Latanoprost as a new horizon in the medical management of
`glaucoma
`Johan Stjernschantz, MD, PhD, and Albert Alm, MD, PhD
`
`Latanoprost is a new prostaglandin F2" analogue specifically
`developed for the treatment of glaucoma. Latanoprost is a se(cid:173)
`lective FP receptor agonist, with a primary mode of action of
`increased uveoscleral outflow of aqueous humor. A dose of 50
`µg/mL (0.005%) once daily has been found optimal in clinical
`trials. Latanoprost reduces the nocturnal intraocular pressure
`in addition to the diurnal, and has been shown to be additive to
`other glaucoma medication. In long-term phase Ill clinical trials,
`latanoprost 0.005% once daily has been proven to be at least
`as effective as timolol 0.5% twice a day. The main side effect
`of latanoprost is increased iridial pigmentation, which is rela(cid:173)
`tively frequent in patients with mixed color of the iris. This
`unique side effect is based on the ability of prostaglandins to
`stimulate melanin formation in melanocytes. The advantages of
`latanoprost compared with other glaucoma medication com(cid:173)
`prise different mode of action, good intraocular pressure(cid:173)
`reducing effect, once-daily dosing, and absence of systemic
`side effects. The long-term consequences of increased iridial
`pigmentation need to be further studied.
`
`Glaucoma Research Laboratories, Pharmacia and Upjohn, and Department of
`Ophthalmology, University Hospital, Uppsala, Sweden.
`
`Current Opinion in Ophthalmology 1996, 7;2:11-17
`
`Abbreviations
`
`FNA
`IOP
`
`fine·needle aspiration
`intraocular pressure
`
`© 1996 Rapid Science Publishers
`ISBN 1-85922-821-6 ISSN 1040-8738
`
`Several prostaglandins have been shown to reduce the
`intraocular pressure (IOP) effectively in animals [1,2] as
`well as in humans [3,4], and these ocular hypotensive au(cid:173)
`tacoids represent a potentially important new class of
`drugs for the treatment of glaucoma. What makes the
`prostaglandins interesting, particularly the F za type, is
`their unique mode of action and increased uveoscleral
`outflow of aqueous humor [5-8]. Because the drainage
`capacity of the uveoscleral route probably is high, pro(cid:173)
`vided the fluid can enter the supraciliary-suprachoroidal
`space, drugs enhancing this outflow mechanism can be
`expected to have a good !OP-lowering effect. It is also
`appealing that the obstructed site of the normal drainage
`pathway, the trabecular meshwork, which is the cause of
`the elevated IOP in glaucoma, is bypassed in this out(cid:173)
`flow pathway. Enhanced outflow of aqueous humor
`through the uveoscleral route offers a new principle for
`the reduction of IOP in the medical management of
`glaucoma. The mechanism is reminiscent of a cyclodialy(cid:173)
`sis brought about pharmacologically. The purpose of this
`article is to review recent preclinical and clinical data ob(cid:173)
`tained with latanoprost.
`
`Chemistry of latanoprost
`Latanoprost (code name, PhXA41; 13,14-dihydro-l 7-
`phenyl-18, 19,20-trinor-PGF za-isopropyl ester) differs
`from prostaglandin F za (PG F za), a naturally occurring
`prostaglandin, in three ways. First, carbons 18-20 in the
`w chain have been substituted with a benzene ring. Sec(cid:173)
`ond, the double bond between carbons 13 and 14 has
`been saturated. Lastly, the carboxylic acid moiety on car(cid:173)
`bon 1 in the a chain has been esterified with isopropanol
`(Fig. 1 ). The molecular weight of latanoprost is 432.6 and
`that of the free acid (hydrolysed compound) is 390.5.
`The octanol-water partition coefficient (logarithmic P
`value) has been determined to be 4.3 at pH 7.4, and the
`solubility of latanoprost in water is consequently poor.
`Latanoprost has been tested clinically in concentrations
`ranging from 12.5 to 350 µg/mL (0.00125-0.035%). A
`0.005% concentration has been used in the phase III
`clinical trials. The eye drop solution is preserved by ben(cid:173)
`zalkonium chloride.
