢復(fù)的患者比例也較大,。然而，在停止藥物治療后,，療效降低,，最終隨訪評價時，2組之間無顯著差異,，表明療效依賴于藥物的應(yīng)用,。具體而言，治療期間金剛烷胺組能夠?qū)嵤?種具有臨床相關(guān)性的行為之一的患者比例高于安慰劑組,，但最終隨訪時2組之間無顯著差異,。這6種行為分別為始終遵循命令、物體識別,、物體的功能使用,、明了的言語表達(dá)、可靠的肯定或否定溝通,，以及持續(xù)注意力,。
研究者表示，金剛烷胺并不增加不良生理,、神經(jīng)系統(tǒng)和行為事件(包括癲癇發(fā)作)的風(fēng)險,。金剛烷胺能夠有效地加快創(chuàng)傷后長期意識障礙患者的急性康復(fù)速度及加快重要認(rèn)知行為的恢復(fù)。不過,，尚不清楚長期治療對遠(yuǎn)期預(yù)后的影響,，這方面還有待于進(jìn)一步研究。
該研究獲美國國立殘疾與康復(fù)研究所資助,。Giacino博士聲明無相關(guān)經(jīng)濟(jì)利益沖突,，但有一位研究者與愛力根等多家公司存在經(jīng)濟(jì)關(guān)系。其他研究者為TBI和意識障礙患者提供專家鑒定,。（生物谷Bioon.com）
doi:10.1056/NEJMoa1102609
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Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury
Joseph T. Giacino, Ph.D., John Whyte, M.D., Ph.D., Emilia Bagiella, Ph.D., Kathleen Kalmar, Ph.D., Nancy Childs, M.D., Allen Khademi, M.D., Bernd Eifert, M.D., David Long, M.D., Douglas I. Katz, M.D., Sooja Cho, M.D., Stuart A. Yablon, M.D., Marianne Luther, M.D., Flora M. Hammond, M.D., Annette Nordenbo, M.D., Paul Novak, O.T.R., Walt Mercer, Ph.D., Petra Maurer-Karattup, Dr.Rer.Nat., and Mark Sherer, Ph.D.
Background
Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery.
Methods
We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models.
Results
During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P=0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events.
