他汀類藥物在神經(jīng)外科的應(yīng)用

1、Clin Hypertens(Greenwich,2006,8(12:840-849.12Weiss RJ,Weber MA,Car r AA,et al.A randomized,double-blind,placebo-contr olled pa rallel-gr oup study to a ssess the efficacy andsafety of nebivolol,a novel-blocker,in patients with mild to mod-er ate hyper tensionJ.J Clin Hypertens(Greenwich,2007,9(9:667

2、-676.13C leophas TJ,Agr awal R,Lichtenthal A,et al.Na tionwide efficacy-safety study of nebivolol in mildly hypertensive patientsJ.Am JTher,2006,13(3:192-197.14S chmidt AC,Gr af C,B rixius K,et al.Blood pr essure-loweringeffect of nebivolol in hypertensive pa tients with ty pe2diabetesmellitus:the Y

3、ESTONO studyJ.Clin Dr ug Investig,2007,27(12:841-849.15Van Bor tel LM,Fici F,Ma scagni F.Effica cy and tolera bility ofnebivolol compar ed w ith other antihypertensive drugs:a meta-anal-ysisJ.Am J Cardiovasc Drugs,2008,8(1:35-44.16E gan BM,Basile J,Chilton RJ,et al.C ardiopr otection:the r ole ofbet

4、a-blocker thera pyJ.J Clin Hyper tens(Greenwich,2005,7(7:409-416.17B angalor e S,Par kar S,Gr ossma n E,et al.A meta-analysis of94,492patients with hyper tension tr eated w ith beta blocker s to deter-mine the r isk of new-onset diabetes mellitusJ.Am J C ardiol,2007,100(8:1254-1262.18S chmidt AC,Gr

5、af C,B rixius K,et al.Blood pr essure-loweringeffect of nebivolol in hypertensive pa tients with ty pe2diabetesmellitus:the YES TONO studyJ.Clin Drug Investig,2007,27(12:841-849.19Rosendor ff C,Black HR,Cannon CP,et al.Treatment of hyper ten-sion in the prevention and management of ischemic heart di

6、sease:ascientific statement fr om the America n Heart Association Councilfor H ig h Blood Pr essure Resear ch and the Councils on ClinicalCardiology and Epidem iology and PreventionJ.Cir culation,2007,115(21:2761-2788.20Galderisi M,D1Err ico A.Beta-blockers and coronary flow reser ve:the importance

7、of a vasodilator y actionJ.Drug s,2008,68(5:579-590.21Fonar ow GC,Abr aham WT,Albert NM,et al.Influence of beta-blocker continuation or withdrawa l on outcom es in patients hospi-talized with hear t failur e:findings from the OPTIM IZE-HF prog ramJ.J Am Coll C ardiol,2008,52(3:190-199.22Torp-Peder s

8、en C,Poole-Wilson PA,Swedberg K,et al.E ffects ofmetopr olol and carvedilol on cause-specific mortality a nd morbidityin patients w ith chronic heart failur e-COMETJ.Am Hear t J,2005,149(2:370-376.23Dobre D,van Veldhuisen DJ,Mordenti G,et al.Tolerability anddose-related effects of nebivolol in elder

9、ly patients with hea rt fail-ur e:data fr om the S tudy of the Effects of Nebivolol Intervention onOutcomes and Rehospitalisation in Seniors With Heart Failur e(SE-NIORStr ialJ.Am Heart J,2007,154(1:109-115.收稿日期:2011-06-09 修回日期:2011-08-10他汀類藥物在神經(jīng)外科的應(yīng)用王立君,梁紹棟(綜述,趙有志(審校(牡丹江醫(yī)學(xué)院紅旗醫(yī)院神經(jīng)外科,黑龍江牡丹江157011中圖分類

10、號:R453.9文獻標識碼:A 文章編號:1006-2084(201120-3135-03摘要:他汀類藥物常用于治療高脂血癥引起的心血管疾病。其藥物多效性,對一些神經(jīng)外科疾病也有積極治療作用,效果與藥物的種類和劑量有關(guān)。他汀類藥物可以減少蛛網(wǎng)膜下腔出血患者腦血管痙攣及遲發(fā)性腦缺血的發(fā)生,降低病死率;對腦出血和腦損傷也有治療作用。另外,大劑量他汀類藥物能抑制腫瘤生長,特別是膠質(zhì)瘤。但是,上述確切的機制仍需大樣本、多中心研究。關(guān)鍵詞:他汀類藥物;蛛網(wǎng)膜下腔出血;腦出血;外傷性腦損傷;凋亡The Applicat ion o f Statins in Ne uros urgery WANG L i-

