Singulair and montelukast

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 am re-posting this from June. I believe that we have many reasons to suspect that Singulair does indeed penetrate the blood brain barrier. I personally believe that under certain unusual conditions that Singulair can cause neurological damage. I tried before to put together a scenario of brain biochemistry that could explain how this can happen. Of course, I am just hypothesizing and all of my ideas will not prove to be totally correct. From the number of postings here regarding neurological symptoms, I believe that there is an answer out there somewhere. Why the FDA is not searching for this answer is a complete mystery to me.

I believe that it is possible that Singulair causes the same biochemical response in the brain that is cited in this study -- thus causing neurological damage.

"Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicity may contribute to neuronal death in neurological diseases."

IS SINGULAIR CAUSING THE DEATH OF NERVE CELLS IN SOME PATIENTS? DOES THIS HAPPEN - ALTHOUGH INFREQUENTLY- BECAUSE OF GENETIC OR BIOCHEMICAL FACTORS OR BOTH?

June 12th
2008
2:56 AM
I have stated many times that I am not an expert. I just post what I find. This has been a mind boggling journey for me. This is way over my head but I struggle to read and understand. Finding answers to why children are suffering from neuro-psychiatric side effects is worth the effort.

I have made the following observations.

1. Some quinolines are known to be able to cross the blood brain barrier.
2. Molecules that ionize are known to be more likely to be able to cross cell membranes. So if montelukast ionizes as a result of change in blood pH to sufficient acid conditions, then it could be possible that it does in fact cross the blood brain barrier.
3. We know that there are cysLT1 receptors in the brain.
4. We know that researchers believe that montelukast may bind at the arginine of the cysLT1 receptor.
5. We know that arginine contains four nitrogens. And montelukast contains one.
6. We don't know what happens to those nitrogens. Are those nitrogens converted to nitric oxide?
7. We do know what macrophages create nitric oxide as I posted.
8. We do know that if something cause excessive nitric oxide to build in the brain that there would be damage to the neurons.

Some people may remember when I got stuck at the astrocytes, the cysLT1 receptors and glutamate. I keep looking for research reports that may shed more light on this.

Titre du document / Document title
Nitric oxide causes glutamate release from brain synaptosomes
Auteur(s) / Author(s)
MCNAUGHT K. S. P. (1) ; BROWN G. C. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Biochemistry, University of Cambridge, Cambridge, ROYAUME-UNI
Résumé / Abstract
We determined the ability of pathological levels of nitric oxide (NO) to cause glutamate release from isolated rat brain nerve terminals using a fluorometric assay. It was found that NO (0.7 and 2 μM) produced (4 and 10 nmol/mg of synaptosomal protein) Ca2+-independent glutamate release from synaptosomes (after 1 min of exposure). Spermine/NO complex (spermine NONOate; a slow NO donor) and potassium cyanide (an inhibitor of cytochrome oxidase) also caused Ca2+-independent glutamate release. Preincubation of synaptosomes with 5 μM 1H- oxadiazole quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) had no effect on NO-induced Ca2+-independent glutamate release. Ca2+-independent glutamate release produced by NO was greater in a low-oxygen medium. NO, spermine NONOate, and potassium cyanide inhibited synaptosomal respiration with a similar order of potency with respect to their ability to cause glutamate release. Because NO has been shown previously to inhibit reversibly cytochrome oxidase in competition with oxygen, our findings in this study suggest that NO (and cyanide) causes glutamate release following inhibition of mitochondrial respiration at the level of cytochrome oxidase. Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicty may contribute to neuronal death in neurological diseases.
Revue / Journal Title
Journal of neurochemistry ISSN 0022-3042 CODEN JONRA9
Source / Source
1998, vol. 70, no4, pp. 1541-1546 (29 ref.)

INIST-CNRS, Cote INIST : 4037, 35400007527188.0230

My 5 1/2 year old son began taking 4mg Singulair in the p.m. and an inhaler (asmanex) in the a.m. We were still having trouble controlling the asthma and his Sing dose was raised to 5mg. & within 1 week of the increase he began having terrible facial tics and aggravated behavior (defiant, poor listening, easily frustrated and angered) The tics were in the form of opening and closing his mouth, as if you were trying to clear your clogged ears after a plane flight. This caused him much pain in his jaws and facial muscles, so he would tic and then cry as he was in pain. This ramped up his anxiety and it made the ticking worse. He has been off of all asthma medication (cold turkey) for 5 full days. He has episodes where the tics happen for 10 min -1/2 hr, other times during the day it is one here and one there. He does not want to leave the house to do anything, even his favorite activities. Thank god I found this site (and others like it), as I got some answers and some hope. We went to see my cousin this week who is a neurologist and he never heard of the correlation of Singulair and neurologic side effects like these. He said that (hopefully) the medication side effects will cycle through and resolve the ticking and behavioral changes. If not we are probably looking at a Tic Disorder which is in the Tourettes Family.He put my son on a very low dose of Klonopin to mellow out his anxiety and help reduce the tics, but has only been on it for 1 1/2 days and it usually takes a wk or 2 for full absorption and results.I have since sent him and my pediatrician and allergist links to this site and others. I think that I see some improvement in my son, yesterday I thought he did better and my husband thought it was a worse day, I think we have totally lost our perspective and objectivity on this. If anyone out there has a time frame on when they saw significant recovery and positive changes I would love to hear from you. This is a total nightmare and if it is this drug, someone is going to pay. My prayers go out to all who are going thru this.

Welcome a board singulairsurvivor. I received back an email from the woman at the lung association,she was of course sorry for our experiancr,and went on to say the scientist that reviewed the data were some of the best,and the association has no ties to any product.then as i am watching the updates on the hurricanes,i am inendated with singulair commercials as once again it is allergy season,so what a windfall for Merck that this article came out this month and not next....Coincidense i think not shame shame shame on you.To all those unsuspecting people about to get their prescription .i am sorry

I am astounded that this study of old data is being used to reinforce the message that Singulair is not connected to depression / suicide. The study is disputed by the fact that those suffering from the life threatening and incurable "Mental Illness Side Effect" see a complete return to normalcy within 7-10 days off the drug.

My own personal story, like many others, was a complete and total nightmare for my family over many years. In short, I went from a 10 year successful career as an art director with tremendous responsibility at a top international arts museum, to 2 years of full-time disability unable to leave my home with crippling anxiety/panic/depression. I was very lucky to have a loving wife and supportive doctors intervene before I took my own life.

