Montelukast

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Montelukast
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 namesSingulair
AHFS/Drugs.commonograph
MedlinePlusa600014
Pregnancy cat.B (U.S.), B1 (Au)
Legal statusRx Only (U.S.), POM (UK), S4 (Au)
RoutesOral
Pharmacokinetic data
Bioavailability63% to 73%
Protein binding99%
MetabolismHepatic (CYP3A4 and CYP2C9-mediated)
Half-life2.7-5.5 hours
ExcretionBiliary
Identifiers
CAS number158966-92-8 YesY
ATC codeR03DC03
PubChemCID 5281040
DrugBankDB00471
ChemSpider4444507 YesY
UNIIMHM278SD3E YesY
KEGGD08229 YesY
ChEBICHEBI:50730 YesY
ChEMBLCHEMBL787 YesY
Chemical data
FormulaC35H36ClNO3S 
Mol. mass586.184 g/mol
 YesY (what is this?)  (verify)
 
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Montelukast
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 namesSingulair
AHFS/Drugs.commonograph
MedlinePlusa600014
Pregnancy cat.B (U.S.), B1 (Au)
Legal statusRx Only (U.S.), POM (UK), S4 (Au)
RoutesOral
Pharmacokinetic data
Bioavailability63% to 73%
Protein binding99%
MetabolismHepatic (CYP3A4 and CYP2C9-mediated)
Half-life2.7-5.5 hours
ExcretionBiliary
Identifiers
CAS number158966-92-8 YesY
ATC codeR03DC03
PubChemCID 5281040
DrugBankDB00471
ChemSpider4444507 YesY
UNIIMHM278SD3E YesY
KEGGD08229 YesY
ChEBICHEBI:50730 YesY
ChEMBLCHEMBL787 YesY
Chemical data
FormulaC35H36ClNO3S 
Mol. mass586.184 g/mol
 YesY (what is this?)  (verify)

Montelukast (trade names Singulair, Montelo-10 and Monteflo 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. 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 focus of operation, 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]

Contents

Medical uses

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

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). Drowsiness is also a common side effect.

FDA investigation

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 Food and Drug Administration 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

Schering-Plough and Merck have 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]

Patents

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]

On May 28, 2009, the United States Patent and Trademark Office announced their decision to launch a reexamination of the patent covering Singulair. The decision to reexamine 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 around the key ingredient of Singulair, and a previously filed patent in the same technology area.[12]

On December 17, 2009, the U.S. Patent and Trademark Office determined that the patent in question was valid based on the initial reexamination and new information provided.[13]

References

  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. http://www.drugs.com/monograph/montelukast-sodium.html. 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. http://blogs.wsj.com/health/2008/04/28/fda-sneezes-at-claritin-singulair-combo-pill/?mod=WSJBlog.
  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". 03 August 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm314436.htm. Retrieved 15 August 2012.
  12. ^ "U.S. Reexamines Merck's Singulair Patent". Thompson Reuters. May 28, 2009. http://www.reuters.com/article/2009/05/28/merck-singulair-idUSN2834535820090528.
  13. ^ "Merck Says U.S. Agency Upholds Singulair Patent". Thompson Reuters. December 17, 2009. http://www.reuters.com/article/2009/12/17/merck-singulair-idUSWEN770820091217.

External links