© Springer International Publishing Switzerland 2016
Thirumurthy Velpandian (ed.)Pharmacology of Ocular Therapeutics10.1007/978-3-319-25498-2_88. Steroidal and Nonsteroidal Anti-inflammatory Agents for Ocular Use
(1)
Department of Pharmacology, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi, India
(2)
University of Delhi, New Delhi, India
(3)
Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor Darul Ehsan, Malaysia
Abstract
Multiple factors cause ocular inflammation in various anatomical regions of the eye. Such inflammations are usually tackled with limited symptomatic treatment modalities. The poor prognosis of or long-standing ocular inflammation can even culminate into permanent loss of vision. Ocular inflammation can be majorly divided into infections and non-infections conditions. This chapter deals with the various ocular anti-inflammatory agents used in conditions like uveitis, ocular manifestations of Behchets disease, diabetic retinopathy and allergic conditions leading to ocular surface inflammations.
8.1 Introduction
Ocular inflammation is a common condition, albeit multifactorial and originating in different anatomical regions of the eye, that is usually tackled with limited symptomatic modalities. The prognosis of long-standing ocular inflammation can even be permanent loss of vision.
One of the most common inflammatory eye diseases is uveitis. Uveitis can occur either as an autoimmune disorder or as a result of injury, infection, or exposure to toxins. The most common symptoms of uveitis are flares, redness, photophobia, floaters, blurred vision, and sometimes pain. Untreated uveitis can lead to serious sequelae such as permanent vision loss. It accounts for approximately 10 % of visual handicap in the Western World or 30,000 new cases of blindness at an incidence of 20–52 cases per 100,000 person-years (Larson et al. 2011).
The other noninfectious ocular inflammation is Behcet’s disease (BD) that is chronic, relapsing, multisystem disorder characterized by ulcers of the oral and genital mucocutaneous tissue, skin lesions, and nonerosive arthritis.
Diabetic retinopathy, a complication of chronic long-standing diabetes mellitus, is also marked by inflammation of eye.
Diabetic retinopathy is characterized by appearance of microaneurysms, increased vascular permeability, capillary occlusion, and fibrous and neovascular proliferation.
The inflammatory processes play a considerable role in the pathogenesis and progression of DR (Kaštelan et al. 2013). Studies have shown marked presence of inflammatory factors in systemic as well as local (vitreous and aqueous fluid) areas with significant correlation to the development of impaired vision. The Early Treatment DR Study and the Dipyridamole Aspirin Microangiopathy of Diabetes Study have shown that the development of retinal microaneurysms is significantly minimized in patients with early stage of DR when treated with a high dose of aspirin (900 mg/day). Topical administration of COX-2 inhibitor was shown to reduce signs of DR similar to its systematic application without the side effects and holds promise for its therapeutic benefit.
Ocular inflammation is also common after ophthalmic surgery, particularly after surgical removal of cataracts combined with intraocular lens (IOL) implantation. The condition manifests as mild iritis, corneal edema, and flare in the anterior chamber of the eye, accompanied by hyperalgesia. If left untreated, postoperative inflammation can lead to suboptimal vision results or complications such as cystoid macular edema (CME).
Dry eye syndrome has been described as multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface that is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. It is most prevalent among the elderly and postmenopausal women. Chronic dryness of the surface of the eye can lead to neurogenic inflammation, activation of T cells, and release of inflammatory cytokines into the lacrimal glands, tear fluid, and conjunctiva. These inflammatory mediators are known to cause gradual dysfunction and destruction of the lacrimal glands and impairment of conjunctival epithelium.
Literature evidences that oxidative stress is the primary initiating event that leads to the inflammatory state of ocular surface. Thus, oxidative stress with associated inflammatory process can trigger severe injury of retina, cornea, conjunctiva, and lacrimal gland.
8.2 Steroidal and Nonsteroidal Anti-inflammatory Agents for Ocular Inflammation
(4)
Department of Pharmacology, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi, India
(5)
University of Delhi, New Delhi, India
8.2.1 Corticosteroids
Corticosteroids have a broad mechanism of action. They inhibit phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. Thus, the inhibition of the cyclooxygenase and lipoxygenase pathways dramatically reduces the formation of all eicosanoids, which are the active mediators of inflammation. Corticosteroids effectively suppress both the early (capillary dilation, increased vascular permeability, recruitment of leukocytes) and late (deposition of fibrin, proliferation of inflammatory cells and chemokines) phases of inflammation.
