Mast cells symptoms and conditions

Why does Singulair cause these symptoms? I am going to give my explanation which is only a HYPOTHESIS. This should not be categorized as any thing but an educated guess. This is not backed by scientific research because nobody will do any research that would appear to anger
Merck even if people are suffering in the thousands.

1. The original research that preceded the development of Singulair (montelukast) seemed to focus on the theory that asthma was caused by an unusual immune response to certain pathological stimulus. There are many references to the observation that a high percentage of asthma sufferers are people whose asthma is caused by fungus. Many people suffer from asthma and are told that they are allergic to dust mites. Dust mites can live only because the fungus aspergillus pre-digests the
food source that dust mites can then absorb. Other sources of fungus occur in the home due to dampness or problems with wood rot.

2. The body's immune system fights certain categories of pathogens such as bacteria and fungus by creating nitric oxide which kills them at the site where they try to enter the body. The mast cell is the immune cell that is responsible for the production of nitric oxide. Mast cells are found in the skin, airways, intestines etc. The mast cell is capable of many different types of biochemical functions that are designed to signal other cells or other chemical responses. When the mast cell knows that pathogens
are present and nitric oxide is NOT produced, then it signals other immune cells to be sent to the site of the infection. Thus in the case of asthma, it is known that excessive numbers of eosinophils appear in the airways and these cells create inflammation.

3. Singulair was developed for asthma and later allowed to be prescribed for other reasons. I believe that montelukast probably creates a source of nitric oxide that prevents the mast cell from signalling for other immune cells to arrive at the source of infection. I arrived at that conclusion from studying the chemical structure of montelukast, the chemical structure of the gene cysLT1 receptor, and the chemical structure of the cell wall of fungus which would be what the mast cell uses to determine "what to do in order to kill the fungus."

The researchers who invented montelukast first had to clone the gene-cysLT1 receptor meaning that they had to be able to identify the gene and replicate it. Then by trial and error they had a find a "chemical"
that would bind (connect chemically) to the cysLT1 receptor. The theory would be that montelukast would take the place of the fungus or other pathogen and thus prevent the gene from reacting to produce the
responses that the sick patient with asthma produced. Merck says in the literature that montelukast binds with the cysLT1 receptor in order to prevent the mast cell from signalling the eosinophils to arrive in excessive
numbers that cause inflammation. I believe that montelukast is also causing the production of an amount of nitric oxide that is actually killing the pathogens that are present. For one thing, I would think that it
would be dangerous to incapacitate the immune system in that way without providing a way to kill the pathogens. I don't believe that the asthma response is just allergies to something like dust. Pollen from trees and flowers is loaded with fungus spores.

4. IF, IF, IF, montelukast does actually produce nitric oxide, then it does so by binding with the gene. Any place in the body where a molecule of montelukast encounters the cysLT1 receptor (a gene) then the corresponding molecules of nitric oxide are produced before the liver enzymes break the montelukast molecules up. Nitric oxide is TOXIC and
INFLAMMATORY. So let's look at the symptoms in regard to the location of the cysLT1 receptors. The location of these symptoms would not be places in the body where the mast cells normally encounter fungus or bacteria. The cysLT1 also has other functions in that it communicates with the cysLT2 receptors. Obviously, nitric oxide
should not be produced in these locations because of the signalling effect of nitric oxide on other physiological functions.

a. intestinal pain - the cysLT1 receptors are located in the small intestines
b. leg pain actually caused by vasculitis - cysLT1 receptors are found inside blood vessels- consistent with the fact that montelukast causes
Churg-Strauss
c. some people who didn't have asthma develop asthma - the cysLT1 receptors are in the airways
d. nightmares, depression, neurological damage - when montelukast penetrates the blood brain barrier probably due to unusual conditions of blood pH or electrolyte imbalance then nitric oxide in the brain causes neuron damage and excitoxicity

5. Why do some patients not experience side effects? Probably because genetically they are completely compatible with the model that researchers created when they cloned the cysLT1 receptor gene. I didn't not find any information about whether researchers knew that there are many different variations of this gene.

6. IF, my theory is even close to being correct, then why doesn't Merck do anything about researching these side effects. Maybe because nobody in the company knows how this drug works but the researchers who created it. All of the Merck literature is very vague about any biochemical information.

Again, this is just speculation and hypothesis. I have made an attempt to put this in simplistic language and therefore sacrifice scientific accuracy. But, I think that you will get the point.

SINGULAIR IS VERY DANGEROUS TO PATIENTS WHO EXPERIENCE NEGATIVE SIDE EFFECTS. DOCTORS SHOULD JUST REALIZE THAT
THOSE PATIENTS ARE NOT COMPATIBLE WITH THE MODEL FOR THE DRUG.

