JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 6 - N 3/2011
Danh gia hieu qua ha nhan ap ciia Brimonidin tartat 0,15%
trong dieu tri glocom goc mo* nguyen phat
Evaluation the efficacy of reduction iop of Brimonidin tartat 0,15% on treating primary open angle glaucoma
Dao Thi Lam Hudng Benh vien Mdt Trung uong
T o m t a t
Muc dich: 1) Oanh gia ket qua ha NA cua Brimonidin tartat 0,15% (Alphagan P) trong dieu tri glocom goc md nguyen phat. 2) Nhan xet mot so tac dung khong mong muon cua thuoc. Doi tupng: 36 benh nhan glocom goc md nguyen phat dieu tri tai khoa Glocom, Benh vien Mat Trung UPng t d 10/2008 den 4/2010.
PhUPng phap: tien cdu m6 ta, theo doi dpc, t h d nghiem lam sang. Ket qua: sau ngay dau tra Alphagan P mdc NA ha trung binh 12,98 ± 8,25 mm vdi ty le ha NA trung binh la 37,17% va hieu qua dat toi da vao khoang tuan thd 2 (53,45%). Ty le % ha NA trung binh d cac tuan va cac t h i n g theo doi tiep theo la tuong dUPng nhau (p > 0,05). Ty le chung NA ha trung binh la 52,17%. Sau ngay dau dieu tri 37 m i t (61,67%) co NA dieu chinh dUdi 21 mmHg, trong do 36,67% mat cd NA < 18mmHg. Sau 1 tuan so mat co NA dieu chinh tang len 78,33%, trong do co 35 mat NA <18 chiem 53,33%. Tai cac t h i n g theo doi tiep ty le mat dat mdc dieu tri thanh cong hoan toan rat cao (97,37% -100%). Tac dung khong mong muon khi tra Alphagan P co the gap la buon ngu, kho hpng, ngda m i t , com mat, rat mat va cUOng tu ket mac d cac mdc dp khac nhau. Tyf le mat p h i i thay thuoc do tac dung khong mong muon chiem 6,67%. Ket luan: 1. Alphagan P co t i e dung ha NA tot, ty le mat CO NA dieu chinh bang thuoc cao. 2. Alphagan P ft gay t i c dung khong mong muon, ty le mat phai thay thuoc do tac dung khong mong muon cua thuoc rat thap.
TCf khoa: Brimonidin tartat, glocom goc md nguyen phat.
Summary:
Purpose: 1) Evaluate the efficacy of Alphagan P on treating primary open angle glaucoma. 2) Assess some side effects of Alphagan P. Meterials: 36 patients of POAG treated in Glaucoma departement, national institute of ophthalmology from 10/2008 to 4/2010. Methods: prospective, describe, longitudinal, clinical trial. Results: after instillation of Alphagan P, IOP reduction the first day is 12,98 ±8,25 mmHg with the mean IOP reduction is 37,17%, reach maximum efficacy in the second week ( 53,45%). The rate of mean IOP reduction in the following weeks and months is equivalent (p > 0,05). The rate of general IOP reduction is 52,17%. After the first day of treatment, 37 eyes (61,67%) have IOP well controled (< 21 mmHg), whereas 36,67% has IOP < 18 mmHg. After 1 week, the rate of well controled IOP reaches to 78,33%, while 35 eyes have IOP < 18mmHg (53,33%). At the following months, the rate of eyes reaching totally suscesful treatment is very high (97,37% - 100%). Adverse effects of Alphagan P including downsiness, mouth dryness, eyes itchyness, sensation of foreign body at various degree. The rate of changing eyes drops because of side effects is very low (6,67%). Conclusion: 1. The efficacy of IOP reduction of Alphagan P is good, the rate of well controled IOP is very high. 2. Alphagan P causes a little side effects, the eyes changed medication because of adverse effect is very low, only 6,67%.
Keywords: Brimonidin tartat, primary open angle glaucoma.
