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Pre-clinical Department
Efficacy
 Animal model of Ocular Angiogenesis / Neovascularization |
Models:
 CORNEAL angiogenesis: sutures or alkali burn
RETINAL angiogenesis / retinopathy of prematurity (ROP): animal model of oxygen-induced retinopathy (OIR)
CHOROIDAL neovascularization: experimental argon laser-induced CNV (choroidal neovascularization)
RETINAL VASCULAR permeability: VEGF-induced fluorescein leakage
Administration: topical ocular application, intraperitoneal injection, subcutaneous application, intravitreous injection, per os
Animals: albino or pigmented rabbits, rats, mice
Evaluation:
glycemia
electroretinography
fluorotron (fluorescein permeation)
angiography (HRA)
length of new vessels
histology: number of new vessels, retina examination (fundus, HRT), cornea examination (HRT), visualization and quantification of morphologic changes in the CNV model (flatmount evaluation)…
Control substance: Dexamethasone
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| Animal models of Ocular Neurodegeneration and Ischemia |
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Models:
retinal ischemia is induced using high intraocular pressure (high IOP or HIOP) model or the suture ligation (SL) of the optic nerve model
photoreceptor apoptosis in an animal model of light-induced retinal degeneration
Administration: topical ocular application, intravenous injection, intraperitoneal injection
Animals: albino or pigmented rabbits, rats
Evaluation:
electroretinography before and during ischemia, and then in reperfusion
electroretinography to evaluate the photodegeneration
histology
Reference substances: calcium channel blocker (ischemia), DMTU (photodegeneration)
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| Animal model of Glaucoma - Ocular Hypertension |
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Models: normotensive, hypertensive (alpha-chymotrypsin, water loading, corticoid administration) rabbits
Administration: topical ocular administration
Animals: albino rabbits
Evaluation: Medtronics tonometer, TonoPen, or Alcon pneumatonograph
Parameters: Intraocular pressure (IOP) versus time
Reference substances: clonidine, timolol, latanoprost
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| Animal model of Ocular Allergy |
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Models: compound 48/80 instillation, histamine instillation, conjunctival allergen challenge model (CAC), endotoxin model (LPS), uveitis
Administration: topical ocular administration or other
Animals: albino or pigmented rabbits, rats, guinea-pigs
Evaluation:
protein concentration in the aqueous humor
extravasation of a dye in eyelids / eyeball or in aqueous humor / iris ciliary body
clinical scoring
mediator concentration (prostaglandin, leukotriene, interleukin or other)
Reference substances: levocabastine, ketotifen, olopatadine, ketorolac
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| Animal model of Ocular Inflammation |
Models: intra and extraocular surgery, AH paracentesis
Administration: topical ocular administration or other
Animals: albino or pigmented rabbits, rats, guinea-pigs
Evaluation:
protein concentration in the aqueous humor measured using a Laser Flare Meter
extravasation of a dye in conjunctiva…
clinical scoring
mediator concentration (prostaglandin, leukotriene, interleukin or other)
Reference substances: indometacine, dexamethasone, diclofenac
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| Animal model of Ocular Infection |
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Models: injection of pathogens
Administration: topical ocular administration or subconjunctival, intrastromal or intravitreal injection
Animals: albino or pigmented rabbits, rats, guinea-pigs
Evaluation:
colony forming units (CFU)
clinical scoring
Reference substances: according to the pathogens (macrolides, fluoroquinolone…)
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| Animal model of Corneal Wound Healing |
Models: complete or incomplete corneal epithelium debridement induced by mechanical or chemical means
Administration: topical ocular administration or other
Animals: albino or pigmented rabbits, rats
Evaluation:
fluorescein test and image analysis
clinical scoring
Reference substances: corticosteroids
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| Animal model of Diabetic Retinopathy |
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Model: streptozotocin-induced diabetes (STZ), alloxan-induced diabetes (in validation process)
Administration: topical ocular administration, i.v., i.p.