`
`Pharmacology of latanoprost
`Latanoprost is a selective FP receptor agonise, with only
`marginal spill over on most of the other prostanoid recep(cid:173)
`tors [8]. The prostanoid receptor classification has re(cid:173)
`cently been reviewed [9° 0
`] . There are at least eight dif-
`
`11
`
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`

`Latanoprost as a new horizon in the medical management of glaucoma Stjernschantz and Alm 13
`
`treatment (21 "]. This unique effect seems to be based
`entirely on melanogenesis in the melanocytes of the iris
`stroma. Morphometrical analysis of a large number of
`treated animals indicate that there is no proliferative ef(cid:173)
`fect of latanoprost on the melanocytes but rather that the
`effect is based on de novo synthesis of melanin. The
`iridial melanocytes in monkeys have been described as
`postmitotic, but they may retain some melanogenic ca(cid:173)
`pacity throughout life (22). Because the ocular melano(cid:173)
`cytes are continent (23], ie, they do not donate the pig(cid:173)
`ment, pigment dispersion is unlikely to occur. On the
`other hand, this suggests that the change in pigmenta(cid:173)
`tion may be irreversible. Altogether it is likely that this
`new side effect has only cosmetic consequences. Long(cid:173)
`term follow-up of patients affected on continued treat(cid:173)
`ment, however, is needed to determine how progressive
`the pigmentation is.
`
`Other effects in the eye
`Latanoprost causes slight mydriasis in monkeys but has
`no effect on the pupil in rabbits. In cats and dogs, la(cid:173)
`tanoprost causes marked pupillary constriction because
`these species have FP-receptors in the iridial sphincter
`muscle [9 .. ). Neither latanoprost (free acid) nor PGF 2"
`has any effect on the DC electroretinogram when infused
`intravitreally in rabbits at relevant concentrations (24].
`
`Systemic effects of latanoprost
`Intravenous infusion of latanoprost in cynomolgus mon(cid:173)
`keys at 10 times the clinical dose had no cardiovascular
`or pulmonary effects [8]. When latanoprost is used at the
`clinical dose of one drop in each eye once daily (l.S
`µg/eye; total dose approximately 0.04 µg/kg bw) it is un(cid:173)
`likely to exert any significant systemic side effects be(cid:173)
`cause of the low dose and the rapid metabolism.
`
`Pharmacokinetical properties
`Latanoprost is an isopropyl ester prodrug and as such bi(cid:173)
`ologically inactive. The ester moiety has to be hy(cid:173)
`drolyzed for the drug to become active. The prodrug is
`efficiently and quantitatively hydrolyzed to the free acid
`both in the cornea and plasma [8) . All drug that enters
`the aqueous humor has been hydrolyzed to the free acid
`[2S]. However, only a fraction of the drug applied topi(cid:173)
`cally is absorbed into the eye (approximately 1 % ), the
`rest being absorbed into the systemic circulation either
`di rectly through blood vessels in the conjunctiva and the
`nasal mucosa or through the gastrointestinal tract [26] .
`After topical application of latanoprost the peak concen(cid:173)
`tration in the monkey eye is reached after about 1 hour.
`The half-life of latanoprost (free acid) in plasma is about
`10 minutes in monkeys [8) and 17 minutes in humans
`(Unpublished data).
`
`There is practically no metabolism of latanoprost in the
`eye except for the ester hydrolysis. Latanoprost is a poor
`
`substrate for prostaglandin lS-dehydrogenase but under(cid:173)
`goes 13-oxidation in the liver. The major matabolites in
`monkeys and humans are 1,2-dinor- and l,2,3,4-tetranor-
`13,14-dihydro-17-phenyl-18,19,20- trinor-PGF2". Most of
`the metabolites are excreted in the urine but some are
`excreted via the bile [8] .
`
`Clinical studies
`Dose
`Several phase I and phase II dose-finding studies have
`been performed with latanoprost and PhXA34 (20,
`27-31). A concentration of SO to 60 µg/mL (O.OOS%-
`0.006%) has been found optimal with respect to the IOP
`reduction. In two studies it has been demonstrated that
`application of the drug once daily results in maximum ef(cid:173)
`fect. Thus Nagasubramanian et al. [32] treated 49 pa(cid:173)
`tients with ocular hypertension for 2 weeks; 10 with
`placebo, 19 with 0.006% latanoprost twice daily, and 20
`with the same dose applied once daily in the evening.
