Alterations Of The Bloodocular Barrier In Diseased State

The blood-ocular barrier shares similar embryological origin, microanat-omy, and many physiological functions with the blood-brain barrier. There are many natural (e.g., diabetes, hypertension) or iatrogenic (chemotherapy, retinal photocoagulation) conditions that cause blood-ocular barrier breakdown. Disruption of the tight junctions between the endothe-lium of the retinal blood vessels (inner blood-retinal barrier) and the tight junctions between adjacent RPE cells (outer blood-retinal barrier) results in breakdown of the BOB and subsequent changes in drug ocular penetration.

Infectious and noninfectious (uveitis and surgery) causes of ocular inflammation represent one category of retinal vascular disorders causing BOB breakdown. Fungi, viruses, and bacteria can be very destructive when they infect the eye. Candida endophthalmitis occurs in 5-30% of patients with disseminated Candida infections (15). Bacterial endophthalmitis is a severe and often blinding infection of the eye (26,69). Noninfectious inflam mation is associated with diseases of immune regulation. Models for non-infectious uveitis include intravitreal antigen injection or heat-killed bacteria (7,33,34,52). Bacterial lipopolysaccharide induces endotoxin-induced uveitis in rabbits, mice, and rats and is a useful tool for investigating ocular inflammation due to immunopathogenic, rather than autoimmune processes (39,94,95).

The integrity of the blood-retinal barrier can be demonstrated both experimentally and clinically by intravenous injection of tracer molecules normally excluded from the retina by the healthy blood-retinal barrier. Horseradish peroxidase (99) and carboxyfluoroscein (20) are the most commonly used tracers). Disruption of the inner or outer blood-retinal barrier is demonstrated by passage of these tracers either between pigment epithelial cells or of retinal blood vessels. Fluorescein isothiocyanate linked to high molecular weight dextrans of varying size can also be used experimentally to evaluate the significance of the molecular weight on differential passage through the disrupted blood-retinal barrier in different pathological conditions (8).

Chemical, mechanical, inflammatory, and infective insults modulate the penetration of drugs into the eye following systemic administration. This is particularly important, especially when the blood-ocular barrier is sufficiently insulted and reduces the integrity of the barrier against normally nonpermeable drugs. As a result, drugs that are normally excluded from the eye may penetrate into the eye due to degenerative effects on junctional barriers. For example, for hydrophilic antimicrobials such as the ciproflox-acin, infection may increase their mean vitreous concentration by more than fivefold (52).

The role of inflammation in drug penetration is particularly informative. Inflammation reduces the elimination rates of intravitreally injected drugs that are not actively exported by the posterior route. For systemically administered quinolones and other antimicrobials, inflammation increases ocular drug accumulation (i.e., penetration) most likely due to increased entry and decreased efflux rates (45,52).

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