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Delivery of pharmaceuticals to the posterior segment presents challenges that arise from the anatomy and clearance pharmacokinetics of the eye. Systemic and several local administration options [topical, periocular, intravitreal (IVT) and subretinal] are in clinical use, each with a unique benefit to risk profile shaped by factors including the administered agent, frequency of dosing, achievable pharmaceutical concentrations within posterior segment structures versus elsewhere in the eye or the body, invasiveness of the procedure and the inherent challenges with some administration methods. The use of the suprachoroidal space (SCS), which is the region between the sclera and the choroid, is being explored as a potential approach to target pharmacotherapies to the posterior segment via a minimally invasive injection procedure. Preclinical data on agents such as vascular endothelial growth factor inhibitors and triamcinolone acetonide (TA) indicate that administration via suprachoroidal injection results in more posterior distribution of the pharmacologic agent, with higher exposure to the sclera, choroid, retinal pigment epithelium cells and retina, and lesser exposure to the anterior segment, than observed with IVT administration. Based in part on these findings, clinical trials have explored the efficacy and safety of suprachoroidal administration of pharmacologic therapies in conditions affecting the posterior segment. Data on a proprietary formulation of TA administered by suprachoroidal injection show improvement in anatomic and visual outcomes in subjects with noninfectious uveitis, with the potential to mitigate the known risks of cataract and increased intraocular pressure (IOP) associated with the use of intraocular corticosteroids. Suprachoroidal administration appears to be a promising treatment modality and is also in the early stages of investigation for other possible applications, such as injection of antiglaucoma agents into the anterior SCS for long‐lasting control of elevated IOP, and as a mode of delivery for gene‐ or cell‐based therapies for retinal disorders. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions are complicated by neovascularization and macular edema. Multi-targeted kinase inhibitors that inhibit select growth factor receptor tyrosine kinases and/or components of their down-stream signaling cascades (such as Src kinases) are rationale treatment strategies for these disease processes. We describe the discovery and characterization of two such agents. TG100572, which inhibits Src kinases and selected receptor tyrosine kinases, induced apoptosis of proliferating endothelial cells in vitro. Systemic delivery of TG100572 in a murine model of laser-induced choroidal neovascularization (CNV) caused significant suppression of CNV, but with an associated weight loss suggestive of systemic toxicity. To minimize systemic exposure, topical delivery of TG100572 to the cornea was explored, and while substantial levels of TG100572 were achieved in the retina and choroid, superior exposure levels were achieved using TG100801, an inactive prodrug that generates TG100572 by de-esterification. Neither TG100801 nor TG100572 were detectable in plasma following topical delivery of TG100801, and adverse safety signals (such as weight loss) were not observed even with prolonged dosing schedules. Topical TG100801 significantly suppressed laser-induced CNV in mice, and reduced fluorescein leakage from the vasculature and retinal thickening measured by optical coherence tomography in a rat model of retinal vein occlusion. These data suggest that TG100801 may provide a new topically applied treatment approach for ocular neovascularization and retinal edema. J. Cell. Physiol. 216: 29–37, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Although phosphoinositide 3-kinases (PI3Ks) play beneficial pro-cell survival roles during tissue ischemia, some isoforms (γ and δ) paradoxically contribute to the inflammation that damages these same tissues upon reperfusion. We therefore considered the possibility that selectively inhibiting proinflammatory P13K isoforms during the reperfusion phase could ultimately limit overall tissue damage seen in ischemia/reperfusion injuries such as myocardial infarction. Panreactive and isoform-restricted PI3K inhibitors were identified by screening a novel chemical family; molecular modeling studies attributed isoform specificity based on rotational freedom of substituent groups. One compound (TG100-115) identified as a selective PI3K γ/δ inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis. a repair process important to tissue survival after ischemic damage, was not disrupted. In rigorous animal Ml models, TG100-115 provided potent cardioprotection. reducing infarct development and preserving myocardial function. Importantly, this was achieved when dosing well after myocardial reperfusion (up to 3 h after), the same time period when patients are most accessible for therapeutic intervention. In conclusion, by targeting pathologic events occurring relatively late in myocardial damage, we have identified a potential means of addressing an elusive clinical goal: meaningful cardioprotection in the post- reperfusion time period. [ABSTRACT FROM AUTHOR]