Topical Ophthalmic Drug Research Articles

Current Use of Non-steroidal Anti-inflammatory Drugs in the Treatment of Ocular Inflammation Related to Cataract Surgery

Ocular inflammation and pain are a common consequence of cataract surgery, and if left untreated, may lead to extensive ocular damage, resulting in impaired vision as well as decreased satisfaction with the procedure. Effective management of ophthalmic inflammation after surgery is therefore vital. Topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) have become a mainstay of management of ocular pain and inflammation as a result of their anti-inflammatory activity, analgesic property and established safety record. Numerous studies have demonstrated the efficacy of topical NSAIDs in post-operative prevention of ocular inflammation, inhibition of intra-operative miosis, reduction of pain associated with cataract surgery and pre-operative use to prevent cystoid macular oedema. Studies have also indicated that NSAIDs and steroids act synergistically when administered together, and that a combination of steroid and NSAID therapy is recommended to achieve successful outcomes. With appropriate administration, NSAIDs are safe and effective therapeutic agents, which rarely result in serious local and systemic responses.

Review of Bromfenac Ophthalmic Solution 0.09 % Once-daily

Bromfenac ophthalmic solution 0.09 % (BROMDAY™, ISTA Pharmaceuticals, Inc., Irvine, CA) is the first and only once-daily topical ophthalmic non-steroidal anti-inflammatory drug (NSAID) approved by the Food and Drug Administration for the treatment of post-operative pain and inflammation following cataract surgery. Topical NSAIDs are important following surgery to enhance patient comfort and limit inflammation, which may otherwise restrict visual rehabilitation. In a recently published study looking at Early Treatment Diabetic Retinopathy Study (ETDRS) acuities and macular optical computed tomographies (OCTs) in the post-operative period, bromfenac had lower post-operative macular volumes and retinal thicknesses compared with nepafenac, which correlated with a separate retrospective study that found fewer clinical cases of cystoid macular edema (CME) following uneventful phacoemulsification. Since regulatory approval in Japan (2000) and the US (2005 and 2010), bromfenac has been shown to be a safe and effective medication, with more than 26 million ophthalmic uses. Once-daily dosing may confer improvements in compliance and reduce exposure to preservatives, which have been shown to lead to corneal toxicity.

Effects of glaucoma medications and preservatives on cultured human trabecular meshwork and non-pigmented ciliary epithelial cell lines

AimsWe investigated the potential cytotoxicity of various topical ophthalmic glaucoma formulations containing different preservatives in cultured human trabecular meshwork (TM) and non-pigmented ciliary epithelial (NPCE) cell lines.MethodsWe tested 0.004% travoprost...

Corneal Spheres derived from Human Embryonic and Human Pluripotent Parthenogenetic Stem Cells

Corneal blindness is common. Cornea transplants are the most commonly performed organ transplants, but the need for corneal grafts worldwide far outweighs the supply of healthy donor corneas. Here we describe a differentia - tion protocol that yields corneal orbs from human embryonic stem cells (hESC) as well as from human pluripotent parthenogenetic stem cells (hpSC), and therefore can be manufactured free of transmissible pathogens. Cornea and other tissues generated from parthenogenetic stem cells that are homozygous at HLA loci have a distinct im - munologic advantage over fully allogeneic grafts, and this report is the first to describe multilayered cornea gener - ated from hpSC. The differentiated corneal product is layered and anatomically similar to normal human cornea, expresses appropriate corneal markers at the mRNA and protein (and secreted protein) levels, and is permeable to topical ophthalmic drugs. This 3D stem cell-derived cornea is a foundational step in development of appropriately organized, functional corneal grafts from hESC and hpSC for use in in vitro assays as well as regenerative therapies.

Novel mucoadhesive polysaccharide isolated from Bletilla striata improves the intraocular penetration and efficacy of levofloxacin in the topical treatment of experimental bacterial keratitis

The objective of the present study was to evaluate a novel mucoadhesive polymer extracted from Bletilla striata for ocular delivery of 0.5% levofloxacin in rabbits, and to determine its improved efficacy against experimental keratitis. B. striata polysaccharide (BsP) was subjected to cell cytotoxicity and ferning tests. The pharmacokinetics and bioavailability of topically applied 0.5% levofloxacin-BsP eye drops was investigated and compared with 0.5% levofloxacin eye drops (Cravit). Experimental Staphylococcus aureus keratitis was induced and treated with levofloxacin or levofloxacin-BsP eye drops. BsP markedly increased the proliferative capacity of a human corneal epithelial [corrected] cell line. The ferning test showed that BsP exhibited optimal performance as a tear fluid. The polysaccharides significantly increased intra-aqueous penetration and corneal accumulation in rabbits. Treatment with levofloxacin-BsP reduced the number of organisms more significantly than eye drops containing levofloxacin alone. BsP appears to be a promising candidate as a vehicle for topical ophthalmic drug delivery, especially for antibiotics.