`
`Both dose-regimens were better than placebo. On the
`second day of treatment application of latanoprost twice
`daily was slightly more effective than latanoprost given
`once daily, but after 2 weeks of treatment the efficacy was
`reversed for the two groups. Once daily dosage caused a
`36% reduction compared with 28% with twice daily. This
`observation was confirmed in another study in which SO
`glaucoma patients with an IOP of at least 22 mm Hg de(cid:173)
`spite twice daily O.S% timolol treatment were included
`(33"). In this parallel-group study 0.006% latanoprost was
`added to timolol either twice daily or once daily (in the
`evening) for 3 months. Throughout the study latanoprost
`once daily reduced IOP more effectively than latanoprost
`twice daily at all time points. The diurnal IOP reduction
`on the last examination compared with baseline was sig(cid:173)
`nificantly greater in the patients who received treatment
`once daily than the patients who received treatment twice
`daily. The diurnal IOP was reduced from 24.8 to lS.7 mm
`Hg in those who received treatment once daily, and from
`24.9 to 18.0 mm Hg in those who received treatment
`twice daily (33"]. The results of these two dose-regimen
`studies were corroborated by the results of a third study in
`which hospitalized patients were treated with 0.006%
`latanoprost once daily [34].
`
`Effect in normal-tension glaucoma
`Latanoprost has also been shown to have an effect on
`IOP in normal-tension glaucoma. In one study, two
`groups of 10 patients were compared: one treated with
`placebo and the other with latanoprost at 0.006% twice
`daily for 2 weeks [3S]. The mean diurnal IOP was re(cid:173)
`duced in both groups; from 16.8 to 14.3 mm Hg (2.6 mm
`Hg; 1S%) with latanoprost and from 18.3 to 17.2 mm Hg
`( 1.0 mm Hg; S%) with placebo. The difference between
`the two treatment groups was statistically significant. In
`another placebo-controlled, crossover dose
`regimen
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`Latanoprost as a new horizon in the medical management of glaucoma Stjernschantz and Alm 15
`
`was significantly better than timolol. The main differ(cid:173)
`ence between the three studies seems to be the efficacy
`of timolol. In the US study both timolol and latanoprost
`were less effective than in the two other studies. Some
`remaining 13-adrenergic blockage, despite a 3-week
`washout of previous timolol treatment, cannot be ex(cid:173)
`cluded. In the UK study timolol reduced IOP consider(cid:173)
`ably better than in the US and the Scandinavian studies.
`Differences in patient demography may also affect the
`results. In the US study more patients with ocular hyper(cid:173)
`tension (63%) were included than in the other two stud(cid:173)
`ies (UK 50%, Scandinavia 46%), and a meta-analysis of
`the three studies shows that timolol may be less effective
`in ocular hypertension than in primary open- angle glau(cid:173)
`coma. The same meta-analysis demonstrated that timo(cid:173)
`lol seems to be more effective in men than in women,
`and in the UK study 65% of the study population were
`men compared with 43% and 44% in the US and Scandi(cid:173)
`navian studies.
`
`In the three studies an average of 25% of latanoprost(cid:173)
`treated patients and 17% of timolol-treated patients were
`treated in one eye only. Timolol also reduced IOP signif(cid:173)
`icantly in the uncreated fellow eye between 1.1 and 3.0
`mm Hg in the three studies. The effect of latanoprost on
`the fellow eye was smaller, ranging between 0.4 and 1.2
`mm Hg. This difference between timolol and
`la(cid:173)
`tanoprost probably reflects the fact that timolol, unlike
`latanoprost, results in effective plasma levels also when
`applied as eye drops.
`
`The Scandinavian study provided additional information
`on the importance of the time of application of la(cid:173)
`tanoprost. Evening administration of latanoprost was sta(cid:173)
`tistically superior to morning administration. The most
`likely explanation is the fact that IOP measurements at 8
`AM, noon, and 4 PM provide IOP values 24, 4, and 8 hours
`postdose for morning application and 12, 16, and 20
`hours postdose for evening application. A late and pro(cid:173)
`longed maximum for the effect on IOP favors evening
`application when IOP is measured during daytime. In
`patients treated for I year with latanoprost, no long-term
`drift in IOP was detected [43].
