 | This articleis written like apersonal reflection, personal essay, or argumentative essay that states a Wikipedia editor's personal feelings or presents an original argument about a topic. Pleasehelp improve it by rewriting it in anencyclopedic style.(March 2011) (Learn how and when to remove this message) |
 | |
| Names | |
|---|---|
| Preferred IUPAC name Propan-2-yl 2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate | |
| Other names SSR149744C | |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider |
|
| ECHA InfoCard | 100.211.855 |
| UNII | |
| |
| |
| Properties | |
| C34H47NO4 | |
| Molar mass | 533.753 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Celivarone is anexperimental drug being tested for use in pharmacologicalantiarrhythmic therapy.[1]Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms likepalpitations,dizziness,fainting, and even death.[2] They can manifest as slow (bradycardia) or fast (tachycardia)heart rate, and may have a regular or irregular rhythm.[2]
The causes of cardiac arrhythmias are numerous, from structural changes in theconduction system (thesinoatrial andatrioventricular nodes, or His-Purkinje system) andcardiac muscle,[2] tomutations in genes coding forion channels of theheart. Movement of ions, particularlyNa+,Ca2+ andK+, causesdepolarizations ofcell membranes in node cells, which are then transmitted to cardiac muscle cells to induce contraction. After depolarization, the ions are moved back to their original locations, leading to repolarization of the membrane and relaxation.[3] Disruptions in ion flow affect the heart's ability to contract by altering the resting membrane potential, affecting the cell's ability to conduct or transmit anaction potential (AP), or by affecting the rate or force of contraction.[3]
The specific molecular changes involved in arrhythmias depend on the nature of the problem. Ion channel mutations can alterprotein conformation, and so change the amount of current flowing through these channels. Due to changes inamino acids and binding domains, mutations may also affect the ability of these channels to respond to physiological changes in cardiac demand.[4] Mutations resulting in loss of function of K+ channels can result in delayed repolarization of the cardiac muscle cells. Similarly, gain of function of Na+ and Ca2+ channels results in delayed repolarization, and Ca2+ overload causing increased Ca2+ binding to cardiactroponin C, moreactin-myosin interactions and causing an increasedcontractility, respectively.[3] Mutations cause many arrhythmic conditions, includingatrial fibrillation (AF),atrial flutter (AFl), andventricular fibrillation (V-Fib).[5][6][7] Arrhythmias can also be induced by altered activity of thevagus nerve and activation ofβ1 adrenergic receptors.[8]
Celivarone is a non-iodinatedbenzofuran derivative, structurally related toamiodarone, a drug commonly used to treat arrhythmias.[1] Celivarone has potential as an antiarrhythmic agent, attributable to its multifactorial mechanism of action; blockingNa+,L-type Ca2+ and many types ofK+ channels (IKr,IKs,IKACh andIKv1.5), as well as inhibiting β1 receptors, all in dose-dependent manners.[1][9] The mechanisms by which celivarone modifies ion flow through these channels is unknown, but hearts demonstrate longer PQ intervals and decreased cell shortening, indicative of blockedL-type Ca2+ channels, depressed maximum current with each action potential with no change in theresting membrane potential, caused by blocked Na+ channels, and longer action potential duration due to K+ channel blocks.[1][10] Celivarone is therefore described as having class I, II, III, and IV antiarrhythmic properties.[1][10]
Celivarone displays some atrial selectivity, suggesting it may be most effective at targeting atrial arrhythmias like atrial fibrillation and atrial flutter.[1][9][10][11] These conditions are characterized by rapid atrial rates, 400–600 bpm for atrial fibrillation and 150–300 bpm for atrial flutter.[2] Studies have shown celivarone is capable of cardioversion, maintaining normalsinus cardiac rhythms,[1][10] being effective inhypokalemic, vasotonic, and stretch-induced atrial fibrillation, as well as ischemic and reperfusion ventricular fibrillation.[10] Since it affects multiple ion channels, it also shows promise in treating genetic forms of arrhythmia caused by several ion channel mutations.[1][10]
Celivarone may be an effectiveantihypertensive therapy, as it inhibits bothangiotensin II andphenylephrine inducedhypertension in dogs, despite having no affinity for these receptors.[1] Atrial fibrillation is especially common in hypertensive adults[2] so a single drug to combat both problems is desirable. The non-iodinated nature of celivarone means that the harmful side-effects on thethyroid commonly seen with amiodarone therapy are eliminated, making the drug an attractive alternative.[1][10] Higher oralbioavailability, shorter duration of action, and lower accumulation inbody tissues are also benefits of celivarone.[1][10] Presently, two studies are underway to determine if the effects observed in the animal models are reproducible in a human population.[12][13]
