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`Santen/Asahi Glass Exhibit 2058
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`900
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`Rulo, Greve, Hoyng
`
`scopy, Humphrey(Allergan, San Leandro, CA,
`USA) 24/2 visual field examination, hyperaemia
`grading, and IOP measurements. Blood pressure
`and pulse rate were also recorded.
`Ondays 0, 2, 7, 9, and 14 the patients arrived
`in the glaucomacentre between 8 00 am and 9 00
`am. After recording any general or ocular symp-
`toms, hyperaemia wasgraded using the standard
`photographs for comparison. Thereafter three
`consecutive IOP measurements of each eye were
`taken. This procedure wasrepeated at noon and
`400 pm. Visual acuity, blood pressure, and
`pulse rate were recorded during the 800 am
`visits. Both blood pressure and pulse rate were
`measured three times consecutively. After day
`14 a post-study examination was performed.
`This examination wasidentical to the pre-study
`examination. Diurnal IOP values were obtained
`by calculating the mean of the 8 am, noon, and
`4 pm IOPvalues for each patient.
`The IOP values, pulse rate, and blood pres-
`sure were expressed as the arithmetical mean
`(SD). The primary objective of the study was to
`test whether latanoprost and timolol exert addi-
`tive effects on IOP. Thenull hypothesis accord-
`ingly was defined as the diurnal IOP reduction
`on day 7 (monotherapy) being equal
`to the
`diurnal IOP reduction on day 14 (combined
`therapy) from the diurnal IOP on day 0. The
`alternative hypothesis was that the combination
`further reduced the IOP with at least 2 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 on the first drug was assumed to be
`stable after 7 days of treatment. The IOP reduc-
`tion was tested with analysis of covariance with
`baseline IOP as covariate. A comparison of the
`mean IOP reductions between the treatment
`groups was performed on days 7 and 14 using
`three way analysis of covariance with patients,
`days, and treatment groupsas factors and base-
`line IOP as covariate. Wilcoxon’s rank sum test
`wasusedfor analysis of hyperaemia. Differences
`with a p value <0-05 were consideredsignificant.
`The changes in blood pressure and pulse rate
`were analysed statistically with the matched
`paired t test, comparing the values duringtreat-
`mentwith those on baseline.
`The study was approvedbytheethics review
`board of the Academic Medical Center, Amster-
`dam and each patient gave written informed
`consentbefore entering the study. The study was
`performed in accordance with the principles
`adopted by the 18th World Medical Assembly,
`Helsinki, Finland, 1964 andlater revisions.
`
`Results
`Ten patients wereallocated to latanoprost treat-
`ment (group A) and 10 patients to timolol
`treatment(group B). Onepatient in group A was
`excluded because it was found out
`that
`the
`patient had undergone only 2 days instead of
`2 weeks washout of pilocarpine and acetazola-
`mide. There were no major differences between
`the groups with regard to the demographic
`characteristics such as mean age and male/female
`ratio, but
`IOP at day 0 differed markedly
`between the groups(Table 1).
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`In the groupusing latanoprost maximum IOP
`loweringeffect was seen on day2 (Fig 1). On day
`7 an IOP reduction of8-9 (2:5) mm Hg (p<0-01)
`wasobservedin the latanoprost group compared
`with a reduction of 5:9 (2:3) mm Hg (p<0-01) in
`the timolol group (31% and 24% respectively).
`This difference in IOP reduction between the
`groups was not
`significant. The combined
`therapy revealed an additional IOP reduction
`compared with either drug administered alone.
`Latanoprost added to timolol further reduced
`IOP on day 14 compared with day 7 2:6 (2:2) mm
`Hg (p<0-01) and timolol added to latanoprost
`further reduced IOP 2:6 (1-1) mm Hg (p<0-01).
