Clinical Ophthalmology
`
`Open Access Full Text Article
`
`Dovepress
`open access to scientific and medical research
`
`R E V I E W
`
`An evidence-based review of unoprostone
`isopropyl ophthalmic solution 0.15%
`for glaucoma: place in therapy
`
`Derrick S Fung
`Jess T Whitson
`Department of Ophthalmology,
`University of Texas Southwestern
`Medical Center, Dallas, TX, USA
`
`Abstract: Glaucoma is a progressive, neurodegenerative optic nerve disease that can cause
`significant visual morbidity and affects over 60 million people worldwide. The only known
`modifiable risk factor for glaucoma at this time is elevated intraocular pressure (IOP), which
`may be treated with medications, laser therapy, and/or incisional surgery. Topical ocular medica-
`tions are commonly used as first-line therapy for glaucoma, although side effects may limit their
`use. Unoprostone is a novel 22-carbon ocular hypotensive agent that may be advantageous in
`treating some patients with open angle glaucoma or ocular hypertension. Unlike the 20-carbon
`prostanoids, such as latanoprost, that lower IOP primarily through an increase in uveoscleral
`outflow, unoprostone may lower IOP through increased aqueous outflow via the conventional
`trabecular meshwork pathway. Although not as efficacious as other prostanoids, unoprostone
`is effective for IOP reduction both as monotherapy and adjunctive therapy with timolol.
` Unoprostone has decreased affinity for the prostaglandin F2α receptor, which may explain its
`well tolerated ocular and systemic side effect profile compared with other prostanoids.
`Keywords: unoprostone, Rescula®, prostaglandin, glaucoma, medication
`
`Introduction
`Glaucoma is defined as a group of diseases with a characteristic optic neuropathy and
`associated visual function changes. The visual loss that occurs from glaucoma is irrevers-
`ible. It represents a significant public health problem, given that over 60 million people
`have glaucoma worldwide and this number is increasing.1 It is the second most common
`cause of blindness in the world following cataract, and the main cause of irreversible
`blindness.1,2 Risk factors for glaucoma include elevated intraocular pressure (IOP),
`family history, age, race, a thin central cornea, and low ocular perfusion pressure.3,4
`Elevated IOP is currently the only known modifiable risk factor for glaucoma. Lowering
`IOP has been shown to slow visual field deterioration and is protective against both the
`development and progression of glaucoma.5–7 Current glaucoma treatment is focused
`on lowering IOP with medications, laser therapy, and/or incisional surgery.
`Medical therapy is commonly employed as first-line treatment for glaucoma. Current
`options for topical therapy include alpha agonists, beta antagonists, carbonic anhydrase
`inhibitors, miotics, and prostaglandin analogs. Most topical ocular hypotensive agents
`used today are well tolerated, although side effects can limit their effectiveness due to
`poor patient compliance. Having a large selection of ocular hypotensive agents allows
`clinicians to better tailor medication regimens for glaucoma patients to balance clinical
`efficacy and side effects. With increasing medical treatment options, more invasive
`glaucoma therapy, such as laser or surgery, may be delayed or avoided altogether.
`Exhibit 1054
`ARGENTUM
`IPR2017-01053
`
`Clinical Ophthalmology 2014:8 543–554
`© 2014 Fung and Whitson. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
`License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
`permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
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`543
`
`Correspondence: Jess T Whitson
`Department of Ophthalmology, University
`of Texas Southwestern Medical Center,
`5323 Harry Hines Blvd, Dallas,
`TX, USA 75390-9057
`Tel +1 214 648 4733
`Fax +1 214 648 2469
`Email jess.whitson@utsouthwestern.edu
`
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`Fung and Whitson
`
`Unoprostone is an IOP-lowering docosanoid and part
`of a family of lipid IOP-lowering agents, or prostanoids.
