Comparison of the ocular surface changes following the use of two different prostaglandin F2α analogues containing benzalkonium chloride or polyquad in rabbit eyes

Objective: The aim of this study is to compare the effect of prostaglandin analogues preserved with either 0.015% or 0.001% benzalkoium chloride (BAK); or 0.001% polyquad (PQ) on the ocular surface of rabbit eyes.

Methods: Forty white rabbits were randomized to receive four-times daily instillation of either 0.0015% tafluprost (TF) preserved with 0.001% BAK (TF-BAK); 0.004% travoprost (TR) with 0.015% BAK (TR-BAK) or 0.001% PQ (TR-PQ); or preservative-free artificial tears in one eye for a 4-week period. Tear samples collected from the 40 rabbits were analyzed by enzyme-linked immunosorbent assays (ELISA) to identify the presence of inflammatory cytokines: interleukin (IL)-1β and IL-6 on day 14. Subsequently, harvested cornea and bulbar conjunctiva were evaluated using light and transmission electron microscopy (TEM).

Results: IL-6 was significantly increased in TF-BAK and TR-BAK groups compared to controls and TR-PQ group (p?=?0.005); however, IL-1β level was not significantly different among four groups (p?=?0.360). Rabbits treated with TR-BAK showed decreased goblet cell density of bulbar conjunctiva and increased pyknotic change and vacuolization of corneal epithelial cells on light microscopy; similar change occurred but was less severe in TF-BAK group. The TR-PQ group showed similar results as the controls. The destruction of the microvillar architecture of bulbar conjunctiva and cornea was most prominent in the TR-BAK group.

Conclusions: Preservatives included in the anti-glaucoma eye-drops showed different ocular surface changes according to the concentration and type in the rabbits. Prostaglandin analogues preserved with higher level of BAK may cause more harmful effects on the ocular surface than PQ-preserved medications.     

Effects of the folk medicinal plant extract Ankaferd Blood Stopper® on the ocular surface

Purpose: To investigate the effects of Ankaferd Blood Stopper^® (ABS) on the ocular surface.

Methods: Twenty adult male Wistar albino rats, weighing 390–530?g, were used in this prospective, controlled trial. One drop of ABS and one drop of balanced salt solution (BSS) were instilled into the lower conjunctival sac of the right and left eyes, respectively. After the rats were anesthetized, the ocular surface was evaluated based on the Draize criteria, and fluorescein tests were performed at 1, 2, 4, 18, 24, and 48?h. Subsequently, the rats were killed and all eyes were enucleated for histopathological examination.

Results: The outcome of the Draize and fluorescein tests revealed that ABS caused more irritation of the ocular surface than BSS (P?<?0.001). The highest mean ABS score was 4.9 for the Draize test and 0.4 for the fluorescein test, and ABS was considered to be a slight irritant. Histopathological examinations of the cornea and the conjunctiva revealed no significant difference between the eyes instilled with BSS and those instilled with ABS.

Conclusions: ABS is a hemostatic drug that exerts a slight toxic effect on the ocular surface. Given its ease of use and antibacterial activity, as well as its efficiency in stopping bleeding, the use of ABS during ocular surgery should be further investigated in experimental and clinical studies.     

Corneal damage and its recovery after instillation of preservative-free versus preserved latanoprost eye drops

Abstract

Purpose: Latanoprost ophthalmic solution is highly effective as a therapeutic agent for glaucoma and is applied worldwide. However, harmful effects on the corneal surface have been reported regarding the commercially available latanoprost ophthalmic solution. Corneal surface toxicity may be caused by the added preservative of the ophthalmic solution. In order to ascertain whether latanoprost itself can damage the cornea or if this is solely due to the added preservatives, this study attempted to determine the corneal changes that occur at different time periods following usage of preservative-free versus preserved latanoprost eye drops.

