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Youmans:脊髓受損疾病與治療-3

WCH | 2021-06-23 18:54:26 | 巴幣 118 | 人氣 255


脊髓受損相關治療

腦脊髓液排放

  • The importance of perfusion pressure is well established in the field of TBI treatment, as is that of monitoring blood pressure and intracranial pressure to optimize perfusion pressure. Numerous investigators have wondered whether the same approach may have value in the management of SCI. Indeed, in thoracoabdominal aortic aneurysm surgery, CSF drainage has been found to significantly reduce the incidence of ischemic paraplegia, presumably by lowering intrathecal pressure and improving spinal cord perfusion.
創傷性腦傷的治療一直都很強調血液灌流壓力,因此會透過監控血壓以及顱內壓來優化灌流壓力。很多研究討論脊髓損傷是不是也需要如此考量。確實在胸腹主動脈瘤的手術中,腦脊髓液排放被發現可以顯著降低缺血造成的半癱可能性,可能是因為降低髓鞘內壓力和改善脊髓灌流有關。
  • In 2009 investigators at the University of British Columbia published results of a safety and feasibility study evaluating CSF drainage through a lumbar intrathecal line as a neuroprotective strategy after acute SCI. In 22 carefully selected patients randomly allocated to treatment, the investigators found no major adverse events related to CSF drainage, such as CSF leak, neurological worsening, and meningitis. The treatment did not, however, achieve a significant decrease in intrathecal pressure, although the investigators employed a conservative drainage protocol with a limit of 10mL/hour. Paradoxically, they found that intrathecal pressure was normal preoperatively and increased as a result of surgical decompression. Currently plans are being made for a new, larger trial involving CSF pressure monitoring only. A separate multicenter effort led by the University of Alabama at Birmingham will also explore spinal cord perfusion and CSF drainage.
因此2009年的一個研究討論了急性脊髓損傷透過腰椎脊髓髓鞘內置入導管來排放腦脊髓液,這個治療的可行性與安全性。在22位病人小心接受這個治療後,發現和一些主要的副作用,例如脊髓液滲漏、神經功能惡化或是腦膜炎沒有太大關連。但這個治療也沒有很成功地降低髓鞘內的壓力。雖然每小時都給予排放10ml的量。很矛盾的,他們卻發現這個治療反而使原本正常的髓鞘內壓力上升了。而最近的研究也只是監測腦脊髓液壓力。

震盪電場刺激(Oscillating Field Stimulation)

  • Neurites grow toward the negative pole (cathode) in an electrical field. Researchers at Indiana University Medical Center thus developed an implantable “oscillating field stimulator” capable of generating an electrical field along the rostrocaudal axis of the spinal cord. In order to promote axonal growth in both directions, the device changes polarity every 15 minutes. Preliminary results of their trial were reported in 2005. Investigators implanted the device in 10 patients with complete SCI within 18 days of injury and removed it 15 weeks after injury. At 1 year, treated patients exhibited improvement in light touch (25.5 points; P = .02), and pinprick sensation (20.4 points; P = .02) over baseline performance. Motor improvement was also seen but it was only 6.3 points ( P = .02). A wound infection developed in 1 of the patients and device failure occurred in a second. Spontaneous neurological improvement from baseline examination is, of course, expected following SCI. On the basis of comparison with spontaneous improvement seen in historical controls from NASCIS III, the investigators of this study believe that device efficacy is suggested, but results of such a comparison with historical controls must be interpreted with caution, especially in such a small sample size.
神經突會朝著電場負極方向生長,因此研究人員發展了可植入的「震盪電場刺激」來產生電場給脊髓軸突。為了使軸突可以往兩側生長,這個裝置每15分鐘會改變一次電場極性。這個試驗最早於2005年開始,研究了10位完全脊髓損傷的病人,在發病18天內植入裝置並於15周後移除。發病1年後,這些病患輕觸覺(25.5分)和針刺感覺(20.4分)有所改善。運動功能也有改善但只有進步6.3分。在一個病患發現傷口感染並立刻發現裝置失效。但些病患本來就被預期會有自發性的神經改善。不過在第三期國家急性脊髓損傷研究中,還是有建議使用這個裝置。但這項研究樣本太少,使用還是要很小心。
  • On the basis of the initial results, the U.S. Food and Drug Administration (FDA) approved enrollment of additional patients in this study. Cyberkinetics Neurotechnology Systems, Inc. (Foxboro, MA), purchased the intellectual property for this technology, and to our knowledge the trial is not active at this time. A similar trial involving pulsed electrical stimulation was reportedly conducted by investigators Xu and Liu in 100 patients in Beijing, 38 but the results have never been published to our knowledge.
因此美國食品藥物管理局同意讓更多病患參與這個試驗,但本書所知情的是這項計畫還沒實施。有一個很類似的研究開始於中國北京,但結果還是未知。

