A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs

Impagnatiello, Francesco; Borghi, Valentina; Gale, David C.; Batugo, Minerva; Guzzetta, Massimiliano; Brambilla, Stefania; Carreiro, Samantha; Chong, Wesley K. M.; Prasanna, Ganesh; Chiroli, Valerio; Ongini, Ennio; Krauss, Achim H.-P.

doi:10.1016/j.exer.2011.02.006

Cited by 30 publications

(30 citation statements)

References 24 publications

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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

127

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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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Section: Systemic Therapiesmentioning

confidence: 99%

Pharmacotherapy of Glaucoma

Schmidl

Schmetterer²,

Garhöfer³

et al. 2015

Journal of Ocular Pharmacology and Therapeutics

127

View full text Add to dashboard Cite

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“…Although different forms of glaucoma are known, the most common condition is adult-onset open chamber-angle glaucoma ("open angle glaucoma" or OAG), which is age related and characterized by an open chamber angle, elevated IOP, a visual field defect and an area of pallor around the cupped optic nerve head, as well as constriction of blood flow through the vasculature [1][2][3] . Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS) is involved in aqueous humour outflow within the eye, local modulation of ocular blood flow, and retinal ganglion cells death by [4][5][6] . It has been observed that hypertensive glaucoma patients have a decreased NO/cGMP content in the aqueous humour 3 and that several classes of NO-donors decrease IOP in normal and pathological conditions [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS) is involved in aqueous humour outflow within the eye, local modulation of ocular blood flow, and retinal ganglion cells death by [4][5][6] . It has been observed that hypertensive glaucoma patients have a decreased NO/cGMP content in the aqueous humour 3 and that several classes of NO-donors decrease IOP in normal and pathological conditions [4][5][6][7] . Sulfonamides acting as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) are clinically used as antiglaucoma agents for decades [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

Fabrizi

Mincione

Somma

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

149

116

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“…The purpose of this study was to test this hypothesis in a head-to-head comparison of NCX 470 and bimatoprost at equimolar doses in three well-established animal models of glaucoma. Specifically, transiently ocular hypertensive New Zealand white rabbits (tOHT-rabbits) previously shown to respond to NO 17 and not as much to PGF2a agonists 13,18 were chosen to dissect the NO contribution from that of bimatoprost. Ocular normotensive dogs (ONT-dogs) and hypertensive nonhuman primates (OHTmonkeys) were instead selected as species sensitive to both PGF2a analogues and NO.…”

Section: Methodsmentioning

confidence: 99%

“…We and others have repeatedly reported that tOHT-rabbits are sensitive to most IOP-lowering agents including NO 17 but not to PGF2a agonists, 13,18,19 which makes this species ideal to dissect out the NO-mediated effects of NCX 470. Hypertonic saline injection (0.1 mL) into the vitreous body transiently increased IOP from 18.7 6 0.4 to 46.7 6 1.4 mm Hg within 30 minutes to then gradually return back to baseline over the following 5 hours (Fig.…”

Section: Ncx 470 and Bimatoprost Iop-lowering Activity In Transientlymentioning

confidence: 99%

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

Impagnatiello

Toris

Batugo

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The prostaglandin F2alpha (PGF2a) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470, a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal.METHODS. New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits.RESULTS. NCX 470 (0.14%, 30 lL) lowered IOP in tOHT-rabbits with an E max of À7.2 6 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 lL) was noneffective in this model. NCX 470 (0.042%, 30 lL) was more effective than equimolar (0.03%, 30 lL) bimatoprost in ONT-dogs (IOP change, À5.4 6 0.7 and À3.4 6 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, À7.7 6 1.4 and À4.8 6 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 lL) or bimatoprost (0.03%, 30 lL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing.CONCLUSIONS. NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2a and NO/cGMP signaling pathways.

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A dual acting compound with latanoprost amide and nitric oxide releasing properties, shows ocular hypotensive effects in rabbits and dogs

Cited by 30 publications

References 24 publications

Pharmacotherapy of Glaucoma

Pharmacotherapy of Glaucoma

A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

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