Therapeutics

Montelukast

Overview

Name: Montelukast
Synonyms: Singulair, MK0476
Chemical Name: (R,E)-2-(1-((1-(3-(2-(7-Chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetic acid
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Intelgenx
Approved for: Asthma

Background

Montelukast is a leukotriene receptor antagonist used to treat asthma and allergy symptoms. Leukotrienes are inflammatory mediators released by white blood cells. Specifically, montelukast inhibits the cysteinyl leukotriene CysLT1 receptor. This blocks the action of leukotriene D4 on this receptor in the lungs and bronchi, reducing swelling of the airways. FDA-approved in 1998, the drug is available in generic form as a chewable tablet. It is widely used in the U.S. and other countries.

Common side effects include gastrointestinal disturbances such as diarrhea, nausea, and vomiting. Case reports have also associated montelukast with mental or mood changes that can be serious, including aggression, agitation, anxiety, depression, nightmares and even suicide, especially in adolescents. In 2009, the FDA added a neuropsychiatric adverse event warning to its label, but despite follow-up research, the question remains controversial (Chen et al., 2014Lu et al, 2015Aldea Perona et al., 2016Khalid et al., 2018).

Montelukast has drawn interest as a means to target neuroinflammation. Neurons and microglia express leukotriene receptors, and leukotriene D4 is involved in inflammatory processes of aging, Alzheimer’s disease, Parkinson's disease, stroke, multiple sclerosis, epilepsy, and others (reviewed in Ghosh et al., 2016). Montelukast was reported to inhibit Aβ42 toxicity in cultured primary neurons, and reduced neurotoxicity and memory impairment in mice that received intracerebral Aβ infusions (Lai et al., 2014, Lai et al., 2014). Six weeks of montelukast-fortified chow reportedly boosted neurogenesis, quieted microglia, restored blood-brain-barrier function in old rats and improved their memory to that of young rats (Oct 2015 news on Marschallinger et al., 2015). Montelukast was also reported to broadly reduce neuroinflammation in a rotenone rat model (Mansour et al., 2018).

An epidemiological study showed people who used montelukast for asthma to be slightly less likely to use dementia medicines in old age, live in nursing homes, or die compared to people on other asthma treatments (Grinde and Engdahl, 2017).

Findings

To make montelukast more bioavailable, IntelGenx reformulated it into a dissolving oral strip called Versafilm, which is placed against the cheek for rapid oral delivery. At AD/PD 2017, the company showed data on eight healthy volunteers suggesting the film increased bioavailability by 52 percent over chewable tablets. Montelukast crossed the blood-brain barrier and accumulated to pharmacologically active doses in CSF (May 2017 conference news; 2018 AAIC poster ). 

In November 2018, IntelGenx started a Phase 2 trial of the oral film in 70 people with mild to moderate Alzheimer’s disease, conduted at 11 locations in Canada. Participants must have been on stable dose of donepezil, rivastigmine, or galantamine for more than three months, and will receive a 10 mg montelukast or matching placebo film daily for 26 weeks. The primary outcome is change in a neuropsychological test battery composite score from baseline to 26 weeks. Secondary outcomes include other cognitive, functional and neuropsychiatric measures, and adverse events. The trial will also track suicide risk.

In October, 2019, the company announced by press release the results of an interim analysis by an independent data safety monitoring board. Based on data from 25 participants, of whom 13 had completed the full 26 weeks of daily treatment, the board identified no safety concerns. The trial will continue through October 2020.

Separately, in September 2019, researchers at Emory began a university-sponsored Phase 2 trial of montelukast in tablet form for Alzheimer’s disease. This one-year, placebo-controlled study will enroll 150 people with mild cognitive impairment or early AD, defined by clinical criteria. Participants will receive an escalating dose, from 10 to 40 mg/day, or placebo. Primary outcomes include safety and tolerability measures such as number of participants with GI symptoms, allergic responses, elevated liver enzymes, changes in blood clotting, neuropsychiatric effects, seizures, and discontinuations. Secondary outcomes include cognitive function, CSF, and neuroimaging biomarkers. The trial will run through August, 2021.

For all montelukast clinical trials, see clinicaltrials.gov.

For montelukast trials on Alzheimer’s disease, see clinicaltrials.gov.

Last Updated: 29 Nov 2019

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References

News Citations

  1. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration
  2. Asthma Drug Revitalizes Memory in Old Rodent Brains

Paper Citations

  1. . Asthma and self-harm: a population-based cohort study in Taiwan. J Psychosom Res. 2014 Dec;77(6):462-7. Epub 2014 Sep 6 PubMed.
  2. . Asthma Treatments and Mental Health Visits After a Food and Drug Administration Label Change for Leukotriene Inhibitors. Clin Ther. 2015 Jun 1;37(6):1280-91. Epub 2015 Apr 25 PubMed.
  3. . Psychiatric Disorders and Montelukast in Children: A Disproportionality Analysis of the VigiBase(®). Drug Saf. 2016 Jan;39(1):69-78. PubMed.
  4. . The Association Between Leukotriene-Modifying Agents and Suicidality: A Review of Literature. Psychosomatics. 2018 Jan - Feb;59(1):19-27. Epub 2017 Aug 9 PubMed.
  5. . Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders. CNS Neurosci Ther. 2016 Dec;22(12):943-951. Epub 2016 Aug 19 PubMed.
  6. . Montelukast rescues primary neurons against Aβ1-42-induced toxicity through inhibiting CysLT1R-mediated NF-κB signaling. Neurochem Int. 2014 Sep;75:26-31. Epub 2014 May 28 PubMed.
  7. . Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Aβ1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice. Neuropharmacology. 2014 Apr;79:707-14. Epub 2014 Jan 20 PubMed.
  8. . Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat Commun. 2015 Oct 27;6:8466. PubMed.
  9. . Montelukast attenuates rotenone-induced microglial activation/p38 MAPK expression in rats: Possible role of its antioxidant, anti-inflammatory and antiapoptotic effects. Toxicol Appl Pharmacol. 2018 Nov 1;358:76-85. Epub 2018 Sep 15 PubMed.
  10. . Prescription database analyses indicates that the asthma medicine montelukast might protect against dementia: a hypothesis to be verified. Immun Ageing. 2017;14:20. Epub 2017 Aug 31 PubMed.

External Citations

  1. 2018 AAIC poster
  2. press release
  3. clinicaltrials.gov
  4. clinicaltrials.gov

Further Reading

Papers

  1. . Inhibition of leukotriene receptors boosts neural progenitor proliferation. Cell Physiol Biochem. 2011;28(5):793-804. Epub 2011 Dec 15 PubMed.
  2. . Leukotriene D4 induces cognitive impairment through enhancement of CysLT₁ R-mediated amyloid-β generation in mice. Neuropharmacology. 2013 Feb;65:182-92. Epub 2012 Sep 12 PubMed.
  3. . Improvement of fiber connectivity and functional recovery after stroke by montelukast, an available and safe anti-asthmatic drug. Pharmacol Res. 2019 Apr;142:223-236. Epub 2019 Feb 25 PubMed.
  4. . Case Series Using Montelukast in Patients with Memory Loss and Dementia. Open Neurol J. 2017;11:7-10. Epub 2017 Jan 31 PubMed.
  5. . Montelukast treatment protects nigral dopaminergic neurons against microglial activation in the 6-hydroxydopamine mouse model of Parkinson's disease. Neuroreport. 2017 Mar 22;28(5):242-249. PubMed.
  6. . Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors. Sci Rep. 2015 Dec 17;5:18286. PubMed.