An eye on the dog as a translational model for ocular pharmacology

Today’s high failure rate in ophthalmic clinical trials can be largely explained by two major shortcomings: (i) the animals routinely studied (rabbits, mice, rats) are not representative of the affected population due to apparent anatomical and physiological differences with humans; and (ii) studies conducted in healthy eyes do not account for physiological disturbances in ocular homeostasis present in diseased eyes. Unlike traditional laboratory animals, diseases in dogs better reflect the complex genetic, environmental, and physiological variation present in humans; however, the translational potential of canine research is currently limited by scarce information on normative data specific to dogs, and the limited means to mimic ocular disease in a reliable and non-invasive manner in this species. The work conducted in the dissertation provides a deeper understanding of the canine ocular surface in health and disease states, investigating laboratory Beagle dogs and canine patients of varied breeds and cephalic conformations. Tear fluid was collected from canine eyes in successive experiments – primarily via Schirmer tear strips but also capillary glass tubes and absorbent sponges – and subsequent bioanalytical tools included fluorophotometry (tear film fluorescence), infrared spectroscopy (total protein content), immunoassays (serum albumin, cytokines, chemokines) and liquid chromatography-mass spectrometry (corticosteroids). Data analysis combined conventional statistical tests with nonlinear mixed-effects mathematical modeling to improve the robustness of the predictions. The main research outcomes of the dissertation work are the following: (i) Normative data were established for canine tear film dynamics, including tear volume (65.3 µL), basal tear turnover rate (12.2%/min) and reflex tear turnover rate (50%/min). In both clinical and research settings, successive lacrimal tests should be spaced by ≥ 10 min in dogs to provide sufficient time for the tear film to replenish. (ii) The volumetric capacity of the canine palpebral fissure was 31.3 µL, approximating the volume of a single eyedrop. Kinetic studies confirmed that a single drop is sufficient for topical administration in dogs, any excess being lost predominantly by blinking and spillage over the periocular skin. (iii) Topical histamine solutions of 1, 10, and 375 mg/mL induced mild, moderate, and severe conjunctivitis in dogs, respectively. The resulting disruption of the blood-tear barrier promoted leakage of plasma compounds (eg., albumin) into the tear film, a finding confirmed in dogs with naturally acquired ocular diseases. This ‘large animal’ model was robust, non-invasive, and self-resolving, providing a unique opportunity to investigate the ocular surface in health and disease. (iv) Acute conjunctivitis increased tear quantity and decreases tear stability, although ocular surface homeostasis was rapidly restored. (v) Corticosteroid levels in the tear film did not change significantly between healthy vs. diseased eyes following oral prednisone administration, although findings may differ for drugs with other physicochemical properties. (vi) Albumin in tears lowered the ocular bioavailability of topically administered drugs, as shown for tropicamide and (to a lesser extent) latanoprost in dogs. The thesis concludes with a comprehensive review of key ocular parameters in humans, dogs, and traditional laboratory species (rabbits, mice, rats), detailing species differences in ocular surface anatomy, physiology, tear film dynamics and tear film composition, and highlighting the benefits of integrating dogs into preclinical studies given striking resemblances between the canine and human eyes (One Health approach)

Efficacité des avermectines contre les acarioses du chien : revue systématique

Les formulations à base d’avermectine sont couramment utilisées en médecine vétérinaire. Cependant, dans la lutte contre les acarioses du chien, beaucoup de ces produits sont utilisés hors AMM. A travers une analyse critique de la littérature scientifique vétérinaire, le but de cette thèse est d'accompagner le praticien dans une démarche scientifique fondée sur la preuve, et de fournir ainsi une synthèse raisonnée sur l’utilisation des avermectines contre les acariens du chien. Les acariens concernés par cette étude sont : Demodex spp., Sarcoptes scabiei, Cheyletiella spp., Otodectes cynotis, Notoedres spp., Straelensia cynotis et Pneumonyssoides caninum

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog.

Mucopolysaccharidosis (MPS) is a metabolic storage disorder caused by the deficiency of any lysosomal enzyme required for the breakdown of glycosaminoglycans. A 15-month-old Boston Terrier presented with clinical signs consistent with lysosomal storage disease including corneal opacities, multifocal central nervous system disease and progressively worsening clinical course. Diagnosis was confirmed at necropsy based on histopathologic evaluation of multiple organs demonstrating accumulation of mucopolysaccharides. Whole genome sequencing was used to uncover a frame-shift insertion affecting the alpha-L-iduronidase (IDUA) gene (c.19_20insCGGCCCCC), a mutation confirmed in another Boston Terrier presented 2 years later with a similar clinical picture. Both dogs were homozygous for the IDUA mutation and shared coat colors not recognized as normal for the breed by the American Kennel Club. In contrast, the mutation was not detected in 120 unrelated Boston Terriers as well as 202 dogs from other breeds. Recent inbreeding to select for recessive and unusual coat colors may have concentrated this relatively rare allele in the breed. The identification of the variant enables ante-mortem diagnosis of similar cases and selective breeding to avoid the spread of this disease in the breed. Boston Terriers carrying this variant represent a promising model for MPS I with neurological abnormalities in humans