Local corticosteroids may be used either topically (for anterior uveitis) or as periocular and intravitreal injections, or as implant devices (for inflammation of posterior segment) and remain the drugs of choice in management of ocular inflammation. Systemic corticosteroids are reserved for chronic uveitis involving the posterior segment, invariably affecting both eyes. However, chronic use of corticosteroid therapies is known to cause glaucoma, cataract, impaired glucose tolerance, hypertension, fluid retention, osteoporosis, mental disturbance, impaired wound healing, gastrointestinal bleeding and perforation, thromboembolic disorders, and weight gain. Of these, increased IOP is of most importance as it is understood to be due to structural and biochemical changes in the trabecular meshwork leading to rise in the resistance to aqueous humor outflow. The incidence of steroid-induced IOP elevation is quite high in as many as 18–36 % of users. Older corticosteroids, such as prednisolone and dexamethasone, are associated with a greater impact on IOP compared to newer corticosteroids. The limitations of chronic use of steroids, vis-a-vis lack of efficacy and need for reinjections, have led to the development of novel sustained-release intravitreal steroid delivery methods. These formulations have lower dose of corticosteroids and, therefore, less secondary side effects.
Multiple formulations like oral prednisone, intravenous methylprednisolone sodium succinate, topical prednisolone acetate or difluprednate, and intravitreal triamcinolone are preferentially used as they offer the benefit of avoiding systemic complications (Geltzer et al. 2013).
Recently, fluocinolone acetonide implant (Retisert) has been developed to deliver corticosteroid for up to 30 months for chronic noninfectious posterior uveitis. Dexamethasone implant for intravitreal use (Ozurdex) has also been approved by the FDA for the treatment of noninfectious posterior uveitis. It is available as 0.7 mg biodegradable implant that delivers extended release of dexamethasone through solid polymer delivery system. Although dexamethasone and prednisolone acetate offer good anti-inflammatory efficacy, their use suffers from clinically significant increase in IOP (up to 10 mmHg). In contrast, corticosteroids such as loteprednol etabonate, a novel C-20 ester-based derivative of prednisolone, offer potent anti-inflammatory efficacy, with limited adverse impact on IOP. Loteprednol etabonate (0.5 %) has been established as effective treatment of postoperative inflammation and resolving anterior chamber cells and flare (Amon and Busin 2012).
Another prednisolone derivative, difluprednate with structural modifications that include the addition of fluorine atoms at C-6 and C-9 positions, a butyrate ester at the C-17 position, and acetate ester at the C-21 and C-20 ketone moiety, is significantly effective in controlling secondary events of ocular inflammation like photophobia, chemosis, and corneal edema. The incidence of clinically significant increase in IOP is low.
The efficacy of loteprednol etabonate, rimexolone, and difluprednate in resolving ocular inflammation is similar. The difference lies in the degree of side effect like corticosteroid-induced ocular hypertension and is often the determining factor in clinical use.
8.2.2 Antimetabolites
Antimetabolites refer to a class or drugs which inhibit nucleic acid synthesis to inhibit cell proliferation. Drugs belong to this class include methotrexate, azathioprine, and mycophenolate mofetil.
Methotrexate was first introduced in 1948 as an antineoplastic agent. It is a folate analogue that acts by inhibiting dihydrofolate reductase. It interferes with the synthesis of thymidylate and purine nucleotide, to inhibit the growth of rapidly dividing cells. The most serious side effects of methotrexate include hepatotoxicity, cytopenias, and interstitial pneumonitis. Monitoring of liver function tests is required during treatment. It is teratogenic and thus contraindicated in pregnancy.
Azathioprine is widely used in organ transplantation, inflammatory bowel disease, systemic lupus erythematosus, and other autoimmune conditions. It is a prodrug of 6-mercaptopurine, a purine nucleoside analogue that interferes with DNA replication and RNA transcription. It also inhibits actively dividing immune cells to restrain inflammatory process.