The last few years is a blur of toxiPharmacological hell. A frustrating long string of tests, medications and treatments were attempted without any success... much to the consternation of my care givers. Not one of the dozens of doctors that I saw raised any question about the 10mg of Singuliar they knew I was taking daily.

Financial ruin, forced me off medical insurance. So I stopped all the psychoactive medications and came full circle back to suicidal ideation with more determination. A few months later, in March of 08' I could no longer pay out of pocket for may asthma medication Singulair and was surprised to find the mental illness begin to lift. A few days later the stories broke on the wire that this drug was perhaps connected with the unfortunate suicide of Cody and other teens. A week or so later, I felt myself again after many lost years.

Merck may have quietly updated the patient info several times over that period, but they made no attempt (still haven't) to reach out to prescribing doctors and pharmacists to let them know about potential issues. It seems that Montelukast interacts differently in individuals, and while it may be beneficial for many folks it is criminally dangerous not to increase the awareness of the side effects.

My General Practitioner pointed out that the original Montelukast study was quite large as these things go, but considering that it is prescribed to millions of people it is truly an irresponsibly small fraction sampled over a short period of time. Adding insult is the fact that these studies are conducted by the very company that seeks to benefit from positive findings.

The ALA has done a terrible disservice to the people the ought to represent. Downplaying the verifiable risks of suicide by recycling old data is completely and totally heartbreaking. I am ashamed to say that since I've been off the drug, I have been so preoccupied with trying to rebuild my life that I haven't been as forthcoming an advocate for the issues associated with Singlair. Misbelieving that others would take up the charge of spreading awareness and information so that new patients and their families would at least know the risks and be ever watchful.

Since that no longer seems the case, I offer myself and my well documented medical experiences with this drug, to anyone trying to get the message out. The media will pounce on the ALA study, giving many families a false sense of security.

Be well.

Everyone please go to the American Lung Association home page to read the article on their "research study" into the association between montelukast and depression/suicide and write to: ****** with your experiences. I wrote a letter with my son's negative experience, stating why I thought their study was flawed - they only studied 569 children and adults (I think there are more posts of negative reactions in children on this site alone) and urging them to do a more exaustive and statistically singificant study before releasing the results. This drug is unsafe and we need to take action to get it identified as such by the medical community.

SINGULAIR AND ZYRTEC SAME MEDICATION made by different companies. Be careful!

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

My 10 year old son has taken Singulair on and off since he was 5 years old and has been on it for the past 3.5 years. My son at an early age was affected by a bad marriage and then the divorce when he was 5 yrs old. So we always suspected that his behavior issues were caused by this and I had done everything I possibly could to give them the help he needed to get over and through his issues. He was held back his first year of Kindergarden and during his second year midstream he was placed in a special class for behavioral problem children. Nothing ever seemed to help him, everytime we would see some progress and encouragement we were always blind sighted by a behavior that was always worse. Two steps forward and them 5 steps backwards. I always knew that his problems would never get better overnight so I just kept on going. He was diagnosed with ADHD but because he has some ticking issues I had to put him on Strattera which was did not do a thing for him. I always described him as my Dr. Jeckyll/ Mr. Hyde child. He could be really good and sit still and behave but I think he had to try really hard to do so. He eventually was always overpower by the impulse to show negative behaviors. Defiant, extremely impulsive, always negative and completely miserable all the time. He also went through phases of compulsions. There was always a compulsion of the month- germs, bathroom habits, noises, repetitive words. He hated school and always complained of a stomach ache which i thought he was always faking to get out of school. He had confrontations in school everyday for most of the day. I often thought some of this was because of being tired all the time. We had battled over bedtime every single night. He was terrified to go to bed alone, I tried everything to get him to sleep alone. I wore myself out falling asleep next to him, I would then go to my own bed only to be up with him half the night going back and forth. I gave in many a night and slept with him just so we could get a good nights sleep. At age 8.5 I finally got him to go to sleep alone but the lights haf to be on and he has to know that I am still awake before he will fall asleep. He would always say he didn't want to go to sleep because when he does he has bad thoughts about me and people that he loves. He always had an extremely hard time excepting the word "no"- he would flip out and hit his head with whatever was handy, throw things, break things, scream holler etc. It would take hours to get over it. When he did he would be very remorseful and lovable. He was always in turmoil. Finally in February of this year, this graduated to a new level where he would want to just kill himself and would actually go and pull a knife out of the drawer and just shake with anger as he held the knife to his throat. I was terrified although i really didn't think he was going to harm himself he just wanted to scare me. Then at the end of March when i first heard the news about the possible side effects of Singulair, I had only heard about the suicide effect. Oh great just what I needed was this medicine causing him to do that. The doctor was thinking about taking him off if this summer because he wanted to see if he out grew his seasonal allergies so I took him off immediately. Well I had no idea about the other side effects until my son turned into a completely different kid. School noticed a huge difference in him! His grades went up, his is able to control his behavior, he is happy he is NORMAL. I never suspected this drug as the culprit due to the timing of taking it. Our lives have changed completely. When i first found this site, it seemed as though some of the parents were writing about my child. It is amazing. My son still has some old habits to break but overall he is a wonderful and normal 10 year old boy. He did not outgrow his seasonal allergies but Allegra seems to help in through it. I get so angry- his whole early childhood was ruined by this medicine. He is a labled kid in our school system. This whole experience has opened up my eyes. Thank you for letting me share my story.

I started full body internal itching after taking 10 days of Singulair. The physician that prescribed it said it couldn't cause itching. My new doctor tested for Lupus, I have an autoimmune disorder called Churg Strauss. After undergoing several steroid treatments and 3 days of IV Prednisone I got some relief. This has been going on for 6 months now. The itching becomes severe enough to make me want to commit suicide. Luckily it is pretty controlled by taking nightly doses of Atarax along with Periactin. Thank God I found a doctor who cared enough to search out the symptoms and help me get thru day by day.

Below is the latest ADR report on Singulair from the United Kingdom. I deleted side effects reports by very small numbers of patients in order to keep the post briefer. This shows the total number of reports since Singulair was approved in the UK.

I don't know the total number of prescriptions for Singulair in the UK. It is considered expensive.