`Under the trade name Rescula®, unoprostone isopropyl
` ophthalmic solution 0.12% was developed by R-Tech Ueno,
`Ltd (Tokyo, Japan) and has been marketed there since 1994.8
`It first received approval as a second-line agent for the treat-
`ment of glaucoma and ocular hypertension by the US Food
`and Drug Administration (FDA) in 2000 as a prostaglandin
`analog and was marketed by Ciba Vision, a unit of Novartis
`(Basel, Switzerland), as a 0.15% solution.8 In 2009, Sucampo
`Pharmaceuticals, Inc. (Bethesda, MD, USA) acquired the
`commercialization rights for unoprostone in the USA and
`Canada.8 In 2011, these rights were expanded to include all
`territories worldwide, excluding parts of Asia.8 Last year, the
`FDA revised its formal label for unoprostone to include a
`first-line indication for the treatment of glaucoma and ocular
`hypertension.9 Also, the FDA removed its description of the
`drug as a prostaglandin analog. Unlike the prostaglandin
`analogs, which are 20-carbon derivatives of the eicosanoid
`prostaglandin F2α, unoprostone is a 22-carbon derivative
`of docosahexaenoic acid with little to no affinity for the
`prostaglandin receptor (see Figure 1).8,10 Additionally, recent
`studies show it may work, at least in part, by activating potas-
`sium (BK) and chloride (CIC-2 type) channels, leading to
`relaxation of the trabecular meshwork and increased outflow
`of aqueous humor though the conventional pathway.9
`
`Description
`Unoprostone isopropyl is a synthetic docosanoid molecule
`and a derivative of docosahexaenoic acid, which is a naturally
`occurring omega-3 polyunsaturated fatty acid endogenous to
`the central nervous system and retina.8,11 Its chemical name
`is isopropyl (+)-(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-
`(3- oxodecyl)cyclopentyl]-5-heptenoate, and its chemical
`formula is C25H44O5.9 Docosahexaenoic acid is essential for
`the development and proper functioning of photoreceptor
`cells, and has been shown to prevent photoreceptor apoptosis
`associated with oxidative stress in cell cultures.11–13 Unopro-
`stone 0.15% (Rescula) is formulated as a sterile, isotonic,
`buffered aqueous solution of unoprostone isopropyl with a
`pH of 5.0–6.5 and preserved with 0.015% of benzalkonium
`chloride.9
`
`Pharmacokinetics
`Unoprostone isopropyl is readily hydrolyzed by esterases to its
`active form, unoprostone free acid (M1), (3-[(1R,2R,3R,5S)-
`3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl]propionic acid),
`as shown in Figure 1.8 Unlike the prostaglandin analog
`
`A
`
`HO
`
`HO
`
`B
`
`HO
`
`Dovepress
`
`COOH(CH3)2
`
`O
`
`Unoprostone isopropyl
`
`COOH
`
`HO
`
`OH
`
`PGF2α
`
`C
`
`HO
`
`COOH
`
`HO
`
`O
`
`Unoprostone free acid (M1)
`
`D
`
`COOH
`
`Docosahexaenoic acid
`
`Figure 1 Molecular structure of unoprostone isopropyl and related molecules.
`Notes: Unoprostone isopropyl (A) is a 22-carbon derivative of docosahexanoic
`acid (D), a naturally occurring fatty acid found in the central nervous system and
`retina. Following ocular instillation, unoprostone is hydrolyzed by corneal esterases
`to its active form, unoprostone free acid (C). The 20-carbon prostanoids, such as
`latanoprost, are derived from the eicosanoid, prostaglandin F2α (B).
