Y HQC VIET NAM THANG 7 - SO 2/2013
T O N G Q U A N
TAG DUNG CHONG VIEM CUA CAC MACRQLIDE TRONG BENH LYDUiTNG HO HAP
SUMMARY
Dunng the recent years there has been increasing interest in the potential anti-infammatory effects of macrolide antibiotics. The use of long time and low dose macroiide antibiotics has dramatically increased survival in patients with diffuse panbronchiolitis. This has led to further studies into the potential use of macrolides in chronic inflammatory lung diseases. This review summarizes the proposed anti-inflammatory mechanisms of macrolide antibiotics such as the effects of macrolide antibiotics on the inflammatory cytokine expression, the modulation of these antibiotics on neutrophil and macrophage function, on mucus secretion, and on bacterial adherence. It also discusses the dinical studies of macrolide antibiotics in patients with chronic inflammatory lung diseases such as cystic fibrosis, bronchiectasis, chnanic obstructive pulmonary disease and asthma. Many randomized controlled clinical trials have showed the potential benefits of this group of antibiotics, however, it needs to perform futher studies before routines use can be advised.
Khang sinh dau tien thupc nhom macrolide la erythromycin du'dc gidi thieu tai Phillipine vao nhu'ng nam 40 ciia the ky tru'dc va da diTcfc sd dung rpng rai trong dieu trj cac nhiem khuan Gram du'dng. Sau do nhieu khang sinh cung nhdm khac nhu" troleandomycin, roxithromycin, dirtthromycin, clarithromycin, telithromycin va azithromycin cOng lan lu'dt ra ddi vdi dac tfnh khang khuan, chong viem va dieu tiet mien djch.
Nhd kha nang gan ket vao tieu phan 50s cua ribosome, khang sinh nhdm macrolide cd the t^c che su' tong hdp proteine cua vi khuan, vi vay cac khang sinh nay cd pho khang khuan rdng, tac dyng vdi hau het cac vi khuan gram du'dng, mpt so vi khuan gram am, cac chiing Mycobactena, Chlamydia, f^ycopiasma va Legionella. Do cd pho khang khuan rpng, kha nang tham thau tot vao mo nen khang sinh nhom macrolide du'dc sir dung rpng rai trong dieu trj nhiem trung du'dng ho hap.
Ben canh tac dyng khang khuan, khang sinh
* Benh vien Da khoa tinh Hal Difdng Phan bifn khoa hpc: GS.TS. Ddng K h i c Hu-ng
Bui Ou'c Long * nhdm macrolide con cho thay cd kha nSng chong viem cung nhu" dieu hda mien dich khi du'dc dung keo dai vdi lieu thap trong mpt so benh viem nhiem man tinh du'dng ho hap. Nhu'ng tac dung nay du'dc thay r5 trong cac nghien cii'u su* dyng macrolide cho benh nhan mac viem tieu phe quan lan tda, xd nang phoi, gian phe quan, benh phoi tac nghen man tfnh (COPD) cung nhu'trong mpt sd tru'dng hdp hen phe quan nang. Mac du cd che chinh xac ciia tac dung chong viem, dieu hda mien djch cua khang sinh nhdm nay chu'a du'dc hoan toan lam sang t d , tuy nhien cac nghien ciru cho thay chung cd mpt so tac dung du'di day.
1 . Tac d u n g b a o ve b i e u m o Phdi __nhiem lien tyc vdi cac tac nhan gay benh, nhiem khuan tai phat nhieu lan tai du'dng hd hap lam ton thu'dng, hiiy hoai cau true bieu mo du'dng hd hap, giam tan so van dpng ciia cac long rung tren be mat te bao bieu mo, lam tang tiet, il" dpng chat nhay va gay gian phe quan.
Hau^qua lam cho du'dng hd hap lien tuc nhiem khuan, qua trinh viem lien tyc tien trien. Hien tUdng nay thu'dng gap trong cac benh viem man tmh du'dng ho hap nhu' COPD, gian phe quan...