Drug Analysis Print
Drug name: MONTELUKAST
Drug name: MONTELUKAST Report type: Spontaneous
Report run date: 13-May-2008 Report origin: UNITED KINGDOM
Data lock date: 09-May-2008 08:00:02 PM Route of admin: ALL
Period covered: 01-Jul-1963 to 09-May-2008 Reporter type: ALL
Earliest reaction date: 01-Jan-1997 Reaction: ALL

Cardiac disorders-TOTAL 64
Palpitations 29
Myocardial infarction 6
Tachycardia 6
Diarrhoea 84
Dyspepsia 24
Abdominal pain 98
Abdominal pain upper 22
Nausea 84
Vomiting 52
Dry mouth 15
Asthenia 13
Fatigue 45
Malaise 32
Sudden death 1
Pyrexia 10
Chest discomfort 12
Feeling abnormal 16
Influenza like illness 17
Irritability 18
Drug interaction 13
Chest pain 13
Arthralgia 59
Myalgia 38
Muscle spasms 24
Pain in extremity 14
Balance disorder 10
Lethargy 16
Somnolence 23
Psychomotor hyperactivity 25
Headache 221
Dizziness 68
Neuropathy peripheral 7
Convulsion 6
Epilepsy 7
Dysgeusia 7
Hypoaesthesia 6
Tremor 18
Nervous system disorders TOTAL 526
Abnormal behaviour 13
Agitation 12
Anxiety 18
Aggression 30
Depression 23
Insomnia 58
Abnormal dreams 12
Nightmare 49
Hallucination 21
Sleep disorder 15
Psychiatric disorders TOTAL 364
Asthma 36
Allergic granulomatous angiitis 43
Angioedema 12
Swelling face 12
Erythema 13
Pruritus 32
Rash pruritic 17
Rash 55
Urticaria 33

TOTAL NUMBER OF REACTIONS 2841
TOTAL NUMBER OF FATAL ADR REPORTS* 19
TOTAL NUMBER OF ADR REPORTS* 1489

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

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

Who administers this site? I posted a side effect last night after I registered and then this morning I got an email saying there was a reply to my posting and when I tried to log in, my account was inactive and my posting had been removed, as had the reply to my posting. I don't know if it is because I put a link the an online reporting tool where the FDA is compiling feedback from people/or their children who have experienced terrible side-effects. Here is the link again and I urge you all to report your cases: http://www.fda.gov/cder/drug/early_comm/montelukast.htm

My son is 3.5 and has been on Singular for 2 months and just like all of the other stories about the other young children posted here, he is a different kid after being on Singular. Last night was the first night I took him off of it. All of the side-effects that are mentioned here are the same ones my son is experiencing, nightmares (screaming in the night), hyper, aggressive, reliving injuries from days past, the day care telling me that they now have concerns about how different he has been lately and the even used the term "bad behavior". They said he is hyper, he screams, not listening, aggressive. He is a favorite at day care since he is so loving, polite and kind. I know all parents say that, but pretty much anyone who has met him compliments me on how well behaved he is. I am even nervous to have people over since he seems out of control and I have found myself ensuring people that he isn't normally like this. I have taken him off as of last night and I am hoping he will get back to his old happy-go-lucky self soon. Does anyone know how long it can take to get this poison out of their system? I pray that there are no permanent side-effects.

I have stated many times that I am not an expert. I just post what I find. This has been a mind boggling journey for me. This is way over my head but I struggle to read and understand. Finding answers to why children are suffering from neuro-psychiatric side effects is worth the effort.

I have made the following observations.

1. Some quinoline are known to be able to cross the blood brain barrier.
2. Molecules that ionize are known to be more likely to be able to cross cell membranes. So if montelukast ionizes as a result of change in blood pH to sufficient acid conditions that it ionizes, then it could be possible or maybe like that it does in fact cross the blood brain barrier.
3. We know that there are cysLT1 receptors in the brain.
4. We know that researchers believe that montelukast may bind at the arginine of the cysLT1 receptor.
5. We know that arginine contains four nitrogens. And montelukast contains one.
6. We don't know what happens to those nitrogens.
7. We do know what macrophages create nitric oxide as I posted.
8. We do know that if something cause excessive nitric oxide to build in the brain that there would be damage to the neurons.

Some people may remember when I got stuck at the astrocytes, the cysLT1 receptors and glutamate. I keep looking for research reports that may shed more light on this.

Titre du document / Document title
Nitric oxide causes glutamate release from brain synaptosomes
Auteur(s) / Author(s)
MCNAUGHT K. S. P. (1) ; BROWN G. C. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Biochemistry, University of Cambridge, Cambridge, ROYAUME-UNI
Résumé / Abstract
We determined the ability of pathological levels of nitric oxide (NO) to cause glutamate release from isolated rat brain nerve terminals using a fluorometric assay. It was found that NO (0.7 and 2 μM) produced (4 and 10 nmol/mg of synaptosomal protein) Ca2+-independent glutamate release from synaptosomes (after 1 min of exposure). Spermine/NO complex (spermine NONOate; a slow NO donor) and potassium cyanide (an inhibitor of cytochrome oxidase) also caused Ca2+-independent glutamate release. Preincubation of synaptosomes with 5 μM 1H- oxadiazole quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) had no effect on NO-induced Ca2+-independent glutamate release. Ca2+-independent glutamate release produced by NO was greater in a low-oxygen medium. NO, spermine NONOate, and potassium cyanide inhibited synaptosomal respiration with a similar order of potency with respect to their ability to cause glutamate release. Because NO has been shown previously to inhibit reversibly cytochrome oxidase in competition with oxygen, our findings in this study suggest that NO (and cyanide) causes glutamate release following inhibition of mitochondrial respiration at the level of cytochrome oxidase. Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicty may contribute to neuronal death in neurological diseases.
Revue / Journal Title
Journal of neurochemistry ISSN 0022-3042 CODEN JONRA9
Source / Source
1998, vol. 70, no4, pp. 1541-1546 (29 ref.)

INIST-CNRS, Cote INIST : 4037, 35400007527188.0230

Montelukast - quinoline cysLT1 receptor antagonist

In some cases the introduction of a 7-chlorine atom to the quinoline ring proved beneficial. Correlation of the pKa values of the quinoline nitrogenwith the CysLT1 receptors affinities was reported indicating a possible hydrogen bond interaction between the quinoine nitrogen and the receptor.
The quinoline moiety or its equivalents is suggested to mimic the lipophilic region of the CysLT and the acidic groups mimick either the peptide or the eiocosanoid tail of CysLT.