`
`latanoprost, which is metabolized only by corneal esterases,
` unoprostone undergoes additional metabolism once inside
`the eye by iris and ciliary body esterases.14 This effect may
`explain the shortened clinical efficacy of unoprostone when
`compared with latanoprost. In a study of 18 healthy volunteers
`given unoprostone isopropyl 0.15% ophthalmic solution twice
`daily in both eyes for 14 days, the mean peak unoprostone
`free acid plasma concentration was 1.5 ng/mL and dro pped
`below the lower limit of quantitation (0.250 ng/mL) 1 hour
`following instillation, indicating low systemic absorption
`and rapid plasma excretion.9 Excretion is rapid through the
` kidneys, with a half-life of 14 minutes. Unoprostone will
`begin to reduce IOP 30 minutes after ocular instillation.15
`A clinically sustained effect, however, requires at least
`2 weeks of twice-daily therapy.8
`
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`Unoprostone isopropyl ophthalmic solution 0.15% for glaucoma
`
`Mechanism
`The mechanism of action for the IOP-lowering effect of
`unoprostone is controversial. Early studies showed that
`unoprostone increases aqueous humor outflow through the
`uveoscleral pathway similar to the 20-carbon prostaglan-
`din analogs, such as latanoprost.8 More recent evidence,
`however, shows that it may work, at least in part, through
`stimulation of Ca2+-activated BK and CIC-2 type channels,
`leading to increased trabecular meshwork outflow. It is these
`later studies which have prompted the FDA to remove the
`prostaglandin designation from its formal label.9
`The prostaglandin analogs, including prostaglandin F2α,
`latanoprost, and travoprost, mediate their ocular hypotensive
`effect by stimulating the prostaglandin F2α (FP) receptor.16–18
`These medications have been confirmed in the literature as FP
`receptor agonists, and induce ciliary muscle relaxation leading
`to early IOP reduction via increased uveoscleral outflow.16–20
`The early ocular hypotensive effect of prostaglandin F2α is
`blocked with concurrent use of pilocarpine, which contracts
`the longitudinal muscle of the ciliary body. This contraction
`counteracts prostaglandin-mediated ciliary muscle relaxation,
`thus blocking the early hypotensive effect.16,21
`With long-term prostaglandin use, the ciliary muscle
`undergoes remodeling of the cytoskeletal proteins actin and
`vinculin via mediation of collagen turnover, further contrib-
`uting to increased uveoscleral outflow and sustained IOP
` reduction.16 Other studies have suggested that some aqueous
`humor outflow may also occur at least in part through the
`trabecular meshwork pathway as well.22 The remodeling and
`turnover of the extracellular matrix in the ciliary muscle is
`believed to be related to the balance between matrix metallo-
`proteinase (MMP) and tissue inhibitors of metalloproteinase
`(TIMP). Prostaglandin F2α showed increased c-Fos expres-
`sion in human ciliary muscle cells, which induces expression
`of MMPs.16,23–25 Bimatoprost, latanoprost, and unoprostone all
`increase MMP activity in human ciliary body smooth muscle
`cells except for MMP-2.26 Unoprostone was found to decrease
`MMP-2 activity and increase TIMP activity. This difference
`in MMP/TIMP balance between the prostaglandin analogs
`may explain the lower clinical efficacy of unoprostone.
`In contrast with latanoprost, unoprostone has only weak
`activity on the FP receptor, and its ocular hypotensive effect
`is believed to involve more than FP receptor activation alone.
`As opposed to increasing uveoscleral outflow, unoprostone
`has been shown to increase outflow facility through the
`trabecular meshwork.27
`Unoprostone acts on BK channels that, upon activation,
`lead to cell hyperpolarization.28,29 Endothelin-1 (ET-1) is
`
`known to induce trabecular meshwork contractility mediated
`via glutamate-associated increases in intracellular Ca2+.28,30
`Through BK channel activation, unoprostone is believed to
`block this increase in intracellular Ca2+ in trabecular mesh-
`work cells and contribute to increased trabecular meshwork
`outflow and IOP reduction. This mechanism is supported
`by studies of iberiotoxin, a specific inhibitor of BK channel
`activation. Iberiotoxin was found to inhibit the hyperpolar-
`ization effect of unoprostone.13,28,30 Another study found that
`unoprostone also acts on L-type Ca2+ channel currents in the
`trabecular meshwork and that it reduced trabecular meshwork
`contractility independent of ET-1.31
`The effect of unoprostone on ET-1 is also believed to
`mediate a possible neuroprotective benefit.8 ET-1 is believed
`to play a role in cell apoptosis and ocular blood flow. The
`glutamate-associated hypercalcemia that accompanies injury-
`induced retinal and ganglion cell apoptosis may be mediated
`by ET -1.13,28,29 ET-1 is known to cause vasoconstriction of vas-
`cular smooth muscle, and unoprostone may allow for increased
`ocular blood flow by blocking this vasoconstriction.32–36 This
`effect was studied in healthy subjects and patients with normal
`tension glaucoma using a scanning laser Doppler flowmeter,
`and measures of ocular microcirculation were found to be
`improved with unoprostone treatment.37 A study done in
`healthy individuals given intravenous ET-1 found that topical
`unoprostone significantly decreased the reduction in choroidal
`blood flow induced by ET-1.35
`Several animal studies have found protective effects of
`unoprostone on nerve injury, specifically on retinal ganglion
`cell death,38–40 although one study did find that suppression of
`ET-1 occurred with travoprost and not unoprostone.41 These
`findings suggest possible neuroprotective properties associated
`with unoprostone. A recent study by Tawada et al evaluated
`the effect of twice-daily topical unoprostone on central retinal
`sensitivity in 30 patients with retinitis pigmentosa.42 After
`6 months of therapy, retinal sensitivity improved significantly
`by fundus microperimetry and visual field mean deviation.
