Latanoprostene Bunod, a Dual-acting Nitric Oxide Donating Prostaglandin Analog for Lowering of Intraocular Pressure

US Ophthalmic Review, 2016;9(2):80–7 DOI: https://doi.org/10.17925/USOR.2016.09.02.80

Abstract:

Current topical treatments for glaucoma have limited efficacy in lowering intraocular pressure (IOP) and/or can produce side effects and tolerability problems. At present, IOP remains the only known modifiable risk factor to delay the progression of glaucoma. The novel IOP-lowering treatment latanoprostene bunod (LBN) is a nitric oxide (NO)-donating prostaglandin F2α analog that is rapidly metabolized in situ to latanoprost acid and butanediol mononitrate, an NO-donating moiety. LBN has a dual action in that it enhances aqueous humor outflow via both the uveoscleral and trabecular meshwork pathways. It is undergoing regulatory review by the Food and Drug Administration (FDA) for the reduction of IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). In the dose-ranging VOYAGER study, LBN 0.024%, the lower of the most effective concentrations evaluated, demonstrated significantly greater IOP lowering and comparable side effects compared with latanoprost 0.005%. The recent APOLLO phase III clinical study (n=420) found LBN 0.024% demonstrated significantly greater reductions in IOP than timolol 0.5% in patients with OAG or OHT at various time points over 3 months. The same study found the proportion of patients with IOP ≤18 mmHg was significantly greater with LBN 0.024% than with timolol 0.5%. In the LUNAR study (n=420), LBN 0.024% was non-inferior to timolol 0.5% over 3 months’ treatment. LBN treatment also resulted in significantly greater IOP lowering than timolol at all time-points with the exception of the first post-baseline assessment. In JUPITER, a study of 130 subjects with OAG or OHT, LBN 0.024% was safe and well tolerated when used for up to a year, and provided significant and sustained IOP reduction. Further, in CONSTELLATION, a study of 25 patients with OHT or OAG, IOP lowering with LBN 0.024% was consistently lower than baseline during both the diurnal/wake and nocturnal/sleep periods whereas timolol 0.5% reduced IOP only during the diurnal period. In addition, LBN 0.024% treatment resulted in a significantly increased diurnal ocular perfusion pressure versus baseline and nocturnal ocular perfusion pressure versus timolol 0.05%. Similarly, in KRONUS, a single-arm, single-center, open label study of 24 healthy Japanese subjects, LBN 0.024% significantly lowered mean IOP over a 24-hour period. Across these studies, LBN has demonstrated a favorable safety profile and good ocular tolerability. It is hypothesized that LBN’s dual action on the outflow pathways accounts for the improved efficacy when compared with latanoprost and timolol.
Keywords: Glaucoma, intraocular pressure, nitric oxide, latanoprostene bunod
Disclosure: Robert N Weinreb has been a consultant to Aerie Pharmaceuticals, Alcon, Allergan, Bausch & Lomb, and ForSightV. He has received research grants from Genentech and Quark and research instruments from Heidelberg Engineering, Optovue, Topcon, and Zeiss. Tony Realini has been a consultat to Alcon, Bausch & Lomb/Valeant, Envisia, Inotek, and Smith and Nephew, and received research support from Alcon, Roche, and Aerie. Rohit Varma has been a consultant to Aerie Pharmaceuticals, Allergan, Bausch & Lomb, Genentech, and Isarna. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Acknowledgments: Medical writing assistance was provided by Catherine Amey and James Gilbart at Touch Medical Media, UK with assistance from Michelle Dalton, Dalton & Associates, US.
Received: August 22, 2016 Accepted September 14, 2016
Correspondence: Robert N Weinreb, Shiley Eye Institute, 415 Campus Point Dr, La Jolla, California 92037, US. E: hiiop@aol.com
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit

Glaucoma is a multifaceted disorder resulting from damage to the retinal ganglion cells (RGCs) and their axons, causing progressive optic nerve degeneration and leading to irreversible blindness in some patients.1–4 In most cases the condition develops gradually, with peripheral vision loss typically being followed by loss of central vision.5 In the US, in 2011, openangle glaucoma (OAG) affected 2.71 million persons and is estimated to rise to 7.32 million by 2050.6 Globally, glaucoma affected an estimated 64.3 million people (aged 40–80 years) in 2013.7 Given the aging of the world’s population, this number is expected to rise to 76.0 million in 2020 and to 111.8 million in 2040.7