The resulting model figure 12 suggests multiple intereactions between the antagonists and the arginine residue. Besides the hydrogen bonds between the acidic residues and the guanidine moiety of arginine, quinoline containing CysLT1 antagonists are shown toe form an additional
hydrogen bond beetween the quinoline nitrogen and a guanidine hydrogen atom. This interaction may be an explanation for the importance of the presence and position of a nitrogen atom, as observed for most CysLT1 antagonists of the quinoline class. In addition the antagonists were found to wrap around the arginine and thus "short molecules such as WY48252 are easily fitted in the model. i.e. the variable spacers between the lipophilic and the acidic groups do not post major restrictions to the receptor affinity as long as they are flexible enough to allow
the acidic groups to bend back for interaction with the arginine. The incorporation of Montelukast in the model suggests the presence of an additional binding pocket....Since the affinity of LTD4 itself was little affected, arginine residues were suggested to be important for the binding of antagonists but not for LTD4. These results sustained our relucrtance to derive an antagonist model based on structural similarity
between the agonists and antagonists.

Ming-Qiang Zhang and Mariel Zwaagstra

Current Medicinal Chemistry, 1997, Vol. 4, Nov. 4.

Does anyone who has been having negative side effects ever feel like they have a fishy taste in their mouth, fishy body odor, or fishy breath? This is not related to fish oil of any kind but would be because of pyridine.

You probably ask "how does CC come up with these question?" I am trying to look for clues as to what happens to montelukast if it ionizes.

The example that I am posting below is not the only patent for an aminoquinoline derivative that is proposed for the treatment of neuro-psychiatric disorders. Even though we are not comparing exact chemical structures, it is certainly worth considering how the quinolines relate to this receptor.

It is also worth considering why montelukast, a quinoline, seems to be causing some of the problems that this owners of this particular patent think that they can treat.

As I mentioned before, I have no answers. Regardless of how small Merck believes the population of Singulair patients who suffer neuro-psychiatric disorders is, I do not believe that any patient should be ignored. It also seems that many companies have studied this area in depth and more than one company knows a lot more than we know about why it is possible for these side effects to happen.

" The compounds of formula I have a good activity on the 5-HT.sub.5A receptor. Therefore, the invention further provides methods for the treatment of depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorders and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders, (which includes generalized anxiety and social anxiety disorder, panic disorders, agoraphobia, social phobia, obsessive compulsive disorders, post-traumatic stress disorders, psychotic disorders (which includes schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions), pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviors (including nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders and gastrointestinal disorders such as irritable bowel syndrome (WO 2004/096771). "

******

Singulair, montelukast, contains a chloroquine in it's molecular structure. I am praying that the FDA takes this investigation seriously. Other countries are concerned about the neuro-psychiatric side effects of these categories of drugs for some very good reasons.

"In summary, we have used a combination of electrophysiology, ligand binding, homology modelling and simulated docking to define the mechanisms by which quinine, chloroquine and mefloquine inhibit the 5-HT3 receptor response. Our observations further extend the number of receptors known to be affected by these compounds and the growing diversity of targets may account for the broad spectrum of side effects that have been reported by patients receiving them (Luzzi and Peto, 1993; Palmer et al., 1993; Taylor and White, 2004). Inhibition of the 5-HT3-mediated current could have wide-ranging effects in the nervous system, as 5-HT3 receptors can modulate a variety of neurotransmitter responses such as those to GABA, dopamine and cholecystokinin (Thompson et al., 2006b)."

******

I took my son off Singular a month ago, some slight improvements with the sleep and behavior problems. I voiced my concerns with my doctor twice now he looks at me like Im crazy and then he goes on the PC and says he cant find any of these side affects im talking about. My son was an appointment to see an allergist specialist.

Everybody here knows that I have been interested in trying to find out if Singulair (montelukast), which is a quinoline, ionizes and forms quinolinic acid under physiological conditions that lower blood pH. Some researchers have also mentioned that another montelukast metabolite that occurs is known to be a toxin. In other words, until someone can get blood tests that confirm what the toxic metabolic is, we are just guessing but I would bet that it is a good guess.

One of the strongest cases for that argument would be what happens to some people during sleep. There are some people whose CO2 levels rise. If the levels rise enough to cause change in pH to a more acid condition, then montelukast can possibly ionizes just enough to create minute amounts of neurotoxins that could cause bad dreams, hallucinations, sleep deprivation or a number of other neuro-psychiatric problems. Compound the effect of night after night of minute amounts of neurotoxins caused by CO2 and montelukast ionization then it would be easy to understand how depression and personality change results. There are other conditions that cause elevated CO2 levels and acidosis such as COPD.

If anyone has any data regarding their CO2 levels from sleep studies or other bloods tests, would you please send me a private message?

I have been reading research reports that show that montelukast (Singulair) has a higher pKa than many of the other quinoline malaria drugs. That means that Singulair ionizes more easily than even drugs that are known to cause terrible dreams, hallucinations, depression, anxiety, and suicidal thoughts. Many researchers believed that the problem with Vioxx was that it ionized under certain physiological conditions.

I will report again when I can confirm the numbers. I am not sure if it is confirmed that montelukast's pKa is around 5.8 and the malaria drugs is around 4.8. I need to do more work before I can point out that it is not impossible to theorize that montelukast ionizes like Vioxx.

My 54-year-old fit, social, successful husband was put on Singulair in January for newly diagnosed asthma. He developed a depression with anxiety, irrational fears, avoidance, mood swings and even one episode of suicidal thoughts out of nowhere. He saw a psychiatrist and a therapist, tried medications, yoga, a vacation, meditation, breathing exercises - everything! But he kept getting worse.

The day he was throwing patio furniture then sobbing uncontrollably was the day he realized he couldn't work in his condition. He negotiated a 60-day leave without pay. Even that didn't help. It was crazy. How could a man who managed hundreds of employees and a major health service system for 20 years suddenly be so paralyzed with fear that he couldn't walk down a beach or go into a Walgreen’s?

We found this site May 26th. He stopped the Singulair immediately. It has been 10 days and he is already 80-90% back to normal. Thank God.

Partly I am writing because it is so hard to read of parents' guilt that they "should have known" etc. Look, unlike a child, my husband is mature and very verbal; he is also a psychiatrist (!) with a capacity for self-examination and a language to describe his inner experience. And me, I'm a psychologist (!) trained in understanding people and I know him very well. And yet with all that training and skill and consultation and treatment, WE STILL COULDN’T FIGURE THIS OUT! So please, don't make yourself feel any worse with guilt. This is awful and tragic enough already.

I would add that the onset of mood and behavioral problems is so insidious that it is hard to connect the problems to the Singulair. Also, I suspect that children and adolescents are at greater risk because of their immature emotional developmental level. An adult l suspect may need some genetic or personal predisposition to mood disturbance, or stress, or both, to trigger these side effects. My husband had a depression episode 30 years ago and had recent traumas that certainly could have triggered the depression. But how treatment resistant that depression was, and those strange paralyzing fears and extreme anxiety – all that I blame squarely on the Singulair.