`Further research is needed to investigate the potential role of
`unoprostone as a neuroprotective agent in retinal disease.
`
`Efficacy
`Unoprostone as monotherapy
`Early Japanese studies of unoprostone found modest IOP
`reduction with fewer ocular side effects compared with
`prostaglandins E2 and F2α.42–46 Unoprostone typically lowers
`IOP by 10%–25% from baseline, with a duration of effect of
`2–5 hours compared with a 25%–30% reduction in IOP with
`latanoprost which may last up to 24 hours and beyond.47 Table 1
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`surface dysfunction
`Timolol caused ocular
`
`(P=0.014)
`Timolol  Unoprostone
`
`Timolol 0.5% BID
`Unoprostone 0.12% BID
`
`timolol or unoprostone for 6 weeks
`2 weeks of timolol then switch to
`
`unoprostone
`Increased stinging with
`
`Timolol = Unoprostone
`
`Timolol 0.5% BID
`Unoprostone 0.12% BID
`
`Supported in part by Ciba Vision
`timolol BID for 2 weeks
`unoprostone TID compared with
`timolol BID for 2 weeks, then
`Unoprostone BID compared with
`
`groups
`Similar between both
`
`effect profile
`otherwise similar side
`pressure with timolol;
`Decreased blood
`
`Notes
`
`Side effect profile
`
`NS
`−6.9 (28%)
`−3.8 (16%)
`−4.1 (18%)
`
`Timolol 0.5% BID
`Unoprostone 0.12% TID
`Unoprostone 0.12% BID
`
`2+2 weeks
`
`OHT)
`36 (POAG,
`
`1998
`
`Stewart et al49
`
`Timolol = Unoprostone
`efficacy (mmHg, %)
`IOP reduction
`
`Timolol 0.5% BID
`Unoprostone 0.12% BID
`
`4 weeks
`
`36
`
`1993
`
`Azuma et al48
`
`Comparisons
`
`Duration
`
`Reference
`Table 1 Randomized controlled trials of unoprostone as monotherapy
`
`Patients (n)
`
`Year
`
`8 weeks
`
`8 weeks
`
`4+4 weeks
`
`8 weeks
`
`OHT)
`165 (POAG,
`
`OHT)
`48 (POAG,
`
`OHT)
`56 (POAG,
`
`OHT)
`108 (POAG,
`
`2002
`
`Jampel et al57
`
`2002
`
`Tsukamoto et al56
`
`2001
`
`Aung et al55
`
`2001
`
`Susanna et al54
`
`6+6 weeks
`
`52 (POAG)
`
`2001
`
`Saito et al53
`
`8 weeks
`
`18 (OHT)
`
`2001
`
`Kobayashi et al52
`
`24 weeks
`
`2+6 weeks
`
`NTG, OHT)
`40 (POAG,
`
`OHT)
`40 (POAG,
`
`2000
`
`Shimazaki et al51
`
`1999
`
`Nordmann et al50
`
`4 week dual therapy
`4 week monotherapy followed by
`
`groups
`Similar between both
`
`Corporation
`Supported by Pharmacia
`
`with unoprostone
`event; increased stinging
`No serious adverse
`
`washout, 4 week crossover therapy
`4 weeks of monotherapy, 3 week
`
`No significant difference
`
`redness with latanoprost
`with unoprostone; more
`groups; more irritation
`Similar between both
`
`Corporation
`Supported by Pharmacia
`
`groups
`Similar between both
`
`by 6 weeks of dual therapy
`6 weeks of monotherapy followed
`
`Monocular comparison
`
`No serious adverse event
`
`unoprostone
`Increased stinging with
`
`−6.1 (25%)*
`−4.9 (20%)
`
`−7.2 (28%)*
`−3.9 (15%)
`
`−6.7 (28%)*
`−3.3 (14%)
`
`−6.4 (27%)*
`−4.2 (18%)
`
`−6.7 (28%)*
`−3.3 (14%)
`
`combined therapy
`No benefit with
`−6.0 (26%)*
`−3.3 (15%)
`
`Latanoprost 0.005% QD
`Unoprostone 0.15% BID
`
`Latanoprost 0.005% QD
`Unoprostone 0.12% BID
`
`qPM + placebo qAM
`Latanoprost 0.005%
`Unoprostone 0.12% BID
`
`Latanoprost 0.005% QD
`Unoprostone 0.12% BID
`
`Latanoprost 0.005% QD
`Unoprostone 0.12% BID
`
`−6.3 (28%)*
`−3.0 (13%)
`
`Latanoprost 0.005% QD
`Unoprostone 0.12% BID
`
`Latanoprost QD
`Unoprostone BID
`
`4+4 weeks
`
`OHT)
`28 (POAG,
`
`2002
`
`Aung et al58
`
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`Sponsored by Novartis
`of switch therapy
