Chemical structure symptoms and conditions

hi, im not sure what to do. my 3 1/2 year old daughter was today given the prescription for singulair. i voiced my concerns to the doctor after my friend telling me its no good due to the side effects.she said that there are risks and side effects with any drug you take but for some reason i don't feel right about this. don't doctors know better than this. anyway Would like to know if all the people who take singulair suffer some sort of side affects or is it minimal? or going by this side it looks like its probably best not to give it to her at all.

My nephew is 7 and has been on Singulair for probably 4 years. His symptoms developed over time but recently have exploded. He has epilepsy so most of the things that he has experienced has been blamed on that. However, today his doctor took him off singulair and said he believes his symptoms are caused from the drug. He started having head drop seizures, fell out of his desk and cut his face one day. He has also been depressed, had severe anxiety attacks for the past 8 months. Several months ago, he started having such severe nightmares that it is almost impossible to get him to go to bed and go to sleep. Recently he began "seeing dead people" and "monsters" that we trying to kill him even when he was awake. He has also cried many nights with leg cramps and severe stomach pain. I will update this page in two - three weeks to let you know if these problems go away now that we have stopped the singulair.

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.

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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.

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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.

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.