纳米给药系统在眼底疾病治疗中的研究进展

眼底疾病是全球导致患者视力严重受损甚至丧失的最主要原因，由于各种生理屏障使治疗药物难以进入眼底，严重影响了眼底疾病的治疗。纳米给药系统具有纳米级尺寸、表面积/体积比值大的特点，可以负载不同理化性质的治疗药物，同时可以修饰各种表面活性物质，能够提高药物的溶解度以及生理屏障的穿透性、保护生物药物不被降解而提高药物安全性与生物利用度、并将治疗药物递送到特定的眼部靶点，具有巨大的治疗潜力。目前越来越多围绕利用纳米材料的优势治疗眼底疾病的研究已经展开并引起广泛关注，包括神经退行性病变、眼底新生血管、眼内炎及眼底肿瘤等。本综述通过分析不同给药途径在眼底疾病治疗中面临的挑战及障碍，对近年开展的相关研究中常见纳米药物递送系统的理化性质、在常见眼底疾病治疗研究的进展、优势、局限性及未来发展方向进行了总结。     

Toward new therapies for ocular inflammation

While the use of this type of therapy and its application are far from immediate clinical application, the theory to support this approach is plausible. Most forms of anti-inflammatory therapy employed for ocular inflammatory diseases including iritis, scleritis, and chorioretinitis are derived from the success of these therapies for other organ systems. Just as ophthalmologists have the unique opportunity to visualize the hallmarks of the immune response, so do ophthalmologists have the unique opportunity to test this therapeutic approach which we speculate could offer improved efficacy and specificity over current modalities. Technological advances have helped to create an exciting era in ophthalmology. We believe that this technology can eventually be applied to the treatment of inflammatory diseases involving other body systems, as well as those primarily involving the eye.     

Resolution, the grail for healthy ocular inflammation

Acute inflammation is a frequent, essential and beneficial response to maintain normal tissue function. PMN are the primary effector cells of acute inflammatory responses and their timely resolution by macrophages from an injured, stressed or infected tissues are required for the successful execution of this routine tissue response. Dysregulation of this fundamental program is a major factor in the global disease burden and contributes to many ocular diseases. Counter-regulatory signals are critical to the controlled activation of innate and adaptive immune responses in the eye and recent studies have identified two circuits in the cornea, uvea and/or retina, namely 15-lipoxygenase and heme-oxygenase, which control inflammation, promote resolution of PMN and afford neuroprotection. The role of these counter-regulator and pro-resolution circuits may provide insight into ocular inflammatory diseases and opportunities to restore stressed ocular tissue to a pre-inflammatory state, namely homeostasis, rather than limiting therapeutic options to palliative inhibition of pro-inflammatory circuits.     

托百士滴液治疗眼表细菌性炎症的疗效观察

目的：评价托百士治疗眼青细菌性炎症的临床疗效。方法：应用托百士（妥布霉素）滴眼液治疗27例细菌性结膜炎、25例细菌性角膜炎、5例细菌性泪囊炎,治疗前后做结膜囊分泌物培养,观察患眼的恢复时间和治疗效果。结果：托百士治疗细菌性结膜炎、细菌性角膜炎和细菌性泪囊炎的有效率分别为96．3％、92％、60％,平均恢复时间分别是5．8天、12．4天、14．7天,药物副作用除个别患者用药后有眼睑发痒、轻微刺痛外,无其它副作用,结论：该药是治疗眼表细菌性炎症的有效局部抗菌眼药,尤其对细菌性结膜炎和细菌性角膜炎疗效显著。     

Studies on ocular inflammation and development of a prostaglandin analogue for glaucoma treatment

This review summarizes the Ernst H. Bárány Prize Lecture given at the meeting of the International Society of Eye Research in Geneva 2002. In the paper the path from the author's early studies on neurogenic inflammation in the eye to the search for a suitable prostaglandin analogue for glaucoma treatment, and the development of latanoprost are described. In particular the solution to the nociceptive and hyperemic side-effects of naturally occurring prostaglandins in the eye, the mechanism of action of FP prostanoid receptor agonists as well as the selection of dose for glaucoma treatment are discussed. In addition, pharmacokinetical aspects of latanoprost, and the melanogenic side-effect of prostaglandins in the iris are addressed. The paper is primarily focused on studies performed by the author and complete reference to other previous, or contemporary studies is therefore not always given as the purpose is not to present a comprehensive review article.     

