Mediators symptoms and conditions

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

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

Hopefully this will prove to the doubters that there are genetic reasons for the variation of efficacy and adverse side effective when taking Montelukast.

I have several areas of concern (concerned citizen is concerned). One of the main areas is the reliability of Montelukast due to differences in genetics among populations. The cysLT1 (Singulair) receptor is a GENE. As I said before, it would be possible to predict those patients for which Montelukast would and would not be effective and those patients whose gene expression profile would cause them to have unwanted side effectives.

I have been looking for a way to give reasonable proof of that which could be used to convince your doctors that Montelukast is not for everybody. I happened to locate a researcher who had invented and patented methods for predicting drug sensitivity and efficacy in inflammatory disease. I have quoted below from his patent application. He intended to provide a method for determining efficacy and drug sensitivity for pharmaceuticals which include leukotriene antagonists - Montelukast.

Quoted from:

Methods for predicting drug sensitivity in patients afflicted with an inflammatory disease
US Patent Issued on December 12, 2006

Methods are disclosed for predicting the efficacy of a drug for treating an inflammatory disease in a human patient, including: obtaining a sample of cells from the patient; obtaining a gene expression profile of the sample in the absence and presence of in vitro modulation of the cells with specific cytokines and/or mediators; and comparing the gene expression profile of the sample with a reference gene expression profile, wherein similarities between the sample expression profile and the reference expression profile predicts the efficacy of the drug for treating the inflammatory disease in the patient.

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The field of pharmacogenomics measures differences in the effect of medications that are caused by genetic variations. Such differences are manifested by differences in the therapeutic effects or adverse events of drugs. For most drugs, the genetic variations that potentially characterize drug-responsive patients from non-responders remain unknown.
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In another embodiment, the invention is directed to a method for predicting the efficacy in a human asthma patient of leukotriene antagonists including, but not limited to, montelukast (a.k.a., SINGULAIR™; Merck, Whitehouse Station, N.J.), zafirlukast (a.k.a., ACCOLATE™, AstraZeneca, Wilmington, Del.), and zileuton (a.k.a., ZYFLO™; Abbott Laboratories, Chicago, Ill.), comprising: obtaining a sample of cells from the patient; obtaining a gene expression profile from the sample in the absence and presence of in vitro modulation of the cells with specific mediators; and comparing the gene expression profile of the sample with a reference gene expression profile, wherein similarity in expression profiles between the sample and reference profiles predicts the efficacy in the human asthmatic patient of leukotriene antagonists.

Many of the cells involved in causing airway inflammation are known to produce signaling molecules within the body called "leukotrienes." Leukotrienes are responsible for causing the contraction of the airway smooth muscle, increasing leakage of fluid from blood vessels in the lung, and further promoting inflammation by attracting other inflammatory cells into the airways. Oral anti-leukotriene medications have been introduced to fight the inflammatory response typical of allergic disease. These drugs are used in the treatment of chronic asthma. Recent data demonstrates that prescribed anti-leukotriene medications can be beneficial for many patients with asthma, however, a significant number of patients do not respond to anti-leukotriene drugs.

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The genes selected are those that have been determined to be differentially expressed in either a disease, drug-responsiveness, or drug-sensitive cell relative to a normal cell and confer power to predict the response to the drug. By comparing tissue samples from patients with these reference expression profiles, the patient's susceptibility to a particular disease, drug-responsiveness, or drug-resistance can be determined.

http://www.patentstorm.us/patents/7148008-description.html

The inventor's website: Hakon Hakonarson M.D. The Children's Hospital of Philadelphia

http://stokes.chop.edu/research/profiles/?ID=251

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

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

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

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

PMID: 18415834

(I posted this before but after receiving some e-mail, I have revised a few sentences to hopefully make it more understable. )

I would like to share this information with everyone. First, I would like to caution all that it does not prove anything regarding the negative side effect of Singulair but it does suggest that there might (only might) be a physiological cause for any side effect that could be attributed to brain function. A Chinese team has been studying the receptor (Cysteinyl leukotrienes receptor 1) that is targeted by Singulair and is responsible for the method of action that makes Singulair successful. Here is one of their studies.

