Treatment Of Experimental Uveitis Research Articles

Evaluation of subconjunctival liposomal steroids for the treatment of experimental uveitis

Non-infectious anterior uveitis (AU) is a potentially sight threatening inflammatory condition. The current gold standard for treatment is topical steroids, but low ocular bioavailability and compliance issues with the intensive dosing regimen limit the efficacy of this treatment. Liposomes as a drug delivery system may help to overcome these problems. We studied the efficacy of a PEG-liposomal formulation of liposomal steroids, administered as a single subconjunctival dose, in the treatment of experimental uveitis in rabbit eyes. Rabbits that received subconjunctival liposomal triamcinolone acetonide phosphate (LTAP) or liposomal prednisolone phosphate (LPP) had significantly lower mean inflammatory scores than untreated controls on Day 4 after induction of uveitis (LPP vs controls, p = 0.049) and 8 (LPP vs controls, p = 0.007; LTAP vs controls, p = 0.019), and lower scores than rabbits given topical PredForte1% 4 times a day on Day 8 (p = 0.03). After antigen rechallenge, the subconjunctival liposomal steroid groups continued to have greater suppression of inflammation than untreated controls on Day 11 (p = 0.02). Localization of liposomes in inflamed ocular tissue was confirmed by histology and immunostaining, and persisted in the eye for at least one month. Our study demonstrates that a single subconjunctival injection of liposomal steroids induces effective and sustained anti-inflammatory action.

Ocular Self-Microemulsifying Drug Delivery System of Prednisolone Improves Therapeutic Effectiveness in the Treatment of Experimental Uveitis

ABSTRACTPurpose: The purpose of this study was to investigate the self-microemulsifying drug delivery systems (SMEDDS) for ophthalmic delivery of Prednisolone (PDN) to treat uveitis.Materials and methods: The pseudo-ternary phase diagrams were developed, and various SMEDDS were prepared using Linoleic acid as oil, Cremophore RH 40 as a surfactant, and propylene glycol as a co-surfactant. Physicochemical parameters (globule size, zeta potential, viscosity, and pH) and in vitro release of SMEDDS were studied. The in vivo efficacy of prepared formulations and the marketed drug solution was studied by administering them topically to an endotoxin-induced uveitis rabbit model.Results: All formulations displayed an average globule size less than 100 nm. The developed SMEDDS exhibited acceptable physicochemical behavior and displayed sustained drug release. In vivo studies in a rabbit eye showed a marked improvement in the anti-inflammatory activity of developed formulation compared with a marketed formulation in a uveitis-induced rabbit eye model.Conclusions: The developed SMEDDS are a feasible option to conventional eye drops for its capability to improve bioavailability via its longer precorneal residence time and its capacity to sustain the release of the drug.

Subconjunctival injection of XG-102, a c-Jun N-terminal kinase inhibitor peptide, in the treatment of endotoxin-induced uveitis in rats.

XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design. EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot. XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina. These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.

Intraocular implantation of cyclosporine A drug delivery system in the treatment of experimental uveitis

To investigate the effects and safety of cyclosporine A drug delivery system (CsA DDS) implanted into vitreous cavity on the treatment of experimental rabbit uveitis. A model of uveitis was established in 30 New Zealand white rabbits (30 eyes). The rabbits were randomized into control group (group A, 6 eyes), intravitreal non-medicated DDS group (group B, 6 eyes), oral CsA group (group C, 6 eyes) and intravitreal CsA DDS group (group D, 12 eyes). The inflammatory parameters such as floating cells, flaring and exudation in anterior chamber were graded. The cells infiltration and degree of opacity in vitreous were scored as well. The electroretinography and histopathological examination in eye, liver and kidney were recorded. In addition, CsA level in vitreous cavity was measured by HPLC in another 13 New Zealand white rabbits that received intravitreal implantation of CsA DDS. Uveitis was successfully induced in the 30 eyes. The inflammation in groups A, B and C was more severe than group D. There was no significant difference between groups D and A or B (P < 0.05). The electroretinography showed more significant b-wave depression in groups A and B than group D (P < 0.05). A large amount of inflammatory cells infiltration and marked tissue disorganization were found at ciliary body and retina in groups A and B. The mean drug level in vitreous cavity ws (491.0 +/- 481.6) ng/ml at 4 weeks, (575.2 +/-0373.2) ng/ml at 8 weeks and (301.5 +/- 128.5) ng/ml at 12 weeks. No toxicity could be detected in histological examination by light microscopy. Sustained therapeutic drug level could be achieved by implanting CsA DDS into vitreous cavity. It may effectively reduce the ocular inflammation in the rabbit model of uveitis.