`Conjunctival hyperaemia comparedwith base-
`line was especially seen in the latanoprost treat-
`ment group on day 2 (Table 2). On day7, less
`conjunctival hyperaemia wasregistered than on
`day 2. When latanoprost was added to timolol
`conjunctival hyperaemiaincreasedslightly com-
`pared with day 7, being more pronounced on day
`9. No changes in hyperaemia were observed
`when timolol was added to latanoprost. The
`difference in hyperaemia between the two
`groups was, however, notstatistically significant
`on days 2 and 7 (p>0-05, Wilcoxon rank sum
`test).
`Latanoprost was well tolerated in the study.
`Stinging sensations after both latanoprost and
`timolol were noted in a few patients. The heart
`rate was reduced with 5-8 (6-9) min’
`' (p<0-05)
`on day 7 and 6-9 (8-8) min | (p<0-05) on day 14
`compared with day 0 in the timolol-latanoprost
`group. There was nosignificant effect on the
`systolic or diastolic blood pressure in either
`group.
`
`Discussion
`Previous
`studies using other prostaglandin
`analogues such as PGF2,-IE were hampered by
`clinically unacceptable grades of conjunctival
`hyperaemia, local irritation, and pain sensation
`whenoptimal IOP lowering doses were adminis-
`tered.* Latanoprost, a new PGF,,, analogue,
`seems to have markedly fewer side effects as
`reported in previousstudies.’ '°
`The main mechanism ofaction to account for
`the reduction in IOP following administration of
`prostaglandin F;,, and its analoguesis thoughtto
`be an increase in uveoscleral outflow'*” and not
`
`Table 1 Demographic and clinical characteristics ofthe
`treatment groups
`
`
`
`Latanoprost Timolol
`Age
`ex
`« Mean(range)
`Male/female
`Race
`White
`Asian
`Iris colour
`Blue/green
`Brown
`Grey
`Diagnosis
`Ocular hypertension
`Glaucoma
`Duration (months)
`Median (range)
`Previously treated
`Intraocular pressure
`Mean (SD) (mm Hg)
`
`61-2 (47-84)
`5/5
`9
`1
`
`—OCONo
`
`55 (2-350)
`8
`
`28°5 (5-6)
`
`64-1 (40-82)
`3/7
`
`-~oood
`
`oO
`48 (2-140)
`4
`
`24-2 (2-8)
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`Additiveeffectoflatanoprost, a prostaglandin F,,, analogue, and timololin patients with elevated intraocularpressure
`
`901
`
`(A) Intraocular
`Figure 1
`pressure reduction (mean
`(SD)) in group A,starting
`with latanoprost 60 g/ml
`twice daily. Adding timolol
`0-5% tuncedaily to
`latanoprostin the second
`week gave a further IOP
`reduction of2:5 mm Hg
`(13%). (B) Intraocular
`pressure reduction (mean
`(SD)) in group B,starting
`with timolol 0-5% twice
`daily. Adding latanoprost
`60 pg/mltwice daily to
`umololin the second week
`gaveafurther IOP reduction
`of2-5 mm Hg (14%).
`
`40
`
`30
`
`20
`
`10
`
`(mmHg)
`Intraocularpressure
`
`
`seen mainly duringthefirst week of treatment."
`As a single therapy latanoprost effectively
`reduced IOP in this study. Maximum IOP
`lowering effect was observed after 2 days of
`treatment, the decline in IOP being 42%; after
`1 week an IOP reduction of 31% waspresentin
`patients with a meaninitial IOP of 28-5 mm Hg.
`In the timolol group an IOP reduction of 24%
`wasobserved duringthefirst week of treatment.
`The difference in baseline IOP between the
`treatment groups makes a comparisonin efficacy
`of both drugs difficult. However,
`the results
`indicate that latanoprost 60 pg/ml twicedaily is
`at least as effective in reducing IOP as timolol
`5 mg/ml twicedaily.
`In patients on PGF;,-IE an inconvenient
`hyperaemia and local discomfort have been
`reported.°” In this study, a slight hyperaemia
`was noted in half the patients on latanoprost. No
`significant ocular discomfort or evidence of pain
`sensation were observed. Latanoprost was well
`tolerated by all patients and the slight hyper-
`aemia did not cause them to withdraw from the
`study. Hence, latanoprost, unlike PGF,,-IE, is
`not hamperedbyclinically unacceptable ocular
`side effects. In contrast with timolol, latanoprost
`hadnosignificanteffect on the heart rate whichis
`a clear advantage.
`If long term studies can demonstrate a
`sustained IOP reducing effect with latanoprost,
`it will be a valuable new drug in the therapeutic
`arsenal of glaucoma management.
`
`We thank Thomas Kaponen, MS andJohan Stjernschantz, MD,
`for statistical and scientific advice.
`
`1 Wang RF, Camras CB, Lee PY, Podos SM, Bito LZ. Effects of
`prostaglandins F, alpha, A), and their esters in glauco-
`matous monkey eyes. Invest Ophthalmol Vis Sci 1990; 31:
`2466-70.
`2 Bito LZ, Camras CB, Gum GG,Resul B. The ocular hypoten-
`sive effects andside effects of prostaglandins on the eyes of
`experimental animals. Prog Clin Biol Res 1989; 312: 349-68.
`3 Bito LZ, Miranda OC, Tendler MR, Resul B. Eicosanoidsas
`a new class of ocular hypotensive agents. 3. Prostaglandin
`A,-1-isopropylesteris the most potent reported hypotensive
`agenton feline eyes. Exp Eye Res 1990; 50: 419-28.
`4 Hoyng PF, Groeneboer MC.Theeffects of prostacyclin andits
`stable analog on intraocular pressure. Prog Clin Biol Reg
`1989; 312: 369-78.
`5 Groeneboer MC, Hoyng PF, Kuizenga A. Prostaglandin F,
`alpha isopropylester versusiloprost phenacylester in rabbit
`and beagle eyes. Curr Eye Res 1989; 8: 131-8.
`6 Giuffre G. Theeffects of prostaglandin F,, in the human eye.
`Graefes Arch Clin Exp Ophthalmol 1985; 222: 139-41.
`7 Camras CB, Siebold EC, Lustgarten JS, Serle JB, Frisch SC,
`Podos SM, ef al. Maintained reduction of intraocular
`pressure by prostaglandin F; alpha-1-isopropyl ester applied
`in multiple doses in ocular hypertensive and glaucoma
`patients. Ophthalmology 1989; 96: 1329-36.
`8 Villumsen J, Alm A. Ocular effects of two different prosta-
`glandin F, alpha esters. A doublemasked cross-over study
`on normotensive eyes. Acta Ophthalmol (Copenh) 1990; 68:
`341-3.
`9 Villumsen J, Alm A. Prostaglandin F, alpha-isopropylester
`eye drops: effects in normal human eyes. Br 7 Ophthalmol
`1989; 73: 419-26.
`10 Stjernschantz J, Resul B. Phenyl substituted prostaglandin
`analogs for glaucoma treatment. Drugsofthe Future 1992; 17:
`691-704.
`11 Alm A,Villumsen J. PhXA34, a new potentocular hypoten-
`sive drug. A study on dose-response relationship and on
`aqueous humor dynamics in healthy volunteers. Arch
`Ophthalmol1991; 109: 1564-8.
`12 Villumsen J, Alm A. PhXA34—a prostaglandin F;,, analogue,
`effect on intraocular pressure in patients with ocular hyper-
`tension. Br¥ Ophthalmol 1992; 76: 214-7.
`13 Nagasubramanian S$, Sheth GP, Hitchings RA, Stjernschantz
`J. Intraocular pressure-reducing effect of PhXA41 in ocular
`hypertension. Ophthalmology 1993; 100: 1305-11.
`14 Alm A, Villumsen J. Térnquist P, MandahlA, Airaksinen J,
`Tuulonen A,er al. Intraocular pressure-reducingeffect of
`PhXA4] in patients with increased eye pressure - a one-
`month study. Ophthalmology 1993; 100: 1314-7.
`15 Racz P, Ruzsonyi R, Nagy ZT, Bito LZ. Maintained intra-
`ocular pressure reduction with once-a-day application of a
`newprostaglandin F2,, avahkoy (MX A41). Arch Ophthalmol
`1993; 111: 657-61.
