`
`
`
`
`
`
`
`Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/http://bjo.bmj.com/
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by group.bmj.com on March 4, 2018 - Published by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`75
`
`CLINICAL SCIENCE
`Additive effect of unoprostone and latanoprost in patients
`with elevated intraocular pressure
`Tin Aung, Paul T K Chew, Francis T S Oen, Yiong-Huak Chan, Lennard H Thean,
`Leonard Yip, Boon-Ang Lim, Steve K L Seah
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`BrJOphthalmol 2002;86:75–79
`
`Aims: To assess the additive effect of unoprostone and latanoprost in patients with primary open angle
`glaucoma (POAG) or ocular hypertension (OHT)
`Methods: 32 patients with POAG or OHT were randomised to receive either latanoprost once daily or
`unoprostone twice daily for 4 weeks. After 4 weeks, all patients received both latanoprost and
`unoprostone for another 4 weeks. The IOP was measured at 9 am and 5 pm on the baseline, day 28,
`and day 56 visits, and at 9 am on day 14 and day 42 visits. The medications were given to the patients
`in an open label fashion. The observer was masked to the treatment given. The mean of the measure-
`ments was calculated. Safety parameters were also recorded. The additive effect of the medications
`was assessed by the reduction in intraocular pressure (IOP) when both medications were used,
`compared with when one medication was used.
`Results: 28 patients completed both treatment periods and had IOP data available for evaluation.
`After 1 month of treatment, latanoprost significantly reduced IOP (mean by 6.1 (SEM 0.8) mm Hg
`(p<0.001) and unoprostone by 4.9 (1.0) mm Hg (p<0.001) from the baseline of 24.4 (0.6) mm Hg
`and 24.4 (1.1) mm Hg respectively (p = 0.18). When latanoprost once daily was given to patients
`treated with unoprostone, there was additional IOP lowering of 1.9 (0.6) mm Hg (p = 0.012). How-
`ever, adding unoprostone to those being treated with latanoprost produced an IOP change of +0.4
`(0.5) mm Hg (p = 0.42). Ocular symptoms and findings were mild and equally distributed between
`treatment groups, and after combined therapy. Hyperaemia and ocular irritation were the most
`frequently reported events. Over a third of patients experienced ocular irritation with the combination
`of medications.
`Conclusions: Latanoprost once daily causes additional IOP lowering in eyes which were being treated
`with unoprostone twice a day. However, there was no additional IOP lowering when unoprostone was
`added to eyes which were being treated with latanoprost. Both drugs were well tolerated together with
`few ocular adverse events.
`
`See end of article for
`authors’ affiliations
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Correspondence to:
`Professor P T K Chew,
`Department of
`Ophthalmology, National
`University Hospital, 5
`Lower Kent Ridge Road,
`Singapore 119074;
`ophchewp@nus.edu.sg
`
`Accepted for publication
`23 July 2001
`. . . . . . . . . . . . . . . . . . . . . . .
`
`Therapeutic regimens for glaucoma have changed dramati-
`
`cally in the past few years. Newer glaucoma therapies
`such as the prostaglandin analogues, latanoprost and
`unoprostone, have few side effects and convenient dose
`schedules. Latanoprost, a prostaglandin F2a analogue, has
`proved to be an effective ocular hypotensive drug.1–7 Its main
`mechanism for reducing intraocular pressure (IOP) is an
`increase in the uveoscleral outflow.8 9 In long term studies,
`latanoprost 0.005% applied once daily reduced IOP as
`effectively as the b adrenergic receptor antagonist timolol in
`patients with primary open angle glaucoma (POAG) or ocular
`hypertension (OHT).6 7 Unoprostone isopropylate is a docosa-
`noid derived from a metabolite of a primary prostaglandin,
`13,14-dihydro-15-ketoprostaglandin. It was found to have a
`significant ocular hypotensive effect, and was as effective as
`timolol in reducing IOP in POAG.10 11 It is thought to act by
`increasing uveoscleral outflow, similar to latanoprost.12 13
`et al14 suggested that
`However, a study by Taniguchi
`unoprostone may increase conventional trabecular outflow.
