Montelukast

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Montelukast
Montelukast2DCSD.svg
Montelukast 3D ball-and-stick.png
Systematic (IUPAC) 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
Clinical data
Trade names Singulair
AHFS/Drugs.com monograph
MedlinePlus a600014
Pregnancy cat. B1 (AU) B (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 63% to 73%
Protein binding 99%
Metabolism Hepatic (CYP3A4 and CYP2C9-mediated)
Half-life 2.7-5.5 hours
Excretion Biliary
Identifiers
CAS number 158966-92-8 YesY
ATC code R03DC03
PubChem CID 5281040
DrugBank DB00471
ChemSpider 4444507 YesY
UNII MHM278SD3E YesY
KEGG D08229 YesY
ChEBI CHEBI:50730 YesY
ChEMBL CHEMBL787 YesY
Chemical data
Formula C35H36ClNO3S 
Mol. mass 586.184 g/mol
 YesY (what is this?)  (verify)

Montelukast (trade names Singulair or Pluralair, Montecarlo-10, and Montecarloflo and Lovetas in India) is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.[1][2] It is usually administered orally once a day. Montelukast is a CysLT1 antagonist; it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation.

Because of its method of operation, it is not useful for the treatment of acute asthma attacks. Again because of its very specific mechanism of action, it does not interact with other asthma medications such as theophylline.

Another leukotriene receptor antagonist is zafirlukast (Accolate), taken twice daily. Zileuton (Zyflo), an asthma drug taken four times per day, blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway.

The Mont in Montelukast stands for Montreal, the place where Merck developed the drug.[3]

Medical uses[edit]

Montelukast is used for a number of conditions including asthma, exercise induced bronchospasm, allergic rhinitis, and urticaria.[4] It is mainly used as a complementary therapy in adults in addition to inhaled corticosteroids, if they alone do not bring the desired effect.

Adverse effects[edit]

Side effects include gastrointestinal disturbances, headaches, hypersensitivity reactions, sleep disorders, and increased bleeding tendency, in addition to other generic adverse reactions. Its use is associated with a higher incidence of Churg–Strauss syndrome (whether or not this drug is 'unmasking' subclinical Churg–Strauss is as yet uncertain).[citation needed] Drowsiness is also a common side effect.

FDA investigation[edit]

In March 2008, the U.S. Food and Drug Administration (FDA) announced that it would investigate whether mood changes and suicidal thoughts are possible side effects of drugs in this class, including the popular drug Singulair, which currently lists these side effects.[5]

On June 12, 2009, the FDA concluded their review into the possibility of neuropsychiatric side effects with leukotriene modulator drugs. Although clinical trials only revealed an increased risk of insomnia, post-marketing surveillance showed that the drugs are associated with a possible increase in suicidal behavior and other side effects such as agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, irritability, restlessness, and tremor.[6]

Use with loratadine[edit]

Schering-Plough and Merck sought permission to market a combined tablet with loratadine (Claritin) and montelukast (Singulair), as many patients combine the two themselves. However, the FDA has found no benefit from a combined pill for seasonal allergies over taking the two drugs in combination,[7] and on April 25, 2008, issued a "not approvable" letter for the combination.[8]

Dosage and administration[edit]

The usual dose of Montelukast in adults and teenagers is one 10 mg tablet taken orally a day. In children 6 to 14 years of age the usual dosage is one 5 mg chewable tablet a day.children 6 months to 6 years old 4 mg granules once daily

Patents[edit]

Singulair was covered by U.S. Patent No. 5,565,473[9] which expired on August 3, 2012.[10] The same day, the FDA approved several generic versions of montelukast.[11]

The United States Patent and Trademark Office launched a reexamination of the patent covering Singulair on May 28, 2009. The decision was driven by the discovery of references that were not included in the original patent application process. The references were submitted through Article One Partners, an online research community focused on finding literature relating to existing patents. The references included a scientific article produced by a Merck employee on the active ingredient in Singulair. A previously filed patent had been submitted in the same technology area.[12] Seven months later the U.S. Patent and Trademark Office determined that the patent in question was valid based on the initial reexamination and new information provided, submitting their decision on December 17, 2009.[13]

References[edit]

  1. ^ Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 178, ISBN 0-8160-4404-X
  2. ^ "Asthma / Allergy ". Mascothealth.com. Retrieved 9 April 2011.
  3. ^ http://www.merckfrosst.ca/mfcl/en/corporate/research/accomplishments/singulair.html
  4. ^ "Montelukast Sodium". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  5. ^ FDA Investigates Merck Drug-Suicide Link
  6. ^ Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR). Food and Drug Administration. Published June 12, 2009. Accessed June 13, 2009.
  7. ^ Rubenstein, Sarah (April 28, 2008). "FDA Sneezes at Claritin-Singulair Combo Pill". The Wall Street Journal. 
  8. ^ Schering-Plough press release - Schering-Plough/MERCK Pharmaceuticals Receives Not-Approvable Letter from FDA for Loratadine/Montelukast
  9. ^ 5,565,473
  10. ^ Singular patent details
  11. ^ "FDA approves first generic versions of Singulair to treat asthma, allergies". 3 August 2012. Retrieved 15 August 2012. 
  12. ^ "U.S. Reexamines Merck's Singulair Patent". Thompson Reuters. May 28, 2009. 
  13. ^ "Merck Says U.S. Agency Upholds Singulair Patent". Thompson Reuters. December 17, 2009. 

External links[edit]