Phan bien khoa hoc: PGS.TS. NGUYEN HONG GIANG
94
TAP CHl Y DLTOC LAM S A N G 108 Tip 6-S6 3/2011 I . D a t v l n d e
Glocom la nguyen nhan thd hai g i y mu loi d nddc ta cung nhd tren the gidi. Cic phddng phap dieu tri glocdm deu nhim muc dich ha nhan ap (NA) den mdc an t o i n cho thj t h i n kinh. Bien phap Ida chpn dau ti#n trong di^u trj gidcdm gdc md la ha NA bing thuoc tra mit. Trong thdi gian gan day thudc Brimonidin tartat 0,15% (Alphagan P) thudc nhdm cddng aj adrenergic ddpc sd dung nhd la bi§t ddpc chinh de ha nhan i p vdi 2 co ch^: giim tiet thiiy djch va tang thoit thOy djch qua dddng mang bo dao cCing mac [2].
Nhim dinh gia chfnh xic t i c dung cua Alphagan P trong di^u trj glocom gdc md tren benh nhan Vi§t Nam chung tdi ti^n hinh nghien cdu niy vdi muc tieu:
1. Ddnh gid ket qud hg NA cCia Alphagan P trong diiu tri gidcdm gdc md. 2. Nhdn xit mdt sd tdc dung khdng mong mudn cilia Alphagan P.
2. Doi tUqrng va phUorng phap nghien cufu 2.7. Doi tUcfng nghien cdu
36 BN gidcdm gdc md nguyen phit, ddpc dieu trj tai khoa Glocdm, B^nh vien M i t Trung dong t d 10/2008 den 4/2010.
3.Ketquii
3.1. Kit qui ve nhan ap
Tieu chuan loai trd: benh nhan glocom NA khong cao, BN dang cd thai hoac dd djnh mang thai.
2.2. PhUcfng phap nghien cdu
Tien cdu mo t i , theo ddi dpc, thd nghiem lim sing.
Cac bddc tien hanh:
Tham khim mit: thd thj Idc (bing Landolt), do nhin i p (NA ke Goldmann), thj trddng (may Humphrey), dinh g i i dia thj (kinh Volk), khim sinh hien vi, soi gde tien phong de phit hien cac bieu hien t6n thdong trong mit.
Tra Alphagan P vao m i t gidcdm 3 lan /ngay.
Oo lai NA vao 8h- 9h sing sau 1 ngiy, 1 tuan, 2 tuin, 3 tuan, 1 t h i n g , 2 thing, 3 thing, 4 thing, 5 thing, 6 thing d i l u trj. Ghi nhan cic bieu hien khic kdm theo tai m i t va toan t h i n neu cd.
- Oinh g i i ket q u i dieu trj theo tieu chuIn cua AGIS (Advanced Glaucoma Intervention Study):
t h i n h cdng tuy§t ddi neu NA<18 mmHg; thinh cdng tddng doi neu 18 s NA < 21 mmHg; that bai neuNA&21 mmHg.
Trudc Saul Saul Sau2 Sau3 Saul Sau2 Sau3 Sau4 Sau5 Sau6 dikairi ngiy tdta tuin tuin thdng thing thdng thdng thdng thdng (n=60)(n=60) (n=60) (n=47) (n=45) (n=45) (n=42) (n=40) (n=38) (n=38) (n=37)
BiSu do 3.1. Nhdn dp trung binh tai cdc thdi diim theo doi
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 6-N 3/2011 Sau dieu trj Alphagan P mot ngay NA trung binh (NATB) ha xuong con 21,57 ± 8,54mmHg, thdc sdgiim so vdi trddc dieu trj (p < 0,001). Sau 1 tuan NATB trung binh g i i m con 18,53 ± 8,03mmHg. Trong thing dau dieu trj NATB ed sd khic biet gida ngay 1, tuan 1, tuan 2 (p < 0,05); giCira tuan 2, tuan 3, tuan 4 va cac thing sau do khong cd sd khac biet (p > 0,05).
BSng 3.1. 1^ le ha NA tai cac thdi diem theo doi Thdi diem
theo doi Sau 1 ngay
(n=60) Sau 1 tuan
(n=60) Sau 2tuan
(n=47) Sau 3 tuan
(n=45) Sau 4 tuan
(n=45)
Mdc NA ha trung binh 12,98 ±8,25
15,88 ±7,95
18,11 ±7,15
18,44 ±6,6
17,42 ±7,41
% haNA 37,17
45,68
53,45
54,96
52,08
Thdi diem theo doi Sau 2 t h i n g
(n = 42) Sau 3 t h i n g
(n = 40) Sau 4thang
(n = 38) Sau 5 t h i n g
(n = 38) Sau 6 t h i n g
(n = 37)
Mdc NA ha trung binh 18,43 ±6,76
18,85 ±6,69
18,89 ±6,74
18,74 ±6,92
19,24 ±5,73
% haNA 54,49
55,14
55,49
55,65
57,63
Sau ngay dau dieu trj tra thuoc mdc NA ha trung binh 12,98 ± 8,25 mm vdi t^ le ha NA trung binh la 37,17% va hieu q u i dat toi da vao khoing tuan thd 2 (53,45%). J^ le % ha NA trung binh d cic t u i n va cic t h i n g theo doi tiep theo la tdong ddOng nhau (p > 0,05). Ty le chung NA ha trung binh la 52,17%.