I already posted about my son's behavioral changes while on the drug from the time he was 4-7. He is now 9 years old and has been back to "normal now for 18 months. BUT- we recently had his immune system checked though a blood test and he does not have sufficient immunity for ANY viruses. My 6 year old could fight 8 out of the 14, but my son who was on Singulair for almost 4 years has a severely depleted immune system. And from what I have read, could clearly be attributed to the drug. BUYER BEWARE~!

I spent the weekend reading about the development of Singulair. The early studies recognized that the first phase of the acute asthma response bronco-constriction was probably not caused by leukotrienes. They identified histamines and prostaglandins as the probable sources. I don't think that changed because the Singulair literature states that it should not be considered as a treatment for that. Leukotrienes were a source of inflammation caused by eosinophils and mast cells present in greater numbers (than normal) in airway tissue. So, it was beneficial to find a way to decrease that.

The cysLT1 receptor was identified as source of the signals that tell the cells to produce leukotriene. The receptor, a gene, consist of 337 (they think) amino acids. They modified a compound that would bind to that receptor thus blocking the cells ability to produce leukotrienes. This compound is very specific. It was formulated to bind to the "model" receptor. This compound will not even bind to cysLT receptor sub-types. (That is the good thing.) There is an enormous amount of research that discusses the genetic variability of the chemical reactions that occur in the leukotriene (calling it this for simplicity) pathway. We are also seeing that a number of researchers would like to use gene profiles to predict whether patients will respond favorably to different asthma/allergy drugs. ALL PATIENTS HAVE A RIGHT TO KNOW IF IT IS INHERENT THAT SOME PEOPLE WILL NOT RESPOND TO SINGULAIR OR RESPOND ADVERSELY.

There are many studies from the 1998 era that conclude that montelukast is not effective for everyone. Those researchers stated that it can be predicted that those people who are going to respond favorably will do that within the first 14 days or so. That conclusion would be consistent with a genetic component for efficacy and safety of Singulair. Those doctors concluded that those who did not respond within that time frame should not take Singulair for fear of harming them. That makes good sense.

The Italian researchers wanted to know if there was more going on than blocking leukotrienes in the action of montelukast. They set up a "test tube" study regarding montelukast, the cysLT1 receptor, and some t-cells that they selected. Why? Researchers always have something on their minds. They observed the death of these particular t-cells.

Montelukast is a quinoline. We basically know of quinilines and quinolones as compounds that were invented as broad spectrum antibiotics. They work because they interference with bacterial DNA so they cannot replicate themselves. Montelukast is a quinoline modified to bind with the cysLT1 receptor (a gene) and prevent that gene from activating. That's consistent with what a quinoline/quinolone does.

So what does montelukast do in blood plasma if it does not bind to the receptor because of genetic mis-match? (If montelukast does bind, then a chemical reaction has occurred and the liver will break down the by-products. Montelukast metabolized in 10-12 hours.) What happens if it doesn't bind? How long before it breaks down? Does it produce toxic by-products?

I want to know what happens to lymphocytes such as t-cells just because montelukast is a quinoline. Maybe nothing but what's up with the Italians researchers? I want to know if montelukast has the capability to interfere with lymphocytes who can clone themselves. That could be a good thing under circumstances when these lymphocytes are causing inflammation. But it could be a bad thing in the case of normal individuals with no problems.

I want to know if the bad side effects are due to the fact that the body has to break down and metabolize a quinoline that did not bind to the receptor for which it was created. The side effects of Singulair are strangely similar to what is observed in the quinolones such as levaquin. I have not as yet been able to compare montelukast as a quinoline to levaquin as a quinolone. I am hoping to find something on these categories. There may be no reason to worry that they cause similar damage. But frankly, I think that there is. There is some terrible chit happening to some people. The scariest is the neurological damage.

All of these questions would be in the everybody pharma knows to ask category. I don't know where the answers are. I haven't found them as of yet. Maybe there are no answers. We have to remember that Singulair and Vioxx were released in the same year. They have continued to be drugs under the current executive management of Merck. If the Vioxx marketing promoters had their ghost writers, why not the Singulair marketing promoters. The genetic component appears to be widely accepted but we haven't heard one thing about even that.

I think that it is sad that maybe the marketing of Singulair as one stop shopping for asthma/allergies may have destroyed the original concept. I really think from reading the original work that they knew that they couldn't engineer a drug for one size fits all. Everybody gets harmed when information is withheld.

