Genetic component symptoms and conditions

Has anyone been in contact with any doctors, hospitals, or researchers who are willing to recognize that Singulair targets a receptor CysLT1, with known genetic variations? As you know, I have been posting that I know of researchers who are doing work about how the genetic variations can determine the efficacy of Singulair. If genetic variations cause differences in efficacy, then, of course, these variations can also cause unpleasant to very serious side effects. These seems to be some kind of disconnect. How can the genetic component be recognized in the area of efficacy and ignored in the area of adverse drug reactions?

16 days ago on Jan 17, 2009 by chris555, #16131
Sorry to disappoint you, but I have no vested interest in Merck or any other pharmaceutical company for that matter. What I have a vested interest in is providing some balance to those parents who come to this blog site and are scared to death. That is what happened to a very good friend of mine. After reading the posts here, she was so panicked she took her 12 year old off Singulair. A kid who had no problems on it by the way. A few days later my friends kid was rushed to the ER and almost died from an asthma attack. That is what I have a problem with. People here telling others the side effects will creep up, that kids should stop their medication right away, etc.

Reply 8 minutes ago on Feb 03, 2009 by concernedcitizen, #16701
To chris555:

Merck warns on it's Singulair website that Singulair is not an effective replacement for fast acting inhalers in the event of sudden symptoms. Originally when Singulair was developed it's purpose was to prevent damage and inflammation that is caused by excessive number of eosinophils in respiratory tissue. There is no evidence at all that Singulair is effective as the only treatment for asthma to prevent or treat acute asthma attacks. And, Merck makes this very clear in the warning notice.

The efficacy and safety of Singulair has a genetic component. That means that it is entirely possible that some people are not compatible with the way in which Singulair works. Adverse side effects are very possibly the result of compatibility problems.

Sadly, Merck has succumbed to the disease of "corporate greed." Meaning that they care more about profitability and the shareholders than they do about the patients. For this callousness, some day this corporation will suffer the punishment. Merck has always known that the cysLT1 receptor is a gene with more than several variations. If they told doctors to watch out for side effects due to genetic variations, then they wouldn't be able to sell this drug like it's harmless - cherry chewable - candy. The adverse side effects are real. Patients started reporting them immediately when the drug was released. Singulair is dangerous to people with gene variations and it causes unnatural biochemical events to take place.

IMPORTANT SAFETY INFORMATION
SINGULAIR will NOT replace fast-acting inhalers for sudden symptoms. You should still have rescue medication available and continue to take your other asthma medications unless your doctor tells you to stop.

To get the real information in regards to what level of research that is going into this investigation is.go to the Institute for Safe medicine practices click on Quarter watch.
To people like chris555, I believe you are engaging people for sport and say very hurtful things,your day will come and it may just be in the unemployment line.I can only imagine that you must work for Merck or you would not feel so threatened by the good that has come from Parents advocating for their childrens safety.I want you to know, that all who knew our family and our child understand what took place and our reasons for trying to get the proper information where it should have been," on the label". When our child died no one knew about all the added side effects from post marketing reports,which is "a reliable way to track a drugs adverse events".Maybe you should do more research on the legitimate information of causal relationship. Don't be so afraid of a possible drop in revenue for the drug company that I believe you might be an employee of.K. M.

I apologize that the summary is not ready yet. At this time, I am inclined to believe that the FDA will "black box" Singulair. Maybe, I am just hoping but we will see. I also believe that the FDA will also investigate the entire category of drugs with genetic components and warn doctors that these drugs do NOT behave AS EXPECTED when the patient has a genetic variant.

I am posting this again.

I just wanted everyone to know that I am still here and concerned about everyone who is having side effects from Singulair. Sometime within the next few weeks I am going to post a summary and conclusion about all of the research that I have posted. I hope to come up with a well organized concise statement about why everyone who experiences side effects from Singulair should stop using the drug immediately. Not everyone has an adverse reaction to this drug. For those who do, it is very dangerous to continue this medication even for one more day. STOP IMMEDIATELY IF YOU SUFFER SIDE EFFECTS FROM SINGULAR. WHEN YOU SUFFER SIDE EFFECTS FROM SINGULAIR, THE REASON IS THAT YOU ARE NOT COMPATIBLE WITH THE DRUG'S GENETIC BASED MODEL. Singulair targets the CysLT1 receptor, which is a gene. This gene is not the same for everyone. If your doctor does not understand that the mode of action of Singulair has a genetic component, then tell him/her.