The Efficacy of Hyperbaric Oxygen for the Treatment of Experimental Uveitis Induced in Rabbits

Objective: The aim of the present study was to examine the efficacy of hyperbaric oxygen (HBO) therapy in the treatment of experimental uveitis induced in rabbits. It was hypothesized that HBO therapy improves the regression of experimental uveitis induced in rabbits. Research design and methods: An experimental animal study was conducted on 48 rabbits (48 right eyes of these rabbits) to evaluate the effects of HBO therapy on endotoxin-induced acute anterior uveitis in rabbits. To induce acute anterior uveitis, Salmonella typhimurium lipopolysaccharide endotoxin (LPS) was intravitreally injected into the right eyes of the rabbits. The animals were randomly assigned to five groups. No treatment was given to the rabbits in Group A. Prednisolone acetate was topically administered to the rabbits in Group B. Methylprednisolone acetate was administered by anterior subtenon injection to the rabbits in Group C four hours after LPS application. HBO therapy was administered to the rabbits in Group D. Both HBO therapy and anterior subtenon injection of methylprednisolone therapy were administered to the rabbits in Group E. To compare the effects of the different therapies on the progression of endotoxin-induced uveitis, examinations including clinical scoring of anterior uveitis, microscopic examination of aspirated aqueous humor for inflammatory responses, and aqueous protein level assessment were performed once a day after LPS injection. Results: There was a statistically significant difference between the control group (Group A) and other groups (Groups B–E) with respect to the number of inflammatory cells and protein levels in the aqueous one and three days after LPS injection (p < 0.05), indicating that the treatments resulted in less inflammation in Groups B–E compared to Group A. Moreover, there was no statistically significant difference between Groups B and C, Groups B and D, Groups B and E, Groups C and D, and Groups C and E with regard to the number of inflammatory cells in the aqueous at Day 1 after LPS injection (p > 0.05). In addition, Groups B and C and Groups B and D were comparable with regard to cell counts at Day 3 (p > 0.05), showing that HBO was comparable to corticosteroids in reducing inflammation. The differences between Groups B and E and Groups C and E were significant with regard to aqueous cell counts at Day 3 (p < 0.05), showing that HBO plus steroid was more effective than steroids alone. Conclusion: The intensity of ocular inflammation in the group receiving HBO therapy combined with anterior subtenon injection of methylprednisolone therapy was lower than in the other groups. We also demonstrated that HBO therapy was an effective therapeutic modality for the treatment of experimental uveitis induced in rabbits with an efficacy comparable to that of corticosteroids. Moreover, HBO plus steroid was superior to steroids alone in reducing inflammation.

Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis

Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically. By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable. The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.

Pharmacologic Modulation of Acute Uveitis with Aminonicotinamide

The hexose monophosphate shunt inhibitor 6-aminonicotinamide was observed to have an anti-inflammatory effect in the treatment of experimental uveitis. The electrons required for the reduction of molecular oxygen to superoxide radicals are generated by the pentose phosphate pathway in acute inflammatory cells. The inhibition of superoxide production is discussed as one of the potential antiphlogistic mechanisms.

Effect of iron chelation on severity of ocular inflammation in an animal model.

Metabolites of oxygen-free radicals generated by polymorphonuclear leukocytes and macrophages are believed to inflict the initial tissue damage in acute inflammations. Of the various oxygen products, hydroxyl radicals are known to be potent toxic agents, and their generation depends largely on the presence of free iron. Treatment of experimental uveitis in Lewis rats with an iron chelator, deferoxamine mesylate, resulted in marked reduction in choroidal inflammation and suppression of retinal damage. These findings suggest that in experimental uveitis the severity of ocular inflammation and tissue damage may be mediated by the iron-catalyzed generation of hydroxyl radicals, and deferoxamine may thus serve as an anti-inflammatory agent.