Receptor antagonists symptoms and conditions

Our 11 yr. old daughter was prescribed with Singulair. She started taking it today with much hesitation from her parents. She was on this medication years ago for her mild asthma, but her mood swings/depression were terrible. We have a new ENT now and he promises that the mood swings/depressions are NONSENSE and that these rumors were put to rest years ago. We will be watching her side effects closely, but my question is if Singulair helps so much, what other medication can someone take that does not have these side effects? What is the alternative? She is also going to see a pediatric pulmonologist in August.

Singulair associated with Churg-Strauss. A study in France and Germany.

Thorax. 2008 Aug;63(8):677-82. Epub 2008 Feb 14. Links
The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study.Hauser T, Mahr A, Metzler C, Coste J, Sommerstein R, Gross WL, Guillevin L, Hellmich B.
Dr A Mahr, Department of Internal Medicine, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. alfred.mahr@cch.aphp.fr.

BACKGROUND: There has been some concern that leucotriene receptor antagonists might precipitate the onset of Churg-Strauss syndrome (CSS). A study was undertaken to investigate the relationship between the leucotriene receptor antagonist montelukast and the onset of CSS. METHODS: Medication histories of 78 patients with CSS from France and Germany were retraced by questioning the patients, treating physicians and dispensing pharmacists, and from medical records. Using a case-crossover research design, exposures to montelukast and other asthma medications during the 3-month "index" period immediately preceding the onset of CSS were compared with those of four previous 3-month "control" periods. Odds ratios (ORs) were computed by conditional logistic regression. RESULTS: The ORs for CSS onset were 4.5 (95% CI 1.5 to 13.9) for montelukast, 3.0 (95% CI 0.8 to 10.5) for inhaled long-acting beta(2) agonists, 1.7 (95% CI 0.5 to 5.4) for inhaled corticosteroids and 4.0 (95% CI 1.3 to 12.5) for oral corticosteroids. Montelukast exposure during control periods increased temporally over three consecutive calendar periods of CSS onset from 1999 to 2003 (p(trend) <0.0001). CONCLUSION: Montelukast use was associated with a 4.5-fold higher risk of CSS onset within 3 months. However, the positive estimates obtained for other long-term asthma control medications suggest that this link might be confounded by a general escalation of asthma therapy before CSS onset. The association between montelukast and CSS observed in this study is probably also explained by the increasing use of this medication over time.

PMID: 18276721

How does montelukast affect laminin beta2? I don't know but this came up when I cross referenced N106A.

Synthesis of tenascin and laminin beta2 chain in human bronchial epithelial cells is enhanced by cysteinyl leukotrienes via CysLT1 receptor

Cysteinyl leukotrienes (CysLTs) are key mediators of asthma, but their role in the genesis of airway remodeling is insufficiently understood. Recent evidence suggests that increased expression of tenascin (Tn) and laminin (Ln) beta2 chain is indicative of the remodeling activity in asthma, but represents also an example of deposition of extracellular matrix, which affects the airway wall compliance.

We tested the hypothesis that CysLTs affect production of Tn and Ln beta2 chain by human bronchial epithelial cells and elucidated, which of the CysLT receptors, CysLT1 or CysLT2, mediate this effect.

Methods: Cultured BEAS-2B human bronchial epithelial cells were stimulated with leukotriene D4 (LTD4) and E4 (LTE4) and evaluated by immunocytochemistry, Western blotting, flow cytometry, and RT-PCR.

CysLT receptors were differentially blocked with use of montelukast or BAY u9773.

Results: LTD4 and LTE4 significantly augmented the expression of Tn, whereas LTD4, distinctly from LTE4, was able to increase also the Ln beta2 chain.

Although the expression of CysLT2 prevailed over that of CysLT1, the up-regulation of Tn and Ln beta2 chain by CysLTs was completely blocked by the CysLT1-selective antagonist montelukast with no difference between montelukast and the dual antagonist BAY u9773 for the inhibitory capacity.

Conclusion: These findings suggest that the CysLT-induced up-regulation of Tn and Ln beta2 chain, an important epithelium-linked aspect of airway remodeling, is mediated predominantly by the CysLT1 receptor.

The results provide a novel aspect to support the use of CysLT1 receptor antagonists in the anti-remodeling treatment of asthma.

