The study, “Intranasal administration of dantrolene increased brain concentration and duration,” was published in the journal Plos One.
Dantrium, produced by Par Sterile Products, is approved by the U.S. Food and Drug Administration (FDA) for treating chronic spasticity, or muscle spasms, from upper motor neuron disorders caused by multiple sclerosis and other conditions. It acts by reducing calcium levels within cells, which can cause damage to muscle cells and neurons if too high.
Studies using mouse models of Alzheimer’s have shown that Dantrium can lessen certain symptoms, specifically reducing beta-amyloid accumulation and memory loss. Plaques of misfolded beta-amyloid proteins are a hallmark of the disease.
However, the doses of Dantrium needed have raised concerns among researchers.
In most of the animal models in which Dantrium was tested, the medication was given orally or under the skin. While Dantrium was found to stop or slow the progression of neurodegenerative diseases in these models, the studies showed that these methods of delivery were limited. The researchers found it was difficult for the Dantrium to reach, or penetrate the central nervous system or CNS, composed of the brain and spinal cord.
“Due to the limited penetration of dantrolene into the CNS from the blood, oral administration requires high doses of dantrolene to reach the therapeutic concentration threshold in the CNS, making patients prone … to drug toxicity,” the researchers said.
Such high amounts of Dantrium could cause adverse side effects and limit the viability of the therapy as a long-term treatment option.
Now, researchers at the Perelman School of Medicine at the University of Pennsylvania, known as Penn, evaluated whether giving Dantrium through the nose — called intranasal administration — rather than the mouth would allow the medication to penetrate the brain more effectively.
“We know the use of dantrolene in the treatment of Alzheimer’s disease … would require chronic administration,” Huafeng Wei, MD, PhD, the study’s corresponding author and an associate professor of anesthesiology and critical care at Penn, said in a press release.
“Rather than using high doses of the oral form, which could increase the risk of adverse side effects, we sought to test the effectiveness of the intranasal approach via pre-clinical studies in mice,” Wei said.
The team gave mice either the oral or intranasal form of the medication and measured its concentration in the brain and blood at different time intervals. Additionally, a separate group of mice received Dantrium intranasally three times a week for either three weeks or four months, to assess potential adverse side effects that might be associated with chronic use of the medicine.
For a period of three hours after administration, the mice who received Dantrium through the nose had much higher concentrations of the medication in their brain that those who received it orally. These concentrations also persisted in the brain for longer times: at least three hours in animals given the medication intranasally versus less than two hours in animals given the treatment orally.
The data also showed no adverse side effects related to ability to smell or motor function. After three weeks of intranasal chronic treatment, there was no effect on the animals’ ability to smell. The same was true for motor function after four months of the chronic intranasal therapy.
“Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function,” the researchers said.
“While more research in animal models is needed to further evaluate the safety and effectiveness of this approach, our hope is that this will ultimately lead to a new therapeutic approach that can be studied in patients with various neurodegenerative diseases, including Alzheimer’s,” Wei said.
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