11、jun,LIANG S hao-dong,ZH AO You-zhi.(Neuro-sur gery Department,H ongqi H ospital of Mudanjiang Medicial C ollege,Mudanjiang157011,China Abst rac t:Sta tins are drugs used to contr ol cholester ol disor der s a nd prev ent car diova scular diseases.Their denominated pleiotropic effects ha ve dem onstr

12、ated a broad a ction spectrum tha t might profit some neu-rologica l a nd neurosur gical diseases,the effects of w hich ar e cor related to dose and kind of statin.If statinsa re administered after subara chnoid hemorrhage,a significa nt lower incidence of va sospasm as well as delayedischemic defic

13、its and decr eased mortality could be found.In other complex diseases as intra cerebral hem or-rha ge or traumatic br ain injur y,the evidence for positive effects of a trea tment with statin increased.Addition-ally,pr omising experimental results indicate that high statin doses ar e able to promote

14、 cell death in tum or cells,especially in glioma s.M ore tr ials in humans ar e in urgent need to finally deter mine if statins could con-tribute to the curr ent management of neurosurgica l diseases.Key words:Statins;Suba rachnoida l hemor rhage;Intr acer ebral hem orr ha ge;Tra uma tic brain injur

15、 y;Ap-optosis他汀類藥物的分子結(jié)構(gòu)為3-羥基-3-甲基戊二酸單酰輔酶A,臨床上廣泛用于高脂血癥引發(fā)的心血管病的治療?；A(chǔ)及臨床試驗研究證實他汀類藥物具有多效性,如預(yù)防腫瘤、阿爾茨海默病、多發(fā)性硬化及抑制、免疫調(diào)節(jié)及神經(jīng)保護等多方面的功能,并且與他汀類藥物的種類與劑量有關(guān)。但是,與膽固醇代謝通路無關(guān)。目前,機制尚未完全明了,現(xiàn)就其對神經(jīng)外科疾病的可能作用機制進行綜述。1 蛛網(wǎng)膜下腔出血早在2002年M cG uirt 等1就首次報道辛伐他汀對大鼠蛛網(wǎng)膜下腔出血后腦血管痙攣有改善作用。對蛛網(wǎng)膜下腔出血后的大鼠預(yù)防性應(yīng)用辛伐他汀14d后發(fā)現(xiàn),其可以擴張大腦中動脈管徑、減少神經(jīng)功能缺失。之

16、后,人們發(fā)現(xiàn)其可能機制是通過磷脂酰肌醇3激酶(phosphoinositide3-kina se, PI3K途徑使血管周邊粒細胞遷移以及促進血管內(nèi)皮一氧化氮合酶(endothelial nitr ic oxide syntha se,eNO S的增殖有關(guān)2。研究還表明,阿托伐他汀通過抑制天冬氨酸特異性半胱氨酸蛋白酶3、5的表達,從而緩解血管痙攣3。1998 2001年,M cGirt等4在杜克大學(xué)進行了臨床回顧性研究,對115例蛛網(wǎng)膜下腔出血患者應(yīng)用他汀類藥物。結(jié)果表明,他汀類藥物對癥狀性腦血管痙攣有積極的預(yù)防作用,并闡述其作用的程度與他汀藥的種類和劑量無關(guān)。之后,Tseng等5進行了第一次臨

17、床隨機性試驗研究,對80例動脈瘤性蛛網(wǎng)膜下腔出血的患者應(yīng)用普伐他汀40mg安慰劑各14d,結(jié)果治療組中腦血管痙攣的發(fā)生率明顯降低,并且遲發(fā)性腦缺血的發(fā)生率和致死率分別降低了83%和75%,并闡述其機制與膽固醇代謝通路無關(guān)。這也是他汀類藥物用于治療急性蛛網(wǎng)膜下腔出血的首次報道。Chou等6在一項雙盲隨機臨床試驗中,對Fisher分級3級的39例蛛網(wǎng)膜下腔出血患者應(yīng)用辛伐他汀80mg/d(19例和安慰劑(20例,治療組無死亡患者,對照組病死率為15%。腦血管造影也證實辛伐他汀對預(yù)防腦血管痙攣有意義。遺憾的是病例數(shù)有限。K ram er等7對71例動脈瘤性蛛網(wǎng)膜下腔出血的患者應(yīng)用辛伐他汀80m g/

