Asthma drug

Obscure Asthma Drug Shows Promise for Treating Diabetes

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A little-used asthma drug called amlexanox may potentially be repurposed to treat type 2 diabetes, according to findings from a small proof-of-concept study published in the July issue of Cell Metabolism.

Results showed that using the drug for 12 weeks was linked to significantly reduced HbA1c in some patients with obesity, type 2 diabetes, and nonalcoholic fatty-liver disease (NAFLD).

“The overall significant reduction in HbA1c over this relatively short trial indicates that amlexanox can benefit some patients with type 2 diabetes. The reduction in HbA1c is on the order of a [dipeptidyl peptidase-4] DPP-4 inhibitor when given alone over the same time period,” commented first author Elif Oral, MD, director of the MEND Obesity and Metabolic Disorder Program at the University of Michigan, Ann Arbor.

Researchers also looked at baseline inflammation, which revealed an interesting finding: people with higher levels of inflammation responded better.

“Among drug-treated patients, there seemed to be a greater degree of inflammation in responders compared with nonresponders. This is interesting, since we know that inflammatory pathways drive up expression of the targets of amlexanox,” Dr Oral said.

Amlexanox inhibits two enzymes: IKKƐ and TBK1. Studies in mice have shown that inhibiting these enzymes improves weight, insulin resistance, fatty liver, and inflammation.

Another intriguing result: responders showed over 1100 gene changes, and these changes were found only in this group.

“The drug response was characterized by a unique and dramatic molecular signature of gene-expression changes, consistent with what was seen in mouse models, in which expression of energy-expenditure genes were increased. We’re still investigating the importance and significance of these gene-expression changes,” Dr Oral added.

Amlexanox Developed in Japan to Treat Allergies and Asthma

Amlexanox was developed in Japan in the 1980s to treat asthma and allergic rhinitis. However, it requires thrice-daily dosing and was never introduced to the United States, because of heavy competition from more popular medications like montelukast, which can be taken once a day. Even in Japan, the prescription rate was very low, and therefore amlexanox was discontinued this year for commercial reasons.

However, its exact mechanism of action has never been fully investigated. It was not until Dr Oral and colleagues screened 150,000 chemicals, looking for inhibitors of IKKƐ and TBK1, that they hit upon amlexanox as a potential antidiabetes drug.

They first tested amlexanox in mice and did an open-label safety study in humans. Both the animal and human trials pointed to fat tissue as an important target for amlexanox.

So researchers next tested amlexanox in a randomized double-blind placebo controlled study that included 42 obese individuals with type 2 diabetes and NAFLD. Participants were randomized to 12 weeks of 50-mg amlexanox three times daily or placebo.

About one-third of participants showed a robust response to amlexanox, with reductions in HbA1c of ≥ 0.5% percentage points or more, which was significantly different from placebo (P = .05). Responders also showed significant decreases in fructosamine, a marker for shorter-term glucose control (P = .024).

Similar to results in mice, at 2 to 4 weeks responders showed a transient increase in IL-6, followed by decreased fasting glucose and improved insulin sensitivity. A subgroup of responders with NAFLD showed improvement in fatty liver.

Responders also had higher levels of baseline inflammation than nonresponders or placebo patients, including higher levels of CRP, which correlated with the amount of reduction in HbA1c. And analyses of fat biopsies showed they also had higher baseline activation of genes involved in inflammation.

Fat biopsies also replicated findings from the open-label study in humans, showing responders treated with amlexanox had higher expression of genes involved in energy expenditure and “browning” of fat.

Seven patients in the amlexanox group developed a rash at 4 weeks, which resolved within 2 weeks using local treatment. No other adverse events attributable to amlexanox occurred. This is consistent with the long-term safety profile in Japan, in which about 5% of patients developed rash, Dr Oral pointed out.

“We don’t understand the mechanism for why participants with more underlying inflammation responded better. However, previous work has shown that TBKI and IKKƐ are upregulated in the setting of more inflammation. So it is possible that inflammation oversensitizes the pathway that the drug targets,” she explained.

More Studies Planned

The team is now planning a longer 6-month prospective, randomized study in humans that will test whether individuals with elevated CRP and higher levels of fat inflammation at baseline have better responses to amlexanox.

They also plan another trial in humans that will test amlexanox in combination with mirabegron (Myrbetriq, Astellas Pharma), a pure beta agonist used to treat overactive bladder. The idea is to see whether amlexanox can restore catecholamine sensitivity.

Future studies will also determine the optimal safe dose and dosing regimen for amlexanox.

“If we can really prove that those patients with higher inflammation will respond better with this drug, it will be the first time that such an observation will be made, which is exciting. It’s another way of customizing therapy for patients,” Dr Oral stressed.

The group is currently looking for ways to partner with companies and investors, but currently none are involved.

Asthma drug appears to rejuvenate elderly brains, rodent study finds

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We need this.

 

New research in rats has shown that a cheap drug used to prevent asthma attacks could also help our brains to fight the symptoms of old age – including memory loss, inflammation, and loss of cognitive performance.

The drug, known as montelukast, was given to rats over a six-week period and appeared to reduce brain inflammation, while at the same time encouraging the growth of new neurons. Scientists are now planning clinical trials in patients with dementia, to see if the drug has the same effect in humans.

Regardless of whether you develop Alzheimer’s disease, as you get older, your brain is unfortunately going to stop functioning as well as it does right now. Inflammation builds up, the production of brain cells slows down, and memory and learning abilities become impaired.

Scientists have long searched for a way to delay this ageing process, or reverse it altogether, but most of the research has focussed on finding ways to treat Alzheimer’s disease and dementia, rather than general cognitive ageing.

The study was led by Ludwig Aigner, from the Paracelsus Medical University in Austria, and it was inspired after he heard about a link between an inflammatory asthma molecule and more severe cognitive decline.

To test out the involvement between these two pathways, Aigner and his team decided to investigate montelukast, which is an off-patent drug that’s currently used to block inflammation in asthma and prevent asthma attacks.

They gave two groups of rats daily doses of montelukast for six weeks – one group of four-month-old rats and one group of 20-month-old rats, which is the human equivalent age of around 65 to 70 years old. These older rats didn’t have dementia, but they were showing signs of slowing down with age.

Throughout the treatment, the researchers then tested the two groups of rats on their ability to repeatedly find a submerged platform in a pool of water, and remember where objects in their cage had originally been placed.

The older rats initially struggled with both these tasks, but after taking the drug, their performance was much faster than their peers who had only received a placebo – and it almost matched the younger mice.

Further testing also showed that older rats who had been given montelukast also had more freshly grown neurons in their brains than the placebo rats, and had less obvious inflammation.

“The important thing is that while we saw effects on neurogenesis, we also saw effects on other systems in the brain,” Aigner told Ian Sample over at The Guardian. “The drug reduces neural inflammation in the brain. But we also looked at that blood-brain barrier and that is partially restored. We know in aged brains that the blood-brain barrier is leaky and that contributes to neural inflammation.”

The next step is to test the same drug in humans, and Aigner’s team plans to start with dementia patients. The fact that montelukast is already used to treat asthma means that there are less hurdles to overcome when it comes to using it in humans, but because the drug is off-patent it also makes it challenging for a company to recover the money needed to fund clinical trials.

Let’s hope that doesn’t hold the researchers back, because with a rapidly ageing population, we definitely need new ways to keep our brains younger for longer.