Cysteinyl leukotrienes symptoms and conditions

I was reading some research from the 90's where one researcher called montelukast an inverse agonist. So then, I looked for any thing more current on that subject. It would seem that genetic variation is again involved.

1: J Pharmacol Exp Ther. 2004 Apr;309(1):102-8. Epub 2004 Jan 12. Links
Inverse agonist activity of selected ligands of the cysteinyl-leukotriene receptor 1.Dupré DJ, Le Gouill C, Gingras D, Rola-Pleszczynski M, Stanková J.
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4 Canada.

Cysteinyl leukotrienes (CysLTs) are associated with several inflammatory processes, including asthma. Due to this association, considerable effort has been invested in the development of antagonists to the CysLT receptors (CysLT(1)R). Many of these molecules have been shown to specifically interact with CysLT(1)R, but little is known about their impact on the conformation of the receptor and its activity. We were especially interested in possible inverse agonist activity of the antagonists. Using a constitutively active mutant (N106A) of the human CysLT(1)R and the wild-type (WT) receptor coexpressed with the G(alphaq) subunit of the trimeric G protein, we were able to address this issue with ligands commonly used in therapy. We demonstrated that some of these molecules are inverse agonists, whereas others act as partial agonists. In cells expressing the CysLT(1)R mutant N106A exposed to Montelukast, Zafirlukast, or 3- phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), the basal inositol phosphate production was reduced by 53 +/- 6, 44 +/- 3, and 54 +/- 4%, respectively. On the other hand, 6(R)-(4-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid (BayU9773) and 1- -phenyl ethanone] (LY171883) acted as partial agonists and alpha-pentyl-3- benzyl alcohol (REV 5901) as a neutral antagonist. However, in cells expressing CysLT(1)R and G(alphaq), all antagonists used had inverse agonist activity. The decrease in basal inositol phosphate production by ligands with inverse agonist activity could be inhibited by a more neutral antagonist, confirming the specificity of the reaction. We demonstrate here that Montelukast, MK571, and Zafirlukast can act as inverse agonists on the human CysLT(1) receptor.

PMID: 14718577

CysLT1 receptor (the one that Singulair blocks) is also expressed (shows up) in the spleen. I have not seen anything yet that says what it does in the spleen. The spleen has important immune system functions especially in children. It contains B-lymphocytes that fight infection.

: Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:587-97.Links
Cysteinyl leukotriene receptors.Evans JF.
Department of Pharmacology, Merck Research Laboratories, Merck & Co., West Point, PA 19486, USA. jilly_evans@merck.com

The cysteinyl leukotrienes, leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), activate contractile and inflammatory processes via specific interaction with putative seven transmembrane-spanning receptors that couple to G proteins and subsequent intracellular signaling pathways. Pharmacological characterizations identified at least two subtypes of cysteinyl leukotriene (CysLT) receptor based on agonist and antagonist potency for biological responses. The rank potency of agonist activation for the CysLT1 receptor is LTD4 > LTC4 > LTE4 and for the CysLT2 receptor is LTC4 = LTD4 > LTE4. CysLT1 selective receptor antagonists are efficacious in the treatment of asthma. No selective CysLT2 receptor antagonists have been described. Molecular identification of the human and mouse CysLT1 and CysLT2 receptors has confirmed their structure as putative seven transmembrane domain G protein-coupled receptors and largely confirmed the previous pharmacological characterizations. The CysLT1 receptor is most highly expressed in spleen, peripheral blood leukocytes including eosinophils, and lung smooth muscle cells and interstitial lung macrophages. The CysLT2 receptor is most highly expressed in the heart, adrenal medulla, placenta and peripheral blood leukocytes. The molecular identification of the mouse CysLT1 and CysLT2 receptors show similar but not identical profiles to the orthologous human receptors.

PMID: 12432945

Hopefully this will prove to the doubters that there are genetic reasons for the variation of efficacy and adverse side effective when taking Montelukast.

I have several areas of concern (concerned citizen is concerned). One of the main areas is the reliability of Montelukast due to differences in genetics among populations. The cysLT1 (Singulair) receptor is a GENE. As I said before, it would be possible to predict those patients for which Montelukast would and would not be effective and those patients whose gene expression profile would cause them to have unwanted side effectives.

I have been looking for a way to give reasonable proof of that which could be used to convince your doctors that Montelukast is not for everybody. I happened to locate a researcher who had invented and patented methods for predicting drug sensitivity and efficacy in inflammatory disease. I have quoted below from his patent application. He intended to provide a method for determining efficacy and drug sensitivity for pharmaceuticals which include leukotriene antagonists - Montelukast.

Quoted from:

Methods for predicting drug sensitivity in patients afflicted with an inflammatory disease
US Patent Issued on December 12, 2006

Methods are disclosed for predicting the efficacy of a drug for treating an inflammatory disease in a human patient, including: obtaining a sample of cells from the patient; obtaining a gene expression profile of the sample in the absence and presence of in vitro modulation of the cells with specific cytokines and/or mediators; and comparing the gene expression profile of the sample with a reference gene expression profile, wherein similarities between the sample expression profile and the reference expression profile predicts the efficacy of the drug for treating the inflammatory disease in the patient.