Author: Siiri Altraja, Martin Kadai, Erki Rekker and Alan Altraja
Credits/Source: Respiratory Research 2008, 9:44

Published on: 2008-05-26

A smaller recent study from Spain showing a genetic component of montelukast efficacy.

1: Respir Med. 2008 Jun;102(6):857-61. Epub 2008 Mar 12. Links
ALOX5 promoter genotype and response to montelukast in moderate persistent asthma.Telleria JJ, Blanco-Quiros A, Varillas D, Armentia A, Fernandez-Carvajal I, Jesus Alonso M, Diez I.
Institute of Biology and Molecular Genetics (IBGM/CSIC), University of Valladolid, Valladolid, Spain; Department of Pediatrics, University of Valladolid, Valladolid, Spain.

BACKGROUND: It was hypothesized that asthmatic patients with mutant alleles in the leukotriene pathway should not respond to leukotriene receptor antagonists and the concept of a tailored treatment is increasingly supported. METHODS: Sixty-one patients (mean age 24.9 years, range 14-52) with moderate persistent asthma were clinical and immunological assess prior and after a 6-month treatment with montelukast. Tandem repeat polymorphisms were genotyped in the promoter (-147 to -176) of 5-lipoxygenase gene (ALOX5). RESULTS: Thirty-two patients (52.5%) were homozygous for the five repeats allele; 17 (27.9%) were heterozygous (4/5 repeats) and 12 (19.7%) were homozygous for 4/4 repeats. After the montelukast treatment decrease number of asthma exacerbations, improvement of FEV(1) and decreased use of beta(2) agonists was observed in patients with 5/5 or 4/5 repeats. Conversely, the patients with 4/4 repeats genotype did not modify these data after treatment. CONCLUSIONS: It was confirmed that ALOX5 promoter polymorphisms have a clear influence in montelukast response in atopic moderate persistent asthma patients. The genetic study could identify those patients most likely to respond to montelukast.

PMID: 18339529

http://www.ncbi.nlm.nih.gov/pubmed/18339529

I don't have any conclusions to report because I have recruited friends to help me. I got over my head as far as my understanding of this type of chemistry. I am particularly interested in what happens to the quinoline nitrogen during the metabolic break down of montelukast. Nitric oxide is an important molecule to the human body. BUT, however, in excess it is very toxic. The year of this study 1998, some medical researchers got the Nobel prize for their work on nitric oxide.

http://nobelprize.org/nobel_prizes/medicine/laureates/1998/press.html

So I am now working with friends to try to further understand the Merck report on the metabolism of montelukast. I found a Japanese researchers opinion of the connections of montelukast and the cysLT1 receptor showing the nitrogen as a key factor. I was also able to find some work done on mold spores that might give some clues because DPA - 2,6 pyridine dicarboxylic acid in the spore case might yield something about the receptor and/or quinolinic acid 2,3 pyridinedicarboxylic acid. I haven't concluded anything about Fenton reactions as of yet but that is always something to think about.

If anyone has any chemist friends, we could use some real experts in this field not just someone like me, CC, who can read and collect research.

J Med Chem. 1998 Apr 23;41(9):1439-45. Links
Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.Zwaagstra ME, Schoenmakers SH, Nederkoorn PH, Gelens E, Timmerman H, Zhang MQ.
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'- flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.

PMID: 9554877

I had made the point that Merck had looked at structures other than quinolines. I am not making a reference at the time frame just that they looked at other structures. I didn't have the proof of that then so I am posting that now.

L-733,321 a pyridyl analog of montelukast was an alternative leukotriene receptor antagonist.( L-733,560 is Merck's anti-fungal drug Cancidas.)

Bioorg Med Chem Lett. 1998 Mar 3;8(5):453-8. Links
A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair

Guay D, Gauthier JY, Dufresne C, Jones TR, McAuliffe M, McFarlane C, Metters KM, Prasit P, Rochette C, Roy P, Sawyer N, Zamboni R.
Merck Frosst Center for Therapeutic Research, Québec, Canada.

The structure-activity relationship of a series of styrylpyridine analogs of MK-0476 (montelukast, Singulair) is described. This work has led to the identification of a number of potent and orally active cysLT1 receptor (LTD4 receptor) antagonists including 2ab (L-733,321) as an optimized candidate.

PMID: 9871597

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