Experimental Model Development, Translational Pharmacology

Histamine-Induced Conjunctivitis and Breakdown of Blood–Tear Barrier in Dogs: A Model for Ocular Pharmacology and Therapeutics


https://www.frontiersin.org/articles/10.3389/fphar.2019.00752/full

Mild - Moderate - Severe conjunctivitis

Conjunctival inflammation disturbs the blood–tear barrier and thus affects the tear film stability and composition. We aimed to develop a non-invasive and reliable method to induce conjunctivitis in dogs, a large animal model for translational work on ocular surface disease in humans. Six beagle dogs underwent a randomized, vehicle-controlled, balanced crossover trial—on six separate days, one eye received topical artificial tears (vehicle), while the other eye received one of six concentrations of histamine solution (0.005–500 mg/ml). At sequential times after eyedrop administration, a conjunctivitis score was given to each eye based on the degree of palpebral and bulbar conjunctival hyperemia and chemosis, ocular pruritus, and discharge. Total protein content (TPC) and serum albumin were quantified in tear fluid at baseline and 20 min. Additionally, 13 dogs presenting for various ophthalmic diseases with associated conjunctivitis were examined. Experimentally induced conjunctivitis developed rapidly (<1 min) following topical histamine administration and lasted for 1–3 h (four lowest doses) to 6–8 h (two highest doses). The severity of conjunctivitis was dose-dependent. Histamine was overall well tolerated, although transient blepharitis, aqueous flare, and ocular hypertension occurred in a few dogs receiving histamine ≥375 mg/ml. TPC and serum albumin levels increased in tears of eyes receiving histamine ≥1.0 mg/ml, being significantly higher than vehicle and baseline in eyes receiving histamine ≥375 mg/ml. Lacrimal albumin levels were also increased in 13 dogs with naturally acquired conjunctivitis, up 2.7–14.9 fold compared to contralateral healthy eyes. Histamine-induced conjunctivitis represents a robust model for translational work on the ocular surface given the low cost, non-invasiveness, self-resolving nature, ability to adjust the duration and severity of the disease, and shared features with naturally occurring ocular diseases. Histamine solutions of 1, 10, and 375 mg/ml induce mild, moderate, and severe conjunctivitis in dogs, respectively. Leakage of serum albumin in tear fluid of eyes with conjunctivitis suggests a breakdown of the blood–tear barrier.

Pharmacokinetic Modeling

Undersampling Bias on Cmax and Tmax Estimation


In Pharmacokinetic studies, researchers use a controlled research environment to determine the biological fate of a pharmaceutical after administration. In practice, this means determining the typical plasma concentration of the drug from the moment of administration until effective elimination of the drug from the body. From this typical profile, researchers can predict useful clinical metrics like the predicted maximum concentration (Cmax) of the pharmaceutical and the time it takes for the drug to reach peak plasma concentration (Tmax ) after administration. (more…)

Translational Pharmacology

A Review of Relevant Therapeutic Targets for the Management of Congestive Heart Failure in Dogs: Present and Future Directions


Canine CHF Therapeutics Review Mochel 2019 v2 Preprint

ABSTRACT

Congestive heart failure (CHF) is a major cause of morbidity and mortality with an increasing prevalence in human and canine populations. Similar to humans, overactivation of the renin-angiotensin aldosterone system is involved in the pathophysiology of CHF in dogs. Current therapeutic strategies for the management of canine CHF include the use of RAAS inhibitors, diuretics and inodilators. The present review summarizes data from our own research on the modulation of the renin-angiotensin cascade in dogs in dogs, together with new findings (including novel therapeutic targets) from the veterinary and the human literature.

Pharmacokinetic Modeling

Nonlinear Mixed-Effects Pharmacokinetic Modeling of the Novel COX-2 Selective Inhibitor Vitacoxib in Dogs


In this manuscript, we use a nonlinear mixed effects (NLME) framework to develop a compartmental model of vitacoxib disposition kinetics in dogs after intravenous (I.V), oral (P.O) and subcutaneous (S.C) dosing. The influence of age, sex, bodyweight and food intake were evaluated as covariates on model parameters to assess the need for dose adjustment of vitacoxib in dogs.

(more…)

Experimental Model Development

A novel in vivo model of conjunctivitis and breakdown of the blood-tear barrier in dogs


This work was presented at the 2018 American College of Veterinary Ophthalmologists Annual Meeting in Minneapolis, MN, USA.

ABSTRACT

Conjunctival inflammation disturbs the blood-tear barrier and thus affects the tear film stability and composition. We aimed to develop a non-invasive and reliable method to induce conjunctivitis in dogs, a large animal model for translational work on ocular surface disease in humans.

(more…)