低溫治療

  • The remarkable tissue- and cell-preserving effects of hypothermia are well known to biologists and physicians. Indeed, it is said that patients “are not dead until they are warm and dead.” In addition to lowering metabolic rate, hypothermia appears to reduce extracellular glutamate, vasogenic edema, apoptosis, neutrophil and macrophage invasion and activation, and oxidative stress. Hypothermia has thus long been explored for its putative neuroprotective effects despite its risks, which include coagulopathy, sepsis, and cardiac dysrhythmia. Therapeutic hypothermia has become the standard of care for patients resuscitated from an out-of-hospital cardiac arrest, but animal models of traumatic SCI have demonstrated mixed results. Furthermore, some TBI trials had to be stopped early because of poor outcomes in patients treated with hypothermia.
生物學家和醫師都很了解低溫治療對於組織和細胞很顯著的保存功效,所以才有「病患先熱了才會死掉」這個說法。此外低溫能夠降低新陳代謝,減少細胞外glutamate的堆積、血管性水腫,自體凋亡、中性球與巨噬細胞侵入與活化,以及過氧化壓力。低溫治療因此被研究用在神經保護,雖然還是有凝血病變、敗血症以及心律不整的風憲。低溫治療是OHCA病患的基本處置,但對脊髓損傷來說的動物實驗結果很多樣。此外一些創傷性腦傷病患因為低溫治療後果差而被迫提早停止。
  • Later TBI guidelines sought to provide recommendations related to the use of hypothermia for human SCI, but insufficient human data exist. This approach must thus be considered experimental and subjected to scientific investigation; it should not be routinely employed by physicians until supportive evidence emerges. Researchers from the Miami Project to Cure Paralysis began a trial in 2007 exploring the role of systemic hypothermia in SCI. This trial involves rapid cooling with chilled intravenous saline to drop core body temperature to around 33°C and comparison with historical controls. The results of this case-controlled study were published in 2013 and were promising; however, more rigorous confirmatory studies are needed before this therapeutic approach is adopted.
最近的創傷性腦傷尋求著關於脊髓損傷病患使用低溫治療的建議,因此需要透過實驗以及科學的調查來獲知。所以在證據還沒確認前,低溫治療不能常規地給予醫師作為脊髓損傷的治療。一個2007年的試驗透過急速將病患核心溫度降到33度,然後於2013年發表結果,發現低溫治療是可以考慮的。但還是需要更多研究來支持這個治療。

抗生素 Minocycline

  • Minocycline is a synthetic tetracycline derivative commonly used as an antibiotic in dermatology. It has also been noted to inhibit microglial activation and to have anti-apoptotic properties. Preclinical testing in various animal models of SCI reported enhanced functional recovery with its use.
Minocycline是一個四環類的抗生素,廣泛用在皮膚科。它同時也被發現可以抑制微小膠細胞的活性以防止神經細胞自體凋亡。臨床前試驗發現用在脊損損傷的動物身上有功能改善的情況。
  • In 2012 researchers from the University of Calgary published a phase 2 placebo-controlled randomized study examining the utility of intravenous minocycline for human SCI. The 52 patients involved in the study were randomly allocated to treatment groups within 12 hours of their injury and were treated for 7 days. The investigators verified the presence of minocycline in the CSF and noted transient liver enzyme elevation in one patient as the only adverse event attributable to the drug. In patients treated with minocycline, motor recovery was 6 points higher than in those receiving placebo; however, this difference was not statistically significant ( P = .20). No improvement was found in patients with thoracic SCI, although patients with cervical injuries exhibited motor recovery of 14 points ( P = .05). According to the principal investigators a phase 3 trial is under way.
2012年一個二期試驗研究對脊髓損傷的病患靜脈注射Minocycline,將52個病患隨機在發病12小時內給予治療,為期7天。其中只有1位病患短暫有肝指數升高的副作用。對於有經過治療的病患運動功能比起使用安慰劑的增加了6分,但兩者沒有顯著的差異。對於胸椎脊髓損傷的病患沒有發現改善,而頸椎損傷的病患運動功能有改善14分。第三期試驗還在進行中。
  • A similar study is reportedly being conducted by investigators in Saudi Arabia. This SCI trial is studying the efficacy of minocycline when coadministered with the immunosuppressant tacrolimus (FK506)  ; we are uncertain of the trial's status at this time.
另一個類似的沙烏地阿拉伯研究則是關於免疫抑制劑FK506,但對於這個臨床試驗本書不清楚。

