Focus on the Flu : Treating, Drugs

by National Institute of Health

(Page 8 of 15)

Resistance to Popular Flu Drug May Be Higher than Thought

If you come down with the flu, in addition to the added bed rest and fluids, your doctor will likely prescribe one of two possible medications: an M2 ion channel blocker or a neuraminidase inhibitor. The former prevents the virus from making copies of itself inside the cell, while the latter prevents new viruses from breaking free to infect other cells.

One of the benefits of neuraminidase inhibitors, such as zanamivir (Relenza) and oseltamivir (Tamiflu), is they work against both influenza A and B, whereas M2 inhibitors are only effective against influenza A. Also, the influenza virus appears to be less prone to becoming resistant to neuraminidase inhibitors than to M2 inhibitors.

"True," says NIAID-supported researcher Yoshihiro Kawaoka, D.V.M., Ph.D., on the subject of resistance, "but perhaps not as much as we'd originally thought." Dr. Kawaoka, a renowned virologist who holds professorships at the University of Wisconsin, Madison, and the University of Tokyo, recently studied the frequency with which the H3N2 influenza virus developed drug-resistant mutations in 50 Japanese children taking oseltamivir.

Analyzing the virus's gene sequences before and throughout treatment with oseltamivir, the researchers found mutations had occurred on the neuraminidase gene in nine, or 18 percent, of the children studied. All of the muta nts were resistant to the effects of oseltamivir. Earlier clinical trials had demonstrated oseltamivir-resistant mutations in only 4 percent of children ages 1 to 12 and in less than 1 percent of adults. (Resistance to the M2-inhibiting drugs amantadine and rimantadine are much higher, occurring in roughly 30 percent of patients who take those drugs. In another study, Dr. Kawaoka has shown that drug-resistant strains appeared in 80 percent of children taking amantadine.)

The researchers also found that some children who did not experience drug resistance continued spreading the flu virus, even after five days of treatment.

Dr. Kawaoka notes that younger children, who were probably exposed to influenza for the first or second time, developed more drug-resistant viruses than older children, who most likely possessed some pre-existing immunity against other strains. Because this scenario resembles that found during a flu pandemic, these findings could provide helpful insight into the use of neuraminidase inhibitors if a new pandemic should arise, he says.

Fighting Back: New Drugs Against Flu

The traditional advice for treating flu-bed rest and fluids-works quite well in most cases. For the elderly, the very young and people with chronic illness, however, flu and its complications can be life-threatening. While several drugs exist to treat flu, they must be taken within 48 hours of the start of the illness. NIAID grantees, including Jianzhu Chen, Ph.D., and Mang Yu, Ph.D., are exploring ways some futuristic technologies might lead to better flu drugs.

A Welcome Interference

RNA interference (RNAi) is a cellular phenomenon that scientists are just now starting to understand and exploit. Jianzhu Chen, Ph.D., and his colleagues at the Massachusetts Institute of Technology are exploring the possibility of using RNAi to hinder the ability of the flu virus to multiply inside its target cells. RNAi can selectively inhibit gene activity in cells; essentially, the technique allows researchers to "turn off" individual genes. Dr. Chen and his team have experimented with a particular form of RNAi, called short interfering RNA (siRNA), specific for genes that the flu virus requires to reproduce inside human cells.

In laboratory-grown cells and chicken embryos, the siRNAs exhibited a powerful effect on the virus' ability to make new copies of itself. Moreover, the tested siRNAs worked even at extremely small amounts, opening the possibility that they might prevent the flu virus from gaining a foothold and turning into full-blown disease. Also, the researchers note, siRNAs are attractive as potential flu preventives or drugs because they could be given through the nose and upper respiratory tract where flu viruses first enter the body.

A 2003 paper in the Proceedings of the National Academy of Sciences by Dr. Chen and his colleagues describes the technique.

Dr. Chen notes several key benefits of using siRNAs to halt the influenza virus: A cocktail of siRNAs targeting different influenza virus genes can prevent the emergence of resistant virus strains. In mice, siRNAs can be used to both prevent and treat influenza virus. Because siRNAs are designed to target regions of the influenza virus genome that are less likely to mutate, they can be used to prevent or treat influenza strains of both human and avian origin

The latter two points were demonstrated in two studies, one published by Dr. Chen and colleagues in 2004 in Proceedings of the National Academy of Sciences, in which siRNA prevented and treated influenza virus infection in mice, including the highly pathogenic avian influenza viruses H5N1 and H7N7.

Additional publications about the use of siRNAs to prevent and treat flu by Dr. Chen and his colleagues include Expert Opinion on Biological Therapy (2005), Virus Research (2004).

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.