Redefining the Treatment Paradigm for Post-operative Inflammation Control – The Role of Topical Non-steroidal Anti-inflammatory Drugs

Topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of post-operative ocular inflammation and pain following cataract surgery and for some other clinical applications of ophthalmology, including cystoid macular oedema. Products vary by their pharmacological properties, clinical efficacy and tolerability, which affect their place in therapy for new agents in Europe. The pharmacological properties of topical ophthalmic NSAIDs and their place in current treatment of post-operative ocular inflammation are discussed in this article, focussing on bromfenac, which has been submitted for approval by the European Medicines Agency (EMEA).

Validation of Real-Time PCR for Laboratory Diagnosis of Acanthamoeba Keratitis

Confirmation of Acanthamoeba keratitis by laboratory diagnosis is the first step in the treatment of this vision-threatening disease. Two real-time PCR TaqMan protocols (the Rivière and Qvarnstrom assays) were developed for the detection of genus-specific Acanthamoeba DNA but lacked clinical validation. We have adapted these assays for the Cepheid SmartCycler II system (i) by determining their real-time PCR limits of detection and amplification efficiencies, (ii) by determining their ability to detect trophozoites and cysts, and (iii) by testing a battery of positive and negative samples. We also examined the inhibitory effects of a number of commonly used topical ophthalmic drugs on real-time PCR. The results of the real-time PCR limit of detection and amplification efficiency of the Rivière and Qvarnstrom assays were 11.3 DNA copies/10 microl and 94% and 43.8 DNA copies/10 microl and 92%, respectively. Our extraction protocol enabled us to detect 0.7 Acanthamoeba cysts/10 microl and 2.3 Acanthamoeba trophozoites/10 microl by both real-time PCR assays. The overall agreement between the assays was 97.0%. The clinical sensitivity and specificity of both real-time PCR assays based on culture were 100% (7 of 7) and 100% (37 of 37), respectively. Polyhexamethylene biguanide was the only topical drug that demonstrated PCR inhibition, with a minimal inhibitory dilution of 1/640 and an amplification efficiency of 72.7%. Four clinical samples were Acanthamoeba culture negative and real-time PCR positive. Our results indicate that both real-time PCR assays could be used to diagnose Acanthamoeba keratitis. Polyhexamethylene biguanide can inhibit PCR, and we suggest that specimen collection occur prior to topical treatment to avoid possible false-negative results.

Prospective assessment of systemic side effects of topical ophthalmic drug administration for screening for retinopathy of prematurity

Prospective assessment of systemic side effects of topical ophthalmic drug administration for screening for retinopathy of prematurity

Prospective assessment of systemic side effects of topical ophthalmic drug administration for screening for retinopathy of prematurity

Prospective assessment of systemic side effects of topical ophthalmic drug administration for screening for retinopathy of prematurity

Constant rate infusion for topical ocular delivery in horses: a pilot study

To assess the efficacy and kinetics of a continuous infusion modality for topical ophthalmic drug delivery via subpalpebral lavage in horses. Five ophthalmically normal horses A constant-rate continuous delivery pump was used to apply 0.01% fluorescein solution to the eyes of five ophthalmically normal horses via subpalpebral lavage. Fluorescein was applied at a rate of 0.14 mL/h for 72 h. Tear samples were collected from the ventral conjunctival fornix at regular intervals via capillary tube and tear fluorescein concentrations were determined via spectral assay. Laboratory studies to evaluate the procedures used in the study also were performed. Overall mean tear film fluorescein concentration was approximately 20% of the applied concentration of fluorescein. However, tear film fluorescein concentrations varied considerably between horses and over time. Dilution varied from 0.62% to 60% of the applied concentration. Air pockets sporadically appeared in subpalpebral lavage tubing lines, resulting in discontinuous topical application of fluorescein. Constant-rate delivery of ophthalmic medications using a continuous infusion pump may provide a valuable method of topical drug delivery if tear film dilution of drugs is taken into account.

