Pharmacodynamic effects of a novel prokinetic 5-HT4receptor agonist, ATI-7505, in humans

ATI-7505, an investigational 5-HT4 receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T1/2, colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T1/2. Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T1/2 (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T1/2 (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency

Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tearflow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on \-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches