Receptor antagonist symptoms and conditions

Hi
My husband has been prescribed 2 different blood pressure meds Lisionpril and metoprolol back in June. Come mid July he started to have trouble sleeping and slight tingling in hands and feet. Then it progressed to the arms and legs and then the face and chest. We have seen cardiologist, neurologist, sleep apnea doctors, Had EKG, MRI, Heart sonograms, Nerve test done due to the symptoms. Everything came back normal. He is miserable. The burning and pain is unbearable to wear he wants to cut his feet off and the only thing we keep hearing is well LETS DO ANOTHER TEST or TRY THIS MED. So now he is taking a a sleep med for insomnia and some seizure med for the nerve pain, thinking he may have neuropathy. This is going on 2 months now of trial and error and after reading 20 minutes of experiences, I THINK ITS THE MED!!!!!!!
What do we do then? He had high blood pressure so what meds are good with no side affects of burning or insomnia? Any suggestions or help would be of great appreciation. Thank you!!!

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

Here is an example of the fact that the medical community recognizes that there are gene based drugs. Because Singulair is modeled to be a receptor antagonist to the cysLT1 receptor and the cysLT1 receptor is a gene, I'd say that Singulair should be described as a gene based drug. I don't really care how anybody wants to play with the definition. CysLT1 is a gene with known variations. Why isn't there just an "across the board" warning for all gene based drugs that unexpected side effects are possible???? And, that doctors should watch out for individual reactions.

WMJ. 2005 Aug;104(6):61-6.Links
Gene-based drug prescribing: clinical implications of the cytochrome P450 genes.Musana AK, Wilke RA.
Department of General Internal Medicine, Marshfield Clinic, WI, USA.

The Institute of Medicine recently mandated an increased effort to improve patient safety and reduce medical error. With the description of genetic polymorphisms in the drug metabolizing enzymes, the field of pharmacogenetics may improve medical care through a reduction in both therapeutic failure and adverse drug reaction. Investigators at the Marshfield Clinic in central Wisconsin are piloting the process of gene-based drug prescribing in a variety of contexts. This paper reviews the field of cytochrome P450 (CYP) genetics and explores factors that impact the utility of this information in clinical practice.

PMID: 16218319

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.

"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

Montelukast toxicity in two patients with inherited defects in liver enzymes.

CASE REPORT: MONTELUKAST-INDUCED ACUTE CHOLESTASIS

Ajay Jain1, Flavio Habal2

1Department of Medicine, Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario; 2Division of Gastroenterology and Hepatology, University Health Network, Toronto General Hospital, Toronto, Ontario

INTRODUCTION: Drug-induced liver disease may occur as an unexpected idiosyncratic phenomenon to a normally non-hepatotoxic drug or be an expected consequence of the intrinsic hepatotoxicity of a drug consumed in sufficiently large doses to cause liver damage (eg. acetaminophen). We describe the first two cases ever reported of acute cholestasis as a result of the administration of montelukast (SingulairÒ, Merck Frosst), a potent and specific cysteinyl leukotriene (LTD4) receptor antagonist, for the treatment of chronic asthma.

CASES: Patient 1 was a 36-year-old female who developed a low- grade fever, fatigue, nausea and a diffuse urticarial rash after treatment with montelukast for chronic asthma. She had marked liver enzyme abnormality with a predominantly cholestatic pattern. Peripheral blood analysis revealed eosinophilia. Patient 2 was a 43-year-old female who developed fatigue after initiation of montelukast. Routine blood-work revealed mild elevation of transaminases and alkaline phosphatase, all of which were normal prior to taking the drug. In both patients, all signs, symptoms and biochemical parameters normalized upon discontinuation of montelukast.

Metabolism of montelukast occurs by cytochromes P-450 3A4, 2C9, and 2A6. Patients that have demonstrated idiosyncratic toxicity, as in these two cases with montelukast, have inherited defects in detoxification enzymes. We propose that the toxic metabolite, acyl glucoronide, is responsible for montelukast-induced liver injury. A genetic basis for deficiencies in various hepatic detoxification enzymes likely accounts for an individual’s susceptibility to drug-induced liver disease.

CONCLUSION: We suggest that montelukast and possibly other leukotriene receptor antagonists may result in idiosyncratic hepatic drug reactions.

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

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.

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.

For those people with gastro-intestinal side effects, there is a cysLT1 receptor in gastro-intestinal mucosa - at least in rats, there is. Now, Merck cannot claim the blood-brain barrier on this one. We need to know how montelukast affects these gastro-intestinal receptors (if present in humans) for those people on montelukast long term.

This study in rats suggests that montelukast does possibly (if proven in humans) interact with the cysLT1(singulair) receptor in gastro-intestinal mucosa. How? Good under what circumstance? Bad under what circumstance?

Prostaglandins Leukot Essent Fatty Acids. 2008 Mar;78(3):189-97. Epub 2008 Apr 1. Links
Leukotriene D4 receptor antagonist montelukast alleviates water avoidance stress-induced degeneration of the gastrointestinal mucosa.Ersoy Y, Cikler E, Cetinel S, Sener G, Ercan F.
Department of Histology and Embryology, School of Medicine, Marmara University, 34668 Istanbul, Turkey.

We investigated the role of montelukast (ML), a cysteinyl leukotriene-1 receptor antagonist, on the water avoidance stress (WAS)-induced degeneration of the rat gastric, ileal and colonic mucosa. One group of Wistar albino rats were exposed to chronic WAS (WAS group) 2h daily for 5 days. Another group was administered ML (10mg/kg; i.p.; WAS+ML group) following every WAS exposure for 5 days. Control rats were injected with the vehicle solution only. The stomach, ileum and colon were dissected and investigated for histopathological changes with a light microscope as well as for topographical changes with a scanning electron microscope. The levels of malondialdehyde (MDA, a biomarker of oxidative damage) and glutathione (GSH, a biomarker of protective oxidative injury) were also determined in all dissected tissues. In the WAS group, the stomach epithelium showed ulceration in some areas, dilatations of the gastric glands, degeneration of gastric glandular cells, and prominent congestion of the capillaries. In a similar fashion, degenerated epithelium and severe vascular congestions were observed in the ileum and colon. In all the tissues dense inflammatory cell infiltration and mast cell degranulation in mucosa were observed. The levels of MDA were significantly increased whereas those of GSH were significantly decreased in all test tissues in the WAS group compared to the control group. The morphology of gastric, ileal and colonic mucosa in WAS+ML group showed a significant amelioration showing a reduction in inflammatory cell infiltration and mast cell degranulation. Increased MDA and decreased GSH levels in the WAS group were also ameliorated with ML treatment. Based on the results, ML supplement seems attenuated inflammatory effects of WAS induction in gastrointestinal mucosa.

PMID: 18387287

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

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.

I know that many here would like the FDA to take a very serious took at the problem