I just wanted everyone to know that I am still here and concerned about everyone who is having side effects from Singulair. Sometime within the next few weeks I am going to post a summary and conclusion about all of the research that I have posted. I hope to come up with a well organized concise statement about why everyone who experiences side effects from Singulair should stop using the drug immediately. Not everyone has an adverse reaction to this drug. For those who do, it is very dangerous to continue this medication even for one more day.

STOP IMMEDIATELY IF YOU SUFFER SIDE EFFECTS FROM SINGULAR. WHEN YOU SUFFER SIDE EFFECTS FROM SINGULAIR, THE REASON IS THAT YOU ARE NOT COMPATIBLE WITH THE DRUG'S GENETIC BASED MODEL.

Singulair targets the CysLT1 receptor, which is a gene. This gene is not the same for everyone. If your doctor does not understand that the mode of action of Singulair has a genetic component, then tell him/her.

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

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

More evidence of what I have been saying about genetics and the leukotriene pathway that Singulair blocks. FLAP's as mentioned below are actually the same era as Singulair (late 90's)--many scientists were looking at this pathway.

The genetic component is so "in your face" every where that I am quite appalled that Merck has not at least addressed that issue by now.

Monday, June 02, 2008
Amira Pharmaceuticals Achieves Milestones in FLAP Inhibitor Program With GlaxoSmithKline
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SEND ComtexDigg It StumbleUpon Newsvine Reddit SAN DIEGO, Jun 02, 2008 (PR Newswire Europe via COMTEX) ----GSK exercises option for AM803, a FLAP inhibitor which recently completed phase I studies

Amira Pharmaceuticals today announced that under the terms of a worldwide exclusive agreement entered into in Feb 2008, GlaxoSmithKline (GSK: 43.65, -0.88, -1.97%) will exercise its right to a second FLAP compound, AM803. Under the original agreement, GSK has rights to develop, manufacture and commercialize FLAP (5-Lipoxygenase Activating Protein) inhibitors for the treatment of respiratory and cardiovascular disease. The decision to develop AM803 follows the successful completion of a phase I study by Amira, which demonstrated its potential as a once-daily FLAP inhibitor.

"Exercise of this option by GSK caps a productive first few months during which Amira has hit a number of near term milestones. Hitting these milestones early has not only further strengthened our relations with GSK, but has resulted in meaningful economic benefit to Amira," said Hari Kumar, Chief Business Officer, Amira. "The project has started extremely well and we are very pleased at the commitment of GSK and the progression of development."

About FLAP Inhibitors

FLAP (5-Lipoxygenase Activating Protein) is a key component early in the leukotriene pathway, a complex signaling process that exerts control over biological processes, such as inflammation and immunity. Excessive production of leukotrienes exacerbates inflammatory diseases, such as asthma; the FLAP gene has also been linked to a significant increase in the risk of myocardial infarction and stroke. AM103 and AM803 bind to FLAP, inhibiting the synthesis of leukotrienes that cause inflammation.

About Amira

Founded in 2005 and headquartered in San Diego, Amira Pharmaceuticals is a small molecule pharmaceutical company focused on the discovery and early development of compounds to treat inflammatory disease linked to the eicosanoid pathway.

The company combines the rigor of a big pharmaceutical company with the ingenuity and energy of a small company, creating an environment for efficient and effective pre-clinical and clinical program decisions. Its scientific founders have successfully worked together for more than a decade and were pivotal in the discovery of a number of inflammatory drugs, including Singulair(R: 73.05, -0.38, -0.51%). The drug hunters at Amira are now actively leveraging their history of success to create high-value compounds for the future. For more information, visit http://www.amirapharm.com.

Web site: http://www.amirapharm.com

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.

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

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

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

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

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

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

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

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

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

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

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

I noticed a lot of postings about weight gain on Singulair, which is nowhere listed by Merck as a possible side effect. My 15 y.o. daughter experienced sudden weight gain at the age of 9 when she was actually underweight (BMI went from 17 to 21). To make a long story short, after being off Singulair for over a year, she is now over-weight, and diet/exercise have never made a big difference (gymnastics, swim team, figure skating, trampoline, etc.) Extensive labwork is always normal & there is no family history of obesity. It's a shame the quality of life of a child is RUINED by a drug that is deemed to have "no side effects", and the many drs. & specialists out there take it very lightly. We continually worry about our daughter's self-esteem, risk of diabetes, and other complications from weight gain which is not hereditary and goes on unexplained by the drug co. Reversing this weight gain has been nearly impossible. Everytime I hear a news report about our children being overweight and obese, it makes me angry because I think about the many kids that are taking this highly prescribed drug (for even the mildest allergy or asthma) and who knows how many parents don't make the connection!

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

quote:

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

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

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

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

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

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

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

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

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