18、d,連續(xù)應(yīng)用14d,對預(yù)防腦血管痙攣和遲發(fā)性腦缺血的發(fā)生沒有意義。但是,試驗的樣本不均衡并且是回顧性研究使其缺乏說服力。在另一個308例患者的回顧性研究中,在蛛網(wǎng)膜下腔出血發(fā)生之前應(yīng)用過他汀類藥物的患者腦血管痙攣的發(fā)生率為23%,而未服用者為31%8。其弊端為患者年齡分布不均衡,藥物組的平均年齡較大。荷蘭的一則大宗病例報道:應(yīng)用他汀類藥物的人群中蛛網(wǎng)膜下腔出血的發(fā)生率較低,一旦停藥后其蛛網(wǎng)膜下腔出血的發(fā)生率顯著升高9。2 腦出血S eyfried等10于2004年首次報道了阿托伐他汀能減少腦細胞壞死、提高神經(jīng)元的可塑性、改善腦出血動物的神經(jīng)功能,并且證實提高藥物的應(yīng)用劑量對結(jié)果無影響。隨后的試

19、驗也證實,阿托伐他汀具有減輕血腫周邊的腦水腫程度和神經(jīng)保護的作用,并且與藥物劑量有關(guān)。臨床試驗中,Na va l等11對125例腦出血患者進行研究發(fā)現(xiàn),在出血之前服用過他汀類藥物的患者其腦水腫的程度明顯輕于未服用者,多元分析也顯示了明確的相關(guān)性既藥物治療組能夠絕對地減輕腦水腫的體積。以色列的國家急性卒中機構(gòu)在28家醫(yī)院對312例腦出血的患者調(diào)查數(shù)據(jù)顯示,89例患者腦出血應(yīng)用他汀類藥物,其國家衛(wèi)生機構(gòu)卒中評分及生存率均優(yōu)于對照組12。但是,有研究13以629例腦出血患者為研究對象,其中149例患者出血前應(yīng)用過他汀類藥物。結(jié)果顯示,藥物的應(yīng)用對神經(jīng)功能保護和生存率沒有影響。也不能增加再出血的發(fā)生率

20、。目前,還沒有臨床的隨機試驗或流行病學(xué)證實降低膽固醇與腦出血的發(fā)生有明確的相關(guān)性。令人驚奇的是,一項29個亞太地區(qū)人口的薈萃分析表明,血總膽固醇每升高1mm ol/L 即可降低20%致死性腦出血的發(fā)生14。一些學(xué)者研究認為,服用大劑量阿托伐他汀對那些高齡的男性腦出血患者,隨著年齡的增長,其再出血的風(fēng)險也將增大,與血中低密度脂蛋白的水平無關(guān)15。另一大宗薈萃分析對14個隨機試驗的90056例個體研究表明,他汀類藥物可以預(yù)防任何類型的腦卒中的首次發(fā)生,但對出血性卒中沒有意義16。3 外傷性腦損傷關(guān)于他汀類藥物對外傷性腦損傷的研究在動物實驗開展得較為廣泛,但是很少應(yīng)用于臨床。腦損傷的大鼠按1mg/(

21、kgd口服阿托伐他汀7d,14d 后發(fā)現(xiàn)神經(jīng)功能缺失明顯減少,神經(jīng)元的成活率明顯增高,鏡下可見損傷灶及海馬周圍的神經(jīng)突觸的發(fā)生。同時發(fā)現(xiàn)阿托伐他汀對改善腦血管灌注,減少血管內(nèi)血栓形成,使腦挫傷更易被診斷,并能促進空間記憶的恢復(fù)17。Wang等18報道阿托伐他汀和辛伐他汀(20mg/kg均可以減少神經(jīng)功能缺失,抑制海馬退化,抑制炎性細胞因子的信使RN A在細胞膜上的表達。Wu等19報道辛伐他汀能增強蛋白激酶B(protein kina ses B,Akt磷酸化程度、糖原合成激酶3的活性和環(huán)磷腺苷結(jié)合蛋白的能力,從而提高細胞的增殖和分化,促進空間學(xué)習(xí)能力的恢復(fù)。近來的研究還證實,辛伐他汀抑制腦損傷

22、小鼠炎性介質(zhì)白細胞介素6(interleukin-6,IL-6、IL-1和腫瘤壞死因子的表達。并且證實在空間學(xué)習(xí)能力的恢復(fù)上辛伐他汀要優(yōu)于阿托伐他汀20。最近,一組小樣本的臨床隨機試驗也在進行,21例格拉斯哥昏迷評分913分的腦外傷的患者,其中8例在受傷后24h 經(jīng)羅舒伐他汀(20mg/d治療,13例為對照組。試驗表明,治療組比對照組有更高的比例、較快的速度促進記憶和空間感的恢復(fù)。作者認為其機制可能與免疫因素有關(guān)21。由于腦外傷患者的傷情差異性較大,各種評估標準的偏倚,他汀類藥物若要在臨床上大規(guī)模應(yīng)用,還需要建立在更深一步的基礎(chǔ)研究之上。4 多形性膠質(zhì)母細胞瘤和其他腫瘤起初的試驗數(shù)據(jù)提示,他汀

