Leukotrienes 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 just came across an article on the online "Huffington Post" by Dr. Doug Bremner, who researched the connection between accutane and depression, called "If Prescription Meds Don't Kill You They Might Drive You Crazy" He explains the link between Singulair, Leukotrienes in the brain and depression. There are numerous articles by him as well that are definitely worth reading.

Jenna M.
Parents United for Pharmaceutical Safety and Accountability

Sales of Merck's asthma and allergy drug Singulair dropped 1% to $1.1 billion for the second quarter. U.S. sales have been hurt by the recent introduction of an over-the-counter version of rival drug Zyrtec by Johnson & Johnson (JNJ), as well as concerns about the Food and Drug Administration's March alert of a possible association between Singulair and suicide and related behavioral side effects Got this off cnn money,i don't know but thought zyrtec and singulair were different drugs,my son at one time was prescribed both to take at bedtime

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

Many people have asked why I suggested that Omega-3 from fish oil MIGHT possibly help those retrying to recuperate from the adverse side effects of Singulair. It is my opinion, that it MIGHT help the body return to balance. And unless we OD on Omega-3 from dietary sources, (avoid tuna fish high in mercury), then it won't hurt.

Mechanisms and innovations

The science behind dietary omega-3 fatty acids
Marc E. Surette, PhD
Marc Surette is Professor and Canada Research Chair in Cellular Lipid Metabolism, Département de Chimie et Biochimie, Université de Moncton, Moncton, NB

Correspondence to: Dr. Marc Surette, Département

"When cells are activated by external stimuli, arachidonic acid is released from cell membranes and is transformed into powerful cellular mediators such as thromboxanes, prostaglandins and leukotrienes.10 These compounds possess a range of activities, including activation of leukocytes and platelets, regulation of gastric secretions, induction of bronchoconstriction and signaling of pain in nerve cells. The importance of these compounds in health and disease is evident by the range of pharmaceutical products that target their biosynthesis or action.11 Indeed, arachidonic acid metabolism is the target of nonsteroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, ibuprofen), cyclooxygenase-2 (COX-2) inhibitors (e.g., rofecoxib, celecoxib12) and leukotriene antagonists (e.g., montelukast, zafirlukast).13 Dietary omega-3 fatty acids directly affect arachidonic acid metabolism because they displace arachidonic acid from membranes and compete with arachidonic acid for the enzymes that catalyze the biosynthesis of thromboxanes, prostaglandins and leukotrienes.8 Thus, the net effect of consuming foods enriched in omega-3 fatty acids is a diminished potential for cells like monocytes, neutrophils and eosinophils to synthesize these powerful arachidonic acid–derived mediators of inflammation and a diminished potential for platelets to produce the prothrombotic agent thromboxane A2." (Surette, 2008).

******

We have all been saying that our issues regard not being informed about all of the possible side effects. And, we know that Singulair works well for some people. Nobody wants to take a good drug away from those for which it probably performs miracles. People who have toxic side effects have a right to know up front.

My observations about montelukast's chemical structure are either general or not quite 100% correct or could be quite vague - so forgive me. I do not claim to be good at organic chemistry. But from doing a little work, I have come up with some observations.

1. It would seem to me that montelukast might work quite well for people who have developed mold category related asthma. I observed that chloroquinolin, a component of montelukast, is a good fungicide effective against Aspergillus, Alternaria, Cladosporium, Penicillium and Candida. Dust mites can only digest if helped by aspergillus so they go into the mold category. Molds produce millions of spores so anyone who lives in contact with mold would be chronically sick from their presence. Then people get hypersensitized to that.

I am probably wrong but I could imagine that montelukast is: 1) a ligand that binds to an empty cysLT1 receptor for a period of time 2) 7-chloroquinolin-2-yl which either acts intact or breaks down into a quinoline fungicide so that it kills the chronic mold/fungus infection and 3) a sulphur/methyl anti-inflammatory component that tells the t-cells that they are not needed so they will die. Wow, that would be great for mold asthma if it was completely non-toxic. It would be also great under controlled circumstances for many people who are mold-miserable. If I am wrong, I better go out into my garage and start inventing such a drug.

This is my visualization to try to explain the side effects of neurotoxicity. So adverse reactions could be to the quinoline component as an allergic reaction or dose related so that it just built up to a toxic level over time. There are many signs that t-cell populations are significantly reduced by montelukast. The fact that the Italians can do it in the test tube might be that it's a chemical component of montelukast designed to cause the t-cells to die.

