Budiodarone (ATI-2042) is an

antiarrhythmic agent Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular ta ...

and chemical analog of

amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrilla ...

that is currently being studied in

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a ''sec''-butyl acetate side chain at position 2 of the

benzofuran Benzofuran is the heterocyclic compound consisting of fused benzene and furan rings. This colourless liquid is a component of coal tar. Benzofuran is the "parent" of many related compounds with more complex structures. For example, psoralen i ...

moiety. This side chain allows for budiodarone to have a shorter

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

in the body than amiodarone (7 hours versus 35–68 days) which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

Creation of arrythmias

Arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

may be caused by changes in ion channel mRNA and protein expression which modify

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

generation through dysfunctional channels and increase the likelihood of inappropriate electrical re-entry (electrical stimulus entering back into the cell to prematurely start the next action potential). The increase in electrical re-entry causes the

fibrillation Fibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regard to the heart. Cardiology There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fib ...

or uncontrolled action potential discord of atrial myocytes. Arrhythmias have historically been treated using atrial

ablation Ablation ( la, ablatio – removal) is removal or destruction of something from an object by vaporization, chipping, erosion, erosive processes or by other means. Examples of ablative materials are described below, and include spacecraft materi ...

or antiarrhythmic drugs to decrease electrical re-entry and therefore fibrillation.

Treatment of arrhythmias

Budiodarone holds much promise as an antiarrhythmic drug to prevent fibrillation. As a drug that spans over many of antiarrhythmic drug classes, the electrophysiological activity of budiodarone includes:

Inhibition of potassium, sodium and calcium channels

Through inhibiting potassium channels, budiodarone causes a decreased efflux of potassium out of the myocyte during the refractory period of its action potential, increasing the time it takes to reach the resting

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

. Through blocking sodium channels, budiodarone causes a decrease in sodium influx into myocytes during the

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

period of its action potential. Through blocking calcium channels, budiodarone causes a decrease in calcium influx into myocytes, decreasing intracellular calcium and decreasing cardiac

contractility Contractility refers to the ability for self-contraction, especially of the muscles or similar active biological tissue *Contractile ring in cytokinesis *Contractile vacuole *Muscle contraction **Myocardial contractility *See contractile cell for ...

, which is beneficial in preventing arrhythmias, but detrimental in ventricular contraction.

Increase in atrial myocyte refractory period

Through prolonging the refractory and depolarization periods of the action potential, there is a decreased likelihood that electrical re-entry will occur.

Increased stimulus-to-atrium and atrium-to-bundle of his intervals

Increasing the time interval between stimulus to atrium and/or atrium to

bundle of his The bundle of His (BH) or His bundle (HB) ( "hiss"Medical Terminology for Health Professions, Spiral bound Version'. Cengage Learning; 2016. . pp. 129–.) is a collection of heart muscle cells specialized for electrical conduction. As part of t ...

in action potential conduction slows the rate of myocyte contraction, thereby slowing heart rate.

Increased MAPD90 and QT-intervals

Increasing the time interval of MAPD90 (response of monophasic action potential duration at 90% repolarization)in action potential conduction, slowing the rate of myocyte contraction, thereby slowing heart rate.

Dose-dependent decrease in heart rate

A decrease in heart rate reduces the risk of atrial fibrillation.

Clinical trials

Preliminary trials of budiodarone have administered the drug orally as a

tartrate A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−. The main forms of tartrates used commercially are pure crystalline ta ...

salt in amounts ranging from 200–800 mg bid. Evidence has shown that 400–600 mg bid doses were associated with the highest reduction in atrial fibrillation burden (54.4% and 75% respectively) while remaining free of the adverse side effects common with amiodarone. In addition to reductions in atrial fibrillation burden, similar dose-dependent reductions in the number of atrial fibrillation episodes and the duration of atrial fibrillation episodes have been demonstrated. There has also been evidence of prolonged budiodarone cardiac effect days after drug discontinuation as the atrial fibrillation baseline measurements were not reached in washout periods. This suggests that budiodarone may promote atrial re-modelling to improve malfunctioning ion channels that once potentiated fibrillation.

Future use

Data on the effects of long-term budiodarone are not yet available. The completion of current clinical trials will examine chronic budiodarone use to confirm or deny its use as an effective and safe antiarrhythmic drug.

References

{{Antiarrhythmic agents Antiarrhythmic agents Diarylketones Iodoarenes Diethylamino compounds Carboxylate esters Ethanolamines