Doubtful Value of Patch Testing for Suspected Contact Allergy to Ophthalmic Products

Sir, Allergic contact dermatitis is the most common cause of peri-orbital eczema (1). It may be caused by allergens brought in contact with the eyelids by hand transfer (like toluene sulfonamide-formaldehyde resin in nail polishes), by airborne contact (like sesquiterpene lactones) or, most frequently, by direct application of cosmetics or topical ophthalmic medicaments. The percentage of sensitization due to cosmetics, such as moisturizing creams or eye-shadows, is estimated to range from 2.5% to 26% (2, 3). However, topical ophthalmic drugs, eye drops and contact lens solutions play a considerable role too. We studied 62 patients with eyelid dermatitis, closely related to the use of topical ocular products, with the aim of discerning the role of ophthalmic products in eyelid allergic contact dermatitis.

Pediatric use of topical ophthalmic drugs

Changes in the policies of the Food and Drug Administration (FDA) have resulted in a rapid increase in the number of drugs now labeled for pediatric use. In topical ophthalmic drugs, there are pharmaceuticals approved for use in children in the treatment of allergy, inflammation, and bacterial and viral infection. Clinicians should anticipate that this trend will continue into the future. This article reviews the history of FDA oversight of drugs used to treat children. Recent shifts in policies and approach are emphasized. Pediatric issues associated with ophthalmic drug use are discussed, including important differences regarding dosage, instillation, distribution, systemic toxicity, and metabolism. A summary of topical ophthalmic drugs approved for pediatric use, including age considerations, is provided. Clinicians should be aware of the increasing number of topical ophthalmic drugs that are approved for pediatric use. Social, regulatory, and economic factors suggest this trend will continue. When prescribing these drugs for use in children, clinicians should remember to refer to details of labeling for Pediatric Use, including the age of the child for whom the drug is approved.

Characterization of Drug Release from Liposomal Formulations in Ocular Fluid

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol. The relationship between lipid composition and encapsulation efficiency, vesicle size, drug leakage upon storage at 4°C, and the release of PCH-loaded liposomes was studied. The encapsulation efficiency was found to be dependent upon the lipid composition used in the liposome preparation. In particular, phosphatidylcholine vesicles containing cholesterol and/or charged lipids had a lower entrapment efficiency than liposomes prepared with phosphatidylcholine alone. However, the drug release rate was reduced significantly by inclusion of cholesterol and/or charged lipids in the liposomes. The release kinetics of the entrapped agent seemed to be a biphasic process and the drug-release in both simulated tear fluid (STF) and pH 7.4 phosphate buffered saline (PBS) solutions followed pseudo first-order kinetics in the early stage of the release profile. The drug-release appeared to be diffusion and/or partition controlled. Drug release from liposomes into STF, pH 7.4 PBS, and five different modified tear formulations was also evaluated. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, it was determined that lactoferrin might be the protein component in tear fluid that has the primary influence on the liposome-entrapped drug release rate.Five local anesthetics, benoxinate, proparacaine, procaine, tetracaine, and benzocaine were entrapped in liposomal vesicles by a reverse-phase evaporation (REV) technique. The release of these structurally similar topical anesthetics entrapped in positively charged liposomes (egg phosphatidylcholine, stearylamine, and cholesterol in a 7:2:1 molar ratio) was evaluated in a simulated tear fluid and pH 7.4 phosphate buffered saline solution. The liposomes appeared to be useful carriers for these drugs to retard their in vitro release in tear fluid and perhaps sustain or control their release in the eye for better therapeutic efficacy. An analysis of the release data demonstrated that for this series of drugs, drug partition coefficient has the largest effect on release rate, with molecular weight exhibiting a smaller effect. Release rate was found to decrease with increased lipophilicity or increased molecular weight.

Tear film, pharmacology of eye drops, and toxicity.

Various new topical ophthalmic drug delivery systems show promise for increasing bioavailability, reducing epithelial toxicity, and improving patient compliance. Microparticulates are drug-containing polymeric particles that are placed in the fornix and release ocular medication by diffusion, chemical reaction, polymer degradation, or ion exchange and can be used to deliver many topical ophthalmic medications, including antibiotics and antimetabolites. Soft drugs are activated enzymatically at the site of application and are rapidly converted to inactive metabolites when exposed to the ocular environment, improving bioavailability at the target site, and reducing the potential for ocular and systemic side effects. Applications include soft beta-blockers, soft corticosteroids, and soft anticholinergics. Collasomes are made up of collagen pieces suspended in a viscous vehicle; this formulation is similar to that of corneal collagen shields, but is more useful for chronic therapy because the collasomes can be instilled by the patient and cause less blurring of vision. Potential uses include delivery of hydrophobic antimetabolites such as cyclosporine to prevent graft rejection and delivery of lipids for the therapy of dry eyes. Ideal replacements for dysfunctional tear layers, especially the lipid layer, have not yet been developed. The toxic effects of preservatives in topical ocular medications, particularly in artificial tears, often outweigh the benefits and preservative-free tear preparations are almost always preferable.