`There is no published literature on the additive effect of
`latanoprost with unoprostone for treatment of primary open
`angle glaucoma and ocular hypertension. In view of the possi-
`bility that they may have differing mechanisms of action, it
`would be interesting to know if the two drugs exert greater
`IOP lowering effect when used together. This is especially so in
`patients who are intolerant or have contraindications to b
`blocker therapy and a prostaglandin analogue may need to be
`used. It would also be useful to determine the side effects in
`patients based on the combined response to these drugs. This
`
`study was thus designed to assess the additive ocular
`hypotensive effect and side effects of using unoprostone and
`latanoprost together in patients with elevated IOP.
`
`MATERIALS AND METHODS
`This two centre study was prospectively carried out at the Sin-
`gapore National Eye Centre and the National University Hos-
`pital, Singapore. After obtaining approval from the ethics
`committees of each centre and by the Ministry of Health of
`Singapore, a signed informed consent was obtained from all
`patients before study enrolment. The study was performed
`according to the Declaration of Helsinki and the Singapore
`guidelines on good clinical practice.
`Patients 21 years of age or older with primary open angle
`glaucoma or ocular hypertension were eligible. All patients
`recruited had IOP >21 mm Hg at the prestudy visit and were
`previously untreated. POAG was defined as glaucomatous
`optic neuropathy with a compatible visual field defect and
`open angles on gonioscopy, while OHT patients had normal
`optic discs and visual fields and open angles. Glaucomatous
`optic neuropathy was defined as a cup:disc ratio of >0.6, or the
`presence of notching. A threshold examination of the central
`24° of visual field (24-2 program) showing a glaucoma hemi-
`field test (GHT) “outside normal limits,” and a cluster of three
`contiguous points on the pattern deviation plot depressed at
`p<5% level (compared with age matched normal subjects) not
`crossing the horizontal meridian, was considered compatible
`with glaucoma. Test reliability was determined by the instru-
`ment’s algorithm.
`
`www.bjophthalmol.com
`
`IPR Page 1/13
`
`Santen/Asahi Glass Exhibit 2036
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`Downloaded from
`
`http://bjo.bmj.com/
`
`
`
`group.bmj.com on March 4, 2018 - Published by
`
`76
`
`Aung, Chew, Oen, et al
`
`Patients requiring bilateral treatment had to fulfil all eligi-
`bility criteria for both eyes to be included. However, if only one
`eye fulfilled the inclusion criteria, that eye was included as the
`study eye and the fellow eye could be treated with the
`allocated study therapy provided that no exclusion criteria
`were met.
`Exclusion criteria were gonioscopic appearance of angle
`closure, secondary glaucoma such as uveitis, neovascular
`glaucoma or post-trauma, previous intraocular surgery, previ-
`ous trauma to the eye with damage of the anterior chamber
`angle, the fellow eye on treatment with another IOP reducing
`drug, previous treatment with glaucoma therapy, previous
`corneal infection or corneal abnormalities, uveitis or dry eyes,
`current use of contact lenses, oral drugs known to affect the
`IOP, and known allergy to benzalkonium chloride. Also, a his-
`tory of cerebrovascular, hepatic, or metabolic disease (except
`diabetes mellitus) was considered a reason for exclusion. Cur-
`rently, pregnant or nursing women, or women considering
`pregnancy were also excluded, as well as patients with a his-
`tory of non-compliance or patients who participated in
`another therapeutic drug study within 1 month.
`There were two treatment periods of 4 weeks each. At the
`prestudy visit, medical and ocular history was taken. Visual
`acuity and refraction, slit lamp examination, ophthalmoscopy,
`and measurement of the IOP were performed. Gonioscopy and
`perimetry were also carried out. Patients were included after
`these eligibility assessments.
`On the baseline day, the patients were randomised (by block
`randomisation) to two parallel study groups: one group was
`assigned to treatment with latanoprost 0.005% in the evening
`and the other group received unoprostone 0.12% twice daily,
`for a duration of 4 weeks. After 4 weeks, all patients were given
`0.12% unoprostone twice daily (in the morning and evening)
`and latanoprost 0.005% in the evening, for another 4 weeks.
`All types of medication were dispensed open label as the
`commercially available preparation,
`latanoprost (Xalatan,
`Pharmacia Corporation, Uppsala, Sweden) and unoprostone
`(Rescula, Ciba Vision Ophthalmics, Bulach, Switzerland).
