A drug the US government, once under the "extremely dangerous and unfit for human consumption "deserves a second chance, a study on rats suggests. Researchers report that a slow-release version of the compound reverses diabetes and diseases of nonalcoholic fatty liver disease (NAFLD), an untreatable condition that can lead to cirrhosis and liver cancer.
Diabetes has already become an epidemic. And up to 30% of people worldwide may have a metabolic disease less known but related NAFLD, in which the lipid-family of molecules that includes fats-accumulate in the liver. Although extra fat often causes some problems, about 10% to 20% of people develop non-alcoholic steatohepatitis (NASH), a serious disease in which inflammation and scarring can cause cancer and liver failure. So far, there are no drugs approved to treat either condition. "This is one of the largest unmet needs in medicine today," said Rohit Loomba hepatologist at the University of California, San Diego.
To meet this need, endocrinologist Gerald Shulman School of medicine and colleagues at Yale University suggested resurrecting a drug with a dark history. 2,4-dinitrophenol (DNP) Originally used as an industrial chemical and explosive, the compound has attracted attention researchers after the french munitions workers were exposed to high levels of it during World War one frequent consequence of this exhibition was losing weight even another consequence was sometimes death. after d other research has suggested that the compound induced obese people to lose weight, drug companies in the 1930s included DNP in diet pills that were available without a prescription. the Food and drug Administration (FDA) has banned compound at the end of the decade, however, as it caused side effects such as cataracts and was responsible for a death grip.
Despite its bad reputation, DNP has some virtues. By modifying the activity of mitochondria power plants that provide cells with energy, it forces the body to burn fat. It provides other metabolic benefits as well. For example, people with NAFLD or diabetes usually have insulin resistance, which means that their cells do not respond normally to the hormone that controls sugar levels in the blood. However, when Shulman and colleagues DNP fed to rats, they found that the drug has stimulated the insulin sensitivity of the animals.
The researchers decided to design a safer version of DNP that would retain its advantages. First, they tried to limit the effects of the drug by creating a version that is active mainly in the liver. In a study published in 2013, researchers have shown that this version of the drug was about one-tenth as toxic as the DNP standard. In addition, the targeted drug reduced fat accumulation in the liver of rats that had NAFLD and improve the insulin sensitivity of the animals.
But the researchers thought they could do better. In their new study, they packed the original form of DNP in a pill that dissolves and releases the drug for 12 to 24 hours slowly. This strategy reduces the amount of drug in the bloodstream. When fed to rats that eat a diet low in fat and loaded develop their own version of NAFLD, the slow release drug reduced their liver lipid levels of about 0%, Shulman and his colleagues report online today in Science . Rodents who have used drugs have also seen improvements in their amounts of insulin sensitivity and glucose in the blood. In rats with NASH, the drug reduced fibrosis, scarring can cause cirrhosis and liver failure. The team also showed that reversed diabetes in rats. Comparing the doses that provide these benefits with the doses that cause side effects, the researchers determined that the slow-release version is safer than the drug targeted liver.
The study suggests that this softer version of DNP could be useful for treating diabetes and NAFLD, says Shulman. It reduces fat accumulation and corrects defective liver metabolism of glucose, so "it is the cause of these diseases." He and his colleagues plan further studies on the drug animals and hope to pass safety tests in people.
Sean Koppe hepatologist at the University of Illinois Hospital & Health Sciences System in Chicago said the results warrant testing the drug in humans. "They show that it has a wide window between therapeutic and toxic levels," he said. Loomba said the drug's ability to slow fibrosis, a characteristic of NASH, is encouraging, and it also supports load safety testing in people. "These preclinical data is very exciting," he said.
Koppe Loomba and agree that if DNP proves to be safe and effective in other trials, it could gain FDA approval, despite its history. prohibited drugs have a prior return. The first example is thalidomide, which was banned in 1960 because it caused birth defects, but has now found a niche in the treatment of cancer and leprosy.
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