MicroPulse™ transscleral cyclophotocoagulation in the treatment of canine glaucoma: Preliminary results (12 dogs)

Objective: To describe the clinical application and effect of MicroPulse™ transscleral cyclophotocoagulation (MP‐TSCPC) in dogs with glaucoma. Animals studied: Twelve dogs with primary (n = 8) or secondary (n = 4) glaucoma, aged 2‐13 years (mean ± SD, 7.2 ± 3.8 years). Procedures: MP‐TSCPC was performed under sedation or general anesthesia. Laser duty cycle was 31.3%, laser power varied from 2000‐2800 mW, and each hemisphere was treated for 90‐180 seconds. The probe was applied to each quadrant in a “sweeping motion,” sparing the 3 and 9 o\u27clock positions. Results: The number of MP‐TSCPC procedures per eye varied from 1 to 3 (1.4 ± 0.7). Intraocular pressure (IOP) was controlled (\u3c25 mm Hg) in 11/12 dogs (92%) within 1‐15 days post‐operatively. The IOP control at 1 month and the duration between repeated procedures were significantly greater in eyes treated with high energy laser (2800 mW) compared to 2000‐2500 mW. Long‐term follow‐up (315.3 ± 100.7 days) showed controlled IOP in 5/12 (42%) and vision retention in 4/8 (50%) dogs. In unsuccessful cases, loss of IOP control or vision loss occurred within 3‐245 days (109.1 ± 93.7 days) and 28‐261 days (114 ± 101.6 days), respectively, resulting in a salvage procedure in 6 dogs. Complications were as follows: corneal hypoesthesia (92%), anterior uveitis (67%), post‐operative ocular hypertension (50%), neurotrophic corneal ulcer (25%), keratoconjunctivitis sicca (8%), and rubeosis iridis (8%). Conclusions: MP‐TSCPC is a viable tool for managing canine glaucoma, although further studies are required to improve the long‐term effect and reduce the complication rate

Lack of effect of a topical regenerative agent on re-epithelialization rate of canine spontaneous chronic corneal epithelial defects: A randomized, double-masked, placebo-controlled study

Spontaneous chronic corneal epithelial defects (SCCEDs) are characteristic ulcers in dogs that are refractory to healing. The aim of the study was to evaluate the use of a topical regenerative agent to promote healing of SCCEDs. Nineteen dogs (20 eyes) were randomized to receive either regenerative agent (10 eyes) or placebo (10 eyes) every 48 h following corneal debridement, which was repeated 1 week later if the SCCED had not yet healed. The mean ± standard deviation time to re-epithelialization was 17.3 ± 12.8 days for the group treated with a topical regenerative agent and 19.3 ± 11.7 days for the group treated with a placebo; the cumulative healing rates were not statistically different (P \u3e 0.650). A positive association was found between the initial size of the ulcer and the time to re-epithelialization (r = 0.555, P = 0.011). Although well tolerated by dogs, there was no therapeutic advantage in using a topical regenerative agent for re-epithelialization of SCCEDs

Altered Corneal Innervation and Ocular Surface Homeostasis in FHV-1-Exposed Cats: A Preliminary Study Suggesting Metaherpetic Disease

Metaherpetic disease is recognized in humans affected by herpes simplex virus-1 but is not reported in cats affected by feline herpesvirus-1 (FHV-1) despite the high prevalence of herpetic disease in this species and strong similarities in viral biology between alphaherpesviruses of humans and cats. This preliminary work evaluated cats naïve to FHV-1 (n = 9 cats, 18 eyes; control population) and cats naturally exposed to FHV-1 (n = 4 cats, 7 eyes), as confirmed by serologic testing and review of medical records. Antemortem assessment included clinical scoring, blink rate, corneal aesthesiometry, tear film breakup time (TFBUT), and Schirmer tear test-1 (STT-1) with or without the nasolacrimal reflex. Post-mortem assessment involved confocal microscopy of the corneas and evaluation of corneal nerves with ImageJ. Groups were compared with Student\u27s t-tests and results are presented as mean ± standard deviation. Compared to control, herpetic cats had significantly higher (P ≤ 0.010) clinical scores (0.2 ± 0.4 vs. 4.6 ± 2.8) and response to nasolacrimal stimulation (7.8 ± 10.8% vs. 104.8 ± 151.1%), significantly lower (P \u3c 0.001) corneal sensitivity (2.9 ± 0.6 cm vs. 1.4 ± 0.9 cm), STT-1 (20.8 ± 2.6 mm/min vs. 10.6 ± 6.0 mm/min), TFBUT (12.1 ± 2.0 s vs. 7.1 ± 2.9 s), and non-significantly lower blink rate (3.0 ± 1.5 blinks/min vs. 2.7 ± 0.5 blinks/min; P = 0.751). All parameters evaluated for corneal nerves (e.g., nerve fiber length, branching, occupancy) were notably but not significantly lower in herpetic vs. control cats (P ≥ 0.268). In sum, cats exposed to FHV-1 had signs suggestive of corneal hypoesthesia and quantitative/qualitative tear film deficiencies when compared to cats naïve to the virus. It is possible these are signs of metaherpetic disease as reported in other species