Treatment of ocular inflammation

Acute immunosuppression induced by total body irradiation (TBI) or cyclophosphamide (Cy) treatment, followed by syngeneic bone marrow transplantation (SBMT), was reported to be effective in inducing long-term tolerance in some autoimmune disease models. We examined the efficacy of this approach in the mouse model of experimental auto-immune uveoretinitis (EAU). Development of EAU induced by the interphotoreceptor retinoid binding protein (IRBP) was abolished almost completely by either TBI or Cy treatment, followed by SBMT, instituted one week after priming. In parallel, IRBP-specific delayed-type hyper-sensitivity (DTH) responses and lymph node cell proliferation were strongly suppressed or abolished. However, when these IRBP-immunized, lympho-ablated and BM reconstituted mice were rechallenged with the immunizing antigen seven weeks after the primary immunization, they were not protected from developing disease, despite the fact that DTH and lymph node cell proliferation to the antigen were suppressed relative to controls. TBI treatment appeared somewhat more effective than Cy treatment as judged by its more profound effect on immunological responses. These results demonstrate the ability of acute immunosuppression followed by reconstitution of the immune system to inhibit the development of EAU, although long-term protection from disease was not achieved.     

Fluorometholone acetate: clinical evaluation in the treatment of external ocular inflammation

Separate, randomized, double-masked clinical studies were conducted to determine the therapeutic efficacy of fluorometholone acetate, a new ophthalmic corticosteroid formulation, in suppressing external ocular inflammation (conjunctivitis, episcleritis, scleritis). Fluorometholone acetate 0.1% was compared to fluorometholone 0.1%, and the acetate formulation was found to be significantly (p = 0.03) more effective. Fluorometholone acetate 0.1% also was compared to prednisolone acetate 1.0%; there was no significant difference (p = 0.49) between these two corticosteroids in their ability to suppress external ocular inflammation. It appears that alteration of fluorometholone from its alcohol base to its acetate derivative changes the drug from a moderately effective to a highly effective anti-inflammatory agent.     

Mycophenolate mofetil in the treatment of ocular inflammation in ANCA-associated vasculitis.

AIM: The aim of this study was to describe the use of mycophenolate mofetil (MMF) in the treatment of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with ocular involvement. METHODS: A retrospective review was performed. Ocular and systemic manifestations, history of previous immunosuppressive drug therapy, concurrent therapy with MMF, response to treatment, side effects related to the use of MMF, and follow-up period were recorded. RESULTS: Nine (9) eyes of 5 patients were evaluated. Ocular involvement included scleritis, choroidal and orbital granuloma, multifocal choroiditis, intermediate uveitis, and lacrimal gland involvement. Mycophenolate was started at 2 g daily. Mean follow-up after the initiation of MMF was 36 months. Mean prednisolone dose at onset of treatment with MMF was 27 mg daily and was reduced to 7 mg daily as disease control was achieved. Visual acuity was maintained or improved in all eyes, apart from 1 eye, which developed cataract formation. One (1) patient required a reduction in the dose of mycophenolate owing to diarrhea. CONCLUSIONS: Our study suggests that mycophenolate mofetil may be a safe, effective therapeutic modality for ocular inflammation associated with ANCA-associated vasculitis.     

