Caryn E. Plummer

Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses.

Glaucoma is the second major cause of blindness in the world after cataract. Glaucoma management through eye drops that reduce the intraocular pressure (IOP) has major deficiencies including low patient compliance and low bioavailability. Extended wear contact lenses that deliver glaucoma drugs for extended periods could increase patient compliance, while also increasing the bioavailability. To develop extended wear contact lenses that can also provide extended glaucoma therapy, we disperse nanoparticles of PGT (propoxylated glyceryl triacylate) that contain a glaucoma drug timolol. The particles can also be loaded into prefabricated lenses by soaking the lenses in a solution of particles in ethanol. The particle loaded gels can release timolol in phosphate buffered saline (PBS) for about a month at room temperature. The most likely rate controlling mechanism is hydrolysis of the ester bond that links timolol to the PGT matrix, but other mechanisms such as water and drug diffusion, drug dissolution, drug-polymer chain cleavage, time-dependent drug permeability within the polymeric matrix, etc. may also be important. Nanoparticle incorporation in the silicone hydrogels results in reduction in ion and oxygen permeabilities, and an increase in modulus, and the impact on each of these properties is proportional to the particle loading. A gel with 5% particle loading can deliver timolol at therapeutic doses for about a month at room temperature, with a minimal impact on critical lens properties. Preliminary animal studies in Beagle dogs conducted with lenses in which particles are loaded by soaking the lenses in ethanol show a reduction in IOP.

Extended drug delivery by contact lenses for glaucoma therapy.

We combine laboratory-based timolol release studies and in vivo pharmacodynamics studies in beagle dogs to evaluate the efficacy of glaucoma therapy through extended wear contact lenses. Commercial contact lenses cannot provide extended delivery of ophthalmic drugs and so the studies here focused on increasing the release duration of timolol from ACUVUE TruEye contact lenses by incorporating vitamin E diffusion barriers. The efficacy of timolol delivered via extended wear contact lenses was then compared to eye drops in beagle dogs that suffer from spontaneous glaucoma. The lenses were either replaced every 24h or continuously worn for 4 days, and the pharmacodynamics effect of changes in the intraocular pressure (IOP) of timolol from the ACUVUE TruEye contact lenses can be significantly increased by incorporation of vitamin E. The in vivo studies showed that IOP reduction from baseline by pure contact lens on daily basis was comparable with that by eye drops but with only 20% of drug dose, which suggested higher drug bioavailability for contact lenses. In addition, by inclusion of vitamin E into the lenses, the IOP was reduced significantly during the 4-day treatment with continuous wear of lens.

Drug Delivery by Contact Lens in Spontaneously Glaucomatous Dogs

Purpose: The efficacy of ophthalmic drug delivery through contact lenses in animal model was explored to evaluate its potential for serving as an alternative to eye drops, which are inefficient vehicles for delivering ophthalmic drugs. Methods: The efficacy of timolol delivered via contact lenses was compared to eye drops in beagle dogs that suffer from spontaneous glaucoma. Experiments were conducted with NIGHT & DAY™ silicone hydrogel contact lenses and NIGHT & DAY™ loaded with vitamin E, which was included in the lens to extend the release duration of the drug. Timolol was loaded into contact lenses by soaking in drug/phosphate buffered saline solution, and the drug-loaded lenses were subsequently inserted in one of the eyes, with the other eye serving as control. The lenses were replaced every 24 hours, and the pharmacodynamics of intraocular pressure (IOP) and pupil size were monitored in both eyes. Results: The IOP reduction from baseline by NIGHT & DAY™ (5.02 ± 0.83 mmHg) was comparable with that by eye drops with similar drug dosing (4.64 ± 0.41 mmHg). In addition, lenses with one-third of the drug loading as eye drops resulted in the similar IOP reduction, suggesting higher bioavailability for contact lenses compared to eye drops. Inclusion of vitamin E into the lenses did not improve the IOP reduction. The IOP in the untreated eye also decreased from baseline for eye drops (3.17 ± 0.42 mmHg) but it remained relatively unchanged with treatments based on lenses, suggesting reduction in systemic absorption for delivery of drugs by contact lenses. Conclusions: Ophthalmic drug delivery through contact lenses increases bioavailability and reduces systemic drug uptake.