`
`Side effects
`Conjunctiva) hyperemia and ocular irritation were pro(cid:173)
`nounced ocular side effects with PG F za-isopropyl ester
`[44). In the three phase III clinical studies, latanoprost
`was also compared with timolol with respect to side ef(cid:173)
`fects. There was no difference between the two drugs
`with respect to ocular irritation or discomfort, but la(cid:173)
`tanoprost caused slightly more conjunctiva) hyperemia.
`the average conjunctiva! hyperemia
`Nevertheless,
`caused by latanoprost was modest and in most cases un(cid:173)
`likely to be clinically important. Conjunctiva) hyperemia
`was reported as an adverse event in 4.6% of patients
`treated with latanoprost and 1.4% of patients treated
`
`with timolol. It was reported more than once in four of
`198 patients treated with latanoprost for 1 year indicating
`that conjunctiva! hyperemia may be a clinical problem in
`about 2% of patients on latanoprost.
`
`Punctate keratopathy was observed in 44 patients (9.6%)
`on latanoprost and 32 (8.7%) on timolol in the three
`phase III clinical studies combined. Most cases of punc(cid:173)
`tate keratopathy were mild and sporadic, but some were
`reported as adverse events, 13 (2.8%) on latanoprost and
`five ( 1.4%) on timolol. One of 460 patients treated with
`latanoprost in the three phase III clinical studies was
`withdrawn from the study because of corneal erosions.
`Latanoprost, as well as the vehicle used as placebo in
`these studies, contained twice the concentration of the
`preservative (benzalkonium chloride) compared with
`timolol eye drops. This may explain the difference be(cid:173)
`tween the two drugs regarding punctate keratopathy par(cid:173)
`ticularly because a placebo drop had to be given daily to
`the latanoprost patients to mask the studies.
`
`Among 460 patients treated for 6 months with la(cid:173)
`tanoprost increased pigmentation of the iris was ob(cid:173)
`served or suspected in 31 patients ( 6. 7% ). Most cases
`have been mild and clinically difficult to detect. The
`change in iris pigmentation has occurred in eyes with an
`iris color that is already partly brown (naevi and freckles
`not included). Thus, a change in iris color of pure blue,
`gray, green, or brown eyes can be expected to be less fre(cid:173)
`quent than in heterochromatic eyes. All patients who de(cid:173)
`veloped increased pigmentation of the iris have been
`withdrawn from treatment. During follow-up for up to 2
`years the change in iris pigmentation has been stable
`without any sign of reversibility or further increase.
`
`No significant systemic side effect that could be attrib(cid:173)
`uted to the use of latanoprost has emerged in any of the
`three phase III studies. Because of the extremely low
`concentration of latanoprost in plasma and the rapid me(cid:173)
`tabolism, significant systemic side effects are unlikely to
`occur with the drug.
`
`In conclusion, latanoprost and other prostaglandins may
`open up a new horizon in the medical management of
`glaucoma in that these drugs are highly effective IOP(cid:173)
`reducing agents with a unique mode of action and proba(cid:173)
`bly good ocular and systemic tolerability. The only dis(cid:173)
`advantage so far seems to be the increased pigmentation
`of the iris, which needs to be further studied.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`Of special interest
`Of outstanding interest
`
`1.
`
`Camras CC, Bite LZ: Reduction of intraocular pressure in normal and
`glaucomatous primate (Aoutus trivirgatus) eyes by topically applied
`prostaglandin F2a· Curr Eye Res 1981, 1 :205-209.
`
`IPR Page 5/7
`
`

`

`16 Glaucoma
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Bito LZ, Camras CB, Glenwood GG, Resul R: The Ocular Hypotensive
`Effects and Side Eects of Prostaglandins on the Eye of Experimental
`Animals. In The Ocular Effects of Prostaglandins and Other Eicosanoids.
`Edited by Bito LZ, Stjernschantz J. New York: Alan R. Liss;
`1989:349-368.
`
`Alm A, Villumsen J: Effects of Topically Applied PGF2a and its lso(cid:173)
`propylester on Normal and Glaucomatous Human Eyes. In The Ocular
`Effects of Prostaglandins and Other Eicosanoids. Edited by Bito LZ,
`Stjernschantz J. New York: Alan R. Liss; 1989:447-458.