I have made a report to the FDA. I urge you to do the same.

Update.... well my 6yr old son came off Singulair on 3-29. His sinuses drained finally (only waiting past year for that to happen) 9 days after coming off. His sinus problems have been gradually going away. He is now only taking claritin and sudafed when absolutely needed. BUT he started with sore throats. He never had a problem with tonsils only adenoids which they took out in Feb. Now since stopping the Singulair his tonsils have become constantly infected and twice the size so he will be having them removed in July. Some of the antibiotic don't seem to be working as he has been on them so much over past year. Im wondering if the Singulair was hiding the fact there was a problem with the tonsils as well.

I am sure that all kinds of people told Kate Miller that Concernedcitizen was a cuckoo or a Merck competitor. I haven't been employed by a pharma company in many years. Everybody ever employed by a pharma company higher than a certain level (practically the mailroom) knows this stuff and what to look for.

I think that I am about ready to say my opinion on how montelukast works and why these problems develop. It will just be my opinion. I need to try to find actual proof but I may forego that and just say it soon.

"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

Leukotriene receptor cysLT1 in intestinal epithelial cells and variation in montelukast blood levels between individuals.

We know many things about this topic:

1. Montelukast enters the blood stream through the intestines
2. the cysLT1 (receptor that Singulair blocks) exists in intestinal epithelial cells
3. montelukast will bind with high affinity to the ideal gene type cysLT1 receptor
4. after montelukast enters into the blood stream is it 99% bound to plasma proteins (that point is hypothesized to be the reason that montelukast does not inhibit CYP2C8 in vivo but it does in vitro if it is true that in vivo it does not inhibit CYP2C8)
5. there is variation between individuals on how much montelukast makes it into the blood stream

Well, did anybody out there in science land think of trying to find out how much montelukast binds to the cysLT1 receptors in intestinal epithelial cells? They got all interested in transport proteins but where are the studies about the cysLT1 receptors in intestinal epithelial. And, what is the effect of montelukast if it binds to intestinal cysLT1receptors?

Now, concernedcitizen believes that if montelukast binds to intestinal epithelial cysLT1receptors that could be a BIG problem because those receptors have a different function than in respiratory tissue. In the one place, we gotta' breathe. In the other place, we gotta' digest food properly.

We have all of these children who have stomach pain. Does anybody want to find out why?

This drug belongs in the science HALL OF SHAME. Somebody please call Arnold Diaz. I am quite discussed today.

Oncogene. 2006 Oct 26;25(50):6660-5. Epub 2006 May 22. Links
Endogenous production of leukotriene D4 mediates autocrine survival and proliferation via CysLT1 receptor signalling in intestinal epithelial cells.Paruchuri S, Mezhybovska M, Juhas M, Sjölander A.
Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.

The cysteinyl leukotriene1 (CysLT1) receptor (CysLT1R) enhances survival and proliferation of intestinal cells via distinct pathways. Here, we have demonstrated that there is significant endogenous production of CysLTs from both non-tumour- and tumour-derived intestinal epithelial cells. Treatment of two non-tumour cell lines, Int 407 and IEC-6, with CysLT1R antagonists led to shrinkage and detachment of cells, confirmed as apoptotic cell death, and a dose-dependent reduction in proliferation. However, in the tumour intestinal cell lines Caco-2, SW480, HCT-116 and HT-29, treatment with CysLT1R antagonists significantly reduced proliferation, but had no effect on apoptosis. A unique characteristic of intestinal cancer cells is the presence of nuclear CysLT1Rs, which are inaccessible to receptor antagonists. In these cells, inhibition of the endogenous production of CysLTs indirectly, by 5-lipoxygenase inhibition, impaired CysLT1R signalling throughout the cell, and resulted in apoptosis of the tumour cells. These data reveal the existence of constitutive CysLT1R signalling that mediates both survival and proliferation in intestinal cells. Importantly, we propose that tumour-derived intestinal cells are resistant to CysLT1R antagonist-induced apoptosis, a phenomena that could be explained by nuclear CysLT1R signalling.

PMID: 16715140

CLINICAL TRIAL - transport proteins and montelukast

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

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

Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV1 (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found.

Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.

http://ajrccm.atsjournals.org/cgi/content/full/173/4/379

In my opinion, we shouldn't blame doctors for what they are not told about medications.

We know definitely that work was being done on genetic profiling of children with asthma. We know definitely that the CysLT1 receptor is a gene with variants. We don't know how many different variants. We know that montelukast binds with high affinity to the gene type used in the research studies that lead to it's approval as a drug for asthma. We know that montelukast is very specific because it won't even bind to CysLT1 receptor sub-types. Now somebody out there knows whether there are patients, for which it would be impossible for montelukast to be effective because the patient has a gene variant that is different.

We know that Merck had clinical trials acknowledging that there was a genetic component. We know that Hakon Hakonarson had all kinds of legal troubles over his data base of genetic profiles. We know that Merck was interested in his company. So where is the answer about the genetic variants and the ability to predict whether Singulair will be effective for a particular patient? And, where is the answer about what happens when montelukast does not bind to the cysLT1 receptor?

Hakonarson testifies deCODE loses partnerships because Stefansson won't share corporate information

A former vice president at deCODE Genetics Inc. testified in U.S. District Court in Philadelphia on Friday that the Icelandic biotech firm has been eager to line up new partnerships with other drug development and research firms, but potential deals have died because the company's chief executive refused to share corporate information with possible partners.

Hakon Hakonarson, who had been the firm's vice president of business development, said deCODE CEO Kari Stefansson wanted to form more development deals with other firms, but was not willing to share enough corporate information for serious negotiations to continue. "Dr. Stefansson was always conservative and somewhat insecure about sending information, even if it was under a confidentiality agreement," said Hakonarson.

deCODE has sued Hakonarson for allegedly stealing trade secrets when he defected from the firm earlier this year to become director of the new Center for Applied Genetics at The Children's Hospital of Philadelphia (CHOP). The center plans to genotype 100,000 children and develop new treatments with private-sector partners.

In its case against Hakonarson and four other former deCODE employees, the company alleges thousands of computer files were stolen from deCODE with the intention of duplicating the company's business model and operations at CHOP in order to compete directly with deCODE. The company is seeking a preliminary injunction to enforce employment contracts that would prevent its former scientists from working at CHOP for two years.