Materials and methods: Preservative-free latanoprost eye drops (Monoprost^®) or preserved latanoprost eye drops (Xalatan^®) containing 0.02% benzalkonium chloride (BAC) were instilled in the corneas of rabbits. For each of the two different eye drop solutions, the rabbits used in this experiment were divided into three exposure groups: 1?minute, 24?hour, and 1?week groups. Corneal transepithelial electrical resistance (TER) and scanning electron microscopy (SEM) were examined immediately (1?minute) after instillation, at 24?hours after instillation, and at 24?hours after 1?week of daily instillations of latanoprost. Hank’s balanced salt solution was used in the control group.

Results: The mean corneal TER of the control group was 933.8?±?279.0 Ω cm². In preservative-free latanoprost instilled corneas, there was no significant decrease in the TER or morphological changes at any of the time points, with the relative TER values of 117?±?38%, 100?±?34%, and 93?±?21% for 1?minute, 1?day, and 1?week time points, respectively. In preserved latanoprost instilled corneas, SEM showed that only the immediate group exhibited superficial cell damage and a significant decrease in the corneal TER compared to the controls and other time points and to the immediate preservative-free latanoprost corneas. In the preserved latanoprost groups, the relative TER values were 18?±?5%, 110?±?28%, and 92?±?10%, for the three respective observation time points.

Conclusions: Preservative-free latanoprost can be safely instilled to the corneal epithelium. Latanoprost with 0.02% BAC has an immediate deleterious impact on the corneal epithelium; however, it disappears within 24?hours after instillation.     

Ocular surface toxicity from glaucoma topical medications and associated preservatives such as benzalkonium chloride (BAK)

Introduction: This review discusses the evidence concerning the effect of topical medications and their preservatives on the ocular surface in glaucoma patients. The role of topical anti-glaucoma medication remains critical in the management of chronic glaucoma worldwide but the beneficial effects of treatment are counterbalanced by the adverse effects of corneal and conjunctival toxicity.

Areas covered: This article covers the effect of topical ocular drops and preservatives, particularly benzalkonium chloride, on the cornea and conjunctiva. Both basic science and clinical evidence will be presented. The first part reviews the relationship between ocular surface disease and benzalkonium chloride and the evidence from non-benzalkonium chloride preserved drops. The second part discusses the effects of benzalkonium chloride on the histopathology of the conjunctiva and its impact on clinical care as well as quality of life.

Expert opinion: Topical anti-glaucoma medication will continue to be used in the management of this blinding disease for the foreseeable future. Treatment outcomes will benefit from minimized exposure to benzalkonium chloride. The development of alternative preservatives, preservative-free topical options, and non-drop therapeutics such as drug-eluting systems for the delivery of ocular medications, will be very helpful in the care of glaucoma patients.     

Topical hyaluronan alone promotes corneal epithelial cell migration whereas combination with benzalkonium chloride impairs epithelial wound healing

Abstract

Purpose: To evaluate the effects of topical hyaluronan (HA) on corneal epithelial wound healing when administered with or without benzalkonium chloride (BAC).

Methods: A cultured human corneal epithelial cell line (HCE-T) was subjected to in vitro scratch assays and in situ epithelial migration was evaluated in organ-cultured rabbit corneas. The corneal epithelium of C57BL/6J mice was also evaluated to determine in vivo wound healing. An in vivo imaging system was also used to evaluate the effects of HA on eye drop retention on the ocular surface.

Results: The findings revealed the promotion of HCE-T migration, in situ rabbit corneal epithelial migration, and in vivo wound healing in mouse corneal epithelium by HA. Pre-treatment with HA also protected against delayed epithelial wound healing in BAC in vitro. However, pre-treatment with 3?mg/mL HA did not show a protective effect against BAC in vivo, but instead delayed epithelial wound healing and increased detection of cleaved caspase-3. This suggested that HA promotes the retention of BAC on the ocular surface. The instilled HA was retained after 15?min, at a significantly higher rate than for phosphate-buffered saline.