`Alm A: The potential of prostaglandin derivates in glaucoma therapy.
`Curr Opin Ophthalmol 1993, 4:44-50.
`Crawford K, Kaufman PL: Pilocarpine antagonizes PGF2a·induced ocu(cid:173)
`lar hypotension: evidence for enhancement of uveoscleral outflow by
`PGF2a· Arch Ophthalmol 1987, 105:1112-1116.
`Nilsson SPE, Samulesson M, Bill A, Stjernschantz J: Increased uveoscle(cid:173)
`ral outflow as a possible mechanism of ocular hypotension caused by
`prostaglandin F2a-1 • isopropyl ester in the cynomologus monkey.
`Exp Eye Res 1989, 48:707-716.
`True Gabel! BA, Kaufman PL: Prostaglandin F2a increases uveoscleral
`outflow in the cynomolgus monkey. Exp Eye Res 1989, 49:389-402.
`Stjernschantz J, Selen G, Sjoquist B, Resul B: Preclinical Pharmacology
`of Latanoprost, a Phenylsubstituted PGF2a Analogue, vol 23. In Ad·
`vances in Prostaglandin, Tromboxane, and Leukotriene Research. Edited
`by Samuelsson B. New York: Raven Press; 1995:513-518.
`Coleman RA, Smith WL, Narumiya S: International union of pharmacol(cid:173)
`ogy classification of prostanoid receptors: properties, distribution, and
`structure of the receptors and their subtypes. Pharmacol Rev 1 994,
`46:205-229.
`
`This review article gives comprehensive and detailed information about the classi·
`fication of prostanoid receptors based on both molecular biological and pharma·
`cologic data. Subtypes and isoforms of prostanoid receptors and their second
`messenger systems are described as well as agonists and antagonists for the dif·
`ferent receptors.
`1 O. Sugimoto Y, Negishi M, Hayashi Y, Namba T, Honda A, Watabe A, Hirata
`M, Narumiya S, Ichikawa A: Two isoforms of the EP3 receptor with dif(cid:173)
`ferent carboxyl-terminal domains. J Biol Chem 1993, 268:2712-2718.
`11 . Adam M, Boie Y, Ruishmore TH, MUiier G, Bastien L, McKee KT, Metters
`KM, Abramovitz M: Cloning and expression of three isoforms of the
`human EP3 prostanoid receptor. Febs Lett 1994, 338:170-174.
`12. Pierce KL, Gil OW, Woodward OF, Regan JW: Cloning of human
`prostanoid receptors. Trends Pharmacol Sci 1995, 16:253-256.
`13. Ocklind A, Lake S, Wentzel P, Krook K, Johansson B, Stjernschantz J: Lo(cid:173)
`calization of the prostaglandln F2a receptor in the monkey eye. Invest
`Ophthalmol Vis Sci 1995, 36:A2765.
`loris CB, Camras CB, Yablonski ME: Effects of PhXA41, a new
`prostaglandin F2a analog, on aqueous humor dynamics in human
`eyes. Ophthalmology 1993, 100:1297-1304.
`15. Astin M, Gjotterberg M, Holst A, Selen G, Resul B, Stjernschantz J: Study
`of the fundus in phakic and aphakic monkey eyes treated with
`PhXA41. Invest Ophthalmol Vis Sci 1992, 33: 1078.
`16. Green K, Paterson CA, Siddiqui A: Ocular blood flow after experimental
`alkali burns and prostaglandin administration. Arch Ophthalmol 1985,
`103:569-571 .
`
`14.
`
`17. Stjernschantz J, Nilsson SPE, Astin M: Vasodynamic and Angiogenic Ef(cid:173)
`fects of Eicosanoids in the Eye. In The Ocular Effects of Prostaglandins
`and Other Eicosanoids. Edited by Bito LZ, Stjernschantz J. New York:
`Alan R. Liss; 1989:155-170.
`18. Astin M, Stjernschantz J, Selen G: Role of nitric oxide in PGF2a·induced
`ocular hyperemia. Exp Eye Res 1994, 59:401-408.
