A Novel Nitric Oxide Releasing Prostaglandin Analog, NCX 125, Reduces Intraocular Pressure in Rabbit, Dog, and Primate Models of Glaucoma

Borghi, Valentina; Bastia, Elena; Guzzetta, Massimiliano; Chiroli, Valerio; Toris, Carol B.; Batugo, Minerva; Carreiro, Samantha; Chong, Wesley K. M.; Gale, David C.; Kucera, David J.; Liu, Jia; Prasanna, Ganesh; Ongini, Ennio; Krauss, Achim H.-P.; Impagnatiello, Francesco

doi:10.1089/jop.2009.0120

Cited by 65 publications

(52 citation statements)

References 21 publications

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“…A nitric oxide-releasing prostaglandin analog was shown to produce a larger IOP reduction compared with latanoprost alone in ocular hypertensive rabbits, dogs, and monkeys. 42 Gene therapy in targeted sites where pharmacologic delivery of nitric oxide donors may not reach sufficient concentrations for therapeutic purposes may be a viable option as well. 43 Endothelial NOS would be a likely candidate.…”

Section: Discussionmentioning

confidence: 99%

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Heyne¹,

Kiland²,

Kaufman³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54:5103-5110. DOI: 10.1167/iovs.12-11491 PURPOSE. To determine the effect of the nitric oxide donor, sodium nitroprusside (SNP), and the nitric oxide synthase (NOS) inhibitor, L-nitro-arginine-methylester (L-NAME), on IOP, mean arterial pressure (MAP), pupil diameter (PD), refraction (Rfx), aqueous humor formation (AHF), and outflow facility (OF) in monkeys.METHODS. Monkeys were treated with single or multiple topical treatments of 500 lg SNP or L-NAME to one eye. IOP was determined by Goldmann applanation tonometry, PD with vernier calipers in room light, Rfx by Hartinger coincidence refractometry, AHF by fluorophotometry, and MAP with a blood pressure monitor. OF was determined by two-level constant pressure perfusion following anterior chamber exchange. RESULTS.Following four topical treatments with 500 lg SNP, 30 minutes apart, IOP was significantly decreased from 2 to 6 hours compared with the contralateral control with the maximum IOP reduction of 20% at 3 hours (P < 0.001). PD, Rfx, and AHF were unchanged. Effects on MAP were variable. OF after SNP exchange was significantly increased by 77% (P < 0.05) at 10 À3 M. Topical L-NAME had no effect on IOP, PD, Rfx, or MAP.CONCLUSIONS. Enhancement of nitric oxide concentration at targeted tissues in the anterior segment may be a useful approach for IOP reduction for glaucoma therapy. Additional studies are warranted before conclusions can be made regarding the effect of NOS inhibition on ocular physiology in nonhuman primates.

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Section: Discussionmentioning

confidence: 99%

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Heyne¹,

Kiland²,

Kaufman³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…A variety of animal studies indicate that the pharmacologically modified drugs are more efficacious than their respective prostaglandin counterparts. [116][117][118] Recently, it was announced that BOL-303259-X, a nitric oxide-donating latanoprost analogue was superior to latanoprost in reducing IOP in patients with glaucoma or OHT. 119 Prostaglandin analogues can also be modified to release hydrogen sulfide (H 2 S), a gas that has antioxidative properties.…”

Section: Systemic Therapiesmentioning

confidence: 99%

Pharmacotherapy of Glaucoma

Schmidl

Schmetterer²,

Garhöfer³

et al. 2015

Journal of Ocular Pharmacology and Therapeutics

131

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Glaucoma is a group of diseases involving the optic nerve and associated structures, which is characterized by progressive visual field loss and typical changes of the optic nerve head (ONH). The only known treatment of the disease is reduction of intraocular pressure (IOP), which has been shown to reduce glaucoma progression in a variety of large-scale clinical trials. Nowadays, a relatively wide array of topical antiglaucoma drugs is available, including prostaglandin analogues, carbonic anhydrase inhibitors, beta-receptor antagonists, adrenergic agonists, and parasympathomimetics. In clinical routine, this allows for individualized treatment taking risk factors, efficacy, and safety into account. A major challenge is related to adherence to therapy. Sustained release devices may help minimize this problem but are not yet available for clinical routine use. Another hope arises from non-IOP-related treatment concepts. In recent years, much knowledge has been gained regarding the molecular mechanisms that underlie the disease process in glaucoma. This also strengthens the hope that glaucoma therapy beyond IOP lowering will become available. Implementing this concept with clinical trials remains, however, a challenge.