Peribulbar poloxamer for ocular drug delivery

Purpose: The use of biopolymers in peribulbar injection for controlled drug delivery provides alternative options to eyedrops and intravitreal or surgical methods. Polymerizable biopolymers are especially likely to have a role because of their particular properties. In liquid form, they can be easily injected into the target site and, after polymerization, they provide a prolonged and controlled release of the drug. This study was undertaken to demonstrate the suitability of a thermopolymerizable biopolymer poloxamer (Lutrol F127) for peribulbar injections and controlled drug release. Methods: The toxicity of injected poloxamer compounds was evaluated by visual inspection and histological and immunohistochemical tissue evaluation. The release of marker substances such as 5(6)‐carboxyfluorescein (376 Da) or fluorescein isothiocyanate‐dextran (FITC‐dextran) (4?40 kDa) from poloxamer was used to simulate drug release and penetration into the eye using in vivo fluorometry. Results: According to our clinical and pathological analyses, poloxamer was well tolerated in peribulbar injections and did not cause acute toxicity at the site of injection. The marker compounds were released from the site of injection during the first 24 hours. Conclusions: Although poloxamer appears to be suitable for peribulbar injections, a more prolonged period of dissolution is desirable for clinical purposes.     

重视眼部给药系统的研究

选择恰当的给药系统能明显增强药物疗效、延长作用时间及减少不良反应。近年来随着高分子化学的研究进展,眼部给药系统研究也快速发展。为了更加重视眼部给药系统的研究,笔者简述了眼部给药系统研究的进展和我国研究发展概况,并就开发我国自主知识产权的高分子聚合物材料,正确开展新型眼部给药系统的眼内药代动力学和眼毒理学研究进行了评述。     

Biodegradable polymers for ocular drug delivery

A variety of ocular drug delivery systems, including a controlled release of the drug, drug targeting, and penetration enhancement of the drug, have been investigated. Biodegradable polymers have been widely used as the drug carrier for controlled-release systems. Biodegradable polymers release the drug as they themselves degrade and are finally absorbed within the body. Several ocular drug delivery systems using different kinds of biodegradable polymers have been studied. In this article, we describe the fundamental mechanisms of drug delivery systems, polymer erosion and drug release, and then review those systems using the most popular biodegradable polymers, poly(lactic acid) and poly(lactic-glycolic acid).     

Prostaglandins and ocular inflammation

Evidence for prostaglandins as mediators of some inflammatory responses is briefly, but critically discussed. The hypothesis that prostaglandins are mediators of ocular inflammation is presented and discussed according to the tenets of Miller & Melmon (1970). Prostaglandins are released after mechanical stimulation, paracentesis, laser irradiation, (non)-immunogenic uveitis in experimental animals, and in patients with acute anterior uveitis. Prostaglandins were neither found after antidromic stimulation of the trigeminal nerve, oculomotor nerve stimulation, intracameral formaldehyde, topical nitrogen mustard, nor in patients with open angle glaucoma.Administering of prostaglandins produces transient ocular hypertension, increased vascular permeability and miosis. Ocular hypotension has been shown to follow the hypertensive response. Hypertension is considered to be due to a breakdown of the blood-aqueous barrier of the ciliary processes and iris. Prostaglandins of the E series are the most potent, and species differences occur. Prostaglandin E₁ potentiates the histamine-induced increase in vascular permeability of the conjunctiva, but not the uvea. Polyphloretin phosphate aspecifically blocks the ocular actions of prostaglandins. Non-steroidal anti-inflammatory drugs inhibit prostaglandin synthetase and the ocular effects of arachidonic acid, its substrate. Prostaglandins are poorly catabolised by the eye, but are removed from ocular fluids by a transport mechanism in the anterior uvea. This becomes inoperative in (non)-immunogenic uveitis in rabbits allowing prostaglandins to accumulate. Anti-inflammatory steroids decrease the availability of arachidonic acid for prostaglandin synthetase. Intermediates formed in the biosynthesis of prostaglandins may well be more important in inflammation than the prostaglandins themselves.Part of this review was presented at the 171st Congress of the Dutch Ophthalmological Society.