Shame on the allergist who yelled at the mother who wanted to discuss issues. Does he know exactly who is allergic to Singulair and who isn't? Get him a dunce hat. Just because Singulair is marketed for allergies does not mean that you cannot be allergic to it. See the power of Madison Avenue? The ad agencies focus group these drugs to death. The ad agencies cleverly craft the product information. A good piece of legislation would be to prohibit consumer drugs ads.

I don't know if my 1 1 /2 year old son's being diagnosed with low igG and low IgA have anything to do with singular. He just got off it 2 weeks ago, had been on it a year. He was tested for allergies everything was negative, but tested very high positive to gliadin IgG (95.5), and positive to gliadin IgA (14.8). Is this related???? HELP!!!!!! The GI Dr want to do an endoscopy on Friday May 2. Any help, I don't want my son under anesthesia unnecessarily..................

My 13 yr old daughter was put on Singulair along with Asmanex and Clarinex for her asthma about 6 weeks ago. Everything seemed to be going very well at first and her symptoms were starting to get controlled. I started noticing after about 3 to 4 weeks that her temper and attitude were getting much worse. Anyone with children this age knows what I mean but this was like a 180 degree turn for her. Her actions were becoming totally out of character. Before I knew it she would cry and get highly upset over the least little thing. Week 5 came around and things totally bottomed out. She came home from school and WAS NOT HERSELF. Made comments about how she hated her life and it was not worth living. Later that evening we had a big argument because I was telling her nothing was worth saying that. She went totally out of control and I had to physically restrain her to calm her down. It appeared everything was better so she went to her room. I went down to check on her and she calmly told me that she had taken advil and tylenol pm and things would be better for her forever now. We went to the ER where they made us wait for at least an hour, then finally took her back. She had to drink two cups of charcoal and was poked and prodded repeatedly. They did a catheter to get a urine sample. She was very cooperative but also was in a complete daze so who knows. The poor child couldn't even lift her head up when she started the vomiting to get rid of the drugs. It was very upsetting and sad. Her heart rate and blood pressure went very low and I really thought in the back of my mind that this was it. Finally, after several hours she started coming out of it and they sent us home. The next evening when she was starting to really come around she proceeded to tell me how she had been seeing a man walking around in her bedroom at night and she was afraid to go down there. Breaking down and crying telling me about all of the horrible nightmares she had been having recently and didn't know why. I thought what am I dealing with here? This just isn't her. Three days ago I heard about singulair in the news and looked it up on the internet. OH MY GOD THIS SOUNDED LIKE US!!!!! I immediately had her stop taking it and the next day phoned her asthma specialist who agreed she should stop now. We are going to watch her for two weeks and see if any symptoms return and then decide if she needs something else or will be fine on just the Asmanex. As a side note, she also mentioned being unable to concentrate in school (unable to do even the simplest math problems) and that her brain felt confused or like something was missing. She said this had been bothering her for several weeks. I know it was this drug. They really need to take this off the market NOW and stop flirting with disaster. The only reason I posted this was to let others know they are not alone.

Unfortunately my lawyer told me that they do not want to take our case because of the lack of evidence that Singulair has caused our daughters problems. :(

Does anyone out there have a pending class action lawsuit that We may be able to get in on? I have tons of proof that Singulair has caused our daughters problems and loss of almost 5 years of her elementary school career!

My phone number is *** and my email is ****** if You email me please put "Singulair" in Your subject line so I know it pertains to this posting.

Thank You in advance,
Chuck & Brenda
Jamestown New York

Effective after two weeks for some people - not effective for others. Side effects for some people - others do not report side effects. So why does Merck have to grow their market before they have any idea what's going on?

This isn't a big group of people in the study but it makes sense from what we are reading here. These researchers did examine the mast cells. We need to know about mast cells (while suppressed by montelukast) on a longer term basis.

J Asthma. 2008 Apr;45(3):243-50. Links
The efficacy of montelukast and airway mast cell profiles in patients with cough variant asthma.Kawai S, Baba K, Matsubara A, Shiono H, Okada T, Yamaguchi E.
Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan.