Ingiy Ituan 2tiian 3 tuin 1 th&ig 2 thing 3 thing 4 thing 5 thing 6 thing
Thdi gian theo doi sau di^u tn
I That bai NA>2i
I Diiu trj th^nh c6ng tuong d6i
I Dieu tri th&nh cong hoin toin
Thdi gian theo doi
Bii'u do 3.2. Ty le dieu chinh NA sau dieu tri
Sau ngay dau dieu trj 37 m i t (61,67%) cd NA da dieu chinh dddi 21 mmHg, trong do 22 m i t (36,67%) co NA dddi 1 SmmHg. Ti l§ m i t cd NA khong dieu chinh la 38,33% (23 m^t). Sau 1 t u i n so m i t co NA dieu chinh
TAP CHl Y DUqC LAM SANG 108 Tap 6-So 3/2011 ting len den 47/60 m i t chiem 78,33%, trong do cd 35 m i t NA <18 chiem 53,33%. Ti le dieu trj that bai g i i m xuong con 13 m i t (21,67%). Sau t h i n g dau dieu trj ti le m i t cd NA dieu chinh I i 93,33% (42/45 mit), trong do 40/45 m i t (88,89%) dieu trj thanh cdng hoan toan. Tai cic thing theo ddi tiep theo hau het cic mat deu duy tri d mdc dieu trj thanh cdng hoan toan vdi NA < IBmmHg (97,37% va 100%). 6 thing thd 5 ed 1 m i t NA khdng dieu chinh.
Bang 3.2. IVloi lien quan gida NA trddc va sau dieu trj 1 ngay NA trudc
dieu tri 21-30 31-40 41-50 Cpng
N A < 1 8 So mat
11 11 0 22
% 50,00 37,93
0 36,67
1 8 < N A < 2 1 So m i t
6 6 3 15
% 27,27 20,69 33,33 25,00
NA>21 So mat
5 12
6 23
% 22,73 41,38 66,67 38,33
Tong so So mat
22 29 9 60
% 100 100 100 100
Biing 3.3. IVIoi lien quan gida nhin i p trddc va sau dieu tri 1 tuan NA trudc dieu
tri 21-30 31-40 41-50 Cpng
NA So mat
14 19 2 35
<18
% 63,64 65,52 22,22 58,33
1 8 < N A < 2 1 So mat
7 3 2 12
% 31,81
10,34 22,22 20,00
NA So mat
1 7 5 13
>21
% 4,55 24,14 55,56 21,67
Tong sd So mat
22 29 9 60
% 100 100 100 100
Nhdm mdc NA trddc dieu tri la 21-30mmHg cd ti le m i t NA dieu chinh (77,27% v i 95,45%) cao hon d cic mdc NA khic (p < 0,05). d mdc NA 41-50mmHg ty le dieu trj that bai ( NA> 21 mmHg) rat cao (66,67%
va 55,56%).
