Li2CO3 is effective for the treatment of mania in bipolar disorder
Lithium is one of the oldest and most widely used drugs for the treatment of neuropsychiatric diseases such as bipolar disorder. It has a serious defect - toxicity. Researchers at the University of South Florida (USF) have been trying to find a safer lithium, and they found that lithium salicylate, an alternative salt form, may be the answer.
Researchers found that oral lithium salicylate can produce stable lithium levels in rats for up to 48 hours without the toxic peak associated with the rapid absorption of FDA approved Li2CO3. They concluded that lithium salicylate may be more effective than lithium carbonate, but it will not be accompanied by toxicity risk, which is a potentially important development of the next generation of lithium therapy.
Their results were published in the latest issue of RSC progress, a journal of the Royal Society of chemistry.
Although Li2CO3 is very effective in treating mania in bipolar disorder and is thought to reduce suicide in the depression stage of the disease, patients taking Li2CO3 often do not comply because of side effects, including hand tremor, diarrhea, vomiting, weight gain and hypothyroidism. New drugs that are as effective as Li2CO3 but have no toxicity have not yet come out.
Dr. Adam J. Smith, the lead author of the study, said: "although the therapeutic window of lithium is very narrow and there are patent substitutes, the lithium therapy approved by FDA in the United States is still regarded as the 'gold standard' for the treatment of manic depression." He is a neuroscientist at the USF health center's center of excellence in neurosurgical aging and brain repair.
"Our previous research shows that redesigning lithium therapy through crystal engineering may produce better performance and reduce toxicity."
Smith said that crystal engineering is the use of intermolecular interactions to design and synthesize molecular solid crystal structures with desired characteristics.
In their latest study, published in RSC progress, researchers tested two previously
untested lithium salts - salicylate and lactate, both of which are structurally different from Li2CO3. In laboratory rats, they found that lithium salicylate and lithium lactate showed "completely different pharmacokinetics" compared with the FDA approved and widely used lithium carbonate. Pharmacokinetics refers to the way the human body absorbs, distributes and expels drugs.
"To our knowledge, this is the first pharmacokinetic study of lithium salicylate and lithium lactate in laboratory animals," Smith said.
The researchers report that these findings support the earlier suggestion that the ideal lithium preparation should be a compound that can both "flatten" the peak of high blood levels and slow down the decline of blood concentration.
"In our study, this is exactly the pharmacokinetic characteristic of lithium salicylate production," said senior author Dr. Doug Shyle, who is also a researcher at the USF center of excellence for healthy aging and brain repair. "It is worth noting that after 48 hours, lithium salicylate produced higher lithium levels in the blood and brain, but there was no sharp peak, leading to the toxicity of lithium currently used."
The researchers said that the 48 hour window period represented a key difference between lithium salicylate and the current FDA approved lithium therapeutic drugs. If these preclinical results are also established in humans, this will allow less frequent dose regimens and may reduce the troublesome side effects that plague traditional lithium therapy.
"Psychiatry has long struggled with the fact that although lithium is very effective in the treatment of bipolar disorder, the narrow therapeutic window and side effects often make lithium difficult and sometimes dangerous in clinical work," said Todd Gould, M.D. of the Department of Theology at the University of Maryland, a neurobiology expert on lithium mechanisms and bipolar disorder.
The pharmacokinetic data of Dr. Smith and his colleagues show that in addition to the commonly used Li2CO3, lithium salt may have a wider therapeutic window and fewer potential side effects. Studies in humans are also needed to confirm its safety and to prove that the pharmacokinetic characteristics observed in rats are similar to those observed in humans. "
Researchers at the University of San Francisco continue to pursue a safer and more effective lithium therapy and expect to carry out the required experiments soon to support early clinical trials.
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