Background. Cough variant asthma (CVA) is characterized by chronic cough without apparent wheezing; its pathophysiology is considered to be similar to that of classic asthma. Objective. The clinical effects of montelukast, a cysteinyl-leukotriene receptor antagonist, on cough variant asthma were assessed, and the activation profile of airway mast cells was examined. Methods. Montelukast (10 mg/day) was given orally to 36 CVA patients (25 women and 11 men; median age, 37.5 years). Before treatment, the patients' bronchial mucosa underwent a biopsy with a fiberoptic bronchoscope. The biopsy specimens were double stained with anti-CD63 antibody and anti-human tryptase antibody. Results. After 2 weeks of montelukast treatment, cough symptoms improved in 22 patients (the effective group) but did not improve in 14 patients (the ineffective group); in the ineffective group, the symptoms disappeared 2 weeks after they were switched to fluticasone propionate (400 mug/day) inhalation therapy. In the effective group, the time interval from the onset of symptoms to the initiation of treatment was significantly shorter than in the ineffective group. The bronchial mucosa biopsy specimens showed that the proportion of CD63-positive cells in tryptase-positive mast cells was significantly higher in the effective group than in the ineffective group; although the total numbers of mast cells were not different between the two groups. Conclusion. There is a subgroup of CVA patients in whom leukotrienes are closely involved in the pathogenesis of their chronic cough; activation of airway mast cells may be an essential feature in these patients.

PMID: 18415834

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.

Doctors should realize that we continue to learn something new every day. Nobody should ever believe that we know the answers. Everything should be constantly questioned.

My life is an example of "who knew" but I am the miracle, the lucky one. I was born pre-mature, very small for almost 60 years ago. Another baby was also born on that day pre-mature. We were placed in the incubator together. No one really knew the dangers of oxygen levels and the eyes. The baby who was next to me has lived as a permanently blind -- never saw anything about the world. I somehow never opened my eyes. I wasn't breathing well and was more knocked out. But one baby lived normally and the other didn't. So there will always be a "who knew."
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I have been concerned that the fact that Singulair binds with a leukotriene receptor on the mast cell and blocks one of it's function has possibly opened up a pandora's box of other problems. As I said before, there is communication between several receptors on the mast cell that determine how it performs it's normal function. I finally found an abstract written pretty clearly that does reference some of these concerns.

J Allergy Clin Immunol. 2004 Jul;114(1):21-7. Links
Mast cells in innate immunity.Marshall JS, Jawdat DM.
Dalhousie Inflammation Group, the Departments of Pathology and Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. jean.marshall@dal.ca

Mast cells have been most extensively studied in their traditional role as an early effector cell of allergic disease. However, in the majority of individuals, it might be the role of this cell as a sentinel in host defense that is most important. Mast cells have been repeatedly demonstrated to play a critical role in defense against bacterial infections, and evidence for their involvement in early responses to viral and fungal pathogens is growing. Mast cells are activated during innate immune responses by multiple mechanisms, including well-established responses to complement components. In addition, novel mechanisms have emerged as a result of the explosion of knowledge in our understanding of pattern-recognition receptors. The mast cell shares many features with other innate immune effector cells, such as neutrophils and macrophages. However, a unique role for mast cells is defined not only by their extensive mediator profile but also by their ability to interact with the vasculature, to expedite selective cell recruitment, and to set the stage for an appropriate acquired response.
Copyright 2004 American Academy of Allergy, Asthma and Immunology

In other words, mast cells play a key role in the development of the immune system. The child's immune system is changing and developing every day. If we block one of the mast cell's receptors, what are we doing to the entire system.

I have been looking for studies that addressed the long term effects of Singulair on the immune system in other animals like pigs. I am still searching.

I know that many here would like the FDA to take a very serious took at the problem. I personally don't see how a review of their data is going to make any difference at all. But, if there are experts who can propose a model of the pathways of cell signalling that include the possibility that these symptoms can occur (and under what circumstance), then maybe the problem will look like something much more than statistics.

This is not my field. But I tried to follow the possible pathways to see if I could identify a possible area of concern. Then I looked for someone who had written in the area and read their abstract. A place to start may be to get an opinion from those who know something about "normal homeostasis of the mast cell." Singular blocks the cysteinyl leukotriene receptor 1 which is a site on the outer membrane of the mast cell (other cells also). The mast cell which is produced in the bone marrow is released in a immature state and matures after it arrives at it's destination. The mast cell does not become active unless it's receptor sites come in contact with the activating agent. So, what happens when a receptor site on the mast cell is suppressed by Singular, a receptor antagonist.

You see, I don't have a clue what the signals are that tell the bone marrow to make mast cells (or what the signals are that tell them where to go after they are made in the bone marrow). Does Singular interfere with something that tells the bone marrow what to do? If Singular does interfere with that process, then what is happening and what period of time does it take to happen? Could we wonder whether Singular is interfering with the NUMBER of mast cells that are produced over time? And, of course, maybe there is some OTHER kind of explanation for why the adverse drug reactions are happening. But, at this level, I got lost and can't go any further.

Maybe this group would be interested in the Singulair problems or could suggest somebody else?

http://www.edata-center.com/journals/2ff21abf44b19838,0a1257122f661a7e,0d8ee7116ef23452.html

I apologize if this lead doesn't produce any results but at least it could be a place to start.