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Diabetes Drugs Could Stop Deadly Sepsis

A new class of diabetes drugs appears to hold promise against sepsis, a severe and often fatal reaction of the immune system to infection. In animal studies, giving a compound from the family of aldose reductase inhibitors stopped the deadly inflammation of sepsis, which is caused by the overreaction of the immune system to a bacterial infection.

"Even if you kill all the bacteria, toxin levels are still too high," explained study author Satish Srivastava, a professor of biochemistry and molecular biology at the University of Texas Medical School Branch at Galveston. "Injected into experimental animals, the aldose reductase inhibitor prevented septic shock."

Sepsis killed more than 120,000 hospitalized people in the United States in 2000, and the incidence has been increasing — from 82.7 cases per 100,000 Americans in 1979 to 240.4 per 100,000 in 2000. "It affects the lungs and kidneys, but the major cause of death in sepsis patients is cardiovascular collapse," Srivastava said.

He has been working for years on aldose reductase, an enzyme that is found throughout the body. It is part of the process by which glucose is converted to fructose and an alcohol called sorbitol. In diabetics, high levels of sorbitol can cause severe eye damage.

Several drug companies have been working on compounds that inhibit aldose reductase activity. One aldose reductase inhibitor, fiderestat, has been approved for use in Japan, and an application for its use in the United States is expected soon.

In the trial reported by the Texas researchers, mice were injected with chemicals that produced the condition of severe sepsis, including severe inflammation and loss of heart function. Injection of an aldose reductase inhibitor called sorbinil restored heart function to near-normal, the researchers reported.

The results were impressive enough for Srivastava to start planning for human trials. "We do plan to go to clinical trials," he said. "We are meeting with people to talk about funding."

In humans, "sepsis is a very complex situation in which the immunological responses play out over time," Wiedemann explained. "In this animal model, treatment was given at one point in time."

Another reason for caution was that the response to the medication appeared to drop off as time passed, he said. The animals were pretreated, and "the efficacy dropped off quite a bit two hours later," Wiedemann said. "In humans, you usually don’t have the opportunity to pretreat."

The work does hold promise, and human trials certainly are warranted, he said. One reason for hope is that the aldose reductase inhibitors appear to stop production of all the toxins causing physical damage, Wiedemann said, but he still counseled caution based on previous experience.

"When you look at these papers, the results are so convincing," he said. "When it works in an animal model, we think we’re home, but this has been going on for years."

If this latest research does not pan out, work has shown these compounds can reduce the damaging inflammatory processes in colorectal cancer, the Texas researchers added.

online issue of the journal Circulation Oct 2006

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