Conclusions: The combination of HA and BAC impaired wound healing in the corneal epithelium.     

Fabrication of a drug delivery system that enhances antifungal drug corneal penetration

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50?μL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4?h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.     

Ocular penetration of moxifloxacin 0.5% and gatifloxacin 0.3% ophthalmic solutions into the aqueous humor following topical administration prior to routine cataract surgery

ABSTRACT

A prospective, double-masked, randomized, parallel-group study (n = 25) was conducted to examine the ocular penetration of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution into the aqueous humor following topical administration prior to routine cataract surgery. One drop of antibiotic was instilled every 10?min for four doses beginning 1?h prior to surgery. Preliminary results showed aqueous humor concentrations for moxifloxacin that were significantly greater (?p < 0.01) than those for gatifloxacin.     

Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis

Background: Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treatment shifted to topical linezolid/ceftazidime from topical vancomycin/ceftazidime due to their vancomycin intolerance.

Methods: A retrospective, interventional case series of bacterial keratitis was treated with topical linezolid (one drop of 0.2% solution per eye), administered hourly until epithelization and then gradually decreased. The number and extent of punctate epithelial erosions were noted across the entire surface of the cornea. Ocular discomfort was assessed by means of (a) patient-reported pain upon instillation of the medication (vancomycin/linezolid), (b) reported burning sensation between doses and (c) reported foreign-body sensation. No ocular surface toxicity related to linezolid use was noted. Patients were followed for at least 2 months after treatment between April and December 2013.

Results: Of the seven patients included in the study (age range: 2–88 years; five females, two males), complete epithelization and resolution was achieved in five patients. One patient was treated with linezolid after penetrating keratoplasty. The second culture of another patient with impending perforation despite linezolid/ceftazidime therapy yielded Fusarium spp., so he underwent tectonic keratoplasty. The mean ocular surface score was 9.4?±?1.6 during vancomycin treatment and 5.9?±?1.3 during linezolid treatment after discontinuation of vancomycin. The topical linezolid score was significantly lower (p?=?0.027).

Conclusions: Topical linezolid may be better tolerated, according to the mean ocular surface score, than topical vancomycin by some patients and can be considered an alternative for patients who do not well tolerate vancomycin.     

Influence of emulsion droplet surface charge on indomethacin ocular tissue distribution

The aim of this study was to compare the corneal penetration of indomethacin from Indocollyre [a marketed hydro-poly(ethylene glycol) (PEG) ocular solution] to that of a negatively and a positively charged submicron emulsion. Male albino rabbits were separated randomly into three groups and each group (N = 15) was treated with either one drop of radiolabeled 0.1% Indocollyre, or 0.1% indomethacin positively or negatively charged submicron emulsion, respectively. The rabbits were sacrificed at selected time points and the eyes were enucleated. The eyes were dissected into the different tissues: cornea, conjunctiva, aqueous humor, iris, lens, vitreous, sclera, and retina. The samples were weighed before radioactivity counting. Regardless of the preparation instilled, the highest concentration of indomethacin was achieved in the cornea followed by conjunctiva, sclera retina, and aqueous humor. However, the positively charged emulsion provided significantly higher drug levels than the control solution and negatively charged emulsion only in the aqueous humor and sclera-retina. Furthermore, the spreading coefficient of the positively charged emulsion on cornea is four times higher than that of the negatively charged emulsion. It was therefore deduced that the positively charged submicron emulsions have better wettability properties on the cornea compared to either saline or the negatively charged emulsion. The positive charge may prolong the residence time of the drop on the epithelial layer of the cornea and thus enable better drug penetration through the cornea to the internal tissues of the eye, as confirmed by the animal studies.     