Mycophenolate mofetil (MMF) is commonly used in management of organ transplant rejection and other autoimmune conditions. Its mechanism of action is selective inhibition of inosine-5-monophosphate dehydrogenase in the de novo purine synthesis pathway. As B and T lymphocytes depend on the de novo pathway for proliferation, its selective inhibition effectively curtails inflammatory state. MMF has been shown to be effective in combination with steroids or another immunomodulatory treatment as well as monotherapy.
8.2.3 T-Cell Inhibitors
This class of agents includes cyclosporine, tacrolimus, and sirolimus.
Cyclosporine is an 11 amino acid peptide derived from fungus. Cyclosporine acts by forming a complex with cyclophilin which binds calcineurin that then inhibits the cytosolic translocation of nuclear factors. Consequently, there is preferential inhibition of antigen-triggered signal transduction of T lymphocytes. It is available in two formulations, as oil-based gelatin capsules (Sandimmune, Novartis Pharmaceuticals) and a microemulsion (Neoral, Novartis Pharmaceuticals). Cyclosporine has been used safely in children with severe, sight-threatening uveitis. The adverse effects of cyclosporine therapy include gastrointestinal upset, metabolic abnormalities, paresthesias, tremor, gingival hyperplasia, and hirsutism.
Voclosporin is a calcineurin inhibitor that has been developed for the treatment of uveitis. It has been shown to be more potent and less toxic than cyclosporine. In extensive placebo-controlled clinical studies, voclosporin has been reported to improve vitreous haze that is part of active posterior disease. It significantly reduced eye inflammation but failed to meet the primary endpoint of all-cause therapeutic failure. In the condition of anterior inflammation, voclosporin failed to establish itself from placebo.
Tacrolimus or FK506 is a macrolide isolated from the soil fungus Streptomyces tsukubaensis that was originally used in solid organ transplantation. It has a similar mechanism of action to cyclosporine and binds to an intracellular binding protein, FK-binding protein, that associates with calcineurin and thus inhibits activation of T cells and production of cytokines.
Sirolimus (Rapamune) is another immunosuppressive drug. Its binds to FK-binding protein-12 (FKBP-12) to form a complex that binds to and inhibits the activation of the mammalian target of sirolimus (mTOR) to suppress cytokine-driven T-cell proliferation.
8.2.4 Alkylating Agents
Cyclophosphamide and chlorambucil belong to the class of drugs called alkylating agents as they act by alkylating DNA leading to DNA cross-linking and inhibition of DNA synthesis. Although they were originally developed for the treatment of cancers, they are now widely being used for management of rheumatologic conditions. Owing to their serious, life-threatening side effects, their use is limited to severe, sight-threatening uveitis.
Cyclophosphamide, a mustard gas derivative, alkylates the purines of DNA and RNA resulting in cross-linking and impaired cell division. Thus, the number of inflammatory cells like T and B lymphocytes is reduced.
8.2.5 Biologic Agents
Conventional therapy with corticosteroids and immunosuppressive agents may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary line of therapy and reported to be very useful in such conditions. Strategies for biologics employ formulating new drugs that target specific receptors, cytokines, or signaling pathways (Pasadhika and Rosenbaum 2014).
8.2.5.1 Anti-Tumor Necrosis Factor-α (TNF-α)
TNF-α is a well-known proinflammatory cytokine that has been shown to play a key role in pathogenesis of inflammatory diseases. Thus, inhibiting TNF-α with antibodies has been a well-accepted strategy to suppress autoimmune uveitis (Karampetsou et al. 2010). TNF-α inhibitors include infliximab, a chimeric mAb, and adalimumab, a fully humanized IgG1 mAb, against TNF-α (Verma et al 2013). Certolizumab pegol and golimumab have only been recently introduced and there is limited clinical experience with them. Other agents such as abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab hold promise for the treatment of uveitis in the future. Systemic administration of anti-TNF-α agents has shown encouraging preliminary results in uveitic and diabetic cystoid macular edema and age-related macular degeneration.