`Patients were instructed to instil unoprostone at approxi-
`mately 8 am and 8 pm each day and latanoprost at 8 pm. When
`on both medications, the evening unoprostone and latano-
`prost doses were administered 10 minutes apart. On visit days
`to the clinic (days 14, 28, 42, and 56), those on unoprostone
`administered the eye drops in the mornings at 7 am before the
`clinic visit. Patients were informed to adhere strictly to the
`timing of the drops and the time of administration of drops
`was recorded.
`During each study period there were three scheduled visits;
`at day 0, day 14, and day 28. The IOP was measured at 9 am
`and 5 pm on the baseline, day 28, and day 56 visits, and at 9 am
`on day 14 and day 42 visits. The IOP was measured with a
`Goldmann applanation tonometer. Three measurements were
`performed in each eye, and the mean of
`the three
`measurements was used in the statistical analyses. The
`observer was masked to the treatment given. Best corrected
`Snellen visual acuity and refractive error, systemic blood pres-
`sure, and pulse rate were determined at each visit, and a slit
`lamp examination was performed. The presence of cells and
`flare in the anterior chamber was investigated during slit lamp
`examination. Flare was graded as none, moderate, or severe,
`and cells present in a slit of 2 mm width were graded as none
`(1–2 cells), mild (3–5 cells), moderate (6–20 cells), or severe
`(>20 cells).
`Adverse events were monitored carefully throughout the
`study. An adverse event was defined as any undesirable event
`occurring in a subject regardless of whether it was considered
`related to the drug being investigated. A serious adverse event
`was defined as an event that was potentially fatal, life threat-
`ening, permanently disabling, requiring hospitalisation, or
`requiring intervention to prevent permanent impairment or
`damage.
`
`www.bjophthalmol.com
`
`Statistical evaluation
`For each patient, the IOP value was calculated at baseline and
`day 28 of each period as the mean of all measurements made
`on the study eye(s) on that day (mean diurnal IOP). If the
`patient had only one study eye, the average was based on the
`measurements made in that eye only. For patients with bilat-
`eral disease, data from one eye chosen at random in each indi-
`vidual were selected for analysis. In the event that the patient
`was missing one or more measurements, the average was
`based on the non-missing measurements.
`The primary objective of the study was to test if latanoprost
`was additive to unoprostone, and vice versa. The null hypoth-
`esis was defined as IOP reduction on day 28 (monotherapy)
`being equal to the IOP reduction on day 56 (combined
`therapy), in both cases compared with the IOP on day 0. The
`alternative hypothesis was that the combination therapy fur-
`ther reduced IOP by 3 mm Hg compared with treatment with
`only one drug. The further reduction was presumed to repre-
`sent the additive effect of the second drug since the effect of
`the first drug is assumed to be stable after 28 days of
`treatment.
`It is anticipated that the between treatment groups SD is 3
`mm Hg. The trial size of 32 will be sufficient to detect a differ-
`ence in IOP between day 42 and day 28 of 3.0 mm Hg, with a
`two sided test size of 5% and power 90%.15
`All statistical tests were conducted at the 5% level using SPSS
`software version 8.0 (Statistical Package for Social Sciences,
`Chicago, IL, USA).
`
`RESULTS
`Of
`the 32 patients randomised to the study, 15 were
`randomised to start with latanoprost and 17 started with
`unoprostone. Two patients starting on unoprostone withdrew
`after day 14 because of side effects.
`At day 28, the remaining 30 patients had the other
`medication added and were on both medications. Two
`additional patients withdrew before the day 42 visit. Both
`subjects (one on unoprostone and the other on latanoprost)
`could not tolerate the side effects.
`Unless otherwise stated, the following analyses will take
`into account 15 subjects on day 28 and 14 subjects on day 56
`in each of the groups.
`Table 1 refers to the baseline demographic characteristics.
`There were no significant differences between the two groups
`with respect to sex, race, and age. As for other factors such as
`laterality of eyes involved, type of glaucoma, medical history,
`use of concomitant treatment, ocular symptoms and findings,
`and vital signs at the prestudy visit, the two treatment groups
`were comparable.
`
`Change in intraocular pressure during the study
`periods
`Table 2 summarises the change in IOP in the two groups in
`each study period.