Ocular Absorption of Pz-Peptide and Its Effect on the Ocular and Systemic Pharmacokinetics of Topically Applied Drugs in the Rabbit

Purpose. To determine the corneal and conjunctival penetration of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (Pz-peptide) and to evaluate its effect on the corneal and conjunctival penetration of hydrophilic solutes as well as on the ocular and systemic absorption of topically applied atenolol and propranolol in the rabbit. The hydrophilic solutes were mannitol, fluorescein, FITC-dextran 4,000, and FITC-dextran 10,000. Methods. Drug penetration across the rabbit cornea and conjunctiva was evaluated using the modified Ussing chamber. Ocular and systemic absorption of topically applied atenolol and propranolol was evaluated by analyzing the drug concentration in various anterior segment tissues at 45 min and in the blood over 240 min, respectively, following topical instillation of 25 l of 20 mM atenolol or propranolol solution to the rabbit eye. Results. The conjunctiva was 29 times more permeable than the cornea to 3 mM Pz-peptide. Conjunctival Pz-peptide transport was 1.7 times more extensive in the mucosal-to-serosal than in the opposite direction, whereas corneal Pz-peptide transport showed no directionality. The apparent permeability coefficient of Pz-peptide across the cornea and the conjunctiva increased over the 1–5 mM range, suggesting that Pz-peptide enhanced its own transport across both epithelial tissues. The cornea appeared to be more sensitive than the conjunctiva to the penetration enhancement effect of Pz-peptide. Thus, whereas Pz-peptide elevated the corneal transport of mannitol, fluorescein, and FD4 by 50%, 57%, and 106%, respectively, it did not affect the conjunctival transport of mannitol and fluorescein, while enhancing FD4 transport by only 46%. Moreover, while Pz-peptide enhanced the ocular absorption of topically applied hydrophilic atenolol, it did not affect the ocular absorption of lipophilic propranolol. Interestingly, Pz-peptide did not affect the systemic absorption of either beta adrenergic antagonist. Conclusions. Pz-peptide appears to facilitate its own penetration across the cornea and the conjunctiva. Pz-peptide appears to increase the ocular absorption of topically applied hydrophilic but not lipophilic drugs, while not affecting the systemic absorption of either type of drugs.     

Experimental studies on soft contact lenses for controlled ocular delivery of pirfinedone: in vitro and in vivo

Context: Pirfinedone (PFD) is a novel agent which has the potential to prevent scarring in the eyes. The 0.5% PFD eye drops exhibits poor bioavailability. Whereas, the feasibility of using contact lens as ocular drug delivery device initiated novel possibilities.

Objective: To evaluate the delivery of PFD by soft contact lens (SCL) in vivo, we screened the most suitable lens material for PFD among various commercially available SCL materials in vitro.

Material and methods: Firstly, 11 different SCLs (?1.00 diopter) were respectively soaked in 2?ml of 0.05% PFD-loading solution for 24?h to fully absorb drug, and then placed in fresh phosphate buffered saline (PBS) to release the drug. PFD concentration in PBS was determined by ultraviolet absorbance at 310?nm. Secondly, by immersing in 2?ml of 0.5% PFD eye drops for 24?h, the polymacon lens (0.00 diopter) was then placed on the cornea of New Zealand rabbits. PFD concentrations were detected by high performance liquid chromatography (HPLC) in tears, aqueous humor, conjunctiva, cornea, and sclera at different time points.

Results: PFD showed some affinity for pHEMA-based lenses and the polymacon lens more slowly released more amount of PFD than any other lens in vitro (p < 0.001). Compared with eye drops, drug-loaded SCLs greatly enhanced the retention time and concentrations of PFD in cornea and aqueous humor and consequently improved the bioavailability of PFD.

Conclusion: Polymacon-based SCL is probably a promising vehicle to be an effective ophthalmic delivery system for PFD.     

