1. 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, Constance Gaya Cremers, Sarah Killeen, Melissa MacPherson. 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: http://medgadget.com/2009/02/eye_imp lant_prevents_lost_vision.html Ocular drug barriers:  FDA approved 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.  Implant holds 4.5-5 mg of the prodrug which is released at a rate of approx. 1- 1.5 µg/hr over 5-8 months.  The 4 mm 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 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 300- 400ng 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 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) : Diabetic Retinopathy: Glaucoma: CMV Retinitis: Diabetic Macular Oedema (DME): Uveitis: Retinal Detachment http://www.beltina.org/health-dictionary/retinal- detachment-symptoms-treatment-surgery-recovery.html Vitreous Haemorrhage http://medweb.bham.ac.uk/easdec/vitreous_ hemorrhage.html Cystoid Macular Oedema http://www.mvretina.com/education/12.html Endophthalimitis http://www.primehealthchannel.com /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 barriers Limited adverse systemic effectsDoes not reach the posterior of the eye ProsCons Does not need to be administered daily.Administration is an invasive procedure Some can deliver drug for up to 3 yearsSurgically implanted. Some don’t need surgical extractionSome need surgical procedure to extract Localised dispersion of the drugMost are specific to the drugs they carry. ProsCons Non-invasive method of drug deliveryPoor bioavailability to eye. Treats the posterior segment of the eyeDifficulty crossing the blood-retinal barrier. Easy for drugs to penetrate the choroid.Higher risk of adverse effect Topical administration Implant Administration Systemic administration Implants Vs. Other Deliveries ProsCons Longer duration than dropsMust be given several times a month More drug availability to eye than systemic drugs Must be administered by a physician Limited adverse systemic effectsNot as long lasting as implants Intraocular Injections Conclusion Ref: http://computerkiddoswiki.pbworks.com/w/page/16304712/Five%20Senses Ref: http://www.engagesite.com/healthwork. html References: http://www.oculist.net/downaton502/prof/ebook/duanes/pages/v3/v3c028a.html, http://www.carolinaretinacenter.com/PE_article5.html, http://www.bausch.co.nz/en_US/ecp/pharma/product/vitrasert.aspx, "Ocular Drug Delivery" Authors : Ripal Gaudana, Hari Krishna Ananthula, Ashwin Parenky, and Ashim K. Mitra (http://www.helsinki.fi/farmasia/biofarmasia/opiskelu/provopinnot/bjktentti/ocular+PK.pdf) "THE CHALLENGES OF OPHTHALMIC DRUG DELIVERY: A REVIEW” AUTHORS: SINGH, AHMAD, HEMING (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895432/), 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), http://www.bauschvrx.com/, http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500068245.pdf, 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), 435-456, Short, Brian G. (2008). Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations. Toxicologic Pathology. 36 (49), 49-64. http://www.oculist.net/downaton502/prof/ebook/duanes/pages/v3/v3c028a.htmlhttp://www.carolinaretinacenter.com/PE_article5.htmlhttp://www.bausch.co.nz/en_US/ecp/pharma/product/vitrasert.aspxhttp://www.helsinki.fi/farmasia/biofarmasia/opiskelu/provopinnot/bjktentti/ocular+PK.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895432/http://www.bauschvrx.com/http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500068245.pdf.http://www.psivida.com/products-iluvien.htmlhttp://www.psivida.com/products-iluvien.html 1.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 http://tpx.sagepub.com/content/36/1/49.full http://depts.washington.edu/hivaids/oit/case7/fig7d.ht ml Pros: Slows down the median time to disease progression in comparison to I.V. Con: Increased risk of developing contralateral eye retinitis and systemic CMV. IOVS- Investigative Ophthalmology & Visual Science (An ARVO Journal) http://en.wikipedia.org/wiki/Macular_degeneration http://diabetestesting-578.com/warning-diabetic- peripheral-neuropathyhttp://diabetestesting-578.com/warning-diabetic- peripheral-neuropathy http://od.pcli.com/articles/a-new-doctor/diabetes-and-cataract- surgery http://www.otm1.com/page/services_otm http://www.medicinenet.com/script/main/art.asp?articlekey= 121809 http://www.eyesite.ca/7modules/Module7/html/Mo d7Case7Ref.html 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.