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About CERTsAnnual Report Year 2Focus on the CentersArizona | Duke | HMO Network | UAB | UNC | UPenn | Vanderbilt | Publications | Ongoing Projects Who Is At Risk for Arrhythmias?www.qtdrugs.org. That's the address for a unique educational and research tool developed by the Georgetown center, which relocated to the University of Arizona Health Sciences Center at the end of Year 2. This Web site contains a list of 72 drugs (so far) that can cause sometimes life-threatening abnormalities in heartbeat (arrhythmias), with an emphasis on drugs associated with an abnormally long QT interval on the electrocardiogram (ECG). Caregivers around the world can look up specific drugs that might pose a risk to their patients, and submit clinical cases of drug-induced arrhythmias to the registry. But that's not the most important aspect of this project. As caregivers submit cases to the registry, they provide clinical information, an ECG tracing, and a swab sample from the inside of the patient's mouth. Why? So that Dr. Raymond Woosley and his colleagues can 1) compile a detailed profile of the people most at risk for drug-induced arrhythmias, and 2) develop a genetic test that can identify them in advance. The registry remains in the active enrollment phase. So far, 12 patients have been fully enrolled as cases, and another 150 are in the submission phase. Larger samples will be needed for meaningful analysis, however. "It is critical for individual physicians to realize that each patient they submit helps us develop ways to allow medications to be used with greater safety," says Woosley. "We have designed the Web site's content to make it easier to submit cases and have provided incentives to encourage their participation." The incentives include a quarterly newsletter, telephone consultations, laminated pocket reference cards, and automatic reporting of their cases to the FDA's MedWatch program, which tracks adverse events associated with drugs. So that the cases can be compared against a "control" group, the registry also is collecting information from 200 family members and healthy volunteers for analysis. A genetics core laboratory has begun screening both the case and control samples for abnormalities in six of the known sites of genetic variation. The first major development from the registry has been reports of cases of drug-induced torsades de pointes (a potentially fatal arrhythmia), prolonged QT interval, and two deaths in patients treated with methadone. "This may be another example in which the serious toxicity of a prescribed drug escapes detection for too many years," notes Woosley. "But this also is an example of how the CERTs-sponsored registry, qtdrugs.org, can be used to identify signals and further evaluate potential drug-induced toxicity." The investigators suspected that methadone, which is used for pain and to treat heroin addiction, might be acting on the potassium channels in the heart's cells. Potassium is required for normal function of the electrical impulses that coordinate heartbeat. “ each patient they (physicians) submit helps us develop ways to allow medications to be used with greater safety,” They examined not only methadone but also morphine and other chemically related substances in the laboratory. Testing human cardiac channels in single cells, they found that methadone was a very potent blocker, severely disrupting the electrical signals. Methadone has been available for over 45 years, and reports of sudden death emerged almost as soon as it came on the market. These deaths generally were thought to result from underlying drug abuse. The results from this project provide the first systematic evidence of another mechanism for this phenomenon. More important, the results suggest a strategy for preventing the deaths and arrhythmias associated with this drug. Woosley and his group have presented information about the registry and its potential effect on public health at two conferences thus far: the Annual Scientific Sessions of the American Society for Clinical Pharmacology and Therapeutics and the annual meeting of the Society for Experimental Biology and Medicine
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