`At the end of period 1 (day 28), the mean decrease in IOP
`was 6.1 (0.8) mm Hg (p<0.0001) for latanoprost treated
`patients, and 4.9 (1.0) mm Hg (p<0.0001) for unoprostone
`treated patients. The mean difference in IOP drop between the
`two groups was 1.2 (1.3) mm Hg in favour of latanoprost (p =
`0.35). Every patient had IOP lowering with the medications in
`this study period (100% response).
`At the end of period 2 (day 56), mean decrease in IOP in the
`latanoprost-unoprostone group was +0.4 (0.5) mm Hg
`(p=0.42). However, for the unoprostone-latanoprost group,
`the mean change in IOP during period 2 was 1.9 (0.6) mm Hg
`(p=0.012). This difference in IOP change of 2.3 (0.8) mm Hg
`between the two groups in period 2 was significant (p=0.009).
`Adjusting for day 28 IOP, this difference increases to 2.5 (0.9)
`(p = 0.009, 95% CI 0.7 to 4.3).
`
`IPR Page 2/13
`
`

`

`Downloaded from
`
`http://bjo.bmj.com/
`
`
`
`group.bmj.com on March 4, 2018 - Published by
`
`Additive effect of unoprostone and latanoprost in patients with elevated intraocular pressure
`
`77
`
`Table 1 Demographic characteristics of study
`groups
`
`Characteristics
`
`No of patients
`Age:
`Mean
`SD
`Sex:
`Male
`Female
`Race:
`Chinese
`Malay
`Indian
`Others
`Type of glaucoma:
`POAG
`OHT
`Laterality:
`Unilateral
`Bilateral
`
`Latanoprost-
`unoprostone
`
`Unoprostone-
`latanoprost
`
`15
`
`58.0
`14.0
`
`4
`11
`
`9
`1
`3
`2
`
`10
`5
`
`1
`14
`
`17
`
`60.8
`14.1
`
`8
`9
`
`14
`1
`2
`0
`
`12
`5
`
`4
`13
`
`Table 3 Adverse events experienced by patients
`
`No of eyes with side effect
`
`Period 1
`
`Latanoprost
`
`Unoprostone
`
`Eye irritation
`Blurred vision
`Eyelid swelling
`Dry eye
`Eye redness/conjunctiva
`hyperaemia
`Cornea PEEs
`Uveitis
`Palpitations
`
`4
`1
`1
`0
`5
`
`0
`0
`0
`
`3
`0
`0
`1
`0
`
`2
`1
`1
`
`Period 2
`
`Eye irritation
`Tearing
`Eye itch
`Conjunctiva
`redness/hyperaemia
`Body itch
`Fatigue
`Giddiness
`
`Latanoprost +
`unoprostone
`
`Unoprostone +
`latanoprost
`
`6
`1
`1
`2
`
`0
`0
`0
`
`4
`0
`1
`1
`
`1
`1
`1
`
`Only 43% of patients on latanoprost had IOP lowering when
`unoprostone was added. In contrast, 86% of patients on uno-
`prostone experienced lowering of IOP when latanoprost was
`added to unoprostone treatment.
`
`Adverse events
`The adverse events experienced by the subjects by period are
`summarised in Table 3.
`There were a few patients with systemic adverse events
`during the study. In the first period, one patient experienced
`palpitations while on unoprostone, stopped the medication on
`day 14, and withdrew from the study. During the second study
`period, there was one patient who had body itch after having
`latanoprost added to her treatment. Another subject experi-
`enced fatigue and giddiness, but neither complaint was of
`sufficient severity to stop treatment. In all cases, the systemic
`symptoms resolved after cessation of treatment.
`There were three subjects who withdrew from the study
`because of ocular side effects. One subject stopped the trial
`medication (in this case unoprostone) on day 14, as she devel-
`oped eye redness and pain after applying the drops. This
`resolved on stopping the medication. The other two subjects
`withdrew on day 42 as they experienced intolerable eye irrita-
`tion after having the second medication added.
