elevated intraocular pressure ( iop ) is a known risk factor for glaucoma progression and reduction of iop can prevent the progression of glaucomatous optic nerve damage and maintain the visual field.1,2 normal tension glaucoma ( ntg ) is a disease characterized by progression of glaucomatous disorders despite the maintenance of iop within the normal range . nonetheless , reduction of the iop is also important in the treatment of ntg , and it has been reported that the target reduction rate of iop should be set at 30%.1,2 numerous reports have indicated that prostaglandin analog ( pga ) therapies are effective in reducing iop in ntg.312 however , since pgas produce only approximately a 20% reduction of iop,312 it is considered that the use of prostaglandin ( pg ) alone may be insufficient for obtaining the required 30% reduction of iop , according to the reports of the collaborative normal - tension glaucoma study group.1,2 the majority of patients eventually require more than one medication to control their iop . when iop control is inadequate with pgas alone , the addition of one of several therapies , including carbonic anhydrase inhibitor , timolol maleate 0.5% , and fixed combination therapies , has been shown to provide additional iop control.1317 however , it is yet unclear which of these therapies are superior in iop control . treatment that is inconvenient or causes undesirable side effects encourages nonadherence in patients with glaucoma . by contrast , reducing the number of products and the number of required daily instillations increases patients adherence.18 in recent years , various fixed combinations have been introduced in the market . combining two medications in one bottle may reduce the time required to administer drops , the frequency or total number of drops , and the number of medication bottles . therefore , the combination formulation may improve the rate of compliance and consequently improve iop control . there are many reports that have demonstrated the efficacy of these drugs in lowering the iop in patients with primary open - angle glaucoma.1317 however , there are no reports on the effect of the fixed combination of dorzolamide 1.0%/timolol maleate 0.5% ( dtfc ) ( cosopt ; mds / santen , tokyo / osaka , japan ) in ntg patients . in addition , there are also no reports on the additional iop - lowering effect of dtfc in ntg patients treated with pgas . therefore , in this study , the additive iop - lowering effect of dtfc on pgas monotherapy as the first - line therapy in japanese patients with ntg was investigated . this was a prospective , clinical , case - controlled study undertaken from december 1 , 2010 to may 30 , 2011 . the study followed the tenets of the declaration of helsinki and had the approval of the ethics committee of mizoguchi eye clinic . written informed consent patients with ntg satisfying all of the following inclusion criteria were eligible for the study : ( 1 ) having had received pg as first - line glaucoma monotherapy ; ( 2 ) in cases of bilateral ntg , the eye with higher iop or the more advanced eye was selected ; ( 3 ) aged 40 years or over ; ( 4 ) refractive error of more than 6 dpt ; ( 5 ) no history of previous treatment of glaucoma . the exclusion criteria were : ( 1 ) patients with exfoliation syndrome ; ( 2 ) patients with diabetic retinopathy ; ( 3 ) refractive error of less than or equal to 6 dpt ; ( 4 ) patients with a history of ocular trauma , ocular inflammatory disease , glaucoma surgery , vitrectomy , and laser trabeculoplasty ; ( 5 ) patients with conjunctivitis , dry eye or periocular cutaneous disease , possibly affecting the results of the investigation ; ( 6 ) currently pregnant or nursing women , or women considering pregnancy were also excluded , as were patients with a history of noncompliance , or patients who had participated in another therapeutic drug study within 1 month ; ( 7 ) history of cerebrovascular and hepatic disease . ntg was diagnosed when glaucoma hemifield test results were outside the normal limits ; the standard deviation had a p - value < 0.05 ; or there was a cluster of three points or more in the pattern of the deviation plot , in a single hemifield , with a p - value < 0.05 , one of which had to have a p - value < 0.01 on the humphrey swedish interactive thresholding algorithm 24 - 2 test ( humphrey visual field analyzer , model 750 , humphrey instruments , san leandro , ca ) and/or a nerve fiber layer defect combined with a corresponding optic disk change . in addition , the iop measured by goldmann applanation tonometer ( haag - streit , koniz , switzerland ) was consistently less than 21 mmhg . patients who had previously received pg as glaucoma monotherapy , and needed to receive additive medications on pgas monotherapy because of inadequate iop reduction , were enrolled in the study . twenty - four eyes were given tafluprost 0.005% ( tapros ; santen pharmaceutical co ltd , osaka , japan ) , ten eyes were given latanoprost 0.005% ( xalatan ; pfizer , inc , new york , ny ) , and six eyes were given travoprost 0.004% ( travatanz , alcon laboratories inc , fort worth , tx ) . patients received pg at a dose of one drop every evening ( 9 pm ) to the study eye . once - daily administration ( at 9 pm ) of pg as monotherapy was continued and dtfc was added twice daily ( 9 am and 9 pm ) for 8 weeks after the baseline visit . all patients enrolled in the study underwent a comprehensive ocular examination , including measurement of best - corrected visual acuity , slit lamp examination , and biomicroscopic fundus examination . static gonioscopy was performed using goldmann 2-mirror lens ( haag - streit ) at the first visit or before cataract surgery . if the difference in iop between any two of the three measurements was greater than 3 mmhg , the median value was used . baseline and post - treatment values were compared by a one - way repeated - measures analysis of variance test . the difference in iop correlation between the baseline iop and percent iop reduction was analyzed by spearman s correlation coefficient by rank test . a p - value of < 0.05 ( two - tailed ) was regarded as statistically significant . statistical analysis was performed using statistical analysis system ( v 8 ; sas institute inc , tokyo , japan ) software . baseline and post - treatment values were compared by a one - way repeated - measures analysis of variance test . the difference in iop correlation between the baseline iop and percent iop reduction was analyzed by spearman s correlation coefficient by rank test . a p - value of < 0.05 ( two - tailed ) was regarded as statistically significant . statistical analysis was performed using statistical analysis system ( v 8 ; sas institute inc , tokyo , japan ) software . in total , 44 patients ( 44 test eyes ) were enrolled in this study . one patient dropped out of the study prematurely because of change of residence and discontinued their visit to the clinic . in three patients , treatment was discontinued because of the development of conjunctival hyperemia and ocular irritation . after excluding these four cases , table 2 shows the iop and the percent iop reduction from the baseline iop at weeks 4 and 8 . significant decrease of the iop was observed at weeks 4 and 8 as compared with the baseline iop ( p = 0.01 ) . the percent reduction from the baseline iop at weeks 4 and 8 was 13.5%  12.3% and 11.7%  13.1% , respectively . table 3 shows the iop and percent iop reduction at each time point of measurement of the patient with a baseline iop of 15 mmhg or higher ( the high teens group ) and those with a baseline iop of less than 15 mmhg ( the low teens group ) . in the high teens group , significant additional iop reduction was observed at each time point of measurement as compared with the baseline iop ( p = 0.01 ) . however , in the low teens group , there was no significant difference in the iop from baseline iop at any time point ( p = 0.182 ) . the percent reduction at week 8 from the baseline in the high teens group and the low teens group was 14.7%  11.7% and 6.6%  14.2% , respectively . tables 4 and 5 show the number and percentage of patients who achieved 10% or more , 20% or more , or 30% or more iop reduction from baseline at week 8 . the percentage of patients whose iop reduction was 10% or more , 20% or more , or 30% or more was 62.5% , 22.5% , and 5% , respectively ( table 4 ) . in the high teens group and low teens group , those were 72% and 53% , 32% and 13% , and 8% and 0% , respectively ( table 5 ) . figure 1 shows the correlation between the baseline iop and percent iop reduction using spearman s correlation coefficient by rank test . the baseline iop was significantly correlated with the percent iop reduction ( p = 0.03 , r = 0.34 ) . the most frequent adverse events related to the study medications were blurred vision , eye irritation , ocular hyperemia , and eye itching ( table 6 ) . a number of reports have indicated that dtfc might be effective in lowering the iop in patients with glaucoma.1317 in addition , there are reports that the iop - lowering effect of the dorzolamide / timolol fixed combination may be equivalent to that of concomitant dorzolamide / timolol therapy , and other reports suggesting that the fixed combination therapy has a significant iop - lowering effect.14,16,17 all these studies were conducted in patients with primary open - angle glaucoma who have elevated iops . there have been no reports on the efficacy of dtfc in ntg patients , reported for the first time in this study . the reported iop - lowering effect of pg is approximately 20% in ntg patients , which suggests that pga alone is insufficient for obtaining the target 30% or more reduction of iop,311 according to the report of the collaborative normal - tension glaucoma study group.1,2 glaucoma progression was seen significantly less frequently in the group in which a 30% or more iop reduction was achieved , as compared with that in the group in which such