Ocular hypertension (OHT) can be defined as a high intraocular pressure (IOP) without observable optic nerve damage.4 OAG and angleclosure glaucoma are the two predominant types of glaucoma, and are characterized by an elevated IOP.9 Normal tension glaucoma (NTG) is a form of OAG that is prevalent in both Japanese and Western populations.10 While damage to the optic nerve occurs without elevation of IOP in NTG, IOP reduction has been shown to reduce visual field damage in patients with NTG.10

Current treatment options target IOP reduction to delay progressive glaucomatous damage and to delay onset of visual field loss in subjects with OHT; these include topical medications, laser trabeculoplasty, and surgical drainage procedures (micro-invasive glaucoma surgery [MIGS], trabeculectomy, tube shunts).11–13 However, commonly used topical treatments (prostaglandin analogs [PGA], beta blockers, carbonic anhydrase inhibitors, and α2-adrenergic agonists) can be limited by ocular and systemic side effects, allergies, the need for multiple administrations every day, poor adherence/compliance, and an inability to consistently control 24-hour IOP (Table 1). A new molecular entity incorporating both the established prostaglandin F (PGF) analog, latanoprost acid and a nitric oxide (NO)-donating group (latanoprostene bunod [LBN, BOL-303259-X] Bausch & Lomb Inc. Bridgewater, NJ, USA) is currently under review by the Food and Drug Administration (FDA) in the US as a novel IOP-lowering monotherapy for glaucoma management. This review discusses the dual mechanism of action of this potential new treatment and evaluates the clinical evidence supporting the compound’s efficacy.

Pathophysiology of glaucoma

Increased IOP raises risk for glaucoma, which is characterized by RGC damage and death that results in changes to the optic nerve head and the visual field. IOP is affected by the balance between aqueous humor (AH) secretion and its subsequent drainage through the trabecular meshwork (TM) and the uveoscleral outflow pathway.5,14–17 AH is secreted into the anterior chamber via the ciliary epithelium and returns to the vasculature through the TM into Schlemm’s canal, draining into collector channels, aqueous and episcleral veins; or it is drained via the uveoscleral route. Recent laboratory studies show cyclic IOP changes, possibly prompted by a reduction in pressure-dependent drainage, alter this aqueous outflow.18 At least 75% of the resistance to AH outflow in humans is localized within the TM, predominantly in the juxtacanalicular portion; in glaucoma, this tissue is altered leading to elevated IOP.16 In addition to IOP, other risk factors affecting the development and/or progression of glaucoma include older age, African ancestry or Hispanic ethnicity, larger optic nerve cup-to-disc ratios, thinner central corneas, family history of glaucoma, diabetes, myopia, history of migraine headaches, and lower ocular perfusion pressure.19,20

Current medical treatments for glaucoma
Topical ocular hypertensive medications which lower IOP have been the mainstay for first-line treatment of OHT and OAG to even before large, population-based clinical studies identified IOP as a modifiable risk factor. The Ocular Hypertension Treatment Study evaluated 1,636 individuals with an IOP of 24–32 mmHg in one eye and 21–32 mmHg in the fellow eye who were randomized to observation or to topical ocular hypotensive medication.21 Early treatment of OHT to lower IOP decreased the cumulative incidence of OAG at a median follow up of 13 years (16% versus 22% overall; p=0.009).

The Early Manifest Glaucoma Trial was a randomized clinical trial that included 255 patients aged 50–80 years (median, 68 years) with early glaucoma, visual field defects (median mean deviation, -4 dB), and a median IOP of 20 mmHg.11 These signs were mainly identified through a population screening. The patients were randomized to no initial treatment or to treatment. The treated patients had laser trabeculoplasty and started receiving topical betaxolol twice daily in eligible eyes. Follow-up visits included tonometry and computerized perimetry every 3 months and fundus photography every 6 months. The results suggest that a reduction of 1 mmHg could be correlated with an approximate 10% decrease in risk for glaucoma progression over a 4–6 year period.11,12 There are five major classes of topical medications currently approved for the treatment of elevated IOP designed to either reduce the production of ocular fluid or facilitate its outflow (Table 1).22–24Until the pathophysiology of glaucoma is better understood, there is little likelihood other therapeutic targets will become a more central component of glaucoma management. Each of these classes of drugs has its own advantages and drawbacks (Table 1). The α2-adrenergic receptor agonists, for instance, decrease the production of aqueous by the ciliary body and act on uveoscleral outflow, but can cause fatigue, high blood pressure or anxiety. While the β-blockers reduce AH secretion to lower IOP, and although rarely cause ocular side effects, may cause respiratory and cardiac side effects.22,23 Also, unlike the cholinergics, β-blockers do not affect pupil size. As miotics, the cholinergic agents target the conventional outflow pathway indirectly, by inducing ciliary muscle contraction that expands the TM and dilates Schlemm’s canal, reducing outflow resistance; however, they are not used widely due to local side effects.25

