lu-208075 and Renal-Insufficiency

Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms.. This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research.. Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan. The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed.. The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg (P = 0.003) to 38.1 m with ambrisentan 5 mg (P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg (P = 0.022) to 59 m with ambrisentan 5 mg (P

Topics: Animals; Drug Interactions; Endothelin A Receptor Antagonists; Female; Hepatic Insufficiency; Humans; Hypertension, Pulmonary; Lactation; Male; Phenylpropionates; Pregnancy; Pyridazines; Renal Insufficiency

Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET)-system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Ambrisentan (LU 208075), a selective ET(A)-receptor antagonist, is an orally active diphenyl propionic acid derivative. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. The pharmacological properties and data from the experimental investigations suggest additional possible uses of ambrisentan in the prevention of reperfusion injury after organ transplantation and in restenosis following coronary artery dilatation. Furthermore, the pharmacological profile of ambrisentan indicates that this drug may also be suitable in the treatment of cerebrovascular disorders. In the present article basic investigations, animal studies and clinical trials with ambrisentan are reviewed. This review may help to define pathophysiological conditions, in which ambrisentan could be indicated and further evaluated in appropriate preclinical and clinical trials.

Topics: Animals; CHO Cells; Clinical Trials as Topic; Cricetinae; Cricetulus; Endothelin A Receptor Antagonists; Humans; Myocardial Ischemia; Phenylpropionates; Pyridazines; Renal Insufficiency; Structure-Activity Relationship