23、類藥物具有潛在的致癌性和致突變性,但隨后的體內(nèi)、外試驗研究證實其具有抗癌作用,但是,目前這兩種觀點的爭論還遠沒有停滯。就其抗癌機制,他汀類藥物通過抑制腫瘤血管的發(fā)生、誘發(fā)瘤細胞凋亡從而起到抗癌作用,并且其抗癌活性的大小與他汀藥物的劑量、種類腫瘤的類型密切相關(guān)22。有研究表明,多形性膠質(zhì)母細胞瘤的病因與脂類代謝失調(diào)有關(guān),他汀類藥物因針對膽固醇代謝通路的干預(yù)從而起到治療作用23。試驗表明,洛伐他汀使膠質(zhì)瘤細胞Ra s通道失活、抑制促分裂原活化蛋白激酶的活性從而導(dǎo)致腫瘤細胞的合成功能障礙,以達到抗腫瘤的效果。另外,洛伐他汀可以導(dǎo)致肌動蛋白纖維斷裂,即使在納摩爾級的濃度也可通過腫瘤壞死因子的表達誘導(dǎo)細

24、胞周期停滯、細胞凋亡。通過抑制膠質(zhì)瘤細胞表皮生長因子受體來抑制其生長24。最新的研究證實,洛伐他汀還可以通過蛋白激酶相關(guān)的促分裂素/血小板源性生長因子途徑和干擾p53基因抑制腦膜瘤和髓母細胞瘤的細胞增殖25。但是,1998年的一項臨床研究表明,洛伐他汀對腫瘤和患者的作用和生存率影響甚微26。但是,較低的藥物劑量與較少的試驗樣本數(shù)與其陰性結(jié)果不無關(guān)系。目前,對其他他汀類藥物的藥效、劑量、脂溶性及血腦屏障的通過性還缺乏透徹的研究,只有洛伐他汀和辛伐他汀用于惡性膠質(zhì)瘤的治療。因此,要進行大規(guī)模的臨床隨機試驗還有待時日。5 其他他汀類藥物對脊髓損傷治療的研究也著實令人感興趣。試驗研究表明,阿托伐他汀通

25、過炎性因子的調(diào)節(jié)和神經(jīng)細胞的保護對大鼠損傷的脊髓起修復(fù)作用。通過調(diào)節(jié)ca spase-3來阻止細胞凋亡27。目前,對其他他汀類藥物的研究及其在臨床上的應(yīng)用還未見報道。另一項動物實驗證實,預(yù)防性應(yīng)用他汀類藥物可以提高腦缺血動物的腦血流量,改善其預(yù)后28。因此,若此項結(jié)果得到證實并能應(yīng)用到臨床,那么神經(jīng)外科醫(yī)師就能通過術(shù)前用藥改善患者狀態(tài),以提高手術(shù)質(zhì)量。由于已經(jīng)證實他汀類藥物在心血管及神經(jīng)血管方面應(yīng)用的安全性,術(shù)前應(yīng)用他汀類藥物作為手術(shù)的佐劑是值得考慮的?？傊?他汀類藥物是令人感興趣、復(fù)雜的藥物,隨著人們對其作用機制更深入的探究,必將給神經(jīng)外科患者帶來更大的利益。參考文獻1M cGir t MJ

26、,Lynch J R,Parr a A,et al.S imvastatin incr eases endo-thelial nitr ic oxide synthase and ameliorates cerebral vasospasm r e-sulting from subar achnoid hemor rhag eJ.S troke,2002,33(12:2950-2956.2S ugaw ara T,Ayer R,J adhav V,et al.Simvastatin attenuation of cer-ebral vasospasm after subarachnoid he

27、morr hage in rats via in-cr eased phosphoryla tion of Akt a nd endothelia l nitr ic ox ide syn-thaseJ.Neurosci Res,2008,86(16:3635-3643.3Cheng G,Wei L,Zhi-Dan S,et al.Atorvastatin amelior ates cer ebr alvasospasm and ear ly br ain injur y after subar achnoid hemor rha geand inhibits caspasedependent