3.2. Mot so tie dung khdng mong muon cua Alphagan P Tie dung khong mong muon toan than:
+ Khd mieng: xuat hien d 01 benh nhan (1/37) + Buon ngu: xuat hien d 01 benh nhin (1/37)
Tie dung khdng mong muon tai m i t
So mat (%) So m i t thay thuoc khac
Ngda mat 13 (21,67%)
Com mat 7(11,67%)
Rat mat 2 (4,44%)
Cuong tu ket mac 17(28,33%)
4 (6,67%)
4. Ban luan
NA I i mot trong nhdng yeu to quan trpng trong sinh benh hpc benh glocdm. IVIde dp ton hai chdc nang thj giie phu thudc v i o mdc dp va thdi gian NA tang cao. Mdc dp NA trddc dieu trj cung I i mot
trong nhdng yeu to quyet djnh sp Ida chpn thuoc phij hpp nhat cho tdng benh nhin. Oe dinh gia khi ning ha NA thdc sd eua thuoc tren m i t ngddi Viet Nam chung toi khdng gidi ban mdc NA trUde dieu trj (22mmHg 50mmHg), die biet nhdm NA trdn
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 6 N°3/2011 36mmHg cd 31 m i t . Trong khi cac t i c g i i nddc
ngoai chi gidi han t d 22mmHg-36mmHg [6][8].Vi vay NA trung binh trddc dieu trj (34,33 ± 6,64mmHg) va mdc ha NA cua chung toi cao hPn ban ket q u i cua cic t i e g i i khac (24,53mmHg). Ket q u i sau mot ngay dieu trj ty le m i t ed NA dieu chinh hoan toan (< IBmmHg) ehi chiem 36,67%, thap hon eua t i e g i i Jess T va cpng sd (62%). NA trung binh d cic thdi diem theo doi cua chung toi thap hon eua t i e g i i nddc ngoai [6][8]. Alphagan P cd ai Idc cao vdi cic md d mat cd sac to melanine.
Nong dp cao nhat eCia thuoc dat ddpc d viJng mong m i t the mi ed sic to cao hon 4 lan vung mong mat the mi khong cd sic to [1]. Cd the do m i t ngddi Viet Nam ed nhieu sac td melanin nen NA trung binh vdi thuoc d benh n h i n cua chung toi thap hon so vdi ket q u i cua 2 t i c g i i tren. IVlat khac trong nghien edu eua minh t i e g i i Sharpe F.D chi tra thuoc Alphagan P 2 lan/ngay, trong khi benh n h i n cua chung toi tra thuoc 3 lan /ngay
Trong t h i n g dau dieu trj ti le dieu chinh nhan ap khong on djnh. Sau 1 tuan dieu trj so mat ed NA dieu chinh t i n g len den 47/60 mat chiem 78,33%, trong do ed 35 mat NA dieu chinh hoan toan chiem 53,33%. Ti le dieu trj that bai g i i m xuong edn 13 mat (21,67%). Sau mot t h i n g dau dieu trj ed 9 mat NA d i dieu chinh dddi 18mmHg nhdng sau mot thdi gian dieu trj NA cao trd lai (td 21-40mmHg) mac diJ dang dung thuoc. Vi vay viec kham lai djnh ky rat quan trpng de p h i t hien kjp thdi nhdng m i t mat dap dng dieu trj vdi thuoc. Sau 1 t h i n g dieu trj nhdm nghien cdu edn 45 mat, tai thdi diem nay ti le mat ed NA dieu chinh la 93,33% (42/45mat), trong do NA <
IBmmHg la 88,89% (40/45 mat), cao hon so vdi ket q u i cua Carrasco F.C va cpng sd (78,3%) [3].
Tai eae thing theo doi tiep theo chung toi nhan thay, d nhdng mat d i p dng dieu trj vdi Alphagan P NA dieu chinh tdong doi on djnh. Ti le dieu trj thanh cdng hoan toan d cic thing theo doi la rat cao (97,37% va 100%). Duy nhat 1 mat NA khong dieu chinh d thing thd 5 nhdng do benh nhan khong tra thuoc deu va dung gid. NA cua mat nay la 40mmHg, chung toi phii phoi hpp them thuoc ha NA khac de b i o ve chdc nang thj giie cho BN.
Ket qua nghien cdu cua chung toi cho thay hieu qua ha nhan ap cua Alphagan P phu thuoc vao mdc nhan ap cao trddc dieu trj. Nhin ap trddc dieu trj cang cao hieu qua ha nhan i p cua thuoc cang giim.
Die biet d mdc NA 41-50mmHg ty le dieu trj that bai (NA> 21 mmHg) rat cao (66,67% va 55,56%). Doi vdi nhdng mat NA qua cao (>36 mmHg), de dat hieu qua ha NA tot can phai phoi hpp vdi thuoc ha NA nhdm khac
Alphagan P 0,15% t i c dpng len receptor d2.