reduction failed to be achieved.1,2 if the targeted iop reduction can not be obtained with pga monotherapy , additional medications are considered necessary . in this study , the iop decreased significantly and remained low for 2 months with dtfc as second - line therapy , even in patients with ntg who had previously received iop - lowering therapy with pga . in 80% of the cases , in addition , the drug combination produced an approximate additional 13% lowering of the iop , as compared with the baseline iop , suggesting that the administration of dtfc can be expected to produce an additional effect in patients in whom the target reduction rate ( 30% ) of iop has not been achieved by administration of pg alone . konstas et al15 have reported that the administration of latanoprost and dtfc had the strongest iop - lowering effect in patients with primary open - angle glaucoma , suggesting that administration of the dtfc in addition to pg might also produce a strong iop - lowering effect in patients with ntg . however , it was also found that the administration of dtfc had no significant iop - lowering effect in patients with iop levels of < 15 mmhg prior to the start of treatment , and no effect can be expected in such patients . the iop was significantly reduced after additional instillation in ntg patients with baseline iop of > 15 mmhg prior to the additional instillation , therefore , additional instillation is considered to be effective in ntg patients with relatively high iop levels . in addition , a significant correlation was found between the baseline iop prior to the additional instillation and the percent iop reduction from the baseline iop ; that is , the higher iop was prior to the start of the additional administration , the higher the percent iop reduction from the baseline iop . these results suggest that additional administration of dtfc is effective , and that it can improve the achievement rate of the target iop in ntg patients , of which the targeted iop could not be obtained with pga monotherapy as first - line therapy . it is considered important to determine the most effective pgs as the first - line medicine . if the target iop can not be achieved with pg monotherapy , additional instillation becomes necessary . it is reported that adherence to glaucoma medication is often poor.1820 multiple factors related to poor adherence have been identified , including more frequent18 and complex dosing.20 therefore , the number of medications should be reduced as much as possible for nonadherence patients . if iop is inadequate with pga as first - line medication , fixed combination should be added as second - line medication , because the therapy is less inconvenient . with regard to safety all of the adverse events were mild . in this study , there was little change in the eyes after treatment compared with condition at the baseline period , suggesting that adverse events are unlikely to pose a significant clinical problem during use of dtfc . this study suggests that a significant iop - lowering effect can be obtained by instillation of dtfc in ntg patients in whom the target iop has not been achieved by pg instillation alone . furthermore , the higher the iop prior to the additional administration , the higher the rate of reduction of iop became . taking treatment adherence into consideration , it was considered that dtfc was useful as a second choice drug for use in elderly patients with ntg after treatment with a pg preparation . however , the number of cases in this study was small , and further studies with a larger number of cases are considered necessary .
purposeto evaluate the intraocular pressure ( iop)-lowering effect of adding dorzolamide 1.0%/timolol 0.5% fixed combination ( dtfc ) to prostaglandin analogs ( pgas ) as monotherapy in patients with normal tension glaucoma.methodsa prospective , clinical , case - controlled study of patients with normal tension glaucoma . 
 patients had been on a once - daily night dose of prostaglandins ( pgs ) as monotherapy and then received dtfc added to pgs for 8 weeks . 
 the iop was measured at 9 am , week 0 ( baseline ) , week 4 , and week 8.resultsthe baseline iop of 40 patients who had previously been treated by prostaglandin monotherapy was 15.6  2.0 mmhg at baseline . 
 the iops at 4 and 8 weeks after adding dtfc to pgs were 13.5  2.1 mmhg and 13.7  2.2 mmhg , respectively . 
 significant decrease of the iop was observed at each time point of measurement as compared with the baseline iop before adding dtfc ( p = 0.01 ) . 
 the percent iop reduction from the baseline iop at week 4 and week 8 was 13.5%  12.3% and 11.7%  13.1% , respectively . 
 the percentage of patients who achieved 10% or more iop reduction from the baseline iop at week 8 was 62.5% . 
 the baseline iop was significantly correlated with the percent iop reduction at week 8 ( p = 0.03 , r = 0.34).conclusiondtfc therapy added to pgas as glaucoma monotherapy is effective in patients with normal tension glaucoma .