Animals: albino or pigmented rats, rabbits
Evaluation:
Glycemia
Angiography (HRA)
Electroretinography (ERG)
Histology
Fundus (slit lamp, HRT)
Reference substances: none
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| Animal model of Allergic and Inflammatory Conjunctivitis |
Model of Non-IgE- mediated Allergic conjunctivitis: compound 48/80 instillation
Administration: topical ocular administration or other
Animals: rats, guinea-pigs
Evaluation:
assessment of clinical conjunctival edema
blood to tissue extravasation of a dye
histology (neutrophil, eosinophil, T cells infiltration)
Reference substances: levocabastine
Model of IgE- mediated Allergic conjunctivitis: sensitization followed by topical challenge with ovalbumin
Administration: topical ocular administration or other
Animals: mice, rats, guinea-pigs
Evaluation:
clinical scoring : lids swelling and edema
blood to tissue extravasation of a dye
histology (eosinophil, T cells infiltration)
Reference substances: ketotifen, olopatadine
Model of Non-allergic conjunctivitis: anterior uveitis using passive ocular anaphylaxis models
Administration: topical ocular administration or other
Animals: albino rabbits
Evaluation:
blood to tissue extravasation of a dye in eyelids / eyeball or in aqueous humor / iris ciliary body
clinical scoring
mediator concentration (prostaglandin, leukotriene, interleukin or other)
Reference substances: ketorolac tromethamine
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Safety
| Corneal Anesthesia
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Guidelines: EMEA (CPMP) note for guidance on non-clinical local tolerance testing of medicinal products (adopted February 2001) CMPM/SWP/2145/00
Formulation: eyedrop, gel, ointment, cream, …
Administration: topical, iontophoresis…
Animals: albino rabbits
Evaluation: Cochet Bonnet´ esthesiometer
Parameters: number of mechanical stimuli necessary to induce a blinking reflex within 1 hour
Reference substances: oxybuprocaine / tetracaine
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| Lacrimation
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Guidelines: EMEA (CPMP) note for guidance on non-clinical local tolerance testing of medicinal products (adopted February 2001) CMPM/SWP/2145/00
Administration: topical, iontophoresis…
Animals: albino rabbits
Evaluation: Schirmer strips
Parameters: mm of tears collected in 5 min
Reference substances: pilocarpine
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| Pupillary diameter
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Guidelines: EMEA (CPMP) note for guidance on non-clinical local tolerance testing of medicinal products (adopted February 2001) CMPM/SWP/2145/00
Administration: topical, iontophoresis…
Animals: albino rabbits
Evaluation: graduated rule
Parameters: measurement in mm versus time
Reference substances: pilocarpine or atropine
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| Acute tolerance |
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Guidelines: European Commission Directive # 92/69/EC (July 31, 1992) Offic. J. Eur. Commun. 1992; 35, L383: 127-131
Administration: topical ocular administration: 1 x 100 µl
Animals: albino rabbits: 3 per group
Evaluation: Draize test at 5 min, 60 min, 1, 2 and 3 days (4 and 7 days if necessary)
Groups: test article, vehicle (when applicable), control substance
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| (Sub-)Chronic tolerance
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Guidelines: European Commission Directive # 92/69/EC (July 31, 1992) Offic. J. Eur. Commun. 1992; 35, L383: 144-148
Administration: topical ocular application, intravitreal injection, subconjunctival injection, subtenon injection, retrobulbar injection, periocular injection, intracameral injection, intracameral, subretinal, intrascleral, transscleral, intrastromal, iontophoresis…
Animals: albino rabbits: 5 males and 5 females per group
Dosage: multiple administration for 28 days or more (a x 50 µl per day)
Evaluation:
Daily: Draize scale
Weekly: McDonald-Shadduck scale and body weight
Daily or weekly: food and water consumptions, autopsy, main organ weight and ocular histology. Hematology, blood biochemistry, ERG, IOP, HRT, toxicokinetics, organ histology will be performed if applicable
Groups: test article, vehicle (when applicable), control substance, reference substance (when applicable).
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Pharmacokinetics
Formulation: eyedrop, eyegel, ointment, insert, particule, implant, patch, cream, …
Administration: topical ocular application, subconjunctival injection, subtenon injection, retrobulbar injection, periocular injection, intracameral injection, intravitreal injection, subretinal injection, intrascleral, transscleral, intrastromal, intravenous, intraperitoneal, intramuscular, iontophoresis …
Animals: rabbits, rats, guinea-pigs, mice (albino and pigmented)
Sampling/Microdissection: tears, eyelids, palpebral or bulbar conjunctiva, nictitating membrane, extra ocular muscles, lacrimal or harderian gland, nasal lacrimal duct, cornea, aqueous humor, iris, ciliary body, lens, vitreous, retina (R), choroid (CH), sclera (SC), optic nerve, whole blood, plasma, urine, feces etc.
Detection:
non radioactive: LC-MS, HPLC UV, EC, refractometric and fluorescence detection, ELISA
radioactive: 14C, 3H, 125I, 51Cr
Parameters: Tmax, Cmax, AUC, % of applied dose, t½
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Albino rat
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Pigmented rat
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