`Ocular adverse effects were generally mild in nature and
`similar in the two groups. The commonest adverse events were
`
`ocular irritation and redness. Over a third of patients
`experienced ocular irritation with the combination of medica-
`tions. There was only one subject who had mild anterior
`chamber inflammation, while on unoprostone only. Interest-
`ingly, there was no case of ocular inflammation found in the
`second study period when subjects were on two medications.
`
`DISCUSSION
`Many glaucoma patients are treated with more than one ocu-
`lar hypotensive medication. This is especially so after the
`introduction of newer medications with fewer side effects and
`convenient dose schedules, such as the prostaglandin ana-
`logues. Determination of additive effects on IOP of such glau-
`coma medications will help define optimum treatment
`regimens for patients. It has been previously reported that
`latanoprost has an additive IOP lowering effect when used
`with timolol,16 17 pilocarpine,18 19 dipivefrin,20 dorzolamide,21
`acetazolamide,22 and the combination of
`timolol and
`dorzolamide.23 The question of whether two of the new
`prostaglandin analogues, latanoprost and unoprostone, are
`additive when used together is interesting. Theoretically, this
`is possible if the two medications have differing mechanisms
`of action on aqueous outflow.
`Our study found that when latanoprost once daily was
`added to patients being treated with unoprostone twice daily,
`
`Table 2
`
`IOP profile in the two groups
`
`Latanoprost-unoprostone
`
`Unoprostone-latanoprost
`
`Day 0
`Mean (SE)
`Day 14
`Mean (SE)
`Day 28
`Mean (SE)
`Day 42
`Mean (SE)
`Day 56
`Mean (SE)
`
`24.4 (0.6)
`
`17.4 (0.7)
`
`17.8 (0.4)
`
`18.5 (0.6)
`
`18.2 (0.6)
`
`24.4 (1.1)
`
`19.4 (1.2)
`
`19.6 (0.9)
`
`18.8 (1.1)
`
`18.0 (1.2)
`
`Change in IOP (mean (SE))
`
`Days 28 and 0
`Days 56 and 28
`
`- 6.1 (0.8 (p <0.001)
`+0.4 (0.5 (p = 0.42)
`
`- 4.9 (1.0 (p <0.001)
`- 1.9 (0.6 (p = 0.012)
`
`www.bjophthalmol.com
`
`IPR Page 3/13
`
`

`

`Downloaded from
`
`http://bjo.bmj.com/
`
`
`
`group.bmj.com on March 4, 2018 - Published by
`
`78
`
`Aung, Chew, Oen, et al
`
`there was an additional IOP lowering of 1.9 (0.6) mm Hg
`(p=0.012) indicating that there was additive effect. However,
`adding unoprostone to those being treated with latanoprost
`produced a negligible effect on IOP (change of +0.4 (0.5) mm
`Hg, p=0.42). The findings are in agreement with those of
`Stewart and colleagues who also found no significant
`reduction in the mean diurnal curve of the IOP compared with
`placebo when adding unoprostone to latanoprost, although
`there was some variance in response that appeared to be based
`on the baseline IOP of latanoprost treated eyes.24
`Several reasons may account for the difference in effect
`found in our study. A plausible explanation is that unopros-
`tone is less effective in reducing IOP at lower IOP levels. This
`was the case at the beginning of study period 2 when the
`mean baseline IOP of latanoprost-unoprostone treated pa-
`tients was 17.8 (0.4) mm Hg, which was in the physiological
`range. A previous report found that unoprostone reduces IOP
`by about 10% in normal tension glaucoma.25 Latanoprost, on
`the other hand, has been previously shown to be effective at so
`called “low” IOPs in patients with this form of glaucoma, and
`produces an IOP reduction of approximately 20%.26 27 In this
`study, the mean baseline IOP of unoprostone-latanoprost
`patients at the start of study period 2 was 19.6 (0.9) mm Hg.
`Although this was also within the physiological range, it was
`within the efficacy range of latanoprost.
`Another possible reason to explain the lack of additive effect
`when unoprostone was added to latanoprost is that there were
`many patients who did not show IOP lowering with unopros-
`tone in the second study period. Only 43% of patients on
`latanoprost had IOP lowering when unoprostone was added.
`In contrast, 86% of patients on unoprostone experienced low-
`ering of IOP when latanoprost was added to unoprostone
`treatment. In the first study period, all patients (100%) in both
`groups had IOP lowering with the study medications. It is
`possible that both latanoprost and unoprostone are competing
`for the same prostaglandin receptor sites, and latanoprost is
`more highly competitive or more potent than unoprostone.