Khang sinh nhdm macrolide t r y t bep bao ve cau tme bieu md du'dng hd hap bang each uTc ch^
viec san xuat cac phan tir dpc ^ bao du'dc tiet ra bdi cac vi khuan cu" tnj tnang du'dng hd hap nhu' Streptocoaiis pneumoniae. Hemophilus InUuenza va Pseudomonas aeruginosi^-^^. Hdr nda vdi kha nang IJ'C che sy" tap trung aia bach rau da nhan trung b'nh, cac khang sinh nhdm macrolide gian tiep bao ve sy toan ven ciia bleu md du'dng ho hap tranh khdi nhutig anh hu'dng cd hai ciia cac thanh phan ddc te bao do bach rau da nhan bijng b'nh t i & ra nhu" neutrophil elastase^-'^
2. Tac dung g i a m t i e t d d m n h a y Tang tiet ddm nhay \a mpt dac diem thu'dng thay trong nhieu benh man tinh du'dng hd hap nhu' COPD, gian phe quan va hen phe quan.
Khang sinh nhdm macrolide cho thay cd kha
Y HOC VigT NAM THANG 7 - S6 2/2013 nang ire che sy tSng tiet nay. Tac dung nay lam
tang them hi^u qua ciia viee sir dung macrolide trong cac benh dydng ho hap. Macrolide u'e che gen tong hdp mucin core protein (mucSac) lam giam tiet djch nhay du'dng hd hap^^'^'. Macrolide cijng lam giam lydng dich nhay nhd lam giam tiet nydc va muoi vao Idng phe quan^"'. Ngoai ra, tac dyng giam tiet dich nhay phe quan cdn do kha nSng ire che tap trung bach cau da nhan trung tinh ciia cac khang sinh nhom nay.
Azithromycin va clarithromycin cd kha narig lam giam san xuat GM-C5F tir cac te bao bieu mo dydng hd hap, nhd dd lam tang sy chet theo chyong trinh ciia bach cau da nhan trung tfnh'^'.
Giam tap trung cua cac te bao viem nay se lam giam tiet ddm nhay vao Idng phe quan.
3. Tac dyng den bach cau da nhan trung tinh va dai thu'c bao
Ngu'di ta da biet mdt so cd che tac dung eiia khang sinh nhdm macrolide doi vdi cac te bao viem nhu' ire che giai phdng cac phan tir ket dinh tren thanh mach va te bao bieu mol^'^ Tuy nhien dieu quan trpng nhat la khang sinh nhdm nay cd kha nang dc che san xuat va giai phdng cac yeu to hoat hda bach cau da nhan trung tinh nhy CXC cytokine, cae yeu to tang trydng, yeu to hoai tir u tir cae te bao trong du'dng ho hap (bach cau ya axit, bach cau ddn nhan, te bao bieu md, te bao cd trdn), tir dd giam sy tap trung va giam hoat hda cac te bao nay.
Hdn nij^ bach cau da nhan trung tinh chet theo chu'dng trinh tai du'dng hd hap du'dc dpn dep bdi cac dai thye bao phe nang. Hoat dpng nay ciia dai thyc bao bi suy giam trong COPD va cae roi loan viem man tinh khae ciia dydng hd hap din den qua trinh viem nhiem keo dai, hoai tor thir phat to chiTc phe quan. Clarithromycin va azithromycin lam tang kha nang thyc bao cac bach cau da nhan trung tinh chet theo chydng trinh trong du'dng hd hap.
Ben canh viee tae ddng den bach cau da nhan trung b'nh, bach cau u^ axit, dai thyc bao, te bao bieu mo va te bao cd trdn phe quan, khang sinh nhdm macrolide cdn ed kha nang kiem scat cac receptor nhan biet ciia cac te bao dudi gai (toll-like receptors, TLRs). Clarithromycin ire che cac toll-like receptors-4 tren te bao ddn nhan, erythromycin dc che hoat ddng eiia NF beta, iam giam nong dp toll- like receptors-3. Hdn nda, clarithromycin yc che giai phdng interleukin (IL)-6 do te bao duoi gai, trong khi dd azithromycin lam tang tong hdp IL- 10 la mpt cytoine cd tac dyng chdng viem. Vi
vay, te bao duoi gai cd le cung la te bao dich quan trpng trong ed che khang viem ciia khang sinh nhdm macrolide.
