Across the Atlantic, Ludwig Aigner of Paracelsus Medical University in Salzburg, Austria, is taking a different approach to modulating the immune system. He evaluates the approved asthma medication montelukast. This small molecule blocks leukotriene receptors that cause bronchial tubes to constrict. Leukotrienes are inflammatory molecules that white blood cells release during an asthma attack. Because neurons and microglia also express leukotriene receptors, Aigner decided to check if this type of signaling plays a role in brain inflammation. In aged, forgetful rats, six weeks of montelukast treatment shrank microglia, restored the blood-brain barrier, and boosted learning in the Morris water maze to that of young rats. Intriguingly, montelukast also boosted neurogenesis, suggesting some regenerative effects (see Oct 2015 news). Notably, leukotrienes rise during aging, and after stroke or brain damage.
The idea of repurposing montelukast for Alzheimer’s disease is buoyed by its excellent safety record; alas, the tablet formulation poorly enters the bloodstream, with only 63 percent of it becoming bioavailable. Because of this, Aigner and colleagues reformulated the drug in collaboration with IntelGenx Corp., Saint-Laurent, Canada. IntelGenx packaged the drug in a thin film that is placed in the mouth, either against the cheek or under the tongue. The film dissolves, delivering the drug to the bloodstream.
The researchers tested this delivery method in eight healthy volunteers, who took 10 mg montelukast, a common asthma dosage, both in the traditional tablet form and by film. The film resulted in higher absorption, reaching 95 percent in the bloodstream, an increase of 50 percent over the tablet’s bioavailability. This formulation will allow lower dosing, Aigner said in Vienna.?
The drug crossed the blood-brain barrier, an essential feature for treating AD. After three hours, participants had 3.5 ng/ml in their CSF, rising to 4.25 ng/ml by seven hours. This is the pharmacologically active range, Aigner noted. The researchers next plan to do a Phase 2 study in AD patients in Canada, in collaboration with the research organization Consortium of Canadian Centres for Clinical Cognitive Research (C5R). Aigner noted that the oral film represents a new product that can be patented for commercial development.
