Anterior Segment Inflammation
acute conditions to chronic sight-threatening conditions and includes iatrogenic post-operative inflammation, SAC, keratoconjunctivitis sicca (dry eye syndrome), superficial punctate keratitis (SPK), AKC, giant papillary conjunctivitis (GPC), uveitis, iritis, blepharitis and scleritis. Conditions involving the lids, cornea, and conjunctiva are often termed ocular surface inflammatory disease (OSID). The signs and symptoms are typical of inflammation, including itching, pain, redness, and swelling. If left untreated, uncontrolled ocular inflammation may result in considerable ocular morbidity or even permanent loss of vision.
Ocular allergy is estimated to affect 15–20% of individuals.3 GPC is one
of the most common complications of contact lens use and the prevalence is highest in soft contact lens wearers.4 reported in 37% of patients seen by ophthalmologists.5 of dry eye has been reported to be between 7 and 33%.6
Blepharitis has been The prevalence Uveitis includes
wide ranges of presentation and pathogenesis, also affecting the retina, choroid, optic nerve, iris, ciliary body, and vitreous. Uveitis—mainly posterior uveitis—is estimated to account for up to 10% of cases of blindness in the US7
and up to 25% in the developing world.8
Northern California reported the incidence of uveitis to be 52.4/100,000 person-years, with a period prevalence of 115.3/100,000 persons.9
Management Options
The main aim of treatment for ocular inflammatory disease is to stop inflammation before permanent damage to ocular tissues and the blood aqueous barrier can occur. Corticosteroids given topically, by periocular or intravitreal injection, and orally are widely used for treating ocular inflammation. Steroids have the broadest pharmacologic impact on the plethora of mechanisms involved in ocular inflammatory events.10 Topical steroids are primarily used in clinical practice since they have the greatest bioavailability for anterior segment inflammation.11
Because
they are administered directly to the surface of the eye, their effects are localized and the risk for systemic effects is minimal.10
Other treatment
options include non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used in allergic conjunctivitis, post-surgical analgesia, and the inflammation associated with corneal abrasion and refractive surgery. Although topical NSAIDs are associated with a low risk for undesirable side effects relative to corticosteroids, their anti-inflammatory effect is less robust. NSAIDs inhibit the production of prostaglandins but not that of other inflammatory mediators such as histamine or leukotrienes and therefore do not have a broad impact upon inflammation. Furthermore, the use of some topical NSAIDs has been associated with adverse corneal events such as burning and irritation, superficial punctate keratitis, delayed wound healing at high doses, and sterile corneal melting in the context of additional comorbidities such as OSID.12
Topical cyclosporin A is an immunosuppressant that is beneficial for topical treatment of most categories of dry eye syndrome, though its use has been associated with a burning sensation.13
Topical cyclosporin can
also be used as an adjunct when other medications fail, when there is concomitant allergic inflammation, or as a steroid-sparing agent for allograft rejection prevention in stable corneal transplant patients. Another common treatment option for dry eye is artificial tears, though these do not address the underlying disease process.14
Lower-grade
inflammatory conditions such as SAC may be treated with antihistamines, mast cell stabilizers, multimechanism compounds, and
58 A study in
Mechanism of Action of Loteprednol Etabonate LE has the same mechanism of action as other corticosteroids. Corticosteroids inhibit the inflammatory process by decreasing the production of inflammatory precursor proteins, suppressing proliferation of important inflammatory cells, including mast cells and lymphocytes, stabilizing the extracellular membranes and mast cell granule membranes, inhibiting the production of histamine, and inhibiting the production of arachidonic acid, which is the precursor of prostaglandins and leukotrienes. However, LE has an important structural difference—the parent molecule, prednisolone, has a ketone at carbon 20 which in LE is substituted by an ester moiety. The ester component allows rapid hydrolysis to an inactive carboxylic acid metabolite. As a result, the unbound LE molecule has a short half-life, and is made inactive by endogenous esterases that are found in most human tissues. LE is therefore associated with a lower incidence of adverse effects than ketone-based steroids.16–19
Furthermore, LE
LE also proved therapeutically superior to all other topical corticosteroid drops that were available at the time in a rabbit model study of lipopolysaccharide-induced uveitis.21
has increased lipophilicity which improves penetration into cells. LE has demonstrated lipophilicity ten times greater—as well as glucocorticoid- receptor (GCR) binding affinity 4.3 times greater—than that of dexamethasone.20
In this model, LE
demonstrated more GCR activation and migration activity than all other drops studied, including proprietary prednisolone acetate 1% (Pred Forte), generic 1% prednisolone acetate, and fluorometholone (FML).
Clinical Utility of Loteprednol Etabonate in Ocular Inflammatory Conditions
LE is employed in clinical practice as a first-line steroid because of its excellent safety profile3,22–25
and is used for virtually all anterior
segment inflammatory conditions. LE is routinely used in clinical practice for acute mild-to-moderate uveitis as well as chronic long-term preventive maintenance therapy for recurrent uveitis. Other ocular surface applications include dry eye, blepharitis, non-infectious blepharitis, non-infectious conjunctivitis, and immune infiltrative keratitis, which limits contact lens wear and comfort. Treatment enables patients to return to wearing contact lenses sooner than would be possible with other drugs. To avoid rebound inflammation, it is typically necessary to taper ketone-based steroids, but because unbound LE is metabolized so quickly, aggressive tapering is generally not required. In fact, in almost all of the clinical trials utilizing LE prior to regulatory approvals, treatment was stopped without tapering and no rebound effects were observed. Numerous clinical studies have demonstrated the efficacy of LE (see Table 1). In clinical studies, LE demonstrated a rapid therapeutic response in the treatment of GPC with a low incidence
US OPHTHALMIC REVIEW
The efficacy of mast cell stabilizers is similar to that of antihistamines though the therapeutic effect of topical mast cell stabilizers may not be as rapid.15
occasionally, decongestants. Topical antihistamines give a rapid onset of relief but a short duration of action, whereas systemic antihistamines have a longer duration of action but with a delayed onset. Furthermore, the latter may be associated with drowsiness and sometimes severe ocular drying.10
More recently, US Food and Drug
Administration (FDA) approved lipoxygenase inhibitors such as montelukast (SingulaiR) have proven effective for allergic disease without the usual sedating and drying side effects of oral antihistamines.
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