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The field of pharmacogenomics measures differences in the effect of medications that are caused by genetic variations. Such differences are manifested by differences in the therapeutic effects or adverse events of drugs. For most drugs, the genetic variations that potentially characterize drug-responsive patients from non-responders remain unknown.
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In another embodiment, the invention is directed to a method for predicting the efficacy in a human asthma patient of leukotriene antagonists including, but not limited to, montelukast (a.k.a., SINGULAIR™; Merck, Whitehouse Station, N.J.), zafirlukast (a.k.a., ACCOLATE™, AstraZeneca, Wilmington, Del.), and zileuton (a.k.a., ZYFLO™; Abbott Laboratories, Chicago, Ill.), comprising: obtaining a sample of cells from the patient; obtaining a gene expression profile from the sample in the absence and presence of in vitro modulation of the cells with specific mediators; and comparing the gene expression profile of the sample with a reference gene expression profile, wherein similarity in expression profiles between the sample and reference profiles predicts the efficacy in the human asthmatic patient of leukotriene antagonists.

Many of the cells involved in causing airway inflammation are known to produce signaling molecules within the body called "leukotrienes." Leukotrienes are responsible for causing the contraction of the airway smooth muscle, increasing leakage of fluid from blood vessels in the lung, and further promoting inflammation by attracting other inflammatory cells into the airways. Oral anti-leukotriene medications have been introduced to fight the inflammatory response typical of allergic disease. These drugs are used in the treatment of chronic asthma. Recent data demonstrates that prescribed anti-leukotriene medications can be beneficial for many patients with asthma, however, a significant number of patients do not respond to anti-leukotriene drugs.

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The genes selected are those that have been determined to be differentially expressed in either a disease, drug-responsiveness, or drug-sensitive cell relative to a normal cell and confer power to predict the response to the drug. By comparing tissue samples from patients with these reference expression profiles, the patient's susceptibility to a particular disease, drug-responsiveness, or drug-resistance can be determined.

http://www.patentstorm.us/patents/7148008-description.html

The inventor's website: Hakon Hakonarson M.D. The Children's Hospital of Philadelphia

http://stokes.chop.edu/research/profiles/?ID=251

If anyone has any access to databases that can describe the history of drug licensing in other countries and whether Merck had to amend product statements, this is worth investigating. I do know that montelukast was at least not initially licensed for seasonal allergies in the United Kingdom when the FDA granted approval in the US. As of 2006, seasonal allergies were not on the approved listed in the UK.

More to add to the files:

Safety of leukotriene antagonists
United Kingdom — The Medicines Control Agency
has published a review of adverse drug reactions to
a new class of asthma drugs, leukotriene antagonists.
Zafirlukast and moltelukast, competitive cysteinyl
leukotriene type-1 receptor antagonists, were
both marketed for the first time in 1998.
Cysteinyl leukotrienes are inflammatory mediators
and potent constrictors of bronchial smooth muscle
that attract human eosinophils and cause airway
oedema, mucus hypersecretion and reduced
mucociliary clearance. By blocking this action, leukotriene
antagonists can improve respiratory function
and lessen symptoms in patients with asthma.
The pharmacological action of leukotrienes is quite
complex and varying side effects have been
reported. Zafirlukast inhibits the hepatic cytochrome
P4502C9, and interacts with warfarin, theophyllin,
terfenadine, acetylsalicylic acid and erythromycin.
Montelukast is metabolized by hepatic cytochrome
P450CYP3A4 and co-administration of such drugs
as phenytoin, phenobarbitone and rifampicin, which
induce this enzyme, result in a marked reduction in
plasma levels.
Side-effects identified during clinical trials were
headache, abdominal pain, nausea, diarrhoea,
gastro-enteritis, influenza, pharyngitis, sinusitis,
cough, nasal congestion, dizziness, fatigue and insomnia.
Since marketing of montelukast, 173 reports
of 317 suspected adverse drug reactions
have been received in the United Kingdom. These
include oedema (50), psychiatric reactions, including
including agitation/restlessness (15), allergy, including
anaphylaxis, angioedema and urticaria (10), chest
pain (7), tremor (5), mouth dryness (5), vertigo (4)
and arthralgia (3).
Reference: Current Problems in Pharmacovigilance,
Volume 24, August 1998.
https://www.who.ch/druginformation/vol12/12-4.pdf

From Canada:

Leukotriene receptor antagonists: suspected adverse reactions

The cysteinyl leukotrienes are inflammatory mediators that bind to cysteinyl leukotriene receptors found in the human airway and cause a number of airway actions including bronchoconstriction, mucous secretion, vascular permeability and eosinophil recruitment.1 Zafirlukast (Accolate®) and montelukast sodium (Singulair®), marketed in Canada since November 1997 and August 1998 respectively, are competitive cysteinyl leukotriene receptor antagonists. Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in patients 12 years of age and older.2 Montelukast is indicated for the prophylaxis and chronic treatment of asthma, the treatment of asthma in ASA-sensitive patients and the prevention of exercise-induced bronchoconstriction in pediatric patients 6-14 years of age and adults 15 years of age and older.1

As of June 1, 1999, the CADRMP has received 41 reports of suspected adverse drug reactions associated with the use of zafirlukast and 22 associated with the use of montelukast. This article will discuss a serious and rare adverse reaction associated with the use of these agents, drug-drug interactions and unexpected adverse reactions that have been reported to the CADRMP.

http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v9n4_e.html

Conditions are discussed in the article.