Abstract
Introduction: :
Moli1901, a Type B lantibiotic, is being investigated for the treatment of dry eye. Moli1901 is considered a "secretagogue" because it stimulates secretion of water and chloride in the epithelium. Its molecular target is the phospholipid phosphatidylethanolamine (PE) present in the cellular membranes. Moli1901 binds to the polar head of PE which induces changes in intracellular calcium levels, activating calcium–dependent chloride channels. These channels generate an output of chloride and water, increasing hydration. It is hypothesized that Moli1901 administered topically will hydrate the eye surface and/or the epithelial tissues of the eye structure while normalizing mucus hydration, thus preventing the irritation and possible ocular injury associated with dry eye syndrome.
Purpose: :
To evaluate preliminary efficacy and safety and tolerability of Moli1901 in preclinical models.
Methods: :
In a 1–day study, New Zealand white rabbits received one instillation of Moli1901 0.15%, Moli1901 0.3%, or vehicle (3% glycerin aqueous solution). In a 28–day study, rabbits were exposed to 3 concentrations of Moli1901––high dose (0.2%), middle dose (0.1%), and low dose (0.05%)––or its vehicle four times daily.
Results: :
A single administration of Moli1901 at 0.15% and 0.3% concentrations was efficacious in increasing tear production as measured by pre– and post–treatment Schirmer’s tests. In 28–day dosing with 0.2%, 0.1%, and 0.05% concentrations, dose–response relationships were observed in clinical observations, ocular scores, ophthalmic examinations, and histopathology. Possible adverse observations, changes in the corneas of 2 of 4 high–dose treated rabbits and ocular scores in the iris of all high–dose treated rabbits, reverted to normal during the recovery period post treatment. The no observed adverse events level (NOAEL) was determined to be equivalent to dosing with 0.1% Moli1901 QID in both eyes in this 28 day study.
Conclusions: :
Moli1901 induces lachrymal secretion in rabbits through a mechanism of action that postulates increases in chloride channel permeability and water transport. In dry eye, this same property regarding chloride channel permeability, particularly its effect of increased epithelial chloride secretion, suggests that treatment with Moli1901 may have a beneficial effect by stimulating tear secretion and by restoring the natural tear film. Moli1901 at concentrations up to 0.1% was found to be safe and tolerable dosed QID for up to 28 days in rabbits.
Keywords: cornea: tears/tear film/dry eye • cornea: epithelium • drug toxicity/drug effects