The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma.

BACKGROUND AND PURPOSE: Late secondary glaucoma is an often-severe complication after acute events like anterior segment surgery, trauma and infection. TNF-α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF-α antibodies are in animals very effective in protecting the retinal cells and the optic nerve-and might therefore be useful prophylactically against secondary glaucoma in future such patients. Here we evaluate (1) toxicity and (2) efficacy of two TNF-α inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration. METHODS: For drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub-set of eyes were stained ex vivo after 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified. RESULTS: Subconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated. Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group. CONCLUSIONS: Subconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long-term (90 days). Our total. accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF-α biologics to reduce inflammation and future secondary glaucoma.

Sub-tenon Versus Sub-conjunctiva Anaesthesia for Intraocular Surgery.

Objective: To compare the pain relief achieved using sub-Tenon anesthesia with that of sub-conjunctival anesthesia technique in intraocular surgery at the Guinness Eye Centre Onitsha Nigeria. Materials and Methods: Consecutive adult patients who had intraocular surgery under local anesthesia were randomized into having sub-Tenon (3 mL) or sub-conjunctival (0.5 mL) injections using xylocaine ± adrenaline. The manual suture-less surgery technique was used for cataract surgery alone and cataract surgery with pterygium excision; the extra-capsular cataract extraction technique was adopted for combined trabeculectomy and cataract surgery. Surgery duration was recorded. Patient's pain perception graded as none, mild, moderate or severe. Results: 100 patients made up 51 (51.0%) males and 49 (49.0%) females, age range was 31-88 years, median - 68 years, participated. Sub-Tenon anesthetic technique was used in 52 (52.0%) and sub-conjunctival in 48 (48.0%) participants. Seventy-eight (78.0%) patients had cataract surgery; 10 (10.0%) had trabeculectomy; 7 (7.0%) had combined trabeculectomy and cataract surgery and 5 (5.0%) had pterygium excision with cataract surgery. The mean surgery duration in the sub-Tenon anesthesia group was 31.8 ± 8.5 minutes and 30.2 ± 9.8 minutes in the sub-conjunctival group (P > 0.05). Fifty (96.2%) patients in the sub-Tenon group and 38 (79.2%) in the sub-conjunctival group experienced mild or no pains; 2 (4.2%) patients in the sub-Tenon group and 10 (20.8%) in the sub-conjunctival group experienced moderate to severe pains (P < 0.05). Conclusions: Both sub-conjunctival and sub-Tenon anesthetic achieved effective analgesia in intraocular surgery. But sub-Tenon anesthesia is significantly associated with lower incidence of severe pains.

Safety data on in situ gelling bimatoprost loaded nanovesicular formulations.

In vitro cytotoxicity and in vivo acute and 7 days repeat-dose ocular toxicity studies, were conducted in rabbits, in accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines, for bimatoprost loaded nanovesicular aqueous dispersion (BMT-NV) and its in-situ gelling sub-conjunctival implant (BMT-NV-IM). For details on the preparation and evaluation of BMT-NV and its BMT-NV-IM for the control of glaucoma, please refer to 'Bimatoprost loaded nanovesicular long-acting sub-conjunctival in-situ gelling implant: In vitro and in vivo evaluation' (Yadav et al., 2019). The in vivo ocular toxicity was performed only after confirming dermal safety, as required by OECD. Histological evaluation of various ocular tissues, following sub-conjunctival implantation with BMT-NV-IM, was done for ocular tolerance studies.

Pharmacokinetic aspects of retinal drug delivery.

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.