The use of amniotic membrane transplantation for ocular surface reconstruction: a review and series of 58 equine clinical cases (2002–2008)

Amniotic membrane transplantation (AMT) is an effective clinical therapy for reconstruction of the ocular surface in human and veterinary patients. Amnion is avascular and strong, contains antiangiogenic and antiinflammatory properties and growth factors, and has properties that prevent or decrease fibrosis in healing tissue. Indications for its use are steadily growing and include grafting to replace diseased, missing or excised tissue, patching to support diseased tissue during the healing process and as a substrate for the expansion of epithelial cells for transplantation to the cornea. AMT through a combination of mechanical and biologic factors can preserve the integrity of the globe, optimize the visual outcome, and minimize scarring in severely diseased corneas.

Corneal transplantation for inflammatory keratopathies in the horse: visual outcome in 206 cases (1993-2007).

OBJECTIVE To evaluate the visual outcome of three techniques of corneal transplantation surgery in treating severe inflammatory keratopathies in the horse. DESIGN Retrospective medical records study. ANIMALS STUDIED Medical records of 206 horses that received corneal transplantation surgery at the University of Florida Veterinary Medical Center from 1993 to 2007 were reviewed. PROCEDURE Data collected from the medical records included signalment, types of ocular lesions, type of transplant surgery performed, length of follow-up, complications, and visual outcomes. RESULTS Full thickness penetrating keratoplasty (PK) was performed in 86 horses for melting ulcers, iris prolapse/descemetoceles, and medically nonresponsive full thickness stromal abscesses (SA). Posterior lamellar keratoplasty (PLK) and deep lamellar endothelial keratoplasty (DLEK) are split thickness penetrating keratoplasties that were utilized for medically nonresponsive deep stromal abscesses (DSA) in 54 and 66 eyes, respectively. The most common postoperative surgical complication was graft rejection and varying degrees of graft opacification. Wound dehiscence and aqueous humor leakage was also a common postoperative problem. A positive visual outcome was achieved for PK, PLK, and DLEK in 77.9%, 98.1%, and 89.4%, respectively. CONCLUSIONS Corneal transplantation is a tectonically viable surgery in the horse with an overall success rate of 88.5% in maintaining vision when treating vascularized and infected corneal disease in the horse.

Deep lamellar endothelial keratoplasty in 10 horses

OBJECTIVE To describe and evaluate a surgical technique utilized for the therapy of deep corneal stromal abscesses (DSA) in horses. The DSA is excised and replaced with a partial thickness corneal lamellar allograft. METHODS A retrospective clinical study describing the indications for the surgical technique utilized and the outcomes of this procedure in 10 eyes of 10 horses. RESULTS Each affected eye had a discrete DSA within the posterior stroma. An initial partial thickness semicircular corneal incision was made at the limbus, followed by anterior stromal lamellar dissection over the lesion. After excision of the DSA and replacement with a larger diameter split-thickness donor button, the anterior stroma was replaced into its original position and the initial corneal incision was repaired. All of the animals that underwent deep lamellar endothelial keratoplasty (DLEK) procedure healed appropriately and with subjectively less postoperative scarring and complications than previously described surgical approaches to DSA. CONCLUSIONS This procedure is an effective technique for surgical removal of DSA in horses and, in most cases, results in a visual and cosmetically acceptable globe. The advantages of this technique compared to other surgical approaches to DSA are the peripheral location of the incision, shortened anesthesia times, the resultant minimal scarring and shorter healing times associated with DLEK.

Dual drug delivery from vitamin E loaded contact lenses for glaucoma therapy.

Glaucoma patients frequently instill eye drops multiple times each day, which is a cause for reduced compliance. Additionally, eye drops suffer from other limitations including low bioavailability, which can lead to side effects. We propose to develop drug-eluting contact lenses for managing glaucoma with increased bioavailability and improved compliance. Contact lenses are developed for extended simultaneous release of timolol and dorzolamide, both of which are commonly prescribed hydrophilic drugs. The extended release is achieved by loading lenses with vitamin E barriers. In vitro release studies are performed with control and vitamin E loaded lenses for both drugs loaded separately and then together in the same lens. The safety and efficacy of combination therapy by contacts are demonstrated in a Beagle model of glaucoma. Simultaneous loading of timolol and dorzolamide increases the release duration of both drugs. Also vitamin E incorporation is highly effective in increasing the release durations of both drugs to about 2-days. The lenses loaded with both drugs exhibited superior IOP reduction compared to eye drops with about 6-fold lower drug loading. More importantly, combination therapy by continuous wear of vitamin E loaded contact for 2-days, followed by a new set of contacts for another two days, reduced IOP during the 4days of wear time and for another 8days after removal of the contacts. Vitamin E loading is very effective for providing combination therapy by contact lenses due to the increase in release durations of several drugs. The contact lens based therapy reduces IOP with lower drug dose compared to eye drops and may significantly improve the compliance as the effect of the therapy lasts significantly longer than the wear-duration.