References:
1. Kingman S, Glaucoma is second leading cause of blindness globally, Bull World Health Organ, 2004;82:887–8.
2. Pascale A, Drago F, Govoni S, Protecting the retinal neurons from glaucoma: lowering ocular pressure is not enough, Pharmacol Res, 2012;66:19–32.
3. Vidal-Sanz M, Salinas-Navarro M, Nadal-Nicolas FM, et al., Understanding glaucomatous damage: anatomical and functional data from ocular hypertensive rodent retinas, Prog Retin Eye Res, 2012;31:1–27.
4. Weinreb RN, Khaw PT, Primary open-angle glaucoma, Lancet, 2004;363:1711–20.
5. Weinreb RN, Aung T, Medeiros FA, The pathophysiology and treatment of glaucoma: a review, JAMA, 2014;311:1901–11.
6. Vajaranant TS, Wu S, Torres M, Varma R, The changing face of primary open-angle glaucoma in the United States: demographic and geographic changes from 2011 to 2050, Am J Ophthalmol, 2012;154:303–14.e3.
7. Tham YC, Li X, Wong TY, Quigley HA, et al., Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis, Ophthalmology, 2014;121:2081–90.
8. Bengtsson B, Leske MC, Hyman L, Heijl A, Early Manifest Glaucoma Trial G. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial, Ophthalmology, 2007;114:205–9.
9. Quigley HA, Broman AT, The number of people with glaucoma worldwide in 2010 and 2020, Br J Ophthalmol, 2006;90:262–7.
10. Mi XS, Yuan TF, So KF, The current research status of normal tension glaucoma, Clin Interv Aging, 2014;9:1563–71.
11. Heijl A, Leske MC, Bengtsson B, et al., Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial, Arch Ophthalmol, 2002;120:1268–79.
12. Leske MC, Heijl A, Hussein M, et al., Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial, Arch Ophthalmol, 2003;121:48–56.
13. Kass MA, Heuer DK, Higginbotham EJ, et al., The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma, Arch Ophthalmol, 2002;120:701–13; discussion 829–30.
14. Agarwal R, Gupta SK, Agarwal P, et al., Current concepts in the pathophysiology of glaucoma, Indian J Ophthalmol, 2009;57:257–66.
15. Fautsch MP, Johnson DH, Aqueous humor outflow: what do we know? Where will it lead us?, Invest Ophthalmol Vis Sci, 2006;47:4181–7.
16. Goel M, Picciani RG, Lee RK, Bhattacharya SK, Aqueous humor dynamics: a review, Open Ophthalmol J, 2010;4:52–9.
17. Winkler NS, Fautsch MP, Effects of prostaglandin analogues on aqueous humor outflow pathways, J Ocul Pharmacol Ther, 2014;30:102–9.
18. Johnstone MA, Intraocular pressure regulation: findings of pulse-dependent trabecular meshwork motion lead to unifying concepts of intraocular pressure homeostasis, J Ocul Pharmacol Ther, 2014;30:88–93.
19. Coleman AL, Miglior S, Risk factors for glaucoma onset and progression, Surv Ophthalmol, 2008;53 Suppl1:S3–10.
20. Furlanetto RL, De Moraes CG, Teng CC, et al., Risk factors for optic disc hemorrhage in the low-pressure glaucoma treatment study, Am J Ophthalmol, 2014;157:945–52.
21. Kass MA, Gordon MO, Gao F, et al., Delaying treatment of ocular hypertension: the ocular hypertension treatment study, Arch Ophthalmol, 2010;128:276–87.
22. Bettin P, Di Matteo F, Glaucoma: present challenges and future trends, Ophthalmic Res, 2013;50:197–208.
23. Wentz SM, Kim NJ, Wang J, et al., Novel therapies for open-angle glaucoma, F1000Prime Rep, 2014;6:102.
24. Kolko M, Present and New Treatment Strategies in the Management of Glaucoma, Open Ophthalmol J, 2015;9:89–100.
25. Toris CB, Pharmacotherapies for glaucoma, Curr Mol Med, 2010;10:824–40.
26. Aptel F, Cucherat M, Denis P, Efficacy and tolerability of prostaglandin analogs: a meta-analysis of randomized controlled clinical trials, J Glaucoma, 2008;17:667–73.
27. Rao RC, Ballard TN, Chen TC, Iris heterochromia and unilateral eyelash hypertrichosis, JAMA, 2015;313:1967–8.
