The drug is currently approved by the Food and Drug Administration to treat life-threatening and severe disturbances in the heart's natural rhythm, known as arrhythmias. At higher doses or given for a long time, amiodarone's side effects can include damage to the lungs and thyroid. Rao stresses that amiodarone has not been tested in animals or in people to see if it can fight a fungal infection the way it can in a laboratory dish.
In the current study, visiting medical student Soma Sen Gupta and graduate student Van-Khue Ton tested amiodarone on a collection of yeast mutants, each one missing a different gene. Yeast without genes critical to counteracting the drug's activity were particularly susceptible to amiodarone. Genes whose products regulate the transport of calcium into and out of the cell, and those responsible for controlling intracellular stores of calcium, were most important, the researchers discovered.
In another set of experiments, undergraduate student Veronica Beaudry and Kyle Cunningham, Ph.D., an associate professor of biology at The Johns Hopkins University, discovered that amiodarone first causes calcium to pour into the cell's interior from the outside and then causes its release from storage spaces inside the cell. This one-two punch makes the cells begin a death spiral, says Rao.
While yeast isn't life threatening, some fungi can be pretty nasty in people with depressed immune systems. In laboratory experiments, low doses of amiodarone combined with fluconazole killed about 95 percent of two pathogenic fungi, Candida albicans and Cryptococcus neoformans. Fluconazole by itself cut growth of the fungi by 25 percent, and amiodarone alone by just 10 percent, the researchers report.
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
5-Jun-2003