28、 apoptosis pathwayJ.BM C Neu-r osci,2009,21(10:2202-2213.4M cGir t MJ,B lessing R,Alexa nder MJ,et al.Risk of cer ebr al va-sopasm after subar achnoid hemorr hag e reduced by statin therapy:amultivariate a nalysis of an institutional experienceJ.Neur osurg,2006,105(5:671-674.5Tseng MY,C zosnyka M,Ri

29、char ds H,et al.E ffects of acute tr eat-ment with pravastatin on cerebral vasospasm,autoregulation,anddelayed ischemic deficits after aneur ysmal subar achnoid hemor-r hage:a phase II randomized placebo-controlled trialJ.S tr oke,2005,36(8:1627-1632.6Chou S H,Smith EE,Ba djatia N,et al.A randomized

30、,doubleblind,placebo-contr olled pilot study of simvastatin in aneur ism al sub-ar achnoid hemor rhageJ.Str oke,2008,39(10:2891-2893.7Kr amer AH,Gur ka MJ,Nathan B,et al.Statin use was not associat-ed w ith less vasospasm or im prov ed outcome after subar achnoidhemor rhageJ.Neur osurg ery,2008,62(2

31、:422-430.8Moskow itz S I,Ahrens C,Provencio J J,et al.Prehemor rhage statinuse and the risk of vasospasm after aneur ysmal subarachnoid hem-orr hageJ.S ur g Neurol,2009,71(3:311-317.9Risselada R,Str aatman H,van Kooten F,et al.Withdraw al of st-atins and risk of subar achnoid hemorr hag eJ.Stroke,20

32、09,40(8:2887-2892.10Seyfr ied D,Han Y,Lu D,et al,Im provement in neurolog ical out-come after administr ation of atorvastatin following exper imental in-tracer ebr al hemorr hage in ratsJ.Neur osur g,2004,101(1:104-107.11Nav al NS,Abdelhak TA,Urruna ga N,et al.An association of pr iorstatin use with

33、 decrea sed perihematomal edemaJ.Neur ocritCare,2008,8(1:13-18.12Leker RR,Khoury ST,Rafaeli G,et al.NAS IS Investigator s Pr ioruse of statins improv es outcom e in patients with intr acerebra l hem-orr hage.Prospective data fr om the National Acute S tr oke IsraeliSur veys(NAS ISJ.Stroke,2009,40(7:

34、2581-2584.13FitzM aur ice E,Wendell L,Snider R,et al.Effect of sta tins on in-tracer ebr al hem orrhage outcome and recurrenceJ.Str oke,2008,39(7:2151-2154.14Zhang X,Patel A,Hor ibe H,et al.Asia Pacific Cohort S tudies Col-labor ation C holesterol,coronary hear t disease,and stroke in the A-sia Pa c

35、ific regionJ.Int J E pidemiol,2003,32(4:563-572. 15Goldstein LB,Amarenco P,S zarek M,et al.SPARC L InvestigatorsHemorr hagic stroke in the stroke prevention by aggr essive r eductionin cholester ol levels studyJ.Neurology,2008,70(24Pt2:2364-2370.16Baigent C,Keech A,Kear ney PM,et al.Cholesterol Trea

36、tment Tria-lists(CTTCollaborators Efficacy and safety of cholester ol-lower ingtr eatment:pr ospective meta-a nalysis of data from90,056partici-pants in14r andomised tr ials of statinsJ.Lancet,2005,366(9493:1267-1278.17Lu D,Mahmood A,Goussev A,et al.Atorv asta tin r eduction of in-travascular thromb

37、osis,increase in cerebral micr ovascula r patencyand integr ity,and enhancement of spa tia l learning in r ats subjectedto traumatic br ain injuryJ.Neurosur g,2004,101(5:813-821.18Wang H,Lynch J R,S ong P,et al.S imvastatin and atorvastatin im-pr ove behav ioral outcome,reduce hippocam pal degenerat

38、ion,andim prove cerebra l blood flow after experimental traumatic brain inju-ryJ.Ex p Neur ol,2007,206(1:59-69.19Wu H,Lu D,J iang H,et al.S imvastatin-mediated upreg ula tion ofVE GF a nd BDNF,a ctivation of the PI3K/Akt pathw ay,and incr easeof neurogenesis are associated with therapeutic improvement a ftertr aumatic bra in injur yJ.Neur otra uma,2008,25(2:130-139. 20Li B,Mahmood A,Lu D,et al.Simv astatin attenuates micr oglial cellsand astrocyte a ctivation and decr eases interleukin-1beta level a ftertr aumatic bra in injur yJ.Neur osur