Toxicity of intravitreal miconazole in dmso

Abstract

The ocular toxicity of intravitreal miconazole nitrate dissolved in DMSO was determined in rabbits by slit lamp biomicroscopy and indirect ophthalmoscopy after pupillary dilation with atropine 1 % eye drops. Slit lamp examination of the eyes revealed no evidence of toxic injury to the conjunctiva, cornea, lens, or vitreous body of any of the test eyes at the dosage levels tested. Electroretinographic testing revealed no toxic effects to the retina with balanced salt solution control or DMSO control intravitreal injections as well as doses of 2.5,5, and 10–30 /μg miconazole nitrate in DMSO after the 2-month observation period. Histopathologic examination by light and electron microscopy revealed no damage to the retina, retinal pigment epithelium, or choroid at doses ranging from 2.5 to 30 μg. This study shows that intravitreal injections of up to 30 μg of intravitreal miconazole nitrate dissolved in DMSO can be tolerated without ocular toxicity in the rabbit.     

Antioxidant status in rabbit aqueous humor after instillation of ascorbyl laurate-based nanostructures

BackgroundThe aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power.MethodsThe hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 ml dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent.ResultsThe kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 h instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits.ConclusionThis type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases.     

Preparation and Characterization of Demeclocycline Liposomal Formulations and Assessment of their Intraocular Pressure-Lowering Effects

ABSTRACT

The objective of the present study is to enhance the ocular permeability and to study the ocular disposition of demeclocycline (DEM), liposomal topical formulation for treatment of elevated intraocular pressure using Male New Zealand albino rabbits as an animal model. Methods: Different liposomal formulations of the DEM were prepared and characterized for their drug entrapment, drug-liposome affinity and the in vivo distribution of DEM in various ocular tissues. Liposomal formulations of promising drug distribution within the various ocular tissues have been scaled up for the in vivo intraocular pressure (IOP) measurements by Pneuma-tonometer using different dosing regimens. Results: The amounts of drug entrapped in the charged liposomal formulations were comparable and lower than that entrapped with neutral ones. DEM was found to be more concentrated (69–95%) in the lipid phase of the liposome. The concentrations of DEM in the cornea, aqueous humor, and conjunctiva were 4.76, 2.18, and 23.32 µg/g of tissue, respectively. Test formulations have shown significant reductions in the IOP on using different treatment protocols. Conclusion: Preparation of liposomal formulations of DEM has substantially enhanced its transcorneal transport. Furthermore, the test formulations have shown promising and long-lasting intraocular pressure-lowering effect comparable with that of pilocarpine formulation as a control.     

Efficacy,tolerability and comfort of a 0.3% hypromellose gel ophthalmic lubricant in the treatment of patients with moderate to severe dry eye syndrome

ABSTRACT

Objective: To evaluate efficacy, safety and comfort of a 0.3% hypromellose (HM) eye gel (GenTeal Lubricant Eye Gel), with a sodium perborate preservative system and carbomer gelling agent, in patients with dry eye.

Research design and methods: Patients with moderate-to-severe dry eye syndrome were enrolled in this open label study and assessed at three visits; a screening consultation (baseline) and two follow-up visits on day 14 (± 4 days) and day 28 (± 4 days). All screening, evaluation and follow-up visits were carried out at the Tauber Eye Center (formerly the Hunkeler Eye Center), Kansas City. Patients were treated with the product over a 4?week period. They were instructed to use the product at least two times daily, more if necessary, with one drop instilled into the conjunctive sac of both eyes.

Main outcome measures: Efficacy was measured by ocular symptoms (burning, stinging, foreign body sensation, dryness, pain/soreness and photophobia), ocular signs (eyelid erythema, bulbar conjunctival injection and corneal superficial punctate keratitis score), tear breakup time and global assessment of ocular comfort. Tolerability measures were change from baseline in best corrected Snellen visual acuity and monitoring of adverse events.