CHOP's lawyer, William Hangley, elicited responses from Hakonarson indicating that earlier this year, deCODE was in need of new outside partners because some key revenue-generating relationships were winding down. An agreement with Roche Diagnostics was set to expire at the end of June, while another clinical trial program with Merck was in effect, but inactive, Hakonarson testified. He also said he had tried to get Cephalon interested in taking a larger role in deCODE.

Bayer was invited to work on clinical trials for a cardiovascular drug, but the deal never happened, Hakonarson testified. Earlier this month, deCODE announced it was discontinuing work on the drug because of problems with the formulation.

Hakonarson said he became alarmed earlier this year when he saw other biotechs forming partnership deals even though he felt deCODE had a superior pipeline. "I felt we had significant resources and we could not get this done because Dr. Stefansson never allowed it to materialize."

Hakonarson's testimony also touched on computer files. A forensic computer expert hired by deCODE to analyze its systems gave earlier testimony that Hakonarson or people using his login identity and password copied at least 46,795 files from the Hakonarson folder on the deCODE home directory. "In all reasonable probability, those files were written to the Western Digital 250GB external hard disk drive or other smaller removable media devices that Hakonarson is known to have used at deCODE," according to a report filed by John F. Ashley, a forensic computer analyst hired by deCODE.

In his testimony, Hakonarson described one case in which he did remove files from deCODE computers. He said he took files related to a presentation about gene chip equipment by Illumina Inc., which provides technology to deCODE, off the company's 30-day open file system in late May or early June after Stefansson had asked him to resign. Hakonarson and Stefansson have both testified that even after Hakonarson announced he would be taking the job at CHOP in February, the two attempted to work out a collaboration in which Hakonarson would also work part-time for deCODE. Eventually those talks broke down and deCODE filed its suit, which was unsealed Sept. 26.

Hakonarson also said he had been in discussions with Cephalon about working as a consultant until he received a letter from deCODE's attorneys this summer. He said the letter contained some inaccuracies, particularly a charge that deCODE first learned about his intention to move to CHOP in July when the center put out a press release. Harkonarson insisted Stefansson knew about his plans in February and said he was concerned the letter was setting him up for legal problems later.

"I was concerned Kari had been as a chess player making valuable moves to go forward," Hakonarson said.

The complex hearings, which have been before Judge Jan E. DuBois since the suit was unsealed, have been closed frequently as the parties discuss parts of the case they contend are confidential. Hearings are scheduled to resume in November.

Susan Warner
mail@the-scientist.com

All credit to Susan Warner and the-scientist

My 17 year old daughter started Singulair last July for Asthma. She is brilliant and scored in the 99% on the ACT college entrance exam. She won 3 scholarships totaling over 60,000 and earned 27 college AP credits while still in high school, volunteering for the Red Cross, singing in choirs, and playing the lead in her high school musical and 3 plays. She was funny, sweet, and had many friends.
She left for college 3 weeks after starting the medication and saying she was breathing better. Her grades were terrible, even though I was able to check to see she went to class every session, as posted online. She became very depressed, withdrawn, staying in her dorm room. She was sleeping up to 20 hours straight without waking up. She didn't call her friends when she came home and only wanted to sleep. She was like a different person. She was so aggressive that she tried to run out in the middle of the night and attacked me when I tried to block her way, to the point I had to call the police. They diagnosed her with new onset major depression and ADD. They started her on Zoloft for 2 months and she got much worse and was removed from Zoloft as a result. She said she was too tired to stay awake even in class. We had a sleep study done for Narcolepsy and it was negative. Until reading these posts, I didn't connect the Singular. Everything I am reading is so familiar, it makes me feel ill. I can't believe I didn't know, I am a nurse. The guilt is horrible. I hope to get my daughter back, but she lost all her scholarships and only managed to pass 16 hours in one entire year of college. I can't afford to send her back without the money she lost. They even put her on a one time only probationary period to ever get Federal or State Financial aids and loans again. Singular had to be to blame. I am simply thankful my daughter is still here, she was very suicidal. My heart breaks for those of you that lost your children to the side effects of the drug. We have to get the word out by each filing a complaint to the FDA, and filling out adverse event forms.
Please don't let Merck get away with this. We need to act, even if your child was one of the lucky ones and is back to normal now.

Clinical trial of montelukast in the Netherlands.

I noticed two things:

1. The researcher states that sides effects are 10%.
2. The researcher will not allow patients to also take drugs which are metabolized by CYP2C8 because montelukast inhibits that as proved by in vitro (test tube) studies. American studies in vitro said yes montelukast is an inhibitor but in vivo (in people) that it didn't happen. I was always confused by that and would still like to know more
.
******

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

Singulair/Quinolinic acid - skin conditions and myalgia caused by eosinophils

Dear friends for this one I feel like Gomer Pyle "well g-o-o-l-l-l-y." I have been trying to solve the riddle as to whether Singulair might possibly cause skin conditions and myalgia. I found where a researcher actually injected himself with quinolinic acid to see if it caused a reaction from eosoniphils. So hypothetically if there were less than ideal metabolic or genetic conditions that cause the montelukast molecule to break up into a quinolinic acid by-product before it reached the liver then eosinophils will go to where-ever the quinolinic acid is. In the case of this researcher, the quinolinic acid caused skin inflamation conditions because he injected it into his arm.

This study could apply to any quinoline type drug that could break down into quinolinic acid. Now, we don't have proof whether Singulair can break down into quinolinic acid so the doctors won't buy this one as a fact. It is good, however, for a WHAT IF argument for those who would like to do a wait and see if Singulair caused the problem. This researchers eosinophil count took five weeks to drop back down to normal levels.

Clin Exp Med. 2006 Jun ;6 (2):60-4 16820992 (P,S,E,B) Is the L-tryptophan metabolite quinolinic acid responsible for eosinophilic fasciitis?

