EFFECT OF ENVIRONMENT AND CLOZAPINE ON BASAL AND
STIMULATED MEDIAL PREFRONTAL GABA RELEASE IN TWO
Adedoyin Awodele,RAT
Faye Carrington,
Alanna
Cavanagh,
Constance
Gaya
Cremers,
Sarah
Killeen,
Melissa
MODELS OF SCHIZOPHRENIA
MacPherson.
Pharmacology, UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland.
Introduction
Ocular drug barriers:
Why Implants?
•Provide sustained drug delivery to the posterior
or anterior segment of the eye.
Dynamic:
Static:
•Localised drug delivery, therefore reduced dose.
•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.
•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
Diseases of the Eye
•Age-related Macular Degeneration (AMD) :
•Diabetic Retinopathy:
http://diabetestesting-578.com/warning-diabeticperipheral-neuropathy
http://en.wikipedia.org/wiki/Macular_degeneration
•Glaucoma:
•Diabetic Macular Oedema (DME):
What are they?
•.Usually made of polymers that release a drug over a
prolonged period of time. There are two types:
Implant Type:
Biodegradable
http://www.otm1.com/page/services_otm
NonBiodegradable
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.
http://od.pcli.com/articles/a-new-doctor/diabetes-and-cataractsurgery
•CMV Retinitis:
•Uveitis:
http://www.eyesite.ca/7modules/Module7/html/Mo
d7Case7Ref.html
http://www.medicinenet.com/script/main/art.asp?articlekey=
121809
Ref: http://computerkiddoswiki.pbworks.com/w/page/16304712/Five%20Senses
Vitrasert
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.
Surgical 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
•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 300400ng 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.
Structure
Silicone cup
Top View
containing
drug
2mm
Iluvien
.http://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.
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
http://www.primehealthchannel.com
/endophthalmitis.html
Side Effects and
Complications of
Implants
Vitreous Haemorrhage
http://medweb.bham.ac.uk/easdec/vitreous_
hemorrhage.html
Release
orifice
PVA
structure
tab
Retinal Detachment
Cystoid Macular Oedema
http://www.beltina.org/health-dictionary/retinaldetachment-symptoms-treatment-surgery-recovery.html
http://www.mvretina.com/education/12.html
Implants Vs. Other Deliveries
Implant Administration
Pros
Cons
Does not need to be administered daily.
Administration is an invasive procedure
Some can deliver drug for up to 3 years
Surgically implanted.
Some don’t need surgical extraction
Some need surgical procedure to extract
Localised dispersion of the drug
Most are specific to the drugs they carry.
Topical administration
5mm
•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
•The release orifice is
separated from the drug
by a PVA membrane.
•The structure is held
together with silicone
glue
Side View
Endophthalimitis
•0.59mg tablet is held in
a silicone elastomer cup.
3mm
Ref:
http://www.engagesite.com/healthwork.
html
Ozurdex
Biodegradable Implant
Non-Biodegradable Implants
http://tpx.sagepub.com/content/36/1/49.full
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. 11.5 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).
Implants: The Way Forward?
Retisert
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 noninfectious uveitis (posterior).
Pros
Cons
Self-administration
Patient compliance poor
Easy accessibility
Limited Bioavailability due to barriers
Limited adverse systemic effects
Does not reach the posterior of the eye
Systemic administration
Pros
Cons
Non-invasive method of drug delivery
Poor bioavailability to eye.
Treats the posterior segment of the eye
Difficulty crossing the blood-retinal barrier.
Easy for drugs to penetrate the choroid.
Higher risk of adverse effect
Intraocular Injections
IOVS- Investigative Ophthalmology &
Visual Science (An ARVO Journal)
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
Above : Implant on day 3 (A) and day 180 (B)
Pros
Cons
Longer duration than drops
Must be given several times a month
More drug availability to eye than systemic
drugs
Must be administered by a physician
Limited adverse systemic effects
Not as long lasting as implants
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.
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.