`6 weeks of monotherapy + 6 weeks
`
`Dovepress
`
`Sponsored by Novartis
`
`Corporation
`Supported in part by Pharmacia
`pulsatile ocular blood flow
`Latanoprost showed increased
`
`placebo
`unoprostone similar to
`Hyperemia with
`bimatoprost
`Increased hyperemia with
`unoprostone
`compared with
`the prostaglandins
`angiographic CME with
`Increased flare,
`
`unoprostone
`Increased stinging with
`
`unoprostone
`and hyperemia with
`burning, stinging, itching,
`except for increased
`Similar between groups
`
`reported
`No adverse event
`
`−0.4 (3%)
`−5.9 (29%)**
`−5.8 (28%)**
`−5.4 (26%)**
`−3.1 (14%)*
`
`BAK (placebo)
`Lubricant drop with
`Travoprost 0.004%
`Bimatoprost 0.03%
`Latanoprost 0.005%
`Unoprostone 0.12%
`
`6 months
`
`aphakia)
`pseudophakia,
`80 (POAG,
`
`2005
`
`Arcieri et al62
`
`diurnal IOP reduction
`Unoprostone: complete
`peak IOP reduction
`Brimonidine: greater
`−3.1 (14%)
`−3.0 (14%)
`
`betaxolol
`unoprostone and
`NS between
`–4.9 (21%)
`−5.8 (25%)*
`−4.3 (18%)
`
`(14%–22%)*
`−2.6, −3.1
`(8%–13%)
`−1.6, −2.4+
`
`Brimonidine 0.2% BID
`Unoprostone 0.15% BID
`
`6+6 weeks
`
`OHT)
`33 (POAG,
`
`2004
`
`Stewart et al61
`
`Betaxolol 0.5% BID
`Timolol 0.5% BID
`Unoprostone 0.15% BID
`
`Latanoprost 0.005% QD
`
`6 months
`
`OHT)
`556 (POAG,
`
`2002
`
`Nordmann et al60
`
`Unoprostone 0.15% BID
`
`4 weeks
`
`OHT)
`25 (POAG,
`
`2002
`
`Sponsel et al59
`
`Unoprostone isopropyl ophthalmic solution 0.15% for glaucoma
`
`evening; BAK, benzalkonium chloride; IOP, intraocular pressure; CME, cystoid macu lar edema.
`Abbreviations: POAG, primary open angle glaucoma; OHT, ocular hypertension; NTG, normal tension glaucoma; NS, no significant difference; QD, once a day; BID, twice a day; TID, three times a day; qAM, every morning; qPM, every
`Notes: *Statistically significant. **Statistically significant difference with unoprostone. +IOP reduction (morning, afternoon).
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`lists published randomized clinical trials of unoprostone
`when used as monotherapy.48–62 Most of these studies
`compared unoprostone with timolol and latanoprost as
`monotherapy. Many studies have documented the superior
`efficacy in IOP reduction of latanoprost compared with uno-
`prostone in primary open angle glaucoma and normal tension
`glaucoma.52–59,63–66 Sponsel et al compared the IOP-lowering
`and hydrodynamic effects of unoprostone and latanoprost
`in paired eyes of 25 patients with open-angle glaucoma or
`ocular hypertension.59 Following one month of therapy, both
`agents produced significant reductions in IOP and increases
`in pulsatile ocular blood flow, although the changes seen with
`latanoprost were nearly two-fold greater than those seen with
`unoprostone, which was statistically significant. Although
`some studies have found equivalent IOP reduction between
`timolol and unoprostone,48–50 Nordmann et al in a 24-month
`multicenter, double-masked, randomized trial of 556 patients
`with glaucoma or ocular hypertension who received either
`twice-daily unoprostone, betaxolol, or timolol for 6 months,
`found similar mean diurnal IOP-lowering efficacy between
`betaxolol and unoprostone monotherapy.60 Both groups
`achieved an IOP reduction of 3–4 mmHg, or 18%–20%,
`from baseline. In this study, however, timolol monotherapy
`produced a significantly greater mean diurnal IOP reduction
`than either unoprostone or betaxolol (see Figure 2).
