Intravitreal injection of bevacizumab was the most effective route of administration for intraocular tissue. Also, bevacizumab injected subconjunctivally was transported into the intraocular tissues of the treated eyes at an effective level. Both intravitreal and subconjunctival injections of bevacizumab resulted in high plasma concentrations. Bevacizumab was distributed into the intraocular tissues in fellow eyes via the systemic circulation. This treatment may be effective for blocking vascular endothelial growth factor activity.

Abstract:Transport of drugs applied by traditional dosage forms is restricted to the eye, and therapeutic drug concentrations in the target tissues are not maintained for a long duration since the eyes are protected by a unique anatomy and physiology. For the treatment of the anterior segment of the eye, various droppable products to prolong the retention time on the ocular surface have been introduced in the market. On the other hand, direct intravitreal implants, using biodegradable or non-biodegradable polymer technology, have been widely investigated for the treatment of chronic vitreoretinal diseases. There is urgent need to develop ocular drug delivery systems which provide controlled release for the treatment of chronic diseases, and increase patient's and doctor's convenience to reduce the dosing frequency and invasive treatment. In this article, progress of ocular drug delivery systems under clinical trials and in late experimental stage is reviewed.

In general, it is difficult to achieve effective levels of drugs in the vitreous and the retina via topical and/or systemic administration. Intraocular drug delivery systems that achieve longer duration of pharmacological effect with lower administration frequency are urgently needed. Intraocular sustained drug release via implantable devices or injectable particles has been investigated for the treatment of various vitreoretinal disorders. Several non-biodegradable implants are available in clinical practice or in the late developmental phase: Vitrasert (ganciclovir intravitreal implant) for cytomegalovirus retinitis, Retisert (fluocinolone acetonide intravitreal implant) for non-infectious uveitis, Iluvien (fluocinolone acetonide intravitreal implant) for diabetic macular oedema, and NT-501 (a polymer implant containing human retinal epithelial cells genetically modified to secrete ciliary neurotrophic factor) for non-neovascular (dry) age-related macular degeneration and/or retinitis pigmentosa. Many biodegradable formulations, including different shapes of rods, nail-like plugs, discs, or micro- or nanoparticles, have also been investigated, but are not available as yet for the treatment of vitreoretinal disorders. The most developed biodegradable device, Ozurdex (dexamethasone intravitreal implant), is approved as first-line therapy for the treatment of macular oedema following branch retinal vein occlusion or central retinal vein occlusion. In this article, we review the progress of major biodegradable drug delivery systems currently in clinical trials or in experimental stages for the treatment of vitreoretinal disorders.

In both rat strains, P-gp operates in the blood-ocular barriers, and the impact of P-gp on BRB permeability to quinidine and verapamil is lower than that on BBB permeability.

A 68-year-old Japanese male with a five-year-history of lung carcinoma showed recurrent blisters and erosions on the oral and genital mucosae and the skin. The patient complained of dyspnea due to severe laryngeal stenosis and underwent a tracheostomy. A skin biopsy specimen showed a subepidermal blister and linear deposits of IgG and C3 at the basement membrane zone of the epidermis. Indirect immunofluorescence examination demonstrated circulating IgG anti-basement membrane zone autoantibodies that reacted to epiligrin on immunoblotting. Based on a diagnosis of anti-epiligrin cicatricial pemphigoid, he was treated with prednisolone, minocycline hydrochloride and nicotinamide. Although no new skin lesions appeared, he died of lung carcinoma five months after the tracheostomy. A review of reported cases with anti-epiligrin cicatricial pemphigoid in Japan disclosed that 5 of 16 cases (31.2%) were complicated by internal malignancies.

Three sesterterpenoids, aplysinoplides A-C (1- 3), were isolated from the marine sponge Aplysinopsis digitata. Their structures were determined on the basis of spectroscopic data. They exhibited cytotoxic activity against P388 mouse leukemia cells.

The Asahi River Dam reservoir is one of the important freshwater resources for Okayama City, Japan. The eutrophication of the reservoir has been warned of since the 1980s. In this study, we discuss the relationship between hydraulic retention time and increase of phytoplankton, and the influence of wind-driven currents on the spatial distribution of phytoplankton based on the observations and numerical simulations. Observations were carried out from 1993 to 1995. The numerical simulation of hydraulics in the reservoir was carried out by applying an orthogonal curvilinear finite difference method. Judging from phosphorus and nitrogen concentrations, the water quality of the Asahi River Dam reservoir is usually eutrophic. However, high concentrations of chlorophyll-a are not always observed. The observed dependence of chlorophyll-a concentration on hydraulic retention time is reproduced fairly well by a simple relationship derived from the balance of phytoplankton based on the assumption of complete mixing. The hydraulic retention time is a limiting factor of an increase in phytoplankton in the Asahi River Dam reservoir. It takes a retention time of 2 weeks for the sufficient increase of phytoplankton. The results obtained by the simulations show that the wind-driven currents play an important role in the spatial distribution of phytoplankton.

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