Trong eo the receptor d2 cd nhieu d he giao cim trung dPng, t i n cung spi than kinh, cP trpn thanh mach. Vi vay khi dung Alphagan P cd the se gap cic t i e dung khong mong muon toan than. Trong thdi gian theo ddi 37 benh n h i n cua chung toi khdng gap t i e dung khdng mong muon toan t h i n nang, p h i i ngdng dieu trj. Trieu chdng kho mieng xuat hien d mot BN nd (1/37) sau 2 tuan dieu trj, keo dai het t h i n g dau va t d mat di d eae t h i n g tiep theo, khong gay khd chju den mdc p h i i ddng thuoc.
Trong khi do cac t i c g i i nddc ngoii gap trieu chdng kho mieng do Brimonidin 0,2% t d 0,23%-!,4%
[5][6][7]. Trieu chdng buon ngu xuat hien d 1/37 benh nhan trong t h i n g dau dieu trj, khdng g i y khd chju cho benh n h i n va t d mat di ma khong can can thiep. Nghien edu eua Raymond P va cpng sd ve hieu qua dieu trj glocom cija Brimonidin 0,2% thay cd 8/292 BN (2,7%) cd trieu chdng buon ngu [7]. Mae du day khong p h i i la trieu chdng toan t h i n ning nhdng rat nguy hiem khi lai xe, dieu khien miy mdc.
Cic t i e g i i khac edn gap t i e dung khdng mong muon khic ciia Brimonidin 0,2% nhd dau dau, met mdi (1,4%)[7]. Tuy nhien nghien edu eCia chung tdi khong gap nhdng trieu chdng toan t h i n nay. Cd the la do Alphagan P ed ham Idpng thuoc 0,15% thap hon b Brimonidin 0,2% nen it g i y t i e dung khong mong muon hon.
Trieu chdng ngda mat xuat hien ngay trong tuan dieu trj dau tien d 13 m i t (21,67%), g i i m di theo thdi gian den t h i n g thd 4. Hau het cic benh nhan deu thay ngda nhieu gde trong mat va xuat hien sau khi tra thuoc khoang 10 phut. Day cd the do thuoc dpng nhieu 6 gdc trong m i t sau khi tra.
Mdc dp ngda cung g i i m dan theo thdi gian, keo dai
TAP CHi Y DUOC LAM SANG 108 Tgp 6-S6 3/2011 td 1 tuan den 2 t h i n g . Tuy nhien khong cd benh
nhin nao p h i i ddng thuoc.
Trieu chdng com mat xuat hien trong tuan dau dieu tri vdi 7/60 m i t (11,67%), g i i m dan trong cic thdi diem theo doi, thddng di kem vdi ngda mit, ft giy khd chju cho benh nhan, keo dai trong khoing 1 tuan.
Cim giie r i t mat la trieu chdng it gap nhdng giy khd chju nhat cho benh nhin. Theo bao cao cua eae t i e g i i nddc ngoai ti le gap trieu chdng r i t mat la 5 - 9%. Trong nghien edu cua chung tdi, den tuan thd 3 sau dieu trj trieu chdng nay mdi xuat hien d 2/45 m i t (4,44%). IVIde dp r i t khdng tang len nhdng thdi gian ton tai keo dai tdtuan thd 3 den thing thd 3. Den thing thd 3 sau dieu tri benh nhin phii thay thudc khic do xuat hien trieu chdng edong tu ket mac ning kem theo, mac du NA dieu chinh tot vdi thuoc.
Cdong tu ket mac la trieu chdng ft g i y c i m giie khd chiu, nhdng i n h hddng nhieu den thi'm my. Sau dieu trj 1 ngay chung tdi d i ghi n h i n ddpc 17/60 mat (28,33%), ed xu hddng tang len d cac tuan theo ddi tiep theo va bieu hien ram rp nhat d tuan t h d 3 (73,33%). Tuy nhien ti le edOng tu ket mac mdc dp nhe nhieu hon ti le cdong tu ket mac mdc dp trung binh. Den het 1 t h i n g dieu trj, ti le m i t bj edOng tu ket mac b i t dau g i i m edn 31,11% (14/45 m i t ) . Trong nghien cdu eua chung toi ed 2 benh n h i n (4 m i t - 6,67%) p h i i thay thuoc khic do edong tu ket mac n i n g mac du NA dieu chinh tot. Tai cac t h i n g theo ddi tinh trang ctrong tu ket mac g i i m , tat c i cic m i t dan dan trd ve trang t h i i binh thddng, khdng can dieu trj. Sau 6 thing dieu trj chi edn 1 m i t (2,7%) cdong tu ket mac d mdc dp nhe. Chung tdi n h i n thay trieu chdng cdpng tu ket mac keo dai nhat I i 2 t h i n g . Trong nghien edu eua minh Jess T d i ghi n h i n ed 34/425 m i t (chiem 8%) bj cdPng tu ket mac do Brimonidin 0,15% [6]
Alphagan P it g i y t i c dung khdng mong muon la nhd chat b i o q u i n cda Alphagan P la Purite. Khi ra anh sing Purite chuyen hoa thanh muoi va nddc vi viy it g i y dpc te bao hon so vdi Benzalkonium chloride (BAK) cd trong Brimonidine.
