Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin-like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin-treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.
In
order to study the role of S1PRs in inflammatory skin disease,
S1PR modulators are dosed orally and topically in animal models of
disease. The topical application of S1PR modulators in these models
may, however, lead to systemic drug concentrations, which can complicate
interpretation of the observed effects. We set out to design soft
drug S1PR modulators as topical tool compounds to overcome this limitation.
A fast follower approach starting from the drug ponesimod allowed
the rapid development of an active phenolic series of soft drugs.
The phenols were, however, chemically unstable. Protecting the phenol
as an ester removed the instability and provided a compound that is
converted by enzymatic hydrolysis in the skin to the phenolic soft
drug species. In simple formulations, topical dosing of these S1PR
modulators to mice led to micromolar skin concentrations but no detectable
blood concentrations. These topical tools will allow researchers to
investigate the role of S1PR in skin, without involvement of systemic
S1PR biology.
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