R Noakes, L Spelman, R Williamson
Qld Skin and Cancer Foundation, Greenslopes Private Hospital, Newdegate St, Greenslopes 4120, Qld, Australia. rnoakes@lagunacom.com.au
The eosinophilia-myalgia syndrome is accompanied by alterations in L-tryptophan metabolism with elevated levels of L-kynurenine and quinolinic acid having been recorded. It has been suggested that this is due to activation of indoleamine 2,3-dioxygenase by interferon-gamma. It is unknown whether these products of tryptophan metabolism play a role in the pathogenesis of this syndrome and the closely related condition of eosinophilic fasciitis. To explore this possibility, the principal author (RN) received a series of subcutaneous injections of quinolinic acid. A total of 1200 mg was administered over a 1-month period. Peripheral blood eosinophil counts were monitored and biopsies taken for H&E and immunohistochemical stains. Over the 1-month period the eosinophil count rose from 0.3x10(9)/l to 0.8x10(9)/l before falling to 0.4x10(9)/l approximately 5 weeks later. H&E sections showed a mixed infiltrate of eosinophils and neutrophils extending through the reticular dermis and septa of the panniculus. No deep fascia was obtained on biopsy. The immunohistochemical stain for transforming growth factor beta 1 showed staining of endothelial cells and dendritic cells. The interleukin-5 stain was negative. Our results suggest that quinolinic acid may play a role in cutaneous eosinophilic disorders.

I am posting the metabolism profile for montelukast. Maybe someone here has chemist friends who might know if it is possible that the dicarboxylic acid major metabolite could also have been derived from quinolinic acid under metabolic circumstances less than ideal. The quinoline ring, is a benzene-pyridine. Quinolinic acid, a dicarboxylic acid with a pyridine is produced by the oxidation of quinoline possibly by acid hydrogen peroxide. So the only structural difference between the dicarboxylic acid mentioned in the study as the major metabolite and quinolinic acid is nitrogen. Fascinating drug Singulair. Macrophages (immune cells) make quinolinic acid and release nitric oxide in order to kill micro-organisms. Quinolinic acid a neurotoxin.

Unless you are someone who plans to get help from experts, I would ignore this post. In my opinion, the only way that real answers will come from the investigation is that there is a provable chemical reason that the brain is affected by Singulair. I just post what I find and hope that eventually there will be experts who can explain why people are having such problems. I am unable to draw any conclusions from the report below.

dmd.aspetjournals.org/.../1/1996&journalcode=dmd

My four old son has been on singulair for about two weeks. The change from wheezing/coughing attacks at night and terrible allergies during the day has been amazing. They are almost non-existent to this point a great plus. However, a i stress however his behavior and speech has been VERY INAPPROPRIATE and quite frankly it concerns me. He now states "im a bad boy" and "i dont listen" and his mornings are very testy to say the least. Granted these sound like normal 4 yr. old sayings that he would pick up from other children on the playground but how do you explain them happening almost simultaneously with his taking singulair. I find it very hard to believe that it is a coincidence and that these are normal things for a 4 yr old to say/do when all other things have remained the same. My advice is to diligently watch your child for these warning signs and find other remedies if you have reservations. Im not promoting natural cures but i am leaning toward a diet change for the whole family and consulting my doctor for food allergen testing. I hope this helps. Be Well.

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

concerned citizen,i enjoy reading your posts and research you have been so helpful,but i do have to say,i do expect the doctors that write prescriptions to do their homework and research on these drugs,i do feel that they should be extremely knowledgeable about what they are giving our children,that is why i pay them the big bucks.I told them of my concerns and they poo pooed me,when as it turns out now i was quite possibly right,i will asked them to do another blood test now he is not on meds,and if as i suspect it has gone down i will loudly shout i told you so and demand answers from them.I so often questioned the meds and was always made to feel dumb,Ignorance is not a defense and someone was very ignorant

Flindy is correct. It is easily possible to be just plain allergic to montelukast- Singulair. Where were the other "allergens" that her child was exposed to? It was, at least hopefully, a sterile environment.

Montelukast is a quinoline. Drugs often are built around a core molecular called a pharmacophore, the molecule responsible for the drug's important characteristics. There is an enormous amount of literature regarding adverse side effects for other drugs in that category.

At the time when Merck was pursuing quinoline as the pharmacophore, other companies were pursing other core molecules. So a quinoline core is not the only choice of drugs. The huge problem is that doctors are not aware that Singulair is not an anti-histamine. They are not warned that the core molecule is a quinoline so they don't know to watch out for allergic reactions especially serious ones.

It would be common knowledge that a quinoline radical (in an acid pH) could react with hydrogen peroxide to produce quinilinic acid, a nasty neurotoxin. When I hear of neuro-psychiatric side effects that appear to coincide with times when hypoglycemia could be happening, then maybe there are some genetically pre-disposed people that actually are experiencing times of ketoacidosis. Scientist have known about quinolinic acid since the 1940's. Malaria drugs containing quinoline come with a warning about hypoglycemia and electrolyte imbalance. Which comes first - the chicken or the egg- the reaction to the drug then the hypoglycemia or the hypoglycemia then the reaction? It would be amazingly easy to prove whether quinolinic acid is responsible for these neurological side effects.

I am appalled by two things. One is that Merck has such power over the FDA that the FDA fails to even recognize basic pharmacophore characteristics. Merck manages to snow them somehow with just words - leukotriene receptor antagonist. So what is the FDA reaction? Merck should review their clinical data. How about find some people who are suffering from Singulair side effects and do some tests? Then you might actually find out why.

If it turns out that anyone at Merck or FDA knew that montelukast carried significant risk of allergic reactions due to it's pharmacophore and they chose not to reveal that in the literature for marketing reasons, those people should be prosecuted. It should not be the job of doctors who prescribe medications to do their own research.

Quinolinic acid and neurotoxicity:

Montelukast contains a quinoline radical. Quinolinic acid, a well known damaging neurotoxin that kills neurons, can be produced from a quinoline and hydrogen peroxide. The body produces hydrogen peroxide for a numbers of reasons. White blood cells produce hydrogen peroxide when activated by antigens such as bacteria, virus, fungus etc. It is also produced under conditions when the body is stressed. It is also produced in the gastrointestinal track.

If we knew how montelukast could break up to free the quinoline radical, then we might be able to define a number of different scenarios under which hydrogen peroxide could cause montelukast to generate the neurotoxin quinolinic acid.

If we could prove that montelukast is capable of produce quinolinic acid under unusual circumstances (doesn't happen to everybody), then we would have a very good explanation for all of the psychiatric adverse drug reactions that are mentioned here which include hallucinations, anxiety, depression, suicidal ideations, night mares, etc. etc.

Anyone looking for answers should try to pursue the possibility that quinolinic acid is causing bad side effects. I wish that I was much better at chemistry. I am stuck here at the moment. I keep hoping that somebody else with more expertise will come here to tell us how it happens.

Here is the best example of what is wrong with our medical system. Look what the Italian doctors do when a patient developed a skin rash after taking Singulair. It seems like they have a procedure to follow. If the case then meets the standards for a drug reaction, they write about it so that others will know. If you look at examples on this board, if somebody gets a skin rash from Singulair the doctor gives them prednisone because they never heard of adverse reactions to Singulair.