Sau 6 t h i n g dieu trj nhdm nghien edu cua chung tdi chi cd 4 mat (6,67%) phii thay thuoc khic do t i e dung khdng mong muon cua thudc, thap hon so vdi Jess T va cpng sd (17%), Raymond P v i cpng Slid4,7%) [6][7].
5. Ket luan
1. Hieu q u i dieu trj cua Alphagan P tren benh nhin glocom gdc md:
- Alphagan P la mot thuoc ed t i e dung ha nhin i p tot, ty le mat cd NA dieu chinh bang thuoc cao, ed k h i nang ha nhin ap trung binh tdi 17,69 mmHg, ti/ong dng vdi mdc ha ddpc 52,17% so vdi nhin i p ban dau.
- Mot minh Alphagan P khdng ha dupc nhin i p den mdc an t o i n d nhdng mat ed nhin i p cao > 40 mmHg (theo Goldmann).
2. Nhdng t i e dung khdng mong muon khi diJng thuoc Alphagan P ed the gap la buon ngu, khd hpng, ngda mit, com mit, r i t m i t v i cdong tu ket mac d cic mdc dp khic nhau. Ty le m i t phii thay thuoc do t i c dung khdng mong muon eua thudc rat thap, chi chiem 6,67%.
Tai lieu tham khio
1. Acheampong A.A., Shackleton M.{1995),
"Comperative ocular pharmacokinetics of brimonidine after single dose appllication to the eyes of albino and pigmented rabbits". Drugs Metab Dispos,23,p.708-712(18).
2. Adkins CJ., Balfour A.J. (1998), "Brimonidine A Review of its Pharmacological Properties and Clinical Potential in the Management of Open-Angle Glaucoma and Ocular Hypertention", Drugs Aging,12(3),p.225-241(18).
3. Carrasco F.C, Arias P.A., Garcia Saenz M.C., Villarejo.
Diaz-Maroto I.. (2004), "Efficiency of brimonidine 0,2% and dorzolamide 2% as adjuntive therapy to beta-blocker". Arch Soc Esp Oftalmol, 79(4). p.l63- 168(22).
JOURNAL OF 108 - CLINICAL MEDICINE AND PHARMACY Vol 6 N°3/2011 4.
5.
Chien D.S., Luo A., Tang LO. (1991), "Ocular melanin binding of brimonidine(AGN 190342) in vitro", Pharm Res, 8, p.260 (23).
David A.L.(2001), "Effectiveness and safety of brimonidine as adjuntive therapy for patients with elevated intraocular pressure in a large, open-label communitytrial",JGIaucoma,10, p.220-225. (24) Jess T., Whitson M.D., Katherine I., Ochsner M.D., Marlene R., Moster M.D. (2006), 'The safety and Intraocular Pressure Lowering Efficacy of Brimonidine Tartat 0,15% Preserved with Polyquaternium-1", Ophthalmology, 113(8), p.758- 763(31).
Raymond P.. LeBlane M. D. and Brimonidine Study Group 2 (1998), 'Twelve-month result ofan ongoing randomized trial comparing brimonidine tartat 0,2%
and timolol 0,5% given twice daily in patients with glaucoma or ocular hypertension". Ophthalmology, 105(10), p.l 960-1967. (47).
Sharpe E.D., Day D.G., Beischel C.J., Rhodes J.S.
(2004), "Brimonidine purite 0,15% versus dorzolamide 2% each given twice daily to reduce intraocular pressure in subjects with open angle glaucoma or ocular hypertension", British Journal of Ophthalmology, 88, p.953-956 (50).
