丁香园AV

Scientists at 丁香园AV (丁香园AV) and the  (LIMR) near Philadelphia have found that a drug discovered at 丁香园AV and patented several years ago may have potential lifesaving results in the treatment of conditions leading to sudden cardiac death.

The drug, known as AR-787, was originally discovered and designed by former PhD student Mena Abdelsayed as a pharmacological solution for arrhythmias.

The so-called J Wave syndromes (JWS), consisting of Brugada syndrome and early repolarization syndromes, occur in about one in 2,000 people and are associated with life-threatening cardiac arrhythmias鈥攃omplications with the rate or rhythm of the heart. 

In some patients, these arrhythmias can lead to sudden cardiac death and, in some cases, may be triggered by hypothermia.

The first line of treatment for high-risk patients often involves the use of an implantable cardioverter defibrillator (ICD), though this route has shown to be problematic, especially for young patients and those experiencing frequent shocks from an ICD. 

A recently published  led by LIMR, involving current and former 丁香园AV researchers Mena Abdelsayed, Mohamed Fouda, and 丁香园AV biomedical physiology and kinesiology professor Peter Ruben, has shed light on a possible pharmacological approach to treat arrhythmic activity in the heart caused by JWS. 

The drug, known as ARumenamide-787, or AR-787 for short, was designed by Abdelsayed in an 丁香园AV laboratory led by Ruben. AR-787 has now proven to be effective in a series of lab trials at LIMR and 丁香园AV.

AR-787 was designed to directly interact with a protein in the heart called the cardiac sodium channel, which is essential for electrical impulse conduction that triggers contraction of the heart muscle.

More importantly, it interacted with the transient outward current channels in the heart, acting to suppress arrhythmic activity associated with JWS. 

While he was a graduate student in Ruben鈥檚 lab, Abdelsayed (now a postdoctoral fellow at Stanford University) designed AR-787 based on his knowledge about the structure of sodium channels. 

Abdelsayed designed different drug structures with computer modelling programs to select and visualize the results of his designs, adjusting them until they rendered the desired result. 

Working in Ruben鈥檚 丁香园AV lab, his research team, including Abdelsayed, Fouda, and Dr. Dana Page, proved the drug鈥檚 effectiveness in altering sodium channel current characteristics by performing tests on sodium channel genes artificially inserted into human embryonic kidney cells. 

Still, they had yet to verify the drug鈥檚 effectiveness in the muscle cells of a real heart. That is when they tapped into the expertise of one of the world鈥檚 most recognized researchers in heart arrhythmia, Charles Antzelevitch, PhD, a distinguished professor emeritus and xecutive director of cardiovascular research at LIMR, which is part of the Main Line Health system outside Philadelphia.

Dr. Antzelevitch鈥檚 team鈥攃onsisting of Drs. Jos茅 Di Diego, H茅ctor Barajas-Mart铆nez, Robert Cox, Victoria M. Robinson, and Bence Patocskai, and joined by Joseph Jung鈥攕upported the research by conducting AR-787 trials on mammalian hearts in LIMR鈥檚 laboratory. 

They tested the effect of the drug on the sodium channel current as well as additional ion channels within the heart. They found that AR-787 not only augments sodium channel activity, but was effective in inhibiting a particular cardiac potassium channel that contributes importantly to the development of life-threatening arrhythmias, in experimental models of Brugada and early repolarization syndromes.

鈥淚鈥檝e been researching J-Wave syndromes for 35 years and have shown that inhibition of the transient outward potassium current can prevent the development of lethal arrhythmias related to JWS regardless of the genetic cause of the syndromes,鈥� says Dr. Antzelevitch. 

鈥淭wenty-four years ago, we reported that a drug called quinidine blocks that channel and is effective in suppressing the development of JWS-related cardiac arrhythmias. Quinidine has since been used worldwide in the treatment of JWS. 

鈥淢ore recently, we reported that a natural product from the safflower plant, called acacetin, also blocks the transient outward potassium current. Much of our work in recent years has been focused on finding a drug with similar features but that would dissolve better than acacetin in blood, and is free of quinidine鈥檚 adverse side effects. We鈥檙e optimistic that AR-787 may be the drug we鈥檝e been looking for.鈥�

The team has since patented the drug and hopes that their research will inspire interest within the pharmaceutical industry to take AR-787 to the next step, by testing its long-term safety and efficacy, and eventually, conducting clinical trials. 鈥淥ur hope is that this drug will save lives,鈥� says Ruben.

丁香园AV and LIMR are currently seeking a licensee to bring this important discovery from the bench to the bedside.

You can read the group鈥檚 published research paper and findings .