1: Ann Pharmacother. 2004 Jun;38(6):999-1001. Epub 2004 Apr 27. Links
Montelukast-induced generalized urticaria.Minciullo PL, Saija A, Bonanno D, Ferlazzo E, Gangemi S.
Department of Human Pathology, Division and School of Allergy and Clinical Immunology, University of Messina, 98123 Messina, Italy.

OBJECTIVE: To report a case of generalized urticaria induced by montelukast treatment. CASE SUMMARY: A 28-year-old man with allergic rhinitis and moderate persistent asthma developed generalized urticaria 5 days after the initiation of montelukast and inhaled fluticasone. Symptoms disappeared within one day after suspension of both drugs. Two months later, after the resumption of montelukast and fluticasone, the patient developed generalized urticaria and eyelid angioedema, which were successfully treated with intravenous betamethasone, achieving complete remission within hours. After 2 days, the patient resumed inhaled fluticasone only and continued this therapy for several months without any adverse reaction. DISCUSSION: We attributed the adverse reaction to montelukast because of the temporal relationship between use of montelukast and urticaria, the absence of other identified causative factors and other explanations for allergic reactions, and the positive dechallenge and rechallenge. The Naranjo probability scale showed a probable relationship between skin manifestations and montelukast treatment. CONCLUSIONS: The use of antileukotrienes is increasing in asthma therapy. In cases of generalized urticaria in asthmatic patients undergoing montelukast therapy, physicians should be aware of a potential adverse reaction to this drug.

PMID: 15113985

Sorry, I can't just walk away.

When you find patents or patent applications for certain purposes, then you know that your ideas are well founded. There are several patents for using an anti-malaria drug for asthma. I would bet that somebody had that idea all the way back to the 1960's. So it is very possibly no coincidence at all that a chloroquinoline or other quinoline ring would be part of montelukast's chemical structure.

Here is one of the patents.

******

It is well known that quinoline rings can be toxic to some people even very rapidly. As in this very extreme example.
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PEDIATRICS Vol. 27 No. 1 January 1961, pp. 95-102 This Article

FATAL ACUTE CHLOROQUINE POISONING IN CHILDREN
Howard M. Cann M.D.1 and Henry L. Verhulst M.S.1

1 National Clearinghouse for Poison Control Centers, Accident Prevention Program, Public Health Service, U. S. Department of Health, Education, and Welfare
Four cases of acute chloroquine poisoning in children are presented. In three instances death occurred within 2 hours of ingestion of larger than therapeutic amounts of the drug. The rapid occurrence of death in acute chloroquine poisoning is probably explained by complete and rapid absorption of the drug from the gastrointestinal tract resulting in high blood concentrations which depress vasomotor function and respiration. Cardiac arrest follows and may be caused by the direct myocardial action of chloroquine, to anoxia, or to both. The similarity of the manifestations of acute chloroquine poisoning and those of acute quinine and quinidine poisoning suggests that acute toxicity may be attributed to the quinoline ring portion of these drugs.

----------------------------------------------------------------------------------

I don't think that we are seeing extreme examples. But we may be seeing less extreme immediate reactions or reactions where the toxicity builds up over time.

Quinoline rings are know to cause neurotoxicity. There are theories about how that happens. One of the theories is about blocking connexins which are gap junction proteins in the brains.

I don't know how montelukast could be breaking up so that it causes toxicity. Or if the problem is the how rapidly the liver enzymes can metabolize it. But there is plenty, plenty, plenty of clinical evidence that there is a quinoline ring culprit somewhere in the picture. Or some by-product of that causing problems.

Somehow it was decided that montelukast did not have the safety issues that the other drugs in the same category have. See this.

"The starting point in the development of montelukast appears to be a quinoline-containing structure, likely identified as a weak random screening lead (Figure 3). The Merck group hypothesized that this molecule was mimicking the olefin backbone of cysLTs, and that the addition of mimics for the acid and peptide regions of LTD4, might improve its potency. As a first step, the dithioacetal linkage first seen in some SmithKline compounds was incorporated; this led to a compound with greatly increased in vitro potency but poor oral bioavailability. When one of the carboxylic acids was replaced by an amide, forming MK-571, the new antagonist had even greater potency and good efficacy following oral administration. The enantiomers were resolved to yield MK-679 (verlukast), a compound with better clinical effects than MK-571, but whose clinical development was stopped for safety reasons. Further structure-activity relationship studies led to the development of montelukast (16), an antagonist that appears free of the safety concerns plaguing earlier members of this series."

If we can find out why the earlier versions were not safe and how they thought fixed it, then maybe we can find out what is going on with the quinoline ring in some people.

I would be very surprised if the FDA will address our concerns. Why does it always seem like they wait for enough people to die like in Vioxx? Wasn't Vioxx responsible for thousands of deaths?

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.

OH and to those of you have taken the time to read these posts and have posted your own accounts and have not been offensive. Thank you! I appreciate you increasing awareness. Concerned citizen I am very thankful that you have done so much research. It has been very useful to me!

Here is a story about another type of quinoline drug that also causes psychiatric side effects including suicide. Considering the side effects of Singulair, it may be worth investigating whether montelukast breaks up (in certain individuals) into chemicals that act in the same neurotoxic way that Lariam does. The neurological and psychiatric side effects of Lariam are very similar to Singulair in some individuals, of course, not all.

www.cbsnews.com/stories/2003/01/27/60II/main538144.shtml - 95k

FYI: Go to

http://www.drugs.com/fda/singulair-montelukast-12368.html

Singulair (montelukast)
March 27, 2008
Audience: Pulmonologists, respiratory therapists, other healthcare professionals, patients
FDA informed healthcare professionals and patients of the Agency's investigation of the possible association between the use of Singulair and behavior/mood changes, suicidality (suicidal thinking and behavior) and suicide. Singulair is a leukotriene receptor antagonist used to treat asthma and the symptoms of allergic rhinitis, and to prevent exercise-induced asthma. Patients should not stop taking Singulair before talking to their doctor if they have questions about the new information. Healthcare professionals and caregivers should monitor patients taking Singulair for suicidality (suicidal thinking and behavior) and changes in behavior and mood.

This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs. Due to the complexity of the analyzes, FDA anticipates that it may take up to 9 months to complete the ongoing evaluations. As soon as this review is complete, FDA will communicate the conclusions and recommendations to the public.

Latest FDA MedWatch Alerts...

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.