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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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`Rule, Grave, Hoyng
`
`In the group using latanoprost maximum IOP
`lowering effect was seen on day 2 (Fig 1). On day
`7 an IOP reduction of8-9 (2-5) mm Hg (p<0-01)
`was observed in 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 compared with base-
`line was especially seen in the latanoprost treat-
`ment group on day 2 (Table 2). On day 7, less
`conjunctival hyperaemia was registered than on
`day 2. When latanoprost was added to timolol
`conjunctival hyperaemia increased slightly 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, not statistically 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 no significant effect on the
`systolic or diastolic blood pressure in either
`group.
`
`Discussion
`Previous
`studies using other prostaglandin
`analogues such as PGFZu—IE were hampered by
`clinically unacceptable grades of conjunctival
`hyperaemia, local irritation, and pain sensation
`when optimal IOP lowering doses were adminis-
`tered.‘ Latanoprost, a new PGFZu analogue,
`seems to have markedly fewer side effects as
`reported in previous studies.9 ” ‘5
`The main mechanism of action to account for
`the reduction in IOP following administration of
`prostaglandin F2“ and its analogues is thought to
`be an increase in uveoscleral outflow'”J and not
`
`Table 1 Demographic and clinical characteristics ofthe
`treatment groups
`
`
`
`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.
`On days 0, 2, 7, 9, and 14 the patients arrived
`in the glaucoma centre between 8 00 am and 9 00
`am. After recording any general or ocular symp-
`toms, hyperaemia was graded using the standard
`photographs for comparison. Thereafter three
`consecutive IOP measurements of each eye were
`taken. This procedure was repeated at noon and
`400 pm. Visual acuity, blood pressure, and
`pulse rate were recorded during the 8 00 am
`visits. Both blood pressure and pulse rate were
`measured three times consecutively. After day
`14 a post—study examination was performed.
`This examination was identical to the pre-study
`examination. Diurnal IOP values were obtained
`by calculating the mean of the 8 am, noon, and
`4 pm IOP values 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. The null 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 groups as factors and base-
`line IOP as covariate. Wilcoxon’s rank sum test
`was used for analysis of hyperaemia. Differences
`with a p value <0-05 were considered significant.
`The changes in blood pressure and pulse rate
`were analysed statistically with the matched
`paired I test, comparing the values during treat-
`ment with those on baseline.
`The study was approved by the ethics review
`board of the Academic Medical Center, Amster-
`dam and each patient gave written informed
`consent before entering the study. The study was
`performed in accordance with the principles
`adopted by the 18th World Medical Assembly,
`Helsinki, Finland, 1964 and later revisions.
`
`Results
`Ten patients were allocated to latanoprost treat-
`ment (group A) and 10 patients to timolol
`treatment (group B). One patient 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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`Latanoprost Timolol
`Age
`Mean (range)
`Sex
`Male/female
`Race
`White
`Asian
`Iris colour
`Blue/green
`Brown
`Grey
`Diagnosis
`Ocular hypertension
`Glaucoma
`Duration (months)
`Median (range)
`Previously treated
`lntraocular pressure
`Mean (SD) (mm Hg)
`
`64-l (40-82)
`3/7
`
`I
`
`—OO00
`
`9l
`
`61-2 (47—84)
`5/5
`9
`1
`
`-covum
`
`55 (Z—350)
`8
`28-5(5-6)
`
`48 (2—140)
`4
`24-2(Z-8)
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`Additive effect oflatanoprost, a prostaglandin F2., analogue, and timolol in patients with elevated intraocularpressure
`
`901
`
`(A) Intraocular
`Figure I
`pressure reduction (mean
`(SD)) in group A, starting
`with latanoprost 60 rig/ml
`twice daily. Adding timolol
`05% twice daily to
`latanoprost in the second
`week gave a further 1OP
`reduction of2'5 mm Hg
`(13%). (B) Intraacular
`pressure reduction (mean
`(50)) in group 8, starting
`with tinwlol 05% twice
`daily. Adding latanoprost
`60 pg/ml twice daily to
`timolol in the second week
`gave afurther 1OP reduction
`of2‘5 mm Hg (14%).
