Cys symptoms and conditions

"Montelukast (Merck brand name Singulair) is a selective Cys-LT1 receptor antagonist that is used to control asthma symptoms in children and adults. Although safe and effective, the inter-patient variability in response is substantial (25-60% response rate), which is due in part to genetic variability. For example, we recently reported that polymorphisms in candidate genes that encode proteins in the LT pathway influence responsiveness to the drug."

Co-sponsored by Merck

http://clinicaltrials.gov/ct2/show/record/NCT00513760

One of the most important questions we should be asking as parents is:

How does Singulair - a leukotriene receptor antagonist (blocks the receptors) affect the normal function of the mast cell?

The mast cell is the FRONT LINE DEFENSE against invading micro-organisms. When Singulair was invented, there was limited knowledge regarding the mechanisms by which the mast cell performed it's function. In my opinion, the focus was very narrow - those interested zeroed in on how the leukotriene receptor performed a role in the cause of asthma attacks and how ashma attacks could be prevented. Well, that's good preventing asthma attacks. But what happens to the mast cell if that receptor is blocked on a long term basis. I am not suggesting that blocking the receptor is bad but what if the long term effect is different than what we are are lead to believe-which is this is a safe medication with no known long term effects. What if the leukotriene receptor was just blocked short term a week or two to allow the body to clean up the mess from the last attack?

I seriously question what is going on with all of these infections. Are they related to crippling the mast cell? Parents should be allowed to question. If Merck doesn't want to answer questions regarding what happens to the mast cell (including are the numbers of mast cell decreased on Singulair), then something really BIG is missing. If by any chance (unknown at the moment) that the mast cell is significantly changed and therapy by montelukast is proper on a short but not long term basis, so freakin' what if Singulair is not a huge money maker any more.

Parents deserve every answer possible when decisions regarding their child's growth and development is on the line. I hope that we get some answers.

Of course, what was there in 2002 were new questions-not necessarily answers about the mast cell. Did anybody apply this to Singulair studies?
May 2002

From Journal of Clinical Investigation

Pattern recognition receptors on mast cells
The Toll-like receptors (TLRs) fit the definition of pattern-recognition molecules, which were originally postulated to allow the innate immune system to detect the 'molecular signatures' of various infectious agents. Although the innate immune system has no memory, it shows a degree of specificity, in part because the various TLRs recognize different sets of pathogen-associated molecules. Dermal mast cells are usually associated, not with the innate immune system, but with atopic dermatitis, but Supajatura et al. have found that these cells also express TLRs. They report here that TLR4, which binds the gram-negative product lipopolysaccharide (LPS), and TLR2, which binds peptidoglycan (PGN) from gram-positive organisms like Staphylococcus aureus, induce distinct mast cell responses. Staphylococcus is known to exacerbate allergic dermatitis, but it has generally been thought to act by inducing antibacterial IgE's, which trigger mast cell degranulation by stimulating the IgE receptor. Interestingly, the authors show that the interaction between PGN and TLR2 can provoke mast cell degranulation directly, sidestepping the need for IgE receptor engagement.

When I saw that researchers acknowledged the number of potential gene variants that are involved in determining the efficacy of montelukast and then I am reading the reports of the side effects, I am wondering why montelukast was ever approved for seasonal allergies. Asthma is potentially life threatening. But why take Singulair -montelukast for annoying allergies that won't kill you.

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" However, logically one might predict that it will be the combination of the polymorphisms in these different key regulatory enzymes and receptors that may ultimately determine treatment response. There have been some attempts to tease out the possible contribution of different genes important in this pathway for treatment response to a Cys leukotriene receptor 1 antagonist.18 However, because of the number of potential gene variants that may contribute to efficacy, large studies will be needed to fully evaluate the potential contribution of pharmacogenetic variability in this pathway to treatment response to Cys leukotriene receptor 1 antagonists. Work in the cardiovascular field has demonstrated the potential importance of genetic variants in this pathway to disease risk and also to treatment response,19 suggesting the potential for important effects to be defined in asthma."

(Chest. 2006;130:1873-1878.)
© 2006 American College of Chest Physicians

Pharmacogenetics of Asthma
Ian P. Hall, DM
* From the Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, UK.
Correspondence to: Ian P. Hall, DM, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK; e-mail: Ian.Hall@nottingham.ac.uk

http://www.chestjournal.org/cgi/content/full/130/6/1873

.

Some of you who are following this site may remember that I posted that when I was following the pathways of the leukeotriene receptor antagonist Singulair that I got to a point where I concluded that there has to be a genetic component (meaning that there are different gene groups of people) and that the efficacy of Singulair (and possibly safety) can vary depending upon what gene group people are in. So I took a little time to see if anybody else was already studying that issue. And YES, they are -- including Merck.

quote:

" However, logically one might predict that it will be the combination of the polymorphisms in these different key regulatory enzymes and receptors that may ultimately determine treatment response. There have been some attempts to tease out the possible contribution of different genes important in this pathway for treatment response to a Cys leukotriene receptor 1 antagonist.18 However, because of the number of potential gene variants that may contribute to efficacy, large studies will be needed to fully evaluate the potential contribution of pharmacogenetic variability in this pathway to treatment response to Cys leukotriene receptor 1 antagonists. Work in the cardiovascular field has demonstrated the potential importance of genetic variants in this pathway to disease risk and also to treatment response,19 suggesting the potential for important effects to be defined in asthma."

(Chest. 2006;130:1873-1878.)
© 2006 American College of Chest Physicians

Pharmacogenetics of Asthma
Ian P. Hall, DM
* From the Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, UK.
Correspondence to: Ian P. Hall, DM, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham NG7 2UH, UK; e-mail: Ian.Hall@nottingham.ac.uk

http://www.chestjournal.org/cgi/content/full/130/6/1873

And Merck sponsored a study on this which is now completed.

http://clinicaltrials.gov/ct2/show/NCT00116324?intr=%22Montelukast%22&rank=79

Of course, it was sponsored by Merck and paid for by Merck.

I don't know if the study discovered anything but I believe this is an indication that Merck acknowledges genetic differences in populations that may predict the success of montelukast.

I am not any where close to being an expert in this field. I have another background but I believe that there are experts who can tell you exactly why you had side effects from Singulair.