28. Toris CB, Gabelt BT, Kaufman PL, Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction, Surv Ophthalmol, 2008;53 Suppl1:S107–20.
29. Lee AJ, McCluskey P, Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension, Clin Ophthalmol, 2010;4:741–64.
30. Lewis RA, Levy B, Ramirez N, et al., Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension, Br J Ophthalmol, 2015;100:339–44.
31. Zhong Y, Yang Z, Huang WC, Luo X, Adenosine, adenosine receptors and glaucoma: an updated overview, Biochim Biophys Acta, 2013;1830:2882–90.
32. Myers J, Sall K, DuBiner H, et al., A randomized, phase II study of trabodenoson (INO-8875) in adults with ocular hypertension (OHT) or primary open-angle glaucoma (POAG), Invest Ophthalmol Vis Sci, 2013;54:2261.
33. Myers JS, Sall KN, DuBiner H, et al., A dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of 2 and 4 weeks of twice-daily ocular trabodenoson in adults with ocular hypertension or primary open-angle glaucoma, J Ocul Pharmacol Ther, 2016.
34. Ganesh T, Prostanoid receptor EP2 as a therapeutic target, J Med Chem, 2014;57:4454–65.
35. Prasanna G, Carreiro S, Anderson S, et al., Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma, Exp Eye Res, 2011;93:256–64.
36. Yanochko GM, Affolter T, Eighmy JJ, et al., Investigation of ocular events associated with taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma, J Ocul Pharmacol Ther, 2014;30:429–39.
37. Schachar RA, Raber S, Courtney R, Zhang M. A phase 2, randomized, dose-response trial of taprenepag isopropyl (PF- 04217329) versus latanoprost 0.005% in open-angle glaucoma and ocular hypertension, Curr Eye Res, 2011;36:809–17.
38. Weinreb RN, Ong T, Scassellati Sforzolini B, et al., A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study, Br J Ophthalmol, 2015;99:738–45.
39. Krauss AH, Impagnatiello F, Toris CB, et al., Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2alpha agonist, in preclinical models, Exp Eye Res, 2011;93:250–5.
40. Cavet ME, Vittitow JL, Impagnatiello F, et al., Nitric oxide (NO): an emerging target for the treatment of glaucoma, Invest Ophthalmol Vis Sci, 2014;55:5005–15.
41. Lindsey JD, Kashiwagi K, Kashiwagi F, Weinreb RN, Prostaglandins alter extracellular matrix adjacent to human ciliary muscle cells in vitro, Invest Ophthalmol Vis Sci, 1997;38:2214–23.
42. Richter M, Krauss AH, Woodward DF, Lutjen-Drecoll E, Morphological changes in the anterior eye segment after longterm treatment with different receptor selective prostaglandin agonists and a prostamide, Invest Ophthalmol Vis Sci, 2003;44:4419–26.
43. Gabelt BT, Kaufman PL, Prostaglandin F2 alpha increases uveoscleral outflow in the cynomolgus monkey, Exp Eye Res, 1989;49:389–402.
44. Lutjen-Drecoll E, Tamm E, Morphological study of the anterior segment of cynomolgus monkey eyes following treatment with prostaglandin F2 alpha, Exp Eye Res, 1988;47:761–9.
45. Nilsson SF, Samuelsson M, Bill A, Stjernschantz J, Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2 alpha-1-isopropylester in the cynomolgus monkey, Exp Eye Res, 1989;48:707–16.
46. Gaton DD, Sagara T, Lindsey JD, et al., Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)-isopropyl ester treatment, Arch Ophthalmol, 2001;119:1165–70.
47. Digiuni M, Fogagnolo P, Rossetti L, A review of the use of latanoprost for glaucoma since its launch, Expert Opin Pharmacother, 2012;13:723–45.
48. Alm A, Camras CB, Watson PG, Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States, Surv Ophthalmol, 1997;41 Suppl 2:S105–10.
49. Goldberg I, Li XY, Selaru P, Paggiarino D, A 5-year, randomized, open-label safety study of latanoprost and usual care in patients with open-angle glaucoma or ocular hypertension, Eur J Ophthalmol, 2008;18:408–16.