`Thus, when latanoprost is added to unoprostone therapy, there
`is additional effect, but not vice versa.
`Finally, the additional IOP lowering attributed to the addi-
`tion of latanoprost may actually be due to the delayed
`response of unoprostone. This is possible if unoprostone had
`not achieved maximum IOP lowering at the end of 4 weeks of
`treatment (the first study period), and it only reached its
`maximum response later. The time required for maximum IOP
`lowering effect for unoprostone is not known. However, a pre-
`vious study has shown that after 2 weeks of treatment,
`latanoprost had almost reached maximum response, com-
`pared with 1 and 6 months of treatment.28 Thus, 1 month of
`treatment should have been sufficient to produce a maximum
`response in both study groups.
`The other significant finding in this study is that
`latanoprost and unoprostone can be used together without
`clinically unacceptable systemic or ocular side effects. Overall,
`both drugs were well tolerated individually and together. The
`side effects found in the second study period when the two
`drugs were used together were infrequent and generally mild
`in nature. The most common complaint was ocular irritation
`(10 subjects) but only two subjects found it serious enough to
`stop treatment. There were a few cases of conjunctival hyper-
`aemia. Because prostaglandins are known to be released in the
`inflammatory response,29–31 cells and flare in the anterior
`chamber were regularly monitored during both study periods.
`However, there was no case of uveitis found during combined
`therapy. The only systemic adverse effects found during com-
`bined therapy were vague complaints of giddiness and fatigue
`in one case and body itch in another. We were not able to be
`sure that these systemic adverse events were caused by the
`medications, as the patients were not rechallenged with the
`same eye drops after completion of the study.
`The main limitation of this study was that it was single
`masked to the observer only. A placebo was also not used for
`
`www.bjophthalmol.com
`
`the morning dose in the latanoprost group. Accordingly, the
`side effects found when the second medication was added
`must be interpreted with caution because of the open label
`dosing and lack of placebo in the trial.
`In conclusion, this study has shown that latanoprost once
`daily causes additional IOP lowering in eyes which were being
`treated with unoprostone twice a day. However, there was no
`additional IOP lowering when unoprostone was added to eyes
`which were being treated with latanoprost. Both drugs were
`well tolerated together with few systemic or ocular adverse
`events. It would be interesting to discover the pathway and
`molecular basis through which these medications interact and
`function. Long term studies would be useful to determine if
`these additive effects are sustainable and if the two drugs can
`be used continuously without clinically unacceptable side
`effects.
`
`ACKNOWLEDGMENTS
`Proprietary interest: Nil
`Support: Grant from Singapore Eye Research Institute (SERI). Dr
`Aung is also supported by the National Medical Research Council,
`Singapore.
`
`. . . . . . . . . . . . . . . . . . . . .
`Authors’ affiliations
`T Aung, P T K Chew, F T S Oen, L H Thean, L Yip, B-A Lim, J Soh, S
`K L Seah, Singapore National Eye Centre
`P T K Chew, National University of Singapore
`Y-H Chan, Jade Soh, Clinical Trials and Epidemiology Research Unit,
`Singapore
`
`REFERENCES
`1 Alm A, Widengard I, Kjellgren D, etal. Latanoprost administered once
`daily caused a maintained reduction of intraocular pressure in glaucoma
`patients treated concomitantly with timolol. BrJOphthalmol
`1995;79:12–6.
`2 Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group.
`Effects on intraocular pressure and side effects of 0.005% latanoprost
`once daily, evening and morning. A comparison with timolol.
`Ophthalmology 1995;102:1743–52.
`3 Camras CB, the United States Latanoprost Study Group. Comparison of
`latanoprost and timolol in patients with ocular hypertension and
`glaucoma. A six-month, masked, multicenter trial in the United States.
`Ophthalmology 1996;103:138–47.
`4 Watson P, Stjernschantz J, the Latanoprost Study Group. A six month
`randomized double-masked study comparing latanoprost to timolol in
`open angle glaucoma and ocular hypertension. Ophthalmology
`1996;103:126–37.