中樞系統藥物 Riluzole

  • Riluzole (Rilutek, Sanofi-Aventis, Bridgewater, NJ) is a benzothiazole anticonvulsant that has been licensed for use in patients with amyotrophic lateral sclerosis (ALS) for approximately 10 years.  Riluzole is the only drug to date approved for use as a neuroprotectant. Studies suggest that it prolongs the lives of those with ALS by 2 to 3 months. Its neuroprotective effects appear to result from blockade of voltage-sensitive sodium channels as well as from antagonism of presynaptic calcium-dependent glutamate release. Of interest to the treatment of SCI, synergy with MPSS has been suggested for this agent, and animal models of SCI have demonstrated neuroprotective effects when riluzole was administered as late as 10 days following injury.
Riluzole是一個抗肌肉抽搐的藥物,已經許可用在ALS患者身上用了大約10年。Riluzole也是唯一被允許用來神經保護的藥物。研究發現Riluzole可以延長ALS壽命2-3個月。Riluzole神經保護功能來自於可以阻斷電位敏感的鈉離子通道以及阻止鈣離子依賴glutamate的釋放(這反應跟肌肉收縮有關)。因此這個要被拿來研究於脊髓損傷,跟MPSS藥物綜合使用來看效果。而動物試驗發現就算脊髓損傷10天後再使用Riluzole也能達到神經保護的效果。
  • A phase 1 multicenter trial examining the safety of riluzole in acute SCI (RISCIS) was completed by the North American Clinical Trials Network, and the results were published in February 2014. The 36 enrolled patients in this matched comparison group trial were administered riluzole 50mg PO (by mouth) every 12 hours, starting within 12 hours of injury and continuing for 14 days. Although some patients exhibited liver enzyme elevation, no serious adverse events were attributed to riluzole. Riluzole-treated patients with cervical injuries had an additional 15.5 points of improvement in mean ISNCSCI motor score from admission to 90 days in comparison with registry patients used as controls ( P = .021). A phase 2/3 study is now recruiting patients with ASIA Impairment Scale grades A to C who present to the hospital within 12 hours of a cervical SCI. This placebo-controlled trial will evaluate a dose of riluzole of 2 × 100mg in the first 24 hours followed by 2 × 50mg daily for the following 13 days after injury and will assess change between ISNCSCI motor scores at baseline and at 180 days. Secondary outcomes will include overall neurological recovery, sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality, and adverse events.
在北美臨床試驗網絡中已經完成第一試驗並發表於2014年。36位病患每12小時給予Riluzole,在受傷後12小時內給予並給14天。雖然有些病患肝指數上升,但沒有特別嚴重的副作用發生。Riluzole用在頸椎損傷的病患相比於沒使用的病患運動更加改善了15.5分。而還在進行中的第二第三期試驗,則會研究ASIA等級A和等級C,且頸椎損傷12小時內住院的病患。給予前24小時Riluzole 2 × 100mg的治療並在之後13天給予2 × 50mg的治療。之後在受傷180天後再跟安慰劑組比較運動功能。另外這研究還會再比較神經恢復、感覺恢復、功能改善結果、生活品質結果、健康狀況、死亡率以及不良事件。

鎂以及聚乙二醇

  • Magnesium has long been explored in neurotrauma for its neuroprotective properties and has shown benefit in preliminary studies. Magnesium blocks NMDA receptors, a process that may at least in part account for its beneficial effects. In human TBI magnesium is ineffective. Polyethylene glycol is believed to stabilize and repair injured cell membranes by functioning as a membrane “fusogen.” After receiving received fast track designation from the FDA for its proprietary magnesium/polyethylene glycol formulation, named AC105, Accorda Therapeutics (Ardsley, NY) has initiated a phase 2 trial designed to optimize penetration into the injured spinal cord. The first patient was enrolled in September 2013. In this placebo-controlled trial, participants will receive six intravenous doses, with the first administered within 12 hours of injury.
鎂已經被用在研究神經創傷與神經保護的研究,並初步研究中顯示有利的。鎂可以透過抑制NMDA受體來增加益處。在創傷性腦傷病患使用鎂卻和無反應。聚乙二醇則被視為細胞膜的「融合蛋白」,可以穩定並修復受損的細胞膜。一個美國食品藥物局設計的藥物AC105將鎂和聚乙二醇結合,這個藥物已經開始第二期試驗以研究受損脊髓的優化。最初的病患於2013年9月開始試驗,包含了受傷後12小時內住院的病患給予6個月的靜脈注射。