50. Rouland JF, Traverso CE, Stalmans I, et al., Efficacy and safety of preservative-free latanoprost eyedrops, compared with BAKpreserved latanoprost in patients with ocular hypertension or glaucoma, Br J Ophthalmol, 2013;97:196–200.
51. Allaire C, Dietrich A, Allmeier H, et al., Latanoprost 0.005% test formulation is as effective as Xalatan(R) in patients with ocular hypertension and primary open-angle glaucoma, Eur J Ophthalmol, 2012;22:19–27.
52. Garway-Heath DF, Crabb DP, Bunce C, et al., Latanoprost for openangle glaucoma (UKGTS): a randomised, multicentre, placebocontrolled trial, Lancet, 2015;385:1295–304.
53. Becquet F, Courtois Y, Goureau O, Nitric oxide in the eye: multifaceted roles and diverse outcomes, Surv Ophthalmol, 1997;42:71–82.
54. Palmer RM, Ferrige AG, Moncada S, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor, Nature, 1987;327:524–6.
55. Goldstein IM, Ostwald P, Roth S, Nitric oxide: a review of its role in retinal function and disease, Vision Res, 1996;36:2979–94.
56. Haufschild T, Tschudi MR, Flammer J, et al., Nitric oxide production by isolated human and porcine ciliary processes, Graefes Arch Clin Exp Ophthalmol, 2000;238:448–53.
57. Schneemann A, Dijkstra BG, van den Berg TJ, et al., Nitric oxide/ guanylate cyclase pathways and flow in anterior segment perfusion, Graefes Arch Clin Exp Ophthalmol, 2002;240:936–41.
58. Flammer J, Orgul S, Optic nerve blood-flow abnormalities in glaucoma, Prog Retin Eye Res, 1998;17:267–89.
59. Benedito S, Prieto D, Nielsen PJ, Nyborg NC, Role of the endothelium in acetylcholine-induced relaxation and spontaneous tone of bovine isolated retinal small arteries, Exp Eye Res, 1991;52:575–9.
60. Delaey C, Van de Voorde J, The effect of NO donors on bovine retinal small arteries and posterior ciliary arteries, Invest Ophthalmol Vis Sci, 1998;39:1642–6.
61. Okamura T, Kitamura Y, Uchiyama M, et al., Canine retinal arterial and arteriolar dilatation induced by nipradilol, a possible glaucoma therapeutic, Pharmacology, 1996;53:302–10.
62. Chang JY, Stamer WD, Bertrand J, et al., Role of nitric oxide in murine conventional outflow physiology, Am J Physiol Cell Physiol, 2015;309:C205–14.
63. Doganay S, Evereklioglu C, Turkoz Y, Er H, Decreased nitric oxide production in primary open-angle glaucoma, Eur J Ophthalmol, 2002;12:44–8.
64. Galassi F, Renieri G, Sodi A, et al., Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma, Br J Ophthalmol, 2004;88:757–60.
65. Nathanson JA, McKee M, Alterations of ocular nitric oxide synthase in human glaucoma, Invest Ophthalmol Vis Sci, 1995;36:1774–84.
66. Nathanson JA. Nitrovasodilators as a new class of ocular hypotensive agents. J Pharmacol Exp Ther, 1992;260(3):956–65.
67. Wizemann A, Wizemann V, [The use of organic nitrates to lower intraocular pressure in outpatient and surgical treatment (author's transl)]. Article in German, Klin Monbl Augenheilkd, 1980;177:292–5.
68. Schuman JS, Erickson K, Nathanson JA, Nitrovasodilator effects on intraocular pressure and outflow facility in monkeys, Exp Eye Res, 1994;58:99–105.
69. Lei Y, Zhang X, Song M, et al., Aqueous humor outflow physiology in NOS3 knockout mice, Invest Ophthalmol Vis Sci, 2015;56:4891–8.
70. Kotikoski H, Vapaatalo H, Oksala O, Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits, Curr Eye Res, 2003;26:119–23.
71. Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54(7):5103–10.
72. Dismuke WM, Liang J, Overby DR, Stamer WD, Concentrationrelated effects of nitric oxide and endothelin-1 on human trabecular meshwork cell contractility, Exp Eye Res, 2013;120C:28–35.