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“…In human eyes, NOS reactivity was enriched in major sites of outflow resistance, including the TM and SC, as well as in collecting channels. 16 The NO-donating compounds effectively decrease conventional outflow resistance, leading to a decrease in IOP and outflow rate in different animal models, including rabbits, [21][22][23][24] pigs, 25 dogs, 22 and monkeys, 22,26 and in perfused postmortem human eyes. 27,28 Our previous study 29 further showed that eNOS/NO is a key regulator of outflow facility and IOP in mice.…”

mentioning

confidence: 99%

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Lei

Stamer

et al. 2014

Investigative Ophthalmology & Visual Science

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Citation: Lei Y, Stamer WD, Wu J, Sun X. Endothelial nitric oxide synthaserelated mechanotransduction changes in aged porcine angular aqueous plexus cells. Invest Ophthalmol Vis Sci. 2014;55:8402-8408. DOI: 10.1167/iovs.14-14992 PURPOSE. To investigate effects of aging on endothelial nitric oxide synthase (eNOS) expression and signaling in angular aqueous plexus (AAP) (functional equivalent to human Schlemm's canal) cells subjected to shear stress. METHODS.The AAP cells were isolated differentially from porcine outflow tissues using puromycin selection. Cell aging was induced by culturing cells in hyperoxia condition (40% oxygen and 5% carbon dioxide) for 14 days. The AAP cells grown in chamber slides were exposed to a shear stress of 8 dynes/cm 2 for 24 hours. Expression of eNOS, eNOS-phospho Thr495, eNOS-phospho Ser1177, and Akt-phospho was tested by Western blot analysis and immunofluorescence staining. Nitric oxide (NO) levels were measured using the Griess assay. RESULTS.Compared with control, eNOS levels in aged cells were significantly reduced by 60% (P < 0.05; n ¼ 6). Phosphorylation of eNOS at Ser1177 and Akt at Ser473 was 63% and 80% lower in aged cells, respectively, whereas phosphorylation of the eNOS inhibition site (Thr495) increased by 6.1-fold (P < 0.05; n ¼ 6). Shear stress (8 dynes/cm 2 for 24 hours) increased eNOS abundance (total protein and at cell borders) and phosphorylation at Ser1177 by 1.7-fold and 1.8-fold, respectively (P < 0.05; n ¼ 6), whereas aged cells were unresponsive. In control cells exposed to shear stress, the NO concentration was 1.8-fold higher than in the static group (P < 0.05; n ¼ 4); however, aged cells were unresponsive to shear stress (mean 6 SD, 4.3 6 1.3 vs. 4.1 6 1.4 lM).CONCLUSIONS. Aged AAP cells appear compromised in their mechanotransduction machinery involving eNOS, the protein product of the gene, NOS3, polymorphisms of which impart a risk for the development of glaucoma.Keywords: aging, Schlemm's canal, eNOS G laucoma comprises a group of complex and heterogeneous blinding diseases, affecting almost 60 million people worldwide. 1 Clinically, glaucoma is characterized by cupping of the optic nerve head and visual field loss. Elevated IOP is the primary risk factor for glaucomatous optic nerve damage, and reducing pressure remains the only treatable end point that slows or stops disease progression. The risk of developing POAG also clearly increases with age. 2-8 Primarily, IOP is determined by changes in aqueous humor outflow resistance, which is thought to reside mainly in the juxtacanalicular region, where the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC) cells interact. 9,10 The endothelial cells of the inner wall of SC are important in regulating outflow resistance and thus IOP. 11,12Nitric oxide (NO) regulation appears to have a role in POAG. Family association studies [13][14][15] show a relationship between NOS3 gene polymorphisms, which encode for endothelial NO synthase (eNOS), and POAG. These recent findings are consistent wit...

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A Novel Nitric Oxide Releasing Prostaglandin Analog, NCX 125, Reduces Intraocular Pressure in Rabbit, Dog, and Primate Models of Glaucoma

Abstract: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

Cited by 65 publications

References 21 publications

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys

Pharmacotherapy of Glaucoma

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

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