`
`— 40
`S
`
`B
`
`30
`
`20
`
`10
`
`Timolol
`Latanoprost
`
`0
`2
`7
`9
`14
`Days
`
`= E E
`
`2aSon
`—_
`&
`a_
`
`& 3
`
`°8
`
`E
`
`an increase in true trabecular outflow or an
`inhibition of aqueous humourformation. There-
`fore, when PGF,, analoguesare being combined
`with agentslike timolol which reduce IOP by an
`inhibition of aqueous humourproduction, an
`additive effect may be expected.
`In a previous study by Villumsen and Alm" an
`additive effect of approximately 30% was found
`when PGF,,-IE was administered to patients on
`timolol treatment having a mean IOP of 25 mm
`Hg.
`In another study by Lee et al” ocular
`hypertensivepatients with very highinitial IOPs
`(>40 mm Hg) hada mean IOP of27 mm Hgafter
`1 week of timolol
`treatment. In their study
`PGF,,-IE also induced a similar additive effect
`when combined with timolol indicating more or
`less complete additivity of PGF,,-IEto timolol.
`Although the combination of timolol and
`latanoprost induced an IOP lowering effect of
`not more than 13-14%, in contrast with previous
`observations,
`complete
`additivity may
`be
`present assuming that latanoprostisless effective
`at lower IOPlevels.
`In both groups there was an upwarddrift in
`IOP during latanoprost
`treatment. Such an
`upward drift
`in IOP has previously been
`reported during latanoprost treatment.’ How-
`ever, we do notbelieve that this phenomenon has
`affected the results significantly as the drift is
`
`Table2 Hyperaemia score in the two treatmentgroupsOO
`
`Group A
`Group B
`Hyperaemia
`0
`1-0
`20
`30 0
`10
`20
`3-0
`Score
`0s
`1s
`25
`0-5
`1S
`2:5:
`
`Day 0
`2
`7
`6
`4
`2
`Day 2
`1
`4
`6
`4
`3
`Day 7
`4
`2
`8
`2
`2
`3
`2
`Day 9
`1
`6
`3
`2
`1
`1
`Day 14
`2
`6
`4
`5
`ees
`Thedata indicate the numbers ofpatients with a given hyperaemiascore.
`
`1
`
`1
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`902
`
`Rulo, Greve, Hoyng
`
`16 Villumsen J, Alm A. The effect of adding prostaglandin F,
`alpha-isopropylester to timololin patients with open angle
`glaucoma. Arch Ophthalmol 1990; 108: 1102-5.
`17 Lee PY, Shao H, Camras CB, Podos SM. Additivity of
`prostaglandin F, alpha-l-isopropyl ester
`to timolol
`in
`glaucomapatients. Ophthalmology 1991; 98: 1079-82.
`18 Kerstetter JR, Brubaker RF, Wilson SE, Kullerstrand LJ.
`Prostaglandin F, alpha-1-isopropylester lowers intraocular
`
`pressure without decreasing aqueous humor flow. Am 7
`Ophthalmol 1988; 105: 30-4.
`19 Kaufman PL, Crawford K. Aqueous humor dynamics: how
`PGF,alphalowers intraocular pressure. Prog Clin Biol Res
`1989; 312: 387-416.
`20 Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a
`new prostaglandin F,,, analog, on aqueous humor dynamics
`in humaneyes. Ophthalmology 1993; 100: 1297-304.
`
`
`
`History of ophthalmology
`
`John Martin Wheeler, 1879-1938
`
`a well known
`John Martin Wheeler was
`ophthalmologist
`in the 1930s, whose career
`encompassed episodes of both spectacular
`good fortune and misfortune. His father, a
`country lawyer who had fought
`in
`the
`American civil war, could only afford to send
`his son to the small,
`inexpensive Burlington
`University of Vermont. Having graduated in
`arts and medicine, Wheeler was very lucky to
`obtain his ophthalmological internship in New
`York in 1909. During training, he was remark-
`able for his diligence and his manual dexterity.