4. Mdt 50 nghien cu'u tren dong vat thi nghiem
frong mo hinh hen phe quan cap d chupt, clarithromycin 200mg/kg ire che mot each co y nghTa hien tu'dng tang phan irng phe quan, giam lu'dng baeh cau u^ axits, bach cau da nhan trung tinh cung nhy lam giam nong dp IL-4, IL-S, IL-13, CXCL-1 va MIP-2 trong djch ru^ phe quan. T^c gia ket luan rang clarithromydn dc che mpt each fiieu qua sir tSng phan img phe quan va hien tydng viem trong dydng hd hap, hai dac tinh benh hoc quan trpng nhat b-ong hen phe quan.
Trong mpt nghien cu'u khac, md hinh chupt hen phe quan dj irng, azithromycin 50 mg/kg lam giam bach cau ya axit, bach rau da nhan bung tinh, dai thu'c bao va te bao lympho trong djch rira phe quan. Azithromycin cung lam giam IL-13 va IL-5 trong du'dng hd hap.
Clarithromycin diing trong 6 thang lam giam hien tydng gian va giam ton thu'dng thanh phe nang do khdi thuoc la gay ra d chupt thi nghiem, ddng thdi cung lam giam sy tap trung dai thi/c bao trong nhu mo phoi. Nghien cdu gan day vdi chudt phdi nhiem khdi thuoc la, erythromydn 100 mg/ngay trong 8 ngay da lam giam ca so lu'dng bach cau da nhan trung tinh va bach cau lympho trong dieh phe quan, kem theo la sir giam nong dp mRNA ciia CXCL-1/KC va TNF- alpha trong nhu md phoi. Nhu* vay clarithromycin va erythromycin cd the han che va dieu chinti tinh trang viem trong nhu md phoi gay ra do khoi thuoc la. Ket qua nay iing hp gia ttiuyet cho rang khang sinh nhdm macrolide vdi lieu thap cd the cd ich trong kiem soat COPD.
Nhiem virus dydng hd hap cung la nguyen
nhan thu'dng thay lam khdi phat cdn hen phe
quan, lam tang tan suat biing phat ddt cap
COPD. Trong mo hinh viem phe quan do virus 6
chupt, azithromycin lam giam hien tu'dng sut can
do virus, ire ehe tap trung bach cau dydng ho
hap, dac biet bach eau da nhan trung tinh trong
djch phe quan va trong nhu md phoi. Tac dung
nay eiia Azithromycin gan lien vdi viec lam giam
eac hda chat trung gian gay viem nhy G-CSF,
CCL-1, CCL-2, IL-6, IL-9 va GM-CSF trong djcii
phe quan. Tuy nhien azithromycin khdng anh
hydng den ndng dp IL-17 va CXCL-1/KC trong
mo hinh nay.
Y HOC VigT NAM THANG 7 - S6 2/2013 5. Tac dung chong v i § m va dieu t i e t
mien djch t r o n g m o t so benh v i e m man tinh du'dng ho hap cua Ifhang sinh nhdm macrolide
Viem tieu pfie quan tan toa Viem tieu phe quan lan tda la mot roi loan man tinh dydng hd hap ma qua trinh viem man tinh dydng hd hap di kem vdi sy pha hiiy lien tuc nhu md phoi. Du'dng hd hap ciia nhiirig benh nhan nay thu'dng xuyen cd sy c y t r u , phat trien cac chiing vi khuan nhu' Haemophilus influenzae, Streptococcus pneumoniae, Staphylococus aureus hoac f^eudomonas aeruginosa. Tai Nhat Ban, sau khi sii" dyng rpng rai erythromycin cho nhu'ng benh nhan nay, ty le sdng sdt sau 5 nam tang tu" 8 % len den 9 2 % . Clarithromycin va azithromycin cho thay cung cd nhu'ng ldi fch tu'dng t y nhu" ciia Erythromycin khi du'dc sir dung trong benh nay.
Xdnang pfioi
Rat nhieu cac nghien cirli da chi ra Idi fch ciia khang sinh nhdm macrolide trong viee dieu tri xd nang phoi. Viec sir dung macrolide lam cai thien qua trinh viem do bach cau da nhan trung tfnh gay ra trong benh nay. Benh nhan xd nang phoi du'dc su* dung azithromycin cho thay ed sy cai thien ve chirc nang hd hap, cai thien ve chat lu'dng cupc sdng, giam tan suat nhiJng dot cap tfnh cung nhu' rut ngan thdi gian nam vien.