Topical ophthalmic drug administration: a practical guide.

Of the various routes used to administer drugs to the eye, the topical route is the most commonly used. The safe and effective administration of topical eye medication is often the responsibility of the nurse. The procedure for the administration of topical eye medication involves a sequence of simple steps and an understanding of the drug action.

Simple Techniques Aid Eye Drop Penetration

OPHTHALMOLOGISTS ARE eye-balling a couple of techniques that may help drugs penetrate behind the cornea and sclera. Two techniques described at a Research to Prevent Blindness (RPB) Science Writers Seminar (in Bethesda, Md) may prove to be better ways to get more medication into the poorly-vascularized eye. What's more, the researchers say, their methods will reduce the side effects that patients often experience when treated with ophthalmic drugs. Patients using topical ophthalmic drugs frequently don't get the therapeutic benefit they should and they often experience uncomfortable and/or dangerous side effects, says Thom J. Zimmerman, MD. According to the University of Louisville School of Medicine's professor of pharmacology and toxicology, the solution to both problems is more careful application of the medications. Originally, says Zimmerman, who is also chair of the Department of Ophthalmology at Louisville, the idea was to have people press their index finger on the junction of the

Liposomes and tear fluid. I. Release of vesicle-entrapped carboxyfluorescein

The successful application of liposomes as a topical ophthalmic drug delivery device requires knowledge of vesicle stability in the presence of tear fluid. The release of 5-carboxyfluorescein from large unilamellar liposomes in the presence of rabbit tear fluid was studied in vitro as a function of bilayer cholesterol content. Reverse evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine and varying amounts of cholesterol. Both the rate and the extent of fluorescent dye release were significantly increased in the presence of rabbit tear fluid at all cholesterol levels. However, by incorporating increasing amounts of cholesterol in the vesicle bilayers, tear-induced leakage was reduced. The release kinetics reported in this study are similar to those observed in the presence of human serum. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, reported differences in tear protein composition suggest some other, as yet unidentified, factor.

Semisolid ophthalmic vehicles. III. An evaluation of four organic hydrogels containing pilocarpine

The validity of four hydrogels, based on synthetic polymers as vehicles for topical ophthalmic drugs was evaluated by determining, in rabbits and in humans, the miotic response induced by pilocarpine. The hydrogels were prepared with two different types of poly(acrylic acid), PAA-1 and PAA-2; with poly(acrylamide) PAAm and with ethylene maleic anhydride, EMA. Their biological effect was compared with that induced by an aqueous solution of the drug (AS). The rheological characteristics of the vehicles were investigated: PAA-1, PAA-2 and EMA displayed a plastic type of flow, while PAAm was pseudo-plastic. In rabbits administration of pilocarpine in the hydrogel vehicles doubled the drug bioavailability (as expressed by the area under the miotic response vs time curve, AUC) with respect to AS; however, no statistical differences were apparent among the AUC values of the hydrogels. In humans, the same vehicles showed more pronounced activity differences. While PAA-2 and PAAm produced an approximately 3-fold bioavailability increase with respect to AS, PAA-1 only doubled the bioavailability and EMA showed activity parameters not different from those of the aqueous solution. Possible correlations between the viscosity parameters of the vehicles and ophthalmic bioavailability in the two species are discussed. The present results appear to confirm previous observations on the poor validity of rabbits for studies on the influence of vehicle viscosity on bioavailability of topical ophthalmic drugs.

Diagnostic Drugs – What are the risks?

: This review examines both pharmacological and clinical aspects of adverse reactions to topical ophthalmic diagnostic drugs. Statistics concerning the incidence of such reactions from both optometric and ophthalmological sources are compared and reasons for discrepancies between the figures cited are proposed. This paper is based on the Noel Verney Memorial lecture presented at the Australian Optometrical Association (Queensland Division) State Congress in October, 1984.