Valproic acid (Depakote) may help treat lupus

Nov 20 2005

A common anti-seizure drug may be effective against certain conditions associated with lupus, according to animal research at Wake Forest University School of Medicine.

The drug, valproic acid (Depakote), prevents skin disease and reduces the severity of kidney disease in a mouse model of lupus, said Nilamadhab Mishra, M.D., a rheumatologist at Wake Forest University Baptist Medical Center.

"Valproic acid may be a potential cost-effective disease-modifying agent in lupus," Mishra reported at the American College of Rheumatology meeting in San Diego.

And because the drug has been on the market since 1983, Mishra said that clinical trials to use valproic acid for lupus could begin as early as next year.

"We already know the side effects," he said. That means that researchers can skip over the safety studies and move quickly to clinical trials to test its efficacy. While physicians could prescribe valproic acid "off-label" to lupus patients, "it is better to have a clinical trial to prove that it does help in lupus," Mishra said.

Systemic lupus affects more than 1 million Americans, mostly women. About half of human patients with systemic lupus have kidney problems, but achy joints, skin lesions, frequent fever, arthritis and prolonged or extreme fatigue are far more common.

Mishra's team tested valproic acid in a type of mouse that develops lupus that is similar to the lupus that occurs in people. None of the mice in the treatment group developed skin disease whereas all mice in the placebo group developed the disease, Mishra said. The results were similar for kidney and diseases of the spleen.

For instance, the spleen ordinarily enlarges in lupus. The size of the spleen in the treatment group was nearly one-third less than the size in the control group.

The study, which was paid for by a $250,000 grant from the Alliance for Lupus Research, was just one of several that Mishra presented at the national meeting,

In a second study, he showed that mithramycin, an antibiotic usually used against tumors, also reduces kidney disease in experimental mice with lupus.

Excess protein in the urine – proteinuria – is a symptom of kidney disease, Mishra said. In this study of mice born with lupus, only 33 percent of the mice getting mithrmycin had excess protein in the urine at 16 weeks, compared to 50 percent of the mice that were not treated. By 19 weeks, the gap had widened, with just 22.2 percent of the mithramycin group having excess protein, compared to 60 percent of the untreated group.

Other kidney function measures also showed a wide difference between the mithramycin group and the control mice. Renal vasculitis – inflammation of the tiny blood vessels in the kidney that can lead to kidney failure – occurred in 90 percent of the untreated mice, compared to 30 percent of the mithramycin group.

Mishra said that mithramycin might have a beneficial effect in people with lupus. "Further studies are warranted," he said.

At the same meeting, Mishra also described additional results from his ongoing research using a drug called TSA (Trichostatin A) on lupus. He described testing TSA on a second variety of mice that develop an autoimmune disorder similar to human systemic lupus.

In 2003, he had reported that in the same mouse model he used in the valproic acid and mithramycin studies, TSA led to a significant reduction in excess protein in the urine, inflammation of the kidneys, and spleen weight.

The new study, done in New Zealand Black and New Zealand White mice – which also develop an autoimmune disorder similar to lupus – had similar results.

Lupus is known as an autoimmune disorder because the body's own immune system turns on the rest of the body and attacks tissues and organs including the joints, kidneys, heart, lungs, brain and blood.