Infliximab (Remicade) is a 149 kDa chimeric IgG1 monoclonal antibody composed of human constant region of IgG1 and murine variable binding site for TNF-α. It has been approved for use in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis and Crohn’s disease. It is well accepted for management of various subtypes of refractory uveitis and retinal vasculitis, especially Behcet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Infliximab in BD-associated uveitis is advocated as an add-on therapy to DMARDs. The combination significantly reduced the frequency of uveitis flares compared to administration of DMARDs alone.
Etanercept (Enbrel) is a fusion protein consisting of the binding part of the human type II receptor of TNF-α linked to the Fc portion of IgG1a. It is a blocker of soluble TNF-α receptor that has also been investigated as subcutaneous injection (25 mg/week). But it has been found to be less effective than infliximab or adalimumab in the treatment of uveitis. In retrospective study, when infliximab was compared to etanercept, the number of recurrences and ocular inflammation was improved with former as compared to latter.
Apremilast, a selective cytokine inhibitory drug, inhibits phosphodiesterase IV and TNF-α production to suppress the immune response. It is currently in phase II clinical trials for Behcet’s disease. As the drug is projected for oral administration, the need for injection is circumvented and reduces cost considerably.
ESBA-105 is a topical anti-TNF-α single-chain antibody and possesses good anterior and posterior intraocular penetration. It is under development for the treatment of ocular conditions including uveitis and diabetic retinopathy.
8.2.5.2 Cytokine Receptor Antibodies
Daclizumab is a humanized monoclonal antibody directed against the alpha subunit of the interleukin-2 receptor (CD25) present on activated T cells. The drug is also approved for management of renal allograft rejection and autoimmune diseases such as multiple sclerosis and human T-cell leukemia virus-1-associated T-cell leukemia. The drug can be administered as 1–2 mg/kg infusions every 2–4 weeks. Side effects include rashes, edema, granulomatous reactions, viral respiratory infections, elevated liver enzymes, and leukopenia.
Rituximab, a chimeric monoclonal antibody against CD20, a B-cell marker, results in depletion of B cells. It was originally developed for the treatment of B-cell lymphomas and now finding application in ocular inflammation.
MM-093, a recombinant human alpha-fetoprotein, has recently completed phase II study for sarcoid or birdshot uveitis.
8.2.6 Antiangiogenic Therapy
Vascular endothelial growth factor (VEGF) is a potent vasoactive cytokine that is involved in the breakdown of blood-retinal barrier and angiogenesis in the ischemic retina. The VEGF levels are significantly elevated in patients with DME and its intravitreal concentration increases with the progression of DR. Antiangiogenic therapy acts to reduce vascular permeability, reduce the breakdown of the blood-retinal barrier, inhibit leukocyte adhesion to vascular walls, and inhibit VEGF gene transcription and translation and therefore finds use in ocular inflammatory conditions (Geltzer et al. 2013).
Bevacizumab (Avastin) and ranibizumab (Lucentis) are also monoclonal antibodies to vascular endothelial growth factor (VEGF). Ranibizumab was designed specifically for ocular use and received FDA approval for the treatment of choroidal neovascularization in age-related macular degeneration. Bevacizumab is increasingly finding off-label use for ocular diseases.
Ranibizumab (Lucentis), a recombinant humanized antibody fragment, is active against all isoforms of VEGF-A and approved for the treatment of exudative AMD and DME.
8.2.7 Blocking Oxidative Stress
As a key mediator in inflammation, oxidative stress serves as an important target for anti-inflammatory therapy. The etiology of ocular inflammation involves free radical-mediated oxidative damage, hypoxia, decreased blood supply to ocular tissues, angiogenesis, increased vascular permeability, and leakage of vascular contents.
Flavonoids have been attributed with multi-thronged action including antioxidant, antiangiogenic, reducing fluid retention, and strengthening capillary walls that together contribute to anti-inflammatory activities. Bioflavonoids have been found effective in the prevention and treatment of diabetic retinopathy, macular degeneration, and cataract (Majumdar and Srirangam 2010). Some of the common bioflavanoids that have been documented for their anti-inflammatory action are quercetin, apigenin, hesperidin, hesperetin, luteolin, epigallocatechin gallate, epicatechin gallate, rutin, cyanidin, naringenin, myricetin, chrysin, eriodictyol, and kaempferol.
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