`
`Unoprostone as adjunctive therapy
`Other studies have investigated the use of unoprostone
`as adjunctive therapy to timolol for the treatment of
`glaucoma or ocular hypertension (see Table 2).67–69 In a
`12-week, multicenter, double-masked, randomized trial
`of 146 patients comparing unoprostone, brimonidine, and
`dorzolamide when added to timolol, Hommer et al found
`comparable efficacy in mean diurnal IOP reduction between
`all groups, with each adjunctive agent producing an addi-
`tional drop in IOP of 2–3 mmHg from a timolol-treated
`baseline (see Figure 3).67 Similar results were found in two
`other studies comparing unoprostone, brimonidine, and
`dorzolamide as adjunctive therapy with timolol.68,69 A study
`by Saito et al involving 52 patients with primary open-angle
`glaucoma found no additional IOP-lowering effect when
`unoprostone was added to latanoprost following 12 weeks
`of therapy.53
`
`Safety and tolerability
`The side effects of the lipid IOP-lowering agents are well
`described in the literature, and include conjunctival hype-
`remia, increased iris pigmentation, eyelash and eyelid
`changes, deepening of the upper eyelid sulcus, cystoid macu-
`lar edema (CME), iris cysts, worsening of herpetic keratitis,
`and anterior uveitis.70–73 A summary of trials investigating
`
`UIOS 0.15%
`
`TMOS 0.5%
`
`BHOS 0.5%
`
`24
`
`22
`
`20
`
`18
`
`16
`
`Mean 12-hour diurnal IOP (mmHg)
`
`0
`
`1
`
`2
`
`3
`Time (months)
`Figure 2 Mean 12-hour diurnal IOP comparing unoprostone, timolol, and betaxolol monotherapy.
`Notes: Reprinted with permission from the American Journal of Ophthalmology, Volume 133/edition 1, Nordmann JP, Mertz B, Yannoulis NC, Schwenninger C, Kapik B,
`Shams N; for the Unoprostone Monotherapy Study Group-EU. A double-masked randomized comparison of the efficacy and safety of unoprostone with timolol and betaxolol
`in patients with primary open-angle glaucoma including pseudoexfoliation glaucoma or ocular hypertension. 6 month data, pages 1–100, Copyright 2002, with permission from
`Elsevier.62
`Abbreviations: UIOS, unoprostone isopropyl ophthalmic solution; TMOS, timolol maleate ophthalmic solution; BHOS, betaxolol hydrochloride ophthalmic solution;
`IOP, intraocular pressure.
`
`4
`
`5
`
`6
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`Unoprostone isopropyl ophthalmic solution 0.15% for glaucoma
`
`Table 2 Randomized controlled trials of unoprostone as adjunctive therapy
`Reference
`Year Patients
`IOP reduction
`Duration (Base therapy) +
`(n)
`efficacy (mmHg, %)
`comparisons
`(Timolol 0.5% BID) +
`146 (POAG,
`OHT)
`Unoprostone 0.15% BID
`Brimonidine 0.2% BID
`Dorzolamide 2.0% BID
`
`Hommer et al67
`
`2003
`
`12 weeks
`
`−2.7 (12.3%)
`−2.8 (12.5%)
`−3.1 (14.4%)
`NS
`
`Side effect profile
`
`Notes
`
`No serious adverse
`events; dorzolamide
`had more adverse
`events overall
`
`Second and third
`authors employed
`by Novartis
`
`Day et al68
`
`2003
`
`32 (POAG,
`OHT)
`
`6+6 weeks
`
`(Timolol 0.5% BID) +
`Unoprostone 0.15% BID
`Dorzolamide 2% BID
`
`Sharpe et al69
`
`2005
`
`33 (POAG,
`OHT)
`
`6+6 weeks
`
`(Timolol 0.5% BID) +
`Unoprostone 0.15% BID
`Brimonidine 0.2% BID
`
`6 weeks of
`therapy + 6 weeks
`of crossover
`therapy
`Sponsored by
`Novartis
`6 weeks of
`therapy + 6 weeks
`of crossover
`therapy
`Supported by
`Novartis
`Abbreviations: NS, no significant difference; POAG, primary open angle glaucoma; OHT, ocular hypertension; BID, twice a day; IOP, intraocular pressure.