Results: Thirty-seven patients completed this study. The mean sum symptom score at each visit was significantly lower compared with baseline with approximately 30% reduction in the sum symptom score at 2 weeks and approximately 33% at 4 weeks after treatment initiation (?p < 0.001). Mean individual symptom scores for dryness, stinging and foreign body sensation decreased by approximately 40% at the end of the study (?p < 0.02). Tear breakup time increased from baseline by 53% and 59% at 2 and 4 weeks, respectively (?p < 0.001). The proportion of patients reporting a global evaluation of slightly better or much better was approximately 74% at 2 weeks and 78% at 4 weeks after treatment initiation. The product was well tolerated, with one related adverse event reported.

Conclusions: In a small, open-label study, this 0.3% HM eye gel showed statistically significant effects in relieving ocular symptoms and provides a well-tolerated formula that effectively reduced symptoms and improved ocular comfort in patients with dry eye syndrome.     

The safety of intraocular usage of aspirin

Purpose: To determine the effects of intravitreally injected aspirin on normal ocular tissues.

Methods: Six eyes of 3 rabbits as a control group, 18 eyes of 9 albino rabbits which were injected aspirin intravitreally were studied. In the control group, the same volume of balanced salt solution (BSS) as in drug groups were injected. Clinical examination methods including biomicroscopy, indirect ophthalmoscopy, and Schiotz tonometry, electrophysiological test including ERG, and histopathological examination including light microscopy were used to evaluate the ocular effects after drug injections. All the study tests were performed before the injections and 1?week, 1?month, and 3?months after the injections as well.

Results: No significant toxicity was determined after injection in terms of the clinical examination methods in all eyes. Cataracts were observed in 27.7% (5/18) of the eyes in the study group. All cataracts in 5 eyes disappeared at the end of three months. In tonometry, no value out of the normal range of rabbits (17.5?±?3.1?mmHg) was observed. No toxicity sign was observed at electrophysiological and histopathological evaluations.

Conclusion: After intravitreal injection of aspirin, no significant toxicity sign was observed other than a reversible cataract. Thus, intravitreal aspirin injections may be an additional or alternative treatment option for several anterior or posterior segment ocular diseases in addition to their topical utilization.     

The local vasoconstriction of infant’s skin following instillation of mydriatic eye drops

Background  

Systemic absorption of eye drops is known to occur via the nasal mucosa, cornea, and conjunctiva. Diffusion of eye drops through the skin is previously unrecognized. Here, two cases are presented in which we observed skin pallor around the eyes after instillation of phenylephrine 2.5% drops. Case 1 A 32-week gestational age premature infant had mydriatic eye drops instilled as part of retinopathy of prematurity screening. Case 2 A term newborn dysmorphic infant underwent fundus examination to rule out ocular pathology. In both cases, discoloration of periorbital skin was observed 45 min following administration of drops.     

Fixed topical combinations in glaucomatous patients and ocular discomfort

Objective: The purpose of this study was to verify the ocular comfort of a fixed topical combination of brinzolamide 1% plus timolol 0.5% suspension vs. dorzolamide 2% plus timolol 0.5% solution, both preserved with benzalkonium chloride (BAK), in patients with primary open-angle glaucoma (POAG) through subjective and objective methods. BAK is the most commonly used preservative in topical glaucoma medications.

Methods: 62 subjects were examined and included in the analysis. Each patient was asked to complete a questionnaire on symptoms (Ocular Surface Disease Index) and then underwent a series of examinations. The Ocular Protection Index evaluated the risk of damage to the ocular surface, and was expressed as the ratio between fluorescein breakup time and blinking interval. These and other analyses were repeated 30 days after instillation of the new eye drop treatment.

Results: The results demonstrated that patients enrolled with the preserved fixed combination of dorzolamide or brinzolamide represented a subgroup of patients in which the discomfort symptoms were supposedly justified by the presence of BAK used chronically in antihypertensive drops. Ocular discomfort scores were significantly higher with dorzolamide/timolol than brinzolamide/timolol (p < 0.0001).