`19. Ziai N, Dolan WJ, Kacere RD, Brubaker RF: The effects on aqueous dy(cid:173)
`namics of RhXA41, a new prostaglandin F2 alpha analogue, after topi(cid:173)
`cal application in normal and ocular hypertensive human eyes. Arch
`Ophthalmol 1993, 111: 1351-1358.
`20. Hotehama Y, Mishima HK: Clinical efficacy of PhXA34 and PhXA41, two
`novel prostaglandin F2a • isopropyl ester analogues for glaucoma
`treatment. Jpn J Ophthalmol 1993, 37:259-269.
`21 . Selen G, Stjernschantz J, Resul B, Bito LZ: Prostaglandin-induced in-
`crease in iris pigmentation. Surv Ophthalmol 1996, in press.
`This article describes the melanogenic effect of naturally occurring and synthetic
`prostaglandins in the primate iris.
`
`22. Hu F, Mah K: Changes in melanosomes with age in iridial stromal
`
`melanocytes of rhesus macaques. Mech Ageing Dev 1983,
`23:95-102.
`
`23. Proia G: Melanins and Melanogenesis. San Diego: Academic Press; 1992.
`
`24.
`
`Jarkman SH, Bragadottir R, Nilsson SEG : Effects of PGF2a and PhXA41,
`a prostaglandin analogue, on the corneal and intraretinal D.C. elec(cid:173)
`troretinogram (ERG) of the albino rabbit eye. Invest Ophthalmol Vis Sci
`1994, 35:A3661.
`
`25. Basu S, Sjoquist B, Stjernschantz J, Resul B: Corneal permeability to
`and ocular metabolism of phenyl substituted prostaglandin esters in
`vitro. Prostaglandins Leuko Essent Fatty Acids 1994, 50:161-168.
`
`26. Sjoquist B, Johansson A: The ocular pharmakokinetics of latanoprost, a
`new antiglaucoma drug, studied by autoradiography. Invest Ophthal(cid:173)
`mol Vis Sci 1995, 36:A3809.
`
`27. Alm A, Villumsen J: PhXA34, a new potent ocular hypotensive drug.
`Arch Ophthalmol 1991, 109:1564-1568.
`28. Villumsen J, Alm A: PhXA34-a prostaglandin F2a analogue: effect on in(cid:173)
`traocular pressure in patients with ocular hypertension. Br J Ophthal·
`mol 1992, 76:214-217.
`
`29. Camras CB, Schumer RA, Marsk A, Lustgarten JS, Serie JB, Stjernschantz
`J, Bito LZ, Podos SM: lntraocular pressure reduction with PhXA34, a
`new prostaglandin analogue, In patients with ocular hypertension.
`Arch Ophthalmol 1992, 110:1733-1738.
`
`30. Alm A, Villumsen J, Tornquist P, Mandahl A, Airaksinen J, Tuulonen A,
`Marsk A, Resul B, Stjernschantz J: lntraocular pressure-reducing effect
`of PhXA41 in patients with increased eye pressure. Ophthalmology
`1993, 9:1312-1317.
`
`31. Hotehama Y, Mishima HK, Kitazawa Y, Masuda K: Ocular hypotensive ef(cid:173)
`fect of PhXA41 in patients with ocular hypertension or primary open(cid:173)
`angle glaucoma. Jpn J Ophthalmol 1993, 37:270-274.
`
`32. Nagasubramanian S, Sheth GP, Hitchings RA, Stjernschantz J: lntraocu(cid:173)
`lar pressure-reducing effect of PhXA41 in ocular hypertension. Oph·
`thalmology 1993, 9: 1 305-1 311 .
`
`33. Alm A, Widengard I, Kjellgren D, Soderstrom M, Fristrom B, Heijl A, Stjern·
`schantz J: Latanoprost administered once daily caused a maintained
`reduction of intraocular pressure In glaucoma patients treated con(cid:173)
`comitantly with timolol. Br J Ophthalmol 1995, 1 :12-16.
`- This article describes a dose·regimen study performed with 0.006% latanoprost
`in patients undergoing timolol treatment with IOPs before latanoprost of about 25
`mm Hg. Once·daily administration of latanoprost was superior to twice daily.
