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Abstract #74106 Published in IGR 19-1

The Role of Nitric Oxide in the Intraocular Pressure Lowering Efficacy of Latanoprostene Bunod: Review of Nonclinical Studies

Cavet ME; DeCory HH
Journal of Ocular Pharmacology and Therapeutics 2018; 34: 52-60

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Latanoprostene bunod (LBN) is a topical ophthalmic therapeutic for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT). LBN is composed of latanoprost acid (LA) linked to a nitric oxide (NO)-donating moiety and is the first NO-releasing prostaglandin analog to be submitted for marketing authorization in the United States. The role of latanoprost in increasing uveoscleral outflow of aqueous humor (AqH) is well established. Herein, we review findings from nonclinical studies, which evaluated the role of NO in the IOP-lowering efficacy of LBN. Pharmacokinetic studies in rabbits and corneal homogenates indicate that LBN is rapidly metabolized to LA and butanediol mononitrate (BDMN). NO is subsequently released by BDMN as shown by increased cyclic guanosine monophosphate (cGMP) levels in (1) the AqH and iris-ciliary body after administration of LBN in rabbits and in (2) human trabecular meshwork (TM) cells after incubation with LBN. LBN reduced myosin light chain phosphorylation, induced cytoskeletal rearrangement, and decreased resistance to current flow to a greater extent than latanoprost in TM cells, indicating that NO released from LBN elicited TM cell relaxation. LBN also lowered IOP to a greater extent than latanoprost in FP receptor knockout mice, rabbits with transient OHT, glaucomatous dogs, and primates with OHT. Along with results from a Phase 2 clinical study in which treatment with LBN 0.024% resulted in greater IOP-lowering efficacy than latanoprost 0.005%, these data indicate that LBN has a dual mechanism of action, increasing AqH outflow through both the uveoscleral (using LA) and TM/Schlemm's canal (using NO) pathways.

Pharmaceutical Medical Affairs , Bausch + Lomb, Rochester, New York.

Full article

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Classification:

11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)

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