`
`−3.8 (16%)
`−3.6 (15%)
`NS
`
`−2.7 (12%)
`−2.2 (10%)
`NS
`
`No serious adverse
`event; no significant
`difference
`
`Increased burning
`and dryness with
`unoprostone
`
`the local and systemic safety profile of unoprostone is
`shown in Table 3.51,62,74–79 Many of these studies reported a
` favorable side effect profile of unoprostone when compared
`with timolol and placebo.51,74,75,77 When compared with other
`prostanoids, unoprostone tended to have a better ocular side
`effect profile.62,76,78,79
`In the comparative trial of unoprostone, timolol, and
`betaxolol by Nordmann et al discussed in the Unoprostone
`as monotherapy section, adverse events were similar for
`the three treatment groups except for burning/stinging,
`burning/ stinging upon drug instillation, and ocular itching,
`which were more common with unoprostone than with timolol
`but less common than with betaxolol.60 Hyperemia was also
`more common with unoprostone (10.8%) than with timolol
`(3.6%) or betaxolol (5.0%). Adverse events in this study were
`typically mild to moderate and transient in nature.
`FP receptor activation is believed to lead to enhanced
`tyrosinase activity and melanogenesis in iridial melanocytes
`causing increased iris pigmentation.80 Mouse epidermal
`melanocytes were found to have enhanced tyrosinase activ-
`ity with both latanoprost and unoprostone.81 A prospective
`study in Japan by Chiba et al compared iris pigmentation
`between 48 patients using either latanoprost or unopros-
`tone as monotherapy.76 Patients included in this study all
`had glaucoma and were treated for over 30 months with
`one of the two agents. Photography was performed by
`the same slit-lamp camera with 45 degree illumination at
`16× magnification. Photograph grading was performed by
`three glaucoma specialists who were masked to the patient
`
`and treatment characteristics. Only upon agreement among
`all three specialists was positive pigmentation documented.
`They found that 60% of latanoprost patients had increased iris
`pigmentation compared with 30% of unoprostone patients,
`which was statistically significant.
`A multicenter, prospective, double-masked, randomized
`study by McCarey et al evaluated iris color and eyelash
`changes over 24 months in 1,131 patients randomized to
`twice-daily unoprostone, timolol, or betaxolol.77 Serial color
`photographs of the iris and eyelids were taken at baseline
`and over the course of the 24-month study. Photography was
`performed under standardized conditions, including equip-
`ment, camera settings, flash settings, slit-lamp settings, and
`environmental lighting. Seven views of each eye, a calibra-
`tion photograph, and a patient identification photograph were
`used at each patient visit. Two masked, independent readers
`evaluated baseline and post-treatment photographs. Of the
`659 patients on unoprostone, seven cases of iris color change
`(1.06%) were noted. There were no differences in eyelash
`density or length noted between the three treatment groups.
`The authors concluded that the incidence of iris pigmentation
`change was low with unoprostone and that eyelash changes
`were not clinically significant. The authors proposed that
`this may be related to the lower affinity of unoprostone for
`the FP receptor.
`Deepening of the upper eyelid sulcus is a recently dis-
`covered ocular side effect observed with the prostanoids.
`Two hundred and fifty patients on various prostanoid
` medications were observed with eyelid photographs and
`
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`
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`0
`
`−5
`
`−10
`
`−15
`
`−20
`
`−25
`
`−30
`
`% Change from baseline (SD)
`
`Timolol +
`unoprostone
`
`Timolol +
`dorzolamide
`
`Timolol +
`brimonidine
`
`Figure 3 Change in diurnal IOP (percentage) with unoprostone, dorzolamide, and brimonidine as adjunctive therapy with timolol.