Montelukast is a large molecule so Artie says it cannot penetrate the blood brain barrier. That would be an argument if nobody was complaining about neuro-psychiatric side effects. The neuro-psychiatric side effects are identical to quinoline and quinolones. When I read about Lariam, it just sounds like a more extreme version of Singulair side effects. Chloroquinolins were used before they invented Lariam, which is stronger. The malaria Plasmodiums became immune. Hallucinations, anxiety, depression, suicidal thoughts are completely consistent in all of the quinoline/quinolones. If montelukast breaks into sub-molecules then quinolines easily penetrate the blood brain barrier.

I find clinical evidence that montelukast may act as more than more molecule. And, that there is a rational for the existence of the chloroquinolin and evidence that it may be the source of toxicity.

I am glad to risk being called crazy. That is what the internet is for. We can present our ideas and discuss. So, just take this with a grain of salt. If I am close to the truth, this post will find it's proper home.

These posts about contacting a bad viral infection while the immune system is suppressed by Singulair are particularly worrisome. This was from 2007 so it has nothing to do with the FDA investigation. Epstein Barr causes some really bad illnesses including lymphoma.

The scary part is that children are the most susceptible to viruses. They need to develop immunity at a young age that will build up over time to levels that will protect them for the rest of their lives. Why are we giving children a drug that will suppress the leukotrienes? Why do we think that it is okay to take away one of the bodies defense mechanisms? Wouldn't it be logical that a drug that suppresses the immune system is a last resort option not handed out like lollipops?

www.iddb.org/drugs/singulair/ - 243k
.
Anonymous Immune System Dysfunction September 13th, 2007

Do users of Singulair and Advair understand how these products work? In order to understand how they work, you must first know what happens in the body during an allergic attack.

Allergic response is a function of the body's immune system. When an allergen enters the body through the nose or the lungs (e.g., a bit of pollen or cat dander), it is recognized by the body as a foreign substance, and the immune system then produces histamines to fight the intruder. Singulair and Advair work by disabling the body's immune system, so that there is no allergic response.

I too thought these drugs were wonderful. I was on both Singulair and Advair to combat asthma from my new husband's cat. I took high strengths of these drugs for approximately three years.

During the time I was on these drugs, some disease entity, most likely a virus (e.g., Epstein-Barr, Herpes Simplex I, HTLV I). I have been sick with a fever for the last four and a half years. My immune system seems to have been permanently impaired, and every organ in my body is now compromised. I have a fever, night sweats, liver and spleen enlargement, digestive problems, skin infections, hypertension, rapid-onset insulin-dependent diabetes and other endocrino;ogical problems, blood cell abnormalities, and neurological problems (e.g., tremors, myoclonic seizures, muscle cramps and weakness, vertigo, incoordination).

I am about to undergo a spinal tap and other tests, looking for the causative entity. Whatever it is entered my nervous system when I had an epidural anesthetic while on these immune system depressants. I have not been the same since. I have been too sick to work. This has ruined my life.

As we have all learned from recent reports of heart damage from Vioxx, the FDA no longer has the money to fully test new drugs entering the market. The "clinical trials" are a drug's entry into the population. If it kills or sickens too many people, they withdraw it. However, the drug companies define "too many people" as a number that could potentially ruin profits through lawsuits.

MORAL OF THE STORY: Don't rely on the government to protect you. Before putting any drug into your body, do the research into how it works. Read comments from other users. I wish I had done that.

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.

Does montelukast affect growth in children? Remember the report of identical twins, one took Singulair and one didn't. If I remember correctly, the one who took Singulair was at least two inches shorter in a short period of time.

If anyone would like a reason to look into that, then I refer you to this study. It could suggest that leukotrienes act on the pituitary to release pituitary hormones. We don't know what happens when the production of leukotrienes are blocked by montelukast.

"Finally, leukotrienes have also been found to act on the pituitary to modulate the release of the pituitary hormones."