Doxycycline levels in preocular tear film of horses following oral administration.

OBJECTIVE To determine the concentration of doxycycline in preocular tear film following oral administration in horses as a possible therapeutic modality for infectious and keratomalacic equine keratitis. PROCEDURE Eight broodmares without ocular disease from a Thoroughbred breeding facility were included in this study. Each mare received 20 mg/kg of doxycycline by mouth once daily in the morning for five consecutive days. Tears were collected 1 h after doxycycline administration starting on day one of administration and continuing for 10 consecutive days. Doxycycline levels in the tears were measured using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS). RESULTS Doxycycline was present in the tears of each mare at low microg/mL levels with the highest concentration appearing on the third to fifth days (8.21-9.83 microg/mL). Doxycycline levels had fallen below quantifiable ranges by day 10. No systemic side-effects were noted in any of the horses included in this study. CONCLUSIONS Oral doxycycline is present in preocular tear film of normal horses with noninflamed eyes and may be useful as treatment in equine ulcerative keratomalacia. The oral dose listed was tolerated well by the horses in this study. The drug levels attained at 20 mg/kg once daily orally of doxycycline may aid in the treatment of corneal ulceration in horses, but further study is warranted.

Extraocular lymphoma in the horse

OBJECTIVE To describe the clinical findings and prognosis for extraocular lymphoma in the horse. PROCEDURES   Retrospective medical records study of horses diagnosed with third eyelid, corneoscleral, conjunctival, and/or eyelid lymphoma from multiple academic and private veterinary institutions. Data collected from the medical records included signalment, clinical descriptions of the extraocular lesions, treatment, and treatment outcomes. Nonparametric statistical analysis was performed with Fischers exact tests. RESULTS   Extraocular lymphoma involving the eyelid, third eyelid, cornea, sclera, and/or conjunctiva was diagnosed in 26 horses. Differences in signalment, unilateral vs. bilateral extraocular involvement, and single vs. multiple extraocular lesion locations held no significance in terms of outcome. ANIMALS STUDIED   Horses with lesions localized to the eyelid or other nonextraocular cutaneous locations had a significantly higher chance of negative outcome when compared to the horses with no eyelid or cutaneous involvement (P = 0.019). Lesions to the third eyelid, corneosclera, and conjunctiva were either nodular or diffuse in nature. Nodular lesions when compared to diffuse lesions were associated with a higher chance of a positive outcome (P = 0.007). Surgical resection of the extraocular lesions as part of the treatment produced a statistically higher chance of a positive outcome when compared to horses where resection was not performed (P = 0.03). CONCLUSIONS   The prognosis for clinical remission in horses with extraocular lymphoma is generally fair to good, as long as the affected tissues are completely excised, and there is no eyelid or cutaneous involvement. Horses diagnosed with the nodular form of extraocular lymphoma seem to have the best prognosis with complete excision.

Intranictitans tacking for replacement of prolapsed gland of the third eyelid in dogs

OBJECTIVE To evaluate a new procedure for fixation of prolapsed nictitans glands to the cartilage of the nictitans that will not interfere with the mobility of the nictitating membrane. METHODS A prospective clinical trial utilizing a nonabsorbable suture to anchor the prolapsed gland to the cartilage of the third eyelid was undertaken. Fifteen eyes of 10 dogs were included in the study. A 4-0 nylon suture was passed from the anterior surface of the third eyelid through the base of the cartilage to the posterior aspect and then tunneled circumferentially beneath the conjunctiva over and around the prolapsed gland. The suture was then passed through the cartilage again to the anterior face of the third eyelid. The gland was replaced into its normal position as the suture was slowly tightened and then tied on the anterior aspect of the nictitans. RESULTS Over a period of several weeks, the glands reduced in size and took on a normal appearance. All glands but one remained in place for the length of follow-up, which ranged from 2 weeks to 33 months. CONCLUSIONS This procedure results in acceptable cosmetic effects with the return of the gland to its normal position posterior to the nictitating membrane. The advantage of this technique over traditional tacking to the orbital rim is that the third eyelid retains its normal mobility and, thus, its protective functions. The procedure once mastered is very quick and can be performed in less time than many of the traditional replacement techniques.