EFFECT OF ENVIRONMENT AND CLOZAPINE ON BASAL AND STIMULATED MEDIAL PREFRONTAL GABA RELEASE IN TWO RAT MODELS OF SCHIZOPHRENIA Adedoyin Awodele, Faye Carrington, Alanna Cavanagh, Sarah Kileen, Melissa MacPherson, Constance Gaya Cremers Pharmacology, UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland. Why Implants? What are they?. Usually made of polymers that release a drug over a prolonged period of time. There are two types: Provide sustained drug delivery to the posterior or anterior segment of the eye. Localised drug delivery, therefore reduced dose. Can be applied to various ocular layers depending on disease: subconjuctival/intravitreal/intrasceral. Implants reduce frequency of administration and the risk of side effects. Minimise the importance of patient compliance. Above: Insertion of Retisert Ref: lant_prevents_lost_vision.html Ocular drug barriers:  FDA approved in 1996, Vitrasert was first non-biodegradable, intravitreal implant.  Used for the delivery of the anti-viral drug, ganciclovir to treat AIDs-related Cytomegalovirus (CMV) Retinitis.  Ganciclovir is a synthetic analogue of the nucleoside 2-deoxyguanosine, which causes chain termination, preventing replication.  Each implant holds 4.5-5mg of the prodrug which is released at a rate of approx µg/hr over 5-8 months.  The 4mm device consists of a compressed drug pellet core which is completely covered, except at its top surface, with the impermeable polymer; EVA. This entire assembly is then coated by the permeable polymer; (PVA). S urgical Implantation  The implant is inserted by making a 5-6mm scleral incision into the pars plana. It is then fixed into place using sutures. The wound is closed and a saline solution is injected to restore normal ocular pressure.  Most patients experience blurred vision which usually clears between 2-4 weeks after surgery. Retisert For treatment of chronic, non-infectious uveitis (inflammation) including sympathetic ophthalmia. 3mm x 2mm x 5mm in size Reservoir of fluocinolone acetonide (corticosteroid thought to act by inducing phospholipase A2 inhib. proteins). 600ng a day decreasing to ng over the first month. Inserted through the pars plana into the vitreous humour Active for 2 and a half years Removal can cause problems SEs = Cataracts (observed in 90% of patients after 3 years), increased I.O pressure, eye pain, headache, nasopharyngitis and joint pain. Top View Side View Silicone cup containing drug Release orifice PVA structure tab 5mm 2mm 3mm 0.59mg tablet is held in a silicone elastomer cup. The release orifice is separated from the drug by a PVA membrane. The structure is held together with silicone glue Ozurdex Ozurdex is a biodegradable implant that contains demaxethasone. It is an intravitreal implant that delivers a sustained release of demaxaethasone (700ml) to the retina and vitreous humour. Ozurdex can improve visual acuity and macular thickness. It is used to treat macular edema, Retinal vein occlusion and non-infectious uveitis (posterior). Iluvien Recently approved as a treatment for DME (Diabetic Macular Edema) It weighs 0.18mg and dispenses 0.2µg of the drug daily It is the only drug therapy for DME treatment In phase II trials for the treatment of wet and dry AMD and RVO Active ingredient is fluocinolone acetonide DELIVERY injected intra-vitreally using a 25 gauge needle. minimally invasive procedure, no need for suture Non-erodible insert Designed to deliver drug for up to 3 years Easier to deliver then retisert because of its smaller size Diseases of the Eye Age-related Macular Degeneration (AMD) : Damage to retina by accumulation of drusen can cause loss of central vision. Diabetic Retinopathy is a type of retinal damage that can lead to blindness caused by microvascular changes due to diabetes mellitus. Glaucoma is caused by damage to the optic nerve by loss of retinal ganglion cells and increased fluid pressure in the eye. CMV Retinitis is a chronic, infection of the retina caused by the cytomegalovirus. Predominantly affects immunosuppressed individuals and estimated to affect 15-40% of AIDS patients. Diabetic Macular oedema (DME) is the most common cause of visual loss and is characterised by accumulation of extracellular fluid in the macular which occurs after the break down of the blood-retinal barrier due to dilated hyper-capillaries and micro-aneurysms.. Uveitis is the swelling and irritation of the uvea (anterior segment) and can be caused by autoimmune disorders, infection or exposure to toxins. Retinal Detachment detachment-symptoms-treatment-surgery-recovery.html Vitreous Haemorrhage hemorrhage.html Cystoid Macular Oedema Endophthalimitis /endophthalmitis.html Implant Type:BiodegradableNon- Biodegradable Pros:Will be cleared from body naturally, no need for surgical removal. Drug release can be controlled more precisely. Cons:Control of drug release from degradable systems is more difficult. Must be surgically removed. Non-Biodegradable Implants Biodegradable Implant Vitrasert Structure Dynamic:Static: Tear Dilution- max. only 30µl tear volume comfortably accommodated. In eye when the average eye drop is 50 µl in volume – inevitable spillage! Naso-lacrimal duct- when tears exceed normal tear volume of 7-10 µl Systemic Removal – the conjunctiva is highly vascularised and any drug permeating it is rapidly removed by the systemic circulation and eventually transported to the GIT. Cornea-Hydrophobic and hydrophilic layers connected by tight junctions and containing efflux pumps inducing multidrug resistance. (p-glycoprotein and MRP) Sclera-Opaque matrix of proteoglycans and collagen that acts as a filter with preferred permeability for small, hydrophilic and positively charged molecules due to it’s structure. Blood-Ocular Barriers –the blood-retinal barrier arises from the retinal pigment epithelium prevents transfer of molecules between itself and choroidal blood with tight junctions and according to some studies show P-gp efflux pumps present also. Introduction Implants. The way Forward? Side Effects and Complications of Implants ProsCons Self-administrationPatient compliance poor Easy accessibilityLimited Bioavailability due to the various anatomical barriers of the eye Localised to the eye. Limited adverse systemic effects Doesn’t reach the posterior of the eye ProsCons Doesn’t need to be administered daily so once implant is in, patient compliance is not an issue Administration is an invasive procedure Can deliver drug for up to 3 years (depending on the implant) most implants need to be surgically implanted in clinical settings Biodegradable implants do not need to be taken out after the drug is dispensed Non-degradable implants will require a surgical procedure to extract Dispersion of the drug via implant is localised Most implants are specific to the drugs they carry, so they cannot be used widely to treat every disease ProsCons Non-invasive method of drug deliveryThere is a potential for reduced time of effect for therapeutics due to dilation and degradation of the drug before reaching the target site. Method of accessing the posterior segment of the eye Not localised to the eye. Difficulty in crossing the blood-retinal barrier to get to the posterior segment Easy for drugs to penetrate the choroid once in the blood Risk of adverse effect due to accumulation of drug in other tissues Topical administration Implants Systemic administration Implants Vs. other Deliveries ProsCons Longer duration than dropsInjections must be given several times a month More drug availability to the eye than systemic drugs Must be administered by a physician Localised to the eye. Limited adverse systemic effects Not as long lasting as implants Intraocular Injections Conclusion Due to the physiology of the eye, ocular drug delivery poses a challenge. For this reason, routes which are favoured by patients for ease of administration are not the most effective forms of treatment. The bioavailability of drugs administered topically and systemically reaches a level which is far inferior to implant bioavailability. Intraocular injections also fall short of implants as they must be given every few weeks by a physician which is time consuming and unpleasant for patients. Until these issues are addressed or new less invasive techniques are developed, ocular implants appear to be the most favourable choice for chronic diseases of the eye. They are long lasting and eliminate patient compliance issues while bypassing many of the barriers which limit bioavailability of other administration routes. Ref: Ref: html References: "Ocular Drug Delivery" Authors : Ripal Gaudana, Hari Krishna Ananthula, Ashwin Parenky, and Ashim K. Mitra ( "THE CHALLENGES OF OPHTHALMIC DRUG DELIVERY: A REVIEW” AUTHORS: SINGH, AHMAD, HEMING ( Critical appraisal of the clinical utility of the dexamethasone intravitreal implant (Ozurdex®) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion Annie Chan, Loh-Shan Leung, and Mark S Blumenkranz (Published online 2011 July 26), Dexamethasone intravitreal implant for the treatment of noninfectious uveitis Rebecca S Hunter and Ann-Marie Lobo (published online 2011 November 11), Shalin, S et al. (2010). Drug delivery to the posterior segment of the eye for pharmacologic therapy. Expert Rev Ophthalmol.. 1 (5(1)), 75–93, Kompella, Uday B et al. (2010). Recent advances in ophthalmic drug delivery. Ther Deliv. 1 (3), , Short, Brian G. (2008). Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations. Toxicologic Pathology. 36 (49), Iluvien ™ : a new sustained delivery technology for posterior eye disease Frances E Kane †, Judith Burdan, Antonio Cutino & Kenneth E.Green †Alimera Sciences, Inc. Above : Implant on day 3 (A) and day 180 (B) Ozurdex is made using a solid biodegradable polymer. This polymer is composed of an apolylactic acid-co-glycolic acid (PLGA) matrix. This dissolves completely in vivo. The products of this are lactic acid and glycolic acid, which are converted into Carbon dioxide and Water vaids/oit/case7/fig7d.html Pros: In addition, to having similar actions as other implants, studies show treatment with vitrasert significantly slows down the median time to disease progression in comparison to I.V. ganciclovir therapy. Con: Increased risk of developing contralateral eye retinitis and systemic CMV. IOVS- Investigative Ophthalmology & Visual Science (An ARVO Journal) on com/warning-diabetic-peripheral- neuropathyhttp://diabetestesting- 578.com/warning-diabetic-peripheral- neuropathy doctor/diabetes-and-cataract-surgery /main/art.asp?articlekey= dule7/html/Mod7Case7Ref.html