"The distribution data of HPN321 suggests major role(s) for this receptor in endocrine and cardiovascular systems. CysLTs are well known for their modulatory effects in cardiovascular functions, where they reduce myocardial contractility and coronary blood flow (Letts and Piper, 1982) and have vasoactive effects (Drazen et al., 1980). They are thus considered to be important players in cardiovascular diseases (for review, see Folco et al., 2000). The strong expression of HPN321 in adrenal gland points at a new tissue where to study the influence of CysLTs on endocrine circuits. Finally, leukotrienes have also been found to act on the pituitary to modulate the release of the pituitary hormones (Hulting et al., 1984; Saadi et al., 1990). Our discovery of the existence of the HPN321 message in pituitary adds a molecular credence to this concept. The HPN321 receptor may thus modulate a variety of different physiological functions, which can now be tested using BAY u9773."

Vol. 58, Issue 6, 1601-1608, December 2000

ACCELERATED COMMUNICATION

Molecular Cloning and Characterization of a Second Human Cysteinyl Leukotriene Receptor: Discovery of a Subtype Selective Agonist
Hans-Peter Nothacker, Zhiwei Wang, Yuhong Zhu, Rainer K. Reinscheid, Steven H. S. Lin, and Olivier Civelli

Departments of Pharmacology (H.P.N., Z.W., Y.Z., R.K.R., S.H.S.L., O.C.) and Developmental and Cell Biology (O.C.), University of California at Irvine, Irvine, California; and NeoGene Technologies, Inc., Irvine, CA (H.P.N., Z.W., R.K.R., O.C.)

http://molpharm.aspetjournals.org/cgi/content/full/58/6/1601

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

From 1998 in the US:

Out of 336 children age 6- 14 years old.

"The most common adverse experiences were headache, asthma, and upper respiratory tract infection. Eleven patients were discontinued from the study because of adverse effects."

INDICATION EFFECTIVE IN TREATING ASTHMA IN CHILDREN
Leukotriene blocker offers therapeutic benefit with few adverse effects
CHICAGO—The orally administered drug montelukast, taken once a day, is effective therapy for 6- to 14-year-old children with chronic asthma, according to an article in the April 15 issue of The Journal of the American Medical Association (JAMA).

Barbara Knorr, M.D., of Merck Research Laboratories in Rahway, N.J., and colleagues studied 336 children at 47 outpatient centers in the United States and Canada to determine the effectiveness of montelukast on 6- to 14-year- old children. Montelukast is one of a new class of asthma medications known as leukotriene inhibitors, which block leukotrienes that are produced and released from inflammatory cells. The inhibitors cause narrowing of the airways in the lungs, mucous secretion and increased vascular permeability. Other studies have found that compounds which block leukotrienes can improve asthma control for adults and adolescents.

The children in this study had a history of intermittent or persistent asthma symptoms. Each had a forced expiratory volume in one second (FEV1) between 50 percent to 85 percent. All the children used short-acting inhaled beta-agonists, as needed, to treat their asthma. After a two-week placebo run-in period, 201 children received montelukast in a five-milligram chewable tablet, taken at bedtime. The other 135 children were given a placebo.

Asthma is the most common chronic illness of childhood, affecting approximately ten percent of children. Each year, approximately 2.2 million doctor visits are make by children seeking treatment for asthma.

The researchers found that montelukast significantly improved FEV1. Several secondary outcomes also improved. They write: "Patients treated with either as-needed beta-agonist alone or inhaled corticosteroids had significant improvement in their asthma control when they received montelukast. ... Though the magnitude of the changes observed appeared modest, they were consistent with those reported in other pediatric trials using currently available therapies."

The researchers found that treatment effects usually occurred within one day after the first dose of montelukast. They write: "Montelukast not only demonstrated a rapid onset of action, but its treatment effects were maintained consistently over time. There was no evidence of tolerance in this or a prior adult study, suggesting that montelukast continues to be effective in the long-term treatment of asthma."

Among other findings of the study:

· Montelukast demonstrated a significant improvement in daily as-needed beta-agonist use, and in the percentage of days and percentage of patients with asthma exacerbation.

The effects of montelukast were similar across age, sex, race and other subgroups.
Patients receiving montelukast reported significant improvements in the physical and emotional aspects of their lives.

The most common adverse experiences were headache, asthma, and upper respiratory tract infection. Eleven patients were discontinued from the study because of adverse effects.

The researchers conclude: "Overall, the results of this study suggest that montelukast would be a well-tolerated and effective therapeutic option to current asthma therapies in 6- to 14-year-old patients."
(JAMA. 1998;279:1181-1186)

Note: This research was funded by Merck & Co., Inc.