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Isle doctors find new use for 1890s drug


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POSTED: Monday, February 23, 2009

An old anti-leprosy drug might provide an effective treatment for three devastating autoimmune diseases—multiple sclerosis, psoriasis and type 1 diabetes—say two Hawaii researchers and mainland colleagues.

The finding is reported in the Public Library of Science by Drs. Reinhold Penner and Andrea Fleig of the University of Hawaii John A. Burns School of Medicine and the Queen's Medical Center, and researchers at Johns Hopkins University and Northwestern University.

They said the antibiotic clofazimine—developed in the 1890s for tuberculosis—holds promise as a therapy for autoimmune diseases.

Clofazimine did not work for TB, but was used successfully against leprosy, the Hawaii researchers explained in an interview. Although no longer needed for that disease in the United States, it is still being developed for use in Brazil and other countries where leprosy remains, said Penner, director of the Queen's Center for Biomedical Research.

He and Fleig—world leaders in cellular function research—found the compound acts against a particular type of ion channel, a potassium channel Kv1.3, in lymphocytes, a type of white blood cell. Working with them at Queen's was UH postdoctoral researcher Suhel Parvez, now in Germany.

Johns Hopkins researchers stumbled upon clofazimine as a potential treatment for autoimmune diseases while screening more than 3,000 drugs to identify new uses for them, Penner said. The drugs were assembled over seven years in the Johns Hopkins Drug Library.

The idea was to test old medicines that already have Food and Drug Administration approval (and known side effects) for new disease targets, said Fleig, who heads the Laboratory of Cell and Molecular Signaling at Queen's with Penner.

Clofazimine was among drugs tested against lymphocytes—cells that defend the body against alien organisms, parasites and bacteria.

The drug's “;tremendous effect on human immune cells”; surprised the Johns Hopkins researchers, pharmacologist Jun O. Liu said in a news release.

“;People have been working for years and spending tens of millions of dollars on developing a drug to inhibit a specific molecular target involved in these diseases, and here we have a safe, known drug that hits that target,”; Liu said.

Johns Hopkins contacted Penner and Fleig to find out how clofazimine, thought to be an antibacterial drug, works on human immune cells. They identified the mechanism: It interferes with potassium channel Kv1.3, an important factor in activating lymphocytes, Penner said.

The discovery has been patented between Queen's and Johns Hopkins, and companies have contacted them about licensing, Penner said.

Many companies were looking for blockers for ion channel Kv1.3 but could not find anything that did not have a lot of side effects or affect other potassium channels in the body, Penner said.

“;Until today it was completely impossible to use compounds that are working on Kv1.3 specifically without affecting other potassium channels,”; he said.

Clofazimine is not the most potent blocker against Kv1.3, and higher concentrations are needed, but it does not affect other potassium channels and has no side effects except a purplish skin discoloration, he said.

“;In any case, this is just the start,”; Penner said. “;It's pure serendipity that this compound appears to be effective in this system.”;

The drug now can be modified and optimized so it is more potent, requires a lower concentration and reduces skin problems, he said.

“;The nice thing about this compound is it now can actually enter clinical trials for multiple sclerosis, psoriasis and type 1 diabetes because it's a compound already,”; Penner said. “;It has been through clinical trials already and been used to treat humans. We don't have to start from scratch, although it may not be the best one yet.”;

He said the scientists want to optimize clofazimine to use against rheumatoid arthritis and to replace compounds with significant side effects now used to prevent organ rejections in transplants.

They also are testing other compounds against diseases that involve the immune system. For example, Fleig said, they have identified a blocker for an ion channel they plan to test on a mouse model to see whether they get comparable results for asthma and type 1 diabetes.

“;We're hopeful we can find something beneficial against all sorts of diseases that involve the immune system,”; Penner said.