`5 Mishima HK, Masuda K, Kitazawa Y, etal. A comparison of latanoprost
`and timolol in primary open-angle glaucoma and ocular hypertension. A
`12-week study. ArchOphthalmol 1996;114:929–39.
`6 Camras CB, Alm A, Watson P, etal. Latanoprost, a prostaglandin
`analog, for glaucoma treatment. Efficacy and safety after one year of
`treatment in 198 patients. Ophthalmology 1996;103:1916–24.
`7 Watson PG, the Latanoprost Study Group. Latanoprost—two years’
`experience of its use in the United Kingdom. Ophthalmology
`1998;105:82–7.
`8 Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new
`prostaglandin F2a analogue on aqueous humour dynamics in human
`eyes. Ophthalmology 1993;100:1297–304.
`9 Ziai N, Dolan JW, Kacere RD, etal. The effects on aqueous dynamics of
`PhXA41, a new prostaglandin F2a analogue, after topical application in
`normal and ocular hypertensive human eyes. ArchOphthalmol
`1993;111:1351–8.
`10 Azuma I, Masuda K, Kitazawa Y, etal. Double masked comparative
`study of UF-021 and timolol ophthalmic solutions in patients with primary
`open angle glaucoma or ocular hypertension. JpnJOphthalmol
`1993;37:514–25
`11 Azuma I, Masuda K, Kitazawa Y, etal. Long term study of UF-021
`ophthalmic solution in patients with primary open angle glaucoma or
`ocular hypertension. AtarashiiGanka(JEye) 1994;11:1435–44
`12 Azuma I. Clinical evaluation of UF-021 ophthalmic solution in glaucoma
`patients refractory to maximum tolerable therapy. JJpnOphthalmolSoc
`1993;97:232–8
`13 Taniguchi T, Haque MSR, Sugiyama K, etal. Ocular hypotensive
`mechanism of topical isopropyl unoprostone, a novel prostaglandin
`metabolite-related drug in rabbits. JOculPharmacol 1996;12:489–98.
`14 Taniguchi T, Sawada A, Sugiyama K, etal. Ocular hypotensive effects
`and mechanisms of prostaglandin-related drugs. InvestOphthalmolVis
`Sci 1997;38(Suppl):815.
`15 Machin D, Campbell MJ, Fayers PM, etal.Samplesizetablesfor
`clinicalstudies. Oxford: Blackwell, 1997:96–7.
`
`IPR Page 4/13
`
`

`

`16 Alm A, Widengard I, Kjellgren D, etal. Latanoprost administered once
`daily caused a maintained reduction of intraocular pressure in glaucoma
`patients treated concomitantly with timolol. BrJOphthalmol
`1995;79:12–16
`17 Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a
`prostaglandin F2á analogue, and timolol in patients with elevated
`intraocular pressure. BrJOphthalmol 1994;78:899–902.
`18 Fristrom B, Nilsson SEG. Interaction of PhXA41, a new prostaglandin
`analogue with pilocarpine. ArchOphthalmol 1993;111:662–5.
`19 Diestelhorst M. The additive intraocular pressure-lowering effect of
`latanoprost 0.005% once daily and pilocarpine 2% tid in patients with
`open-angle glaucoma or ocular hypertension, a six-month randomized
`multicenter study. German latanoprost study group. GraefesArchClin
`ExpOphthalmol 2000;238:433–9.
`20 Hoyng PF, Rulo AH, Greve EL, etal. The additive intraocular
`pressure-lowering effect of latanoprost in combined therapy with other
`ocular hypotensive agents. SurvOphthalmol 1997;41(Suppl 2):S93–8.
`21 Arici K, Topalkara A, Guler C. Additive effect of latanoprost and
`dorzolamide in patients with elevated intraocular pressure. Int
`Ophthalmol 1998;22:37–42.
`22 Rulo AH, Greve EL, Hoyng PF. The additive ocular hypotensive effect of
`latanoprost and acetazolamide. A short-term study in patients with
`elevated intraocular pressure. Ophthalmology 1997;104:1503–7.
`23 Susanna R, Nicolela MT, Oga E. Additive effect of latanoprost to the
`combination of timolol and dorzolamide. JGlaucoma 2000;9:183–6.