`Notes: Mean percentage changes in the 8 hour diurnal IOP from a timolol-treated baseline at week 12 were −12.3%, −12.5%, and −14.4% in the unoprostone, brimonidine, and
`dorzolamide groups, respectively. Reproduced from Unoprostone as adjunctive therapy to timolol: a double masked randomised study versus brimonidine and dorzolamide.
`Hommer A, Kapik B, Shams N; for the Unoprostone Adjunctive Therapy Study Group, Volume 87(5), pages 592–598, Copyright 2003, with permission from BMJ Publishing
`Group Ltd.67
`Abbreviations: IOP, intraocular pressure; SD, standard deviation.
`
`subjective questionnaires.78,79 Bimatoprost and travoprost
`were found to have a higher incidence of deepening of the
`upper eyelid sulcus, eyelid pigmentation, and eyelid bristles
`compared with latanoprost, tafluprost, and unoprostone. Fur-
`thermore, unoprostone had a significantly lower incidence of
`abnormal lash growth compared with all other prostanoids.
`A recent review by Arcieri et al investigated the effect of
`prostanoid use on the blood–aqueous barrier and on angio-
`graphic CME.62 Eighty patients with primary open angle glau-
`coma, pseudophakia, or aphakic glaucoma were randomized
`to treatment with bimatoprost (n=16), latanoprost (n=15),
`travoprost (n=17), unoprostone (n=16), or lubricant placebo
`drops (n=16) over 6 months. No patient had angiographic
`CME at baseline; however, four latanoprost-treated patients,
`one bimatoprost-treated patient, and one travoprost-treated
`patient developed CME on fluorescein angiography. The CME
`resolved in all patients with cessation of the prostanoid and
`use of a nonsteroidal anti-inflammatory medication. Of note,
`five of the six patients who developed CME had an absent or
`ruptured posterior capsule. No unoprostone-treated patients
`
`developed CME. The authors concluded that bimatoprost,
`latanoprost, and travoprost may disrupt the blood–aqueous
`barrier in pseudophakic or aphakic eyes and lead to the
`development of angiographic CME. They proposed that this
`may be related to higher affinity of these medications for the
`FP receptor compared with unoprostone.
`Unoprostone is well tolerated systemically. Stewart et al
`compared the cardiovascular effects of unoprostone and
`timolol during exercise using a treadmill test in 30 healthy
`adults.74 Following 5 days of twice-daily dosing, timolol
`significantly reduced exercise-induced heart rate, while
`unoprostone showed no effect. In another study comparing
`unoprostone with placebo in patients with mild to moderate
`asthma, there were no changes in pulmonary function test
`parameters before or after administration of salbutamol.75
`
`Conclusion
`Unoprostone is a novel ocular hypotensive agent which may
`act, at least in part, to increase trabecular meshwork outflow,
`unlike the typical prostanoids which lower IOP primarily by
`
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`Unoprostone isopropyl ophthalmic solution 0.15% for glaucoma
`
`review of eyelid photographs
`Subjective questionnaire and physician
`Monocular treatment
`
`latanoprost, tafluprost, and unoprostone
`bimatoprost and travoprost and occurred less with
`Upper eyelid sulcus deepening occurred more with
`
`review of eyelid photographs
`Subjective questionnaire and physician
`Monocular treatment
`
`and bimatoprost versus others
`eyelid pigmentation and eyelash bristles with travoprost
`of eyelash bristles with unoprostone; significantly more
`No difference in eyelid pigmentation; lower incidence
`
`Sponsored by Novartis
`evaluation
`Masked observer iris photograph
`Sponsored by Novartis
`No positive control with timolol
`
`Supported by Novartis
`Healthy subjects
`
`Notes
`
`Hyperemia with unoprostone similar to placebo
`Increased hyperemia with bimatoprost
`prostaglandins compared with unoprostone
`Increased flare and angiographic CME with the
`
`no difference with eyelash characteristics
`Iris pigmentation with unoprostone (1.06%);
`treated eyes and 30% of unoprostone-treated eyes
`Increased iridial pigmentation in 60% of latanoprost-
`at baseline and post inhaled salbutamol
`No difference between pulmonary function tests
`seen between groups
`compared with placebo; no differences in blood pressure
`with timolol; no differences were seen with unoprostone
`block exercise induced increases in heart rate compared
`Treadmill test crossover study; unoprostone did not
`function index compared with unoprostone
`a decreased Schirmer’s test value, and a decreased tear
`Timolol caused a decreased tear breakup time