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Pharmacological Modulation of Gap Junction Function with the Novel Compound Rotigaptide: A Promising New Principle for Prevention of Arrhythmias
Author(s) -
Kjølbye Anne Louise,
Haugan Ketil,
Hennan James K.,
Petersen Jørgen S.
Publication year - 2007
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00123.x
Subject(s) - medicine , tolerability , atrial fibrillation , gap junction , ventricular tachycardia , cardiology , clinical trial , myocardial infarction , drug , ventricular fibrillation , fibrillation , amiodarone , ischemia , cardiotoxicity , efficacy , pharmacology , adverse effect , toxicity , intracellular , biology , microbiology and biotechnology
Existing anti‐arrhythmic therapy is hampered by lack of efficacy and unacceptable side effects. Thus, ventricular tachycardia and fibrillation remains the strongest predictor of in‐hospital mortality in patients with myocardial infarction. In atrial fibrillation, rhythm control with conventional ion channel blockers provide no therapeutic benefit relative to rate control. Several lines of research indicate that impaired gap junctional cell‐to‐cell coupling between neighbouring cardiomyocytes is critical for the development of cardiac re‐entry arrhythmias. Rotigaptide is the first drug that has been developed to prevent arrhythmias by re‐establishing gap junctional intercellular communication. During conditions with acute cardiac ischaemia, rotigaptide effectively prevents induction of both ventricular and atrial tachyarrhythmia. Moreover, rotigaptide effectively prevents ischaemia reperfusion arrhythmias. At the cellular level, rotigaptide inhibits ischaemia‐induced dephosphorylation of Ser297 and Ser368, which is considered important for the gating of connexin43 gap junction channels. No drug‐related toxicity has been demonstrated at plasma concentrations 77,000 times above therapeutic concentrations. In rats and dogs, rotigaptide reduces infarct size following myocardial infarction. A series of phase I trials has been completed in which rotigaptide has been administered intravenously to ~200 healthy persons. No drug‐related side effects have been demonstrated in healthy human beings. Clinical safety, tolerability and efficacy in patients with heart disease are being evaluated in ongoing clinical trials. Rotigaptide represents a pioneering pharmacological principle with a highly favourable preclinical and clinical safety profile, which makes this molecule a promising drug candidate for the prevention of cardiac arrhythmias.