73. Dismuke WM, Mbadugha CC, Ellis DZ, NO-induced regulation of human trabecular meshwork cell volume and aqueous humor outflow facility involve the BKCa ion channel, Am J Physiol Cell Physiol, 2008;294:C1378–86.
74. Ellis DZ, Dismuke WM, Chokshi BM, Characterization of soluble guanylate cyclase in NO-induced increases in aqueous humor outflow facility and in the trabecular meshwork, Invest Ophthalmol Vis Sci, 2009;50:1808–13.
75. Ellis DZ, Sharif NA, Dismuke WM, Endogenous regulation of human Schlemm's canal cell volume by nitric oxide signaling, Invest Ophthalmol Vis Sci, 2010;51:5817–24.
76. Millar JC, Shahidullah M, Wilson WS, Intraocular pressure and vascular effects of sodium azide in bovine perfused eye, J Ocul Pharmacol Ther, 2001;17:225–34.
77. Shahidullah M, Yap M, To CH, Cyclic GMP, sodium nitroprusside and sodium azide reduce aqueous humour formation in the isolated arterially perfused pig eye, Br J Pharmacol, 2005;145:84– 92.
78. Kaufman PL, Rasmussen CA, Advances in glaucoma treatment and management: outflow drugs, Invest Ophthalmol Vis Sci, 2012;53:2495–500.
79. Kotikoski H, Alajuuma P, Moilanen E, et al., Comparison of nitric oxide donors in lowering intraocular pressure in rabbits: role of cyclic GMP, J Ocul Pharmacol Ther, 2002;18:11–23.
80. Buys ES, Potter LR, Pasquale LR, Ksander BR, Regulation of intraocular pressure by soluble and membrane guanylate cyclases and their role in glaucoma, Front Mol Neurosci, 2014;7:38.
81. Thoonen R, Sips PY, Bloch KD, Buys ES, Pathophysiology of hypertension in the absence of nitric oxide/cyclic GMP signaling, Curr Hypertens Rep, 2013;15:47–58.
82. Wang SK, Chang RT, An emerging treatment option for glaucoma: Rho kinase inhibitors, Clin Ophthalmol, 2014;8:883–90.
83. Arnal JF, Dinh-Xuan AT, Pueyo M, et al., Endothelium-derived nitric oxide and vascular physiology and pathology, Cell Mol Life Sci, 1999;55:1078–87.
84. Cavet ME, Vollmer TR, Harrington KL, et al., Regulation of endothelin-1-induced trabecular meshwork cell contractility by latanoprostene bunod, Invest Ophthalmol Vis Sci, 2015;56:4108–16.
85. Saeki T, Tsuruga H, Aihara M, et al., Dose-Response Profile of PF-03187207 (PF-207) and Peak IOP Lowering Response Following Single Topical Administration to FP Receptor Knockout Mice vs. Wild Type Mice, Invest Ophthalmol Vis Sci, 2009;50:4064.
86. Weinreb RN, Sforzolini Sforzolini B, Vittitow J, Liebmann J, Latanoprostene bunod 0.024% versus timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension, Ophthalmology, 2016;123:965–73.
87. Medeiros FA, Martin KR, Peace J, et al., Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in openangle glaucoma or ocular hypertension: The LUNAR study, Am J Ophthalmol, 2016;168:250–9.
88. Vittitow JL, Liebmann JM, Kaufman PL, et al., Long-term efficacy and safety of latanoprostene bunod 0.024% for intraocular pressure lowering in patients with open-angle glaucoma or ocular hypertension: APOLLO and LUNAR studies, Invest Ophthalmol Vis Sci, 2016;57:3030.
89. Liu JH, Slight JR, Vittitow JL, et al., Efficacy of latanoprostene bunod 0.024% compared with timolol 0.5% in lowering intraocular pressure over 24 hours, Am J Ophthalmol, 2016;169:249–57.
90. Kawase K, Vittitow JL, Weinreb RN, Araie M, Long-term safety and efficacy of latanoprostene bunod 0.024% in Japanese subjects with open-angle glaucoma or ocular hypertension: The JUPITER study, Adv Ther, 2016;33:1612–27.
91. Araie M, Sforzolini BS, Vittitow J, Weinreb RN, Evaluation of the effect of latanoprostene bunod ophthalmic solution, 0.024% in lowering intraocular pressure over 24 h in healthy Japanese subjects, Adv Ther, 2015;32:1128–39.
Keywords: Glaucoma, intraocular pressure, nitric oxide, latanoprostene bunod