`Constantly having good ideas for papers and
`reports, he was so hesitant and cautious that
`most of these ideas were eventually taken up
`and published by colleagues — which he never
`minded!
`His forte was meticulous surgical technique,
`in which he was
`inspired by his boss,
`D W Hunter. One of Hunter’s most daring
`procedures was
`the opening of secondary
`cataract by running a Graefe knife along the
`membrane in a single, rapid act of forearm
`supination. Wheeler describes the result as
`‘sure and beautiful’. He combined his admira-
`tion with pragmatism, in noting that most of
`the surgeons who cameto watch Hunter were
`too terrified of slashing the cornea to use the
`technique themselves. Wheeler then developed
`a less risky method, which he published in
`the British Journal of Ophthalmology, with
`meticulous pencil drawings of exactly how the
`operator’s thumbandforefinger should rest on
`the knife. The reader was exhorted to keep the
`hand and wrist
`joints perfectly immobile,
`creating the incision by a ‘a rapid, free’ move-
`ment of the whole arm. If correctly done, ‘the
`knife handle should rotate as if impaled on a
`pin’, and full drawings of the hypothetical pin’s
`position were included.
`Wheeler frequently stated that the surgeon
`should have nothingless than a keen and fault-
`less knife with which to ply his trade, and that
`this should be ground to perfect sharpness.
`One can imaginehis wrath whenanythingless
`wasfoundon his instrumenttable.
`Duringthe first world war, Wheeler entered
`the medical corps and thecare of blinded and
`disfigured veterans turnedhis interest perma-
`nently towards plastic surgery, on which he
`
`published manyof the landmark papers of the
`time. Most of his patients were soldiers
`wounded by gunshot or explosives in France
`in 1918. Operating under ether, Wheeler
`obviously did his utmost
`to repair
`facial
`fractures, skin defects, and the hasty exentera-
`tions of the battlefield, constantly aware of the
`importance(in view of the extremeyouth ofhis
`patients) of good cosmeticresults.
`Returningto civil practice, Wheeler’s stroke
`of good fortune occurred. The King of Siam,
`arriving in New York with his retinue, chose
`Wheeler to operate on his eye. Although many
`of his colleagues must have felt extreme envy,
`the quiet and retiring Wheeler found the media
`interest quite distressing, miserably trying to
`evade the press whenarriving at the hospital.
`The King was delighted with the result and in
`1931
`awarded a protesting Wheeler
`the
`Commanderofthe Orderof the Cross of Siam.
`He could literally have made a fortune in
`private practice from then on .
`.
`. However,
`having his log cabin in Vermont as a holiday
`home,andsufficient equipmentfor golf, he felt
`no need for a fortune, and coolly cut back his
`private practice to concentrate on postgraduate
`teaching. This must have amazed his envious
`colleagues, and probably arouses incredulous
`feelingsstill.
`in the form of a
`Tragedy then struck,
`necessitated
`the
`choroid
`sarcoma which
`removal of John Wheeler’sleft eye. It seemed
`that a great operative talent would belost, yet
`he adapted to this and continued to show the
`same degree of manual dexterity. (His patients’
`reactions on learning that their surgeon had
`only one eye are not recorded.) Because of
`his fame and the value of his pioneering
`work, Wheeler’s death three years later was
`noted widely by ophthalmologists and plastic
`surgeons. Both
`specialties
`continued
`to
`profit from his operative techniques for long
`afterwards.
`FIONA ROMAN
`
`Wheeler JM. War injuries of the eyelids: plastic operations.
`Arch Ophthalmol 1920; 49: 35-42.
`Wheeler
`JM. Restoration of
`the obliterated eye
`socket.
`Am F Ophthalmol 1921; 4: 481-8.
`Wheeler JM [Obituary]. Arch Ophthalmol 1938; 6: 885-8.
`Wheeler JM [Obituary]. Br 7 Ophthalmol 1938; 22: 76-8.
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