1: Neurosci Lett. 2004 Jun 17;363(3):247-51. Links Expression of cysteinyl leukotriene receptor 1 in human traumatic brain injury and brain tumors.Zhang WP, Hu H, Zhang L, Ding W, Yao HT, Chen KD, Sheng WW, Chen Z, Wei EQ. Department of Pharmacology, School of Medicine, Zhejiang University, 353, Yan An Road, Hangzhou 310031, PR China. Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators. CysLT receptor 1 (CysLT(1)) is one of the two CysLT receptors that has been cloned. Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown. The objective of this study was to examine the distribution of CysLT(1) by immunohistochemical analysis in human brains with traumatic injury or tumors. CysLT(1) was expressed intensely in the microvascular endothelial cells in both normal and abnormal conditions. At 8 days after traumatic injury, microvascular regeneration was found and all of the endothelial cells highly expressed CysLT(1). In gray and white matters of the normal regions of the brain, CysLT(1) was expressed weekly or not at all. However, the CysLT(1) expression increased in the neuron- and glial-appearing cells in gray and white matters after traumatic brain injury. CysLT(1) was also detected in astrocytoma, ganglioglioma and metastatic adenocarcinoma, and the expression in the neuron- and glial-appearing cells around brain tumors increased robustly. PMID: 15182953

Here is the relevant part of the study. "Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown." That sentence says that these scientists believe that CysLT1 exists in the brain but they did not know what the location in the brain was. Then they did this study which showed that the receptor existed in the tissues of the brain that are listed above and are too complicated to discuss here.

It is logical to assume that if a receptor exists in any part of the body that it has a function in other words it does something or tells some other part of the body to do something. They have not proved (that takes many studies) what part of the brain or what the receptor does in the brain or what the effect on the body is if the receptor does not do it's job. We do know that Singular (montelukast, Cysteinyl leukotriene receptor 1 antagonist) blocks this particular receptor so if the receptor exists in the brain that it COULD BE POSSIBLE that Singular prevents this receptor in the brain from doing it's job whatever that is. I know that it is difficult to argue with doctors. This drug has been around a long time. It would be difficult to understand why we are just learning about problems after so long a period of time. I can see from all of these responses that these problems are very real. Of course, we have no idea if Singulair is related or not. But if you need something supportive to show that it is not impossible for them to be related even though there is no proof that they are related, you could print this out and discuss it with your doctor.

This isn't proof of anything but at least it might be a clue. It just shows that it is not impossible that Singular affects brain function in some way.

I would like to share this information with everyone. First, I would like to caution all that it does not prove anything regarding the negative side effect of Singulair but it does suggest that there might (only might) be a physiological cause for any side effect that could be attributed to brain function.

A Chinese team has been studying the receptor (Cysteinyl leukotrienes receptor 1) that is targeted by Singulair and is responsible for the method of action that makes Singulair successful. Here is one of their studies.

1: Neurosci Lett. 2004 Jun 17;363(3):247-51. Links
Expression of cysteinyl leukotriene receptor 1 in human traumatic brain injury and brain tumors.Zhang WP, Hu H, Zhang L, Ding W, Yao HT, Chen KD, Sheng WW, Chen Z, Wei EQ.
Department of Pharmacology, School of Medicine, Zhejiang University, 353, Yan An Road, Hangzhou 310031, PR China.

Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators. CysLT receptor 1 (CysLT(1)) is one of the two CysLT receptors that has been cloned. Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown. The objective of this study was to examine the distribution of CysLT(1) by immunohistochemical analysis in human brains with traumatic injury or tumors. CysLT(1) was expressed intensely in the microvascular endothelial cells in both normal and abnormal conditions. At 8 days after traumatic injury, microvascular regeneration was found and all of the endothelial cells highly expressed CysLT(1). In gray and white matters of the normal regions of the brain, CysLT(1) was expressed weekly or not at all. However, the CysLT(1) expression increased in the neuron- and glial-appearing cells in gray and white matters after traumatic brain injury. CysLT(1) was also detected in astrocytoma, ganglioglioma and metastatic adenocarcinoma, and the expression in the neuron- and glial-appearing cells around brain tumors increased robustly.

PMID: 15182953

Here is the relevant part of the study.

"Although the expression of CysLT(1) in the brain has been demonstrated by Northern blot and RT-PCR analyses, the location of CysLT(1) in the brain remains unknown."

That sentence says that these scientists believe that CysLT1 exists in the brain but they don't know what the location in the brain is.

It is logical to assume that if a receptor exists in any part of the body that it has a function in other words it does something or tells some other part of the body to do something. So we don't know what part of the brain or what the receptor does in the brain or what the effect on the body is if the receptor does not do it's job.

We do know that Singular (montelukast, Cysteinyl leukotriene receptor 1 antagonist) blocks this particular receptor so if the receptor exists in the brain that it COULD BE POSSIBLE that Singular prevents this receptor in the brain from doing it's job whatever that is.

I know that it is difficult to argue with doctors. This drug has been around a long time. It would be difficult to understand why we are just learning about problems after so long a period of time. I can see from all of these responses that these problems are very real. Of course, we have no idea if Singulair is related or not. But if you need something supportive to show that it is not impossible for them to be related even though there is no proof that they are related, you could print this out and discuss it with your doctor.

This isn't proof of anything but at least it might be a clue.