Salman va cs. 2003 da tien hanh nghien cu'u ngau nhien, mii ddi, cd doi chu'ng tren 185 benh nhan x d nang phoi. Benh nhan du'dc diing azithromycin hoac gia du'dc 3 lan/tuan trong 6 thang. The tich thd ra toi da trong giay dau tien (FEVl) tang 4 , 4 % d nhdm dung Azithromycin, ngu'dc lai FEVl giam 1,8% d nhdm diJng gia du'dc (p=0,001). Trong nghien cyu nay azithromycin cung lam giam cac ddt biing phat cap tinh ciia benh.
Tuy nhien trong mpt nghien ciru gan day, Steinkamp va es. 2008 thay sy khac biet khdng cd y nghTa thdng ke ve chirc nang hd hap ciia nhdm benh nhan sir dyng azithromycin so vdi nhdm diing gia du'dc. Chi cd mot nghien ciru danh gia tac dung eua clarithromycin trong benh nay. Khdng ed s y cai thien dang ke nao du'dc ghi nhan ve c\\dc nang hd hap ciia benh nhan xd nang phdi sau 6 thang dieu t n bang clarithromycin.
Mdi day nhat, mdt nghien ciTu phan tich meta cd he thong nam 2011 da thu thap phan tfch sd lieu eiia 8 nghien ciru ngau nhien doi
chirng s y dyng khang sinh nhdm macrolide trong xd nang phoi eho thay sir dung azithromycin tang mot each cd y nghia FEVl % (3,22%; p=0,0006) va dung tfch sdng g l n g sii'c (FVC)% (3,23 % ; p<0,0001) so vdi gia du'dc. s y cai thien nhO'ng thdng so nay con Idn hdn n i i ^ d nhO'ng benh nhan cd nhiem Pseudomonas aeruginosa.
Hen pile quan
Ben canh tinh trang viem man tfnh, hen phe quan thu'dng kem theo hien tydng nhiem triing man tfnh du'dng hd hap du'di bdi Mycoplasma pneumoniae va Chlamydia pneumonia, nhiTng chiing vi sinh nay thu'dng nhay cam vdi khang sinh nhdm macrolide. Sd phdi hdp giO'a viem man tinh vdi nhiem triing man tinh cae ehiing vi sinh vat tren da gdi y eho viee sir dung khang sinh nhdm macrolide trong kiem soat hen phe quan. Hdn nda, mdt vai khang smh trong nhdm nay du'dc coi nhu' eac chat cd the lam giam nhu cau sir dung corticoid d nhOrig benh nhan hen phe quan nang, phu thuoc corticoid.
Nhieu thir nghiem lam sang du'dc thyc hien nham danh gia tac dung eiia khang sinh nhdm macrolide trong hen phe quan. Kraft va es. 2002 sir dung clarithromycin hoac gia du'dc cho 55 benh nhan trong 6 tuan. Clarithromycin da lam tang FEVl, tuy nhien tac dung nay chi du'dc thay tren nhyng benh nhan hen phe quan ed nhiem Mycoplasma pneumoniae hoac Chlamydia pneumonia. Mdt sd nghien ciTu cho thay khang sinh nhdm macrolide lam giam s y t a n g phan yng phe quan ma khdng cd sy cai thien FEVl.
Gan day Sutheriand va cs. 2010 thyc hien nghien ciru d benh nhan hen phe quan dai dang mirc dp nhe va trung binh khd kiem soat bang corticoid it lieu thap. Clarithromycin du'dc dung du'dng uong 500 mg/12h hoac gia du'dc trong 16 tuan cho 92 benh nhan. Clarithromycin da khdng cai thien chirc_nang hd hap d ea benh nhan cd hay khdng nhiem Mycoplasma pneumoniae hoac Chlamydia pneumonia, mac dii cd lam giam sy tang phan iTng eiia phe quan.
Nghien ciru tong hdp Cochrane cap nhat 2007 ehi ra rang su' khac biet khdng cd y nghTa thdng ke ddi vdi cac ehi sd FEVl, FVC va nhu cau su'dung corticoid dydng udng giu'a cac nhdm sir dyng gia du'dc va cac nhdm sir dyng khang sinh macrolide. Tuy nhien khang sinh nhom macrolide lam giam dang ke trieu chyng lam sang so vdi gia du'dc. Tac gia ket iuan rang chu'a dii bang chirng iing hp hay phan ddi viec sir dung khang
Y Hpc VigT NAM THANG 7 - SO 2/2013
sinh nhdm macrolide trong kiem soat hen phe
quan man tfnh.
