Molecular umbrella conjugate for the ocular delivery of siRNA.

The synthesis, computer modeling, and biological activity of an octawalled molecular umbrella short interfacing RNA (siRNA) conjugate is described. This molecular umbrella-siRNA conjugate exhibited mRNA knockdown activity in vitro in the absence of a transfection reagent. Evaluation of this molecular umbrella conjugate in vivo, using the rat eye via intravitreal injection, resulted in sequence specific mRNA knockdown in the retina with no obvious signs of toxicity, as judged by ophthalmic examination.

The effect of cyclooxygenase inhibition on the ocular hypotensive action of topical carbonic anhydrase inhibitors in rabbits.

Experiments were undertaken in normal albino rabbits to determine if cyclooxygenase inhibition by nonsteroidal anti-inflammatory drugs modified the ocular hypotensive activities of topically applied MK-507, MK-927 and L-662,583, three water-soluble carbonic anhydrase inhibitors (CAI). Cyclooxygenase was inhibited either by systemic indomethacin or by topically administered flurbiprofen, and epinephrine was included as a positive control. Both a 1-hr pretreatment with indomethacin (5 mg/kg i.

Effect of a 5-lipoxygenase (5-LO)/cyclooxygenase (CO) inhibitor, WY-47, 288, on cutaneous models of inflammation.

WY-47,288 (2-[(1-naphthalenyloxy)methyl]quinoline) demonstrated topical antiinflammatory activity in several animal models of skin inflammation. Application of WY-47,288 to mouse ear surfaces inhibited arachidonic acid (ED50 = 0.3 mg/ear) and tetradecanoylphorbol acetate (TPA)-induced inflammation (40% at 1 mg/ear).

Pharmacologic modulation of PAF-induced mortality in mice.

The effect of antiinflammatory drugs, phosphodiesterase inhibitors, leukotriene and mediator antagonists and other drug classes were evaluated in a PAF-induced mortality model in mice. By the oral route of administration (-1 hr), dapsone (ED50 = 25 mg/kg), BW 755C (ED50 = 29 mg/kg), theophylline (ED50 = 30 mg/kg) and LY-171,883 (ED50 = 50 mg/kg) protected against PAF-induced lethality in the mouse. Other drugs that afforded protection when given at various dosing schedules and routes were NDGA (100 mg/kg, -18 hr p.

Correlation between mouse skin inflammation induced by arachidonic acid and eicosanoid synthesis.

We and others have shown that arachidonic acid (AA), when applied topically to ear surfaces, causes an intense acute inflammatory reaction within minutes (as measured by ear thickness). In this study, we have investigated the cellular and biochemical changes associated with this phenomenon and have attempted to correlate these changes with the induction of inflammation. Measurement of vascular permeability by the accumulation of [125I]albumin showed that significant plasma exudation was observed at 15 min in AA-treated ears.