`
`24 Stewart WC, Sharpe ED, Stewart JA, etal. Additive efficacy of
`unoprostone isopropyl 0.12% (Rescula) to latanoprost 0.005%. AmJ
`Ophthalmol 2001;131:339–4.
`25 Fujimori C, Yamabayashi S, Hosoda M, etal. A clinical evaluation of
`UF-021, a new prostaglandin-related compound, in low-tension
`glaucoma patients. JJpnOphthalmolSoc 1993, 97:1231–5.
`26 Rulo AH, Greve EL, Geijssen HC, etal. Reduction of intraocular pressure
`with treatment of latanoprost once daily in patients with normal-pressure
`glaucoma. Ophthalmology 1996;103:1276–82.
`27 McKibbin M, Menage MJ. The effect of once-daily latanoprost on
`intraocular pressure and pulsatile ocular blood flow in normal tension
`glaucoma. Eye 1999;13:31–4.
`28 Bucci G, and the Latanoprost Study Group. Intraocular pressure lowering
`effects of latanoprost monotherapy versus latanoprost or pilocarpine in
`combination with timolol:a randomised, observer masked multicenter
`study in patients with open angle glaucoma. JGlaucoma 1999;8:24–30.
`29 Guiffre G. The effects of prostaglandin F2 in the human eye. Graefes
`ArchClinExpOphthalmol 1985;222:139–41.
`30 Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior
`uveitis associated with latanoprost use. Ophthalmology
`1998;105:263–8.
`31 Fechtner RD, Khouri AS, Zimmerman TJ, etal. Anterior uveitis
`associated with latanoprost. AmJOphthalmol 1998;126:37–41.
`
`

`

`Downloaded from
`
`http://bjo.bmj.com/
`
`
`
`group.bmj.com on March 4, 2018 - Published by
`
`Additive effect of unoprostone and latanoprost
`in patients with elevated intraocular pressure
`
`Tin Aung, Paul T K Chew, Francis T S Oen, Yiong-Huak Chan, Lennard H
`Thean, Leonard Yip, Boon-Ang Lim and Steve K L Seah
`
`Br J Ophthalmol
`2002 86: 75-79
`doi: 10.1136/bjo.86.1.75
`
`Updated information and services can be found at:
`
` http://bjo.bmj.com/content/86/1/75
`
`These include:
`
`References
`
`This article cites 26 articles, 2 of which you can access for free at:
`
` http://bjo.bmj.com/content/86/1/75#ref-list-1
`
`Email alerting
`service
`
`Receive free email alerts when new articles cite this article. Sign up in the
`box at the top right corner of the online article.
`
`
`
`next pageAn erratum has been published regarding this article. Please see
`or:
` /content/86/6/707.full.pdf
`
`Articles on similar topics can be found in the following collections
`
` (1006)Angle
`
` (989)Glaucoma
`
` (1002)Intraocular pressure
`
`
`
`Errata
`
`Topic
`Collections
`
`Notes
`
`To request permissions go to:
`http://group.bmj.com/group/rights-licensing/permissions
`
`To order reprints go to:
`http://journals.bmj.com/cgi/reprintform
`
`To subscribe to BMJ go to:
`http://group.bmj.com/subscribe/
`
`IPR Page 6/13
`
`

`

`BrJOphthalmol 2002;86:701–707
`
`701
`
`PostScript..............................................................................................
`
`LETTERS
`
`If you have a burning desire to respond to
`a paper published in the BJO, why not
`make use of our “rapid response” option?
`Log
`on
`to
`our
`website
`(www.bjophthalmol.com), find the paper
`that interests you, and send your response
`via email by clicking on the “eLetters”
`option in the box at
`the top right hand
`corner.
`Providing it isn’t libellous or obscene, it
`will be posted within seven days. You can
`retrieve it by clicking on “read eLetters”
`on our homepage.
`The editors will decide as before
`whether
`to also publish it
`in a future
`paper issue.
`
`Surgically induced diffuse
`scleritis: comparison of incidence
`in phacoemulsification and
`conventional extracapsular
`cataract extraction
`Surgically induced diffuse scleritis (SIDS) is a
`recognised but less well reported cause of pain
`and
`reduced
`vision following
`cataract
`surgery.1
`We have previously reported on complica-
`tions of convent