Binti ptioi tic ngfien m^n tinti (COPD) Cac nghien ciru In vivo cho thay khang sinh nhdm macrolide cd tac dyng chong viem nhd ire che san xuat va gial phdng cac cytokine va chemokine tien viem nhy IL-1 alpha, IL-1 beta, IL-6, TNF alpha, CXCL-8, G-CSF, GM-CSF va lactoferin, dong thdi dieu hda chirc n3ng te bao, dc che giai phdng hat, dc che qua trinh oxy hda trong bach cau da nhan trung tinh, thiic day qua trinh thyc bao ciia cac dai thyc bao phe nang d benh nhan COPD.
Tren lam sang, Seemugal va cs. 2008 thyc hien nghien ciilJ ngau nhien, mil ddi, ddi chirng tren 109 benh nhan COPD. Benh nhan du'dc sir dyng erythromycin 250 mg 2 lan/ngay trong 12 thang da giam dang ke tan suat va thdi gian bijng phat ddt cap eiia benh. Tuy nhien sy eai thien khdng dang ke d chi so FEVl; sy thay doi khdng y nghTa thdng ke ve ndng dp IL-6, CXCL-8 va MPO trong ddm.
Blasi va cs. 2010 da thir nghiem danh gia tac dung va tfnh an toan ciia azithromycin tren benh nhan COPD mirc dp nang. Benh nhan du'dc dieu tn them bang azithromycin 500 mg 3 lan/tuan trong 6 thang. Azithromycin lam giam cd y nghia tan suat cae ddt biing phat sau 3 thang dieu tri. Azithromycin cOng lam giam cd y nghTa sd lan nhap vien, sd lan diing corticoid va eai thien chat lu'dng cupc song d nhyng benh nhan nay. Khdng cd phan irng ed hai nao ciia thudc du'dc ghi nhan do dung azithromycin.
Gan day Albert va cs. 2011 thy nghiem ngau nhien tren 1142 benh nhan COPD. Azithromycin du'dc diing vdi lieu 250 mg/ngay trong 1 nam.
Thir nghiem cung cho thay azithromycin lam giam dang ke eac ddt biing phat cap tfnh, cai thien chat lu'dng cudc sdng ciia benh nhan, tuy nhien azithromycin gay giam thinh lyc d mdt sd it benh nhan.
Khdng chl trong cac benh ve du'dng hd hap, cac nghien cu'u ve tae dyng chong viem, dieu tiet mien djch ciia khang sinh nhdm macrolide cdn dUdc md rdng pham vi tdi cac benh khac nhu"
viem xoang man tinh, xd cirng bi, benh Crohn, benh mach vanh, viem man tinh xu'dng khdp...
Mac du nhieu nghien eiru ehi ra ldi fch cd the cd tren lam sang cung nhu' tfnh de dung nap eua khang sinh nhdm macrolide, viec sir dung
nhO'ng khang sinh nay vdi lieu trinh keo dai co the cd nhO'ng nguy cd tiem an nhy tang tac dung phy, phan irng cd hai ciia thuoc, nhu'ng nguy cd trong viec phoi hdp, tydng tac giu^a cac thudc, dac biet nguy cd tao ra nhuHg chimg vl khuan khang thudc. Mpt loat cac cau hdi dang can du'dc giai quyet, vi du nhy lieu phap macrolide keo dai se anh hydng nhy the nao ddi vdl he vi sinh vat cy tru tai dydng hd hap, nhij'ng lieu phap nay co lam thay ddi hieu qua dieu tri ciia cac khang sinh khac khdng, thay doi nhy the nao? Cd che chgng viem, dieu hda mien djch ciia nhyng khang sinh nay cho den nay van chu'a dydc hoan toan sang td. Vi vay can thyc hien nhieu hdn nu^ cac thf nghiem cung nhu'cac thir nghiem lam sang tru'dc khi nhdm thudc nhieu hira hen nay dydc khuyen cao rpng rai tren lam sang nhy mpt chat chong viem va dieu tiet mien dich.
TAI UEU THAM K H A O
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