`
`
`
`
`
`Intraocularpressure(mmHg)
`
`
`
`
`
`lntraocularpressure(mmHg)
`
`40
`
`w0
`
`—INOO
`
`a.O
`
`(a)O
`
`O
`—INOO
`
`Days
`
`an increase in true trabecular outflow or an
`inhibition of aqueous humour formation. There-
`fore, when PGFZG analogues are being combined
`with agents like timolol which reduce IOP by an
`inhibition of aqueous humour production, an
`additive effect may be expected.
`In a previous study by Villumsen and Alm“ an
`additive effect of approximately 30% was found
`when PGFZa-IE was administered to patients on
`timolol treatment having a mean IOP of 25 mm
`Hg.
`In another study by Lee et a1” ocular
`hypertensive patients with very high initial IOPs
`(>40 mm Hg) had a mean IOP on7 mm Hg after
`I week of timolol
`treatment. In their study
`PGFZn-IE also induced a similar additive effect
`when combined with timolol indicating more or
`less complete additivity of PGFZa-IE to 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 latanoprost is less effective
`at lower IOP levels.
`In both groups there was an upward drift in
`IOP during latanoprost
`treatment. Such an
`upward drift
`in IOP has previously been
`reported during latanoprost treatment." How-
`ever, we do not believe that this phenomenon has
`affected the results significantly as the drift is
`
`Table 2 Hyperaemia score in the two treatment groups“\—
`
`GroupA
`Group B
`Hyperaemt'a
`0
`1'0
`2‘0
`3-0
`0
`[-0
`2'0
`3'0
`score
`0-5
`['5
`2'5
`0-5
`[-5
`2'5
`
`Day 0
`2
`7
`6
`4
`Day 2
`l
`4
`6
`4
`Day 7
`4
`2
`8
`2
`Day 9
`l
`6
`3
`2
`Day 14
`Z
`6
`4
`5
`
`I
`
`Z
`3
`2
`I
`
`3
`
`2
`I
`
`The data indicate the numbers ofpatients with a given hyperaemia score.
`
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`seen mainly during the first 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% was present in
`patients with a mean initial IOP of 28-5 mm Hg.
`In the timolol group an IOP reduction of 24%
`was observed during the first week of treatment.
`The difference in baseline IOP between the
`treatment groups makes a comparison in efficacy
`of both drugs difficult. However,
`the results
`indicate that latanoprost 60 pig/ml twice daily is
`at least as effective in reducing IOP as timolol
`5 mg/ml twice daily.
`In patients on PGFM-IE an inconvenient
`hyperaemia and local discomfort have been
`reported.“7 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 PGFZn-IE, is
`not hampered by clinically unacceptable ocular
`side effects. In contrast with timolol, latanoprost
`had no significant effect on the heart rate which is
`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 and Johan Stiernschantz, MD,
`for statistical and scientific advice.
`
`l Wang RF, Camras CB, Lee PY, Podos SM, Bito LZ. Effects of
`prostaglandins F2 alpha, AZ, and their esters in glauco~
`matous monkey eyes. Invest Ophthalmol VII Sci 1990; 31:
`2466-70.
`2 Bito LZ, Cami-as CB, Gum GG, Resul B. The ocular hypoten-
`sive effects and side effects of prostaglandins on the eyes of
`experimental animals. Prog Clin Biol Res 1989; 312: 349—68.
`3 Bito LZ, Miranda 0C, Tcndler MR, Resul B. Eicosanoids as
`a new class of ocular hypotensive agents. 3. Pmstaglandin
`Az-I -isopropyl ester is the most potent reported hypotensivc
`agent on feline eyes. Exp Eye Res I990; 50: 419—28.
`4 Hoyng PF, Groeneboer MC. The effects of prostacyclin and its
`stable analog on intraocular pressure. Prag Clin Biol Reg
`1989; 312: 369—78.
`5 Groencbocr MC, Hoyng PF, Kuizenga A. Prostaglandin F2
`alpha isopropylcster versus iloprost phenacyl ester in rabbit
`and beagle eyes. Curr Eye Res I989; 8: 131—8.
`6 Giuffre G. The effects of prostaglandin F2“ in the human eye.
`Graefes Arch Clin Exp Ophthalmol 1985; 222: 139—41 .
`7 Camras CB, Sicbold EC, Lustganen JS, Serle JB, Frisch SC,
`Podos SM, et a1. Maintained reducuon of intraocular
`pressure by prostaglandin F2 alpha- l-isopropyl ester applied
`in multiple doses in ocular hypertensive and glaucoma
`patients. Ophthalmology 1989;96: I329—36.