Conclusions: This work shows the better tolerability of brinzolamide 1% plus timolol 0.5% suspension, compared with dorzolamide 2% plus timolol 0.5% solution. Fortunately, some of the adverse reactions induced by preserved eye drop glaucoma medication are reversible after removing the preservatives. Both the potential for added benefit and patient compliance should be considered when selecting ocular hypotensive therapy.     

Ocular Toxicity of Ciprofloxacin/Pssa Fluoroquinolone Antibacterial Solution in Pigmented Rabbits

Abstract

The fluoroquinolone ciprofloxacin in an ophthalmic solution with polystyrene sulfonic acid (PSSA) was investigated for potential ocular toxicity in Dutch Belted rabbits, a pigmented species, following 3 months of daily topical ocular treatment (four times daily administration).

Four groups of 16 rabbits (eight/gender) received 0%/1.5% (vehicle group), 0.3%/1.5%, 0.5%/1.5% Ciprofloxacin/PSSA Ophthalmic Solution, or Tarivid Ophthalmic Solution (0.3% ofloxacin) four times daily to the right eye only. The left eye of each animal was untreated and served as untreated control. An additional group of 16 rabbits was maintained as an untreated control group.

Clinical observations noted during the 3 month treatment period were minimal for all treatment groups and were similar to the untreated controls. Slit-lamp biomicroscopic examinations, indirect ophthalmoscopic examinations, and pachymetry evaluations of the study animals revealed that these ocular parameters in the ciprofloxacin/PSSA-treated animals remained similar to the untreated controls throughout the 3 month treatment period. The integrity of the blood-aqueous barrier, as measured with a flare/cell meter, demonstrated that the barrier function remained intact for all treatment and control groups. Electroretinography (ERG) data demonstrated that the Ciprofloxacin/PSSA Ophthalmic Solutions and the Tarivid Ophthalmic Solution had minimal effects on A-, B-, or C-wave amplitudes or latencies, indicating that neither drug caused functional changes in the photoreceptors, inner retinal layers, or retinal pigment epithelium, respectively. Specular microscopy data demonstrated that the corneal endothelium remained normal in the treatment groups.

Clinical chemistry, hematology, and gross necropsy observations remained within normal limits for rabbits for all treatment and control groups. The appearance of retinal tissues as well as all ocular and adnexal structures were considered within normal histologic limits in all groups.

The ciprofloxacin/PSSA-containing formulations did not produce significant ocular irritation or signs of systemic toxicity following three months of four-times daily topical ocular administration to pigmented Dutch Belted rabbits.     

Systemic and ocular pharmacokinetics of N-4-benzoylaminophenylsulfonylglycine (BAPSG), a novel aldose reductase inhibitor

To better develop N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and selective aldose reductase inhibitor capable of delaying the progression of ocular diabetic complications, the objective of this study was to assess its pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of administration and its distribution to various tissues including those of the eye was studied following intraperitoneal administration. In addition, rat plasma protein binding of BAPSG was studied using ultracentrifugation method and its ocular tissue disposition was assessed following topical administration in rabbits. Plasma and tissue levels of BAPSG were analysed using an HPLC assay. BAPSG exhibited dose-proportionate AUC0 --> infinity (area under the plasma concentration-time curve) following both intravenous and intraperitoneal administration over the dose range (5-50 mg kg(-1)) studied and an erratic oral absorption profile with low oral bioavailability. The fraction bioavailability following oral and intraperitoneal administration was 0.06 and 0.7-1, respectively. BAPSG exhibited short plasma elimination half-lives in the range 0.5-1.5 h. BAPSG was bound to rat plasma proteins and the percent protein binding ranged from 83 to 99.8%. BAPSG was better distributed to cornea, lens and retina than to brain, following intraperitoneal administration in rats. However, the distribution was lower compared with kidney and liver. Following topical administration in rabbits, BAPSG delivery to the surface ocular tissues, cornea and conjunctiva was higher compared with intraocular tissues, aqueous humour, iris-ciliary body and lens. Thus, BAPSG was distributed to ocular tissues following systemic and topical modes of administration.