`
`34. Racz P, Ruzsonyi MR, Nagy ZT, Bito LZ: Maintained intraocular pres(cid:173)
`sure reduction with once-a-day application of a new prostaglandin
`F2a analogue (PhXA41): an in-hospital, placebo-controlled study. Arch
`Ophthalmol 1993, 111 :65 7-661 .
`
`35. Kjellgren D, Douglas G, Mikelberg FS, Drance SM, Alm A: The short-time
`effect of latanoprost on the intraocular pressure in normal pressure
`glaucoma. Acta Ophthalmol Scand 1995, 73:233-236.
`
`36. Rulo AH , Greve EL, Hoyng PFJ: The ocular hypotensive effect of la(cid:173)
`tanoprost in normal pressure glaucoma patients. Invest Ophthalmol
`Vis Sci 1995, 36:A3421.
`37. Racz P, Ruzsonyi MR, Nagy ZT, Gagyi UZ., Bito LZ: Around-the-clock
`intraocular pressure reduction with once-daily application latanoprost,
`by itself or in combination with timolol. Arch Ophthalmol 1996,
`114:268-273.
`
`38. Rulo AH, Greve EL, Hoyng PF: Additive effect of latanoprost, a
`prostaglandin F2a analogue, and tlmolol in patients with elevated in(cid:173)
`traocular pressure. Br J Ophthalmol 1994, 78:899-902.
`
`39. Fristrom B, Nilsson SEG: Interaction of PhXA41, a new prostaglandin
`analogue, with pilocarpine. Arch Ophthalmol 1993, 111 :662-665.
`
`40. Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group: Ef(cid:173)
`fects on intraocular pressure and side effects of 0.005% latanoprost
`once·daily, evening or morning: a comparison with timolol. Ophthal·
`mology 1995, 102:1743-1752.
`This article describes a randomized double·masked multicenter trial including a
`total of 26 7 patients with open-angle glaucoma or ocular hypertension treated
`with either 0.005% latanoprost once daily or 0.5% timolol twice daily. Diurnal
`IOPs were obtained at baseline, 3 months, and 6 months of treatment. Morning
`versus evening administration was also studied in the latanoprost patients. It is
`concluded that latanoprost is at least as effective as timolol. Administration of la·
`tanoprost in the evening resulted in better diurnal IOP reduction than with timolol.
`Side effects are discussed in detail.
`
`IPR Page 6/7
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`

`

`Latanoprost as a new horizon in the medical management of glaucoma Stjernschantz and Alm 1 7
`
`41. Camras CB, the USA Latanoprost Study Group: Comparison of la·
`tanoprost and timolol In patients with ocular hypertension and glau·
`coma·six·month, masked U.S.A. multicenter trial. Ophthalmology 1995,
`103:138-147.
`
`This article describes a randomized double-masked multicenter trial, including a
`total of 268 patients with open-angle glaucoma or ocular hypertension treated
`with either 0 .005% latanoprost once daily or 0.5% timolol twice daily. Diurnal
`IOPs were obtained at baseline and 6 months of treatment. It is concluded that
`latanoprost was more effective than timolol. Side effects are discussed in
`detail.
`42. Watson P, Stjernschantz J, the Latanoprost Study Group in United King(cid:173)
`dom: A six month randomized, double-masked study comparing la·
`
`tanoprost to timolol in open angle glaucoma and ocular hypertension.
`Ophthalmology 1995, 103:126-137.
`
`This article describes a randomized double-masked multicenter trial including a
`total of 294 patients with open-angle glaucoma or ocular hypertension treated
`with either 0.005% latanoprost once daily or 0.5% timolol twice daily. Diurnal
`IOPs were obtained at baseline and 6 months of treatment. It is concluded that la(cid:173)
`tanoprost was at least as effective as timolol. Side effects are discussed in detail.
`
`43. Camras CB, Alm A, Watson P: Glaucoma treatment for 1 year with la(cid:173)
`tanoprost, a prostaglandin analog, in the USA, Scandinavia and UK.
`American Academy of Ophthalmology, Annual Meeting: Atlanta 1995:89.
`44. Villumsen J, Alm A: Prostaglandin F2a·lsopropyl ester eye drops; ef(cid:173)
`fects in normal human eyes. Br J Ophthalmol 1989, 73:419-426.
`
`IPR Page 7/7
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`