`8 Villumscn J, Alm A. Ocular effects of two different prosta-
`glandin F2 alpha esters. A doublemasked cross-over study
`on normotcnsive eyes. Acta Ophthalmol (Copenh) 1990', 68:
`341—3.
`9 Villumsen J, Alm A. Prostaglandin F1 alpha-isopropylestcr
`eye drops: effects in normal human eyes. Br] Ophthalmol
`1989-, 73: 419—26.
`10 Stjemschantz J, Resul B. Phenyl substituted prostaglandin
`analogs for glaucoma treatment. Dntg: ofthe Future I992; 17:
`691—704.
`11 Alm A, Villumsen J. PhXA34, a new potent ocular hypoten-
`sive drug. A study on dose—response relationship and on
`aqueous humor dynamics in healthy volunteers. Arch
`Ophthalmol 1991; 109: ISM-8.
`12 Villumsen J, AIm A. PhXA34 — a prostaglandin F1" analogue,
`effect on intraocular pressure in patients with ocular hyper-
`tension. Br] Ophthalmol 1992; 76: 214—7.
`13 Nagasubramanian S, Sheth GP, Hitchings RA, Stiernschantz
`J. Intraocular pressure-reducing effect of PhXA-fl in ocular
`hypertension. Ophthalmology I993; 100: 1305—1 1.
`I4 Alm A, Villumscn J. Tornquist P, Mandahl A, Airaksinen J,
`Tquonen A, et a1. Intraocular pressure-reducing effect of
`PhXA4] in patients with increased eye pressure ~ a one-
`month study. Ophthalmology I993; 100: 1314—7.
`IS Racz P, Ruzsonyi R, Nagy ZT, Bito LZ. Maintained intra—
`ocular pressure reduction with once-aday application of a
`new prostaglandin F2” (LVUMIY ( I'InXA4 I ). Arch Ophthalmol
`I993; "12657—61.
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`902
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`Rulo, Grew, Hoyng
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`16 Villumscn J, Alm A. The effect of adding prostaglandin F2
`alpha-isopropylester to timolol in patients with open angle
`glaucoma. Arch Ophthalmol 1990; 108: 11025.
`17 Lee PY, Shao H, Camras CB,
`l’odos SM. Additivity of
`prostaglandin F2 alpha-l-isopropyl ester
`to timolol
`in
`glaucoma patients. Ophthalmology 1991;98: 1079—82.
`18 Kerstettcr JR, Brubaker RF, Wilson SE, Kullerstrand LJ.
`Prostaglandin F2 alpha-l-isopropylester lowers intraocular
`
`pressure without decreasing aqueous humor flow. Am 3'
`Ophthalmol 1988', 105: 30—4.
`19 Kaufman I’L, Crawford K. Aqueous humor dynamics: how
`PGFZ alpha lowers intraocular pressure. ng Clin Biol Res
`1989; 312: 387—416.
`20 Toris CB, Camras CB, Yablonski ME. Effects of PhXA4l, a
`new prostaglandin F1“ analog, on aqueous humor dynamics
`in human eyes. Ophthalmology 1993; 100: 1297—304.
`
`
`
`History of ophthalmology
`
`John Martin Wheeler, 1879-1938
`
`a well known
`John Martin Wheeler was
`ophthalmologist
`in the 19303, 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 came to 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 thumb and forefinger 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 nothing less than a keen and fault-
`less knife with which to ply his trade, and that
`this should be ground to perfect sharpness.
`One can imagine his wrath when anything less
`was found on his instrument table.
`During the first world war, Wheeler entered
`the medical corps and the care of blinded and
`disfigured veterans turned his interest perma-
`nently towards plastic surgery, on which he
`
`published many of 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 extreme youth of his
`patients) of good cosmetic results.
`Returning to 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 when arriving at the hospital.
`The King was delighted with the result and in
`1931
`awarded a protesting Wheeler
`the
`Commander of the Order of 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, and sufficient equipment for 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
`feelings still.
`in the form of a
`Tragedy then struck,
`necessitated
`the
`choroid
`sarcoma which
`removal of John Wheeler’s left eye. It seemed
`that a great operative talent would be lost, 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 ] Ophthalmo/ 1921; 4: 481—8.
`Wheeler JM [Obituary]. Arch Ophthalmol 1938; 6: 885—8.
`Wheeler JM [Obituary]. BYJOphI/mlltml 1938; 22: 76—8.
`
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