髓磷脂相關抑制劑

  • Fortunately, the previously described barrier to CNS regeneration imposed by Nogo and more newly discovered myelin inhibitors does not seem insurmountable. Schwab's group not only discovered Nogo but also developed a neutralizing antibody for it. This antibody, which sequesters Nogo, is now being investigated in a human clinical trial (ATI355, Novartis Pharmaceuticals Corporation, East Hanover, NJ).  A second and potentially more potent therapy has been developed by McKerracher and Higuchi in Montreal. Their group created VX-210 (Vertex Pharmaceuticals, Boston, MA), which targets the final common pathway of all known myelin and ECM inhibitors.
慶幸的是過去發現會抑制神經再生的Nogo以及其他新的髓磷脂相關抑制劑,看起來並非難以克服。研究不只是發現了Nogo但也同時發現了它的中性抗體。這個抗體其中一個叫做ATI335並已經開始人體試驗。另一個還在研究的則是VX-210,用來對抗髓磷脂和細胞外基質抑制劑。

ATI335

  • As discussed, Schwab's group demonstrated that oligodendrocytes and their myelin membranes are major inhibitors of axonal growth within the CNS. They employed a monoclonal antibody, IN-1, to isolate and characterize inhibitory fractions within CNS myelin. IN-1 also had the noteworthy property of lessening myelin inhibition in vitro. Subsequent in vivo application of IN-1 resulted in substantial axonal sprouting and some long-distance corticospinal axonal regeneration within the adult mammalian CNS and was associated with improved functional recovery.
如前面所述,研究發現寡樹突細胞和其髓磷脂膜是中樞神經軸突再生的主要抑制劑。他們應用了單株抗體,IN-1同時發現了可以降低髓磷脂的抑制再生功能。接續的研究也被發現IN-1長期下來可以使成年哺乳類動物皮質脊髓路徑的軸突萌生新芽並改善神經功能。
  • The humanized anti-Nogo antibody, ATI355, has been shown to promote axonal sprouting and functional recovery following SCI in numerous animal models; it is a rare therapeutic to have demonstrated functional improvement in a primate model. In a phase 1 human trial initiated by Novartis Pharmaceuticals in 2006, ATI355 was administered via continuous intrathecal infusion in four increasing dose regimens, with the highest dose being delivered over 28 days. The trial was completed in Europe and Canada because the FDA expressed concerns about the external nature of the infusion pump. The trial enrolled patients with complete SCI between C5 and T12 due to injuries incurred 4 to 14 days previously. Although the trial has been completed its account has not been published; we await word on a phase 2 trial.
接續用在人類的抗髓磷脂抗體ATI335,被發現可以促進數種動物的軸突萌芽並使功能改善。這種療效在其他對於靈長類的治療是罕見的。第一期人體試驗開始於2006年,ATI355分四階段連續逐漸增加藥劑給予,並治療超過28天。這個試驗只有在歐洲和加拿大完成,因為美國食品藥物局擔心太過使用注射幫浦可能會對人體造成外在傷害。這個試驗主要對象是在4-14天之前發生的第5頸椎到第12胸椎完全脊髓損傷。目前還在等第二階段的結果。

細菌衍生毒素 Cethrin

  • Cethrin involves a toxin produced by Clostridium botulinum , C3 transferase, which is a specific inhibitor of the guanosine triphosphatase Rho, through which all known myelin and ECM inhibitors identified thus far signal. Additionally, animal studies suggest not only that this agent facilitates axonal growth and functional recovery but also that C3 transferase has additional neuroprotective effects. To improve cellular permeability and permit delivery to the spinal cord via application on intact dura at the time of spinal decompression, McKerracher and Higuchi created a recombinant version of C3 transferase that incorporates a transport sequence. The resulting protein is referred to as VX-210. In the human application, VX-210 is mixed with the fibrin sealant Tisseel (Baxter Healthcare Corporation, Deerfield, IL) before being applied to the dura. The resulting combination, Cethrin, was commercialized by Bioaxone Biosciences, Inc., and was studied in a human clinical trial.
Cethrin和肉毒桿菌製造的毒素有關,是C3轉移酶,會抑制Rho型的GTP酶。而Rho則是髓磷脂和細胞外基質抑制分子的中間訊號傳遞(參考下圖,前面有提到)。研究發現C3轉移酶不只是促進軸突生長與修復,同時也可以達到神經保護的功能。為了在神經減壓時給予能穿透細胞膜的藥物進行治療,VX-210被研究出來,是C3轉移酶和一個傳送序列組合的藥物。VX-210跟著組織修復凝合劑混在一起來治療,被取名為Cethrin。Cethrin還在人體實驗當中。
  • A phase 2/3a multicenter, dose-escalation human trial was initiated under the leadership of this chapter's senior author (MGF) at the University of Toronto, and its results have been published.  This trial sequentially recruited patients with ASIA Impairment Scale grade A thoracic (T2-T12) or cervical (C4-T1) SCI to receive escalating doses of Cethrin ranging from 0.3mg to 9mg. Forty-eight patients were enrolled and followed up for 1 year. No serious adverse events were attributed to the drug. Patients with cervical SCI who were treated with 3mg of Cethrin showed an improvement in ASIA (ISNCSCI) motor score of 27.3 ± 13.3 points at 12 months. Approximately 6% of patients with thoracic SCI experienced enough improvement to be moved from ASIA Impairment Scale grade A to grade C or D, compared with 31% of patients with cervical SCI and 66% of patients with cervical SCI who received 3mg of Cethrin. These findings suggests that VX-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in patients with SCI are being planned.
一個第二第三期人體試驗已經被發表出來。這個研究針對ASIA等級A的胸椎(第2-12節)損傷病患和頸椎(第4節到第1胸椎)病患,給予Cethrin 0.3-9mg的劑量。48名病患參與並追蹤了1年。沒有嚴重的副作用被發現。頸椎損傷的病患使用3mg的Cethrin用了12個月後被發現ASIA有改善27.3 ± 13.3分。大約有6%的胸椎損傷病患甚至改善到ASIA等級C或是D,至於頸椎損傷患者則有31%,而用3mg的頸椎損傷患者則有66%。這個研究認為VX-210是可以增加完全脊髓損傷的神經修復,但仍需要更進一步的研究。

纖維母細胞生長因子類似物

  • After obtaining phase 1 safety data in healthy human controls, Asubio Pharmaceuticals, Inc. (Edison, NJ), is conducting a 164-patient phase 2 randomized, placebo-controlled multicenter trial for its molecule SUN13837. It will be administered to persons with C4 to C7 injuries within 12 hours after injury and for a total of 30 days. SUN13837 is an analog of fibroblast growth factor that has demonstrated neuroprotective and angiogenic properties. Unlike fibroblast growth factor, SUN13837 is designed to not stimulate cellular proliferation because this effect has the potential to induce neoplasia.
另一個已經通過第一期而進入第二期的研究,有164位病患參與並給予SUN13837這個藥物做試驗。主要是針對12小時內第4-7節頸椎損傷的病患,給予30天的治療。SUN13837是一個纖維母細胞生長因子類似物,有神經保護以及血管新生的功能。但跟纖維母細胞生長因子不同,SUN13837並不是主要設計來細胞增殖,因為怕會導致可能的腫瘤生成。

白血球生長激素

  • Granulocyte colony-stimulating factor (G-CSF) drives the differentiation, proliferation, and survival of granulocytic lineage cells and is well known to clinicians for its use in febrile neutropenia and other conditions. G-CSF has also been shown to increase both the mobilization of bone marrow stromal cells from the bone marrow and their presence at sites of SCI. In a rodent model this effect was also associated with white matter sparing and improved hind-limb locomotor function. In a mouse model it was additionally shown to reduce apoptosis of cells within the spinal cord. Like other drugs currently under investigation, G-CSF has the advantage of a known track record in human application. It is currently in early-phase human clinical trials in Japan; few published details are available regarding the trials, however.
白血球生長激素G-CSF對於顆粒球群細胞的分化、增殖以及生存有關,並且被運用在臨床上的中性球低下合併發燒等疾病。G-CSF也被發現可以增加骨髓幹細胞的活動性,進而運用在脊髓損傷的治療。在囓齒動物的實驗中有發現G-CSF可以增加白質的延伸以及促進後肢的運動功能。在老鼠的實驗中則發現可以減少脊髓的細胞凋亡。跟其他藥物研究很類似,G-CSF在人類試驗中目前結果是有利的。最近在日本有展開早期人類臨床試驗,但對於其細節沒有透漏太多。

創作回應

huggie抱抱(廢物mode
這些都是一個字一個字打下來的翻譯嗎…
(佩服
2021-06-23 19:46:27
WCH
沒錯喔,趁機練習一下英文XD
2021-06-23 19:58:19

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