Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

Abstract

Methods: In this Phase I, multicenter, double-masked, randomized, placebocontrolled, ascending-dose study, subjects with bilateral OHT or early POAG (.22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3.Results: Baseline IOPs were 22.9 6 2.4 mm Hg and 23.5 þ 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean 6 SE) by 3.8 6 0.7 mm Hg (P ¼ 0.002) and 0.05% by 3.9 6 1.0 mm Hg (P ¼ 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 6 0.5 mm Hg (adjusted mean 6 SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase ( 2.5%) in central corneal thickness. Conclusions:In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events.Translational Relevance: Lat-B may be a potential therapeutic agent for glaucoma.

Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015)

“…This agent is a macrolide that originated from a sponge from the Red Sea ( Latrunculia ). It inhibits the assembly of actin microfilaments by binding to free actin monomers in the cytoplasm, inducing cellular relaxation and weaker contacts between the cells and the matrix [22] . In a smooth-muscle-independent pathway, trabedonoson is a highly selective adenosine receptor agonist that improves flow by upregulating various proteases that remove accumulated proteins that can impair trabecular flow [23] .…”

Modulation of Schlemm's canal endothelial cell stiffness via latrunculin loaded block copolymer micelles

“…The first treatment group was SC cells with plain culture media; the second was SC cells incubated with unloaded micelles; the third was the SC cells incubated with 0.5 μ M Lat A solution; and the fourth group was the SC cells incubated with the Lat A‐loaded micelles at a latrunculin concentration of 0.5 μ M . Lat A of 0.5 μ M was chosen based on previous studies by our own group and others . All groups were incubated with their corresponding cocktails for 2 h. Coverslips were then gently washed with PBS and fixed with 4% paraformaldehyde (Electron Microscopy Sciences, Hatfield, PA) for 10 min at room temperature.…”

“…Lat A is frequently used to inhibit multiple forms of endocytosis by phagocytic cells, such as macrophages . Both Lat A and its analog latrunculin B have been previously investigated in animal models and in clinical trials for the treatment of ocular hypertension in glaucoma . A phase I clinical trial of latrunculin found only modest reduction in intraocular pressure at latrunculin concentrations that were more effective in primate eyes, and also found a high fraction of corneal disorders at the highest concentrations investigated …”

Medical Management of Glaucoma in the 21st Century from a Canadian Perspective

“…Another novel agent targeting the trabecular meshwork is latrunculin B. In patients with ocular hypertension or early POAG (phase I clinical trial) twice daily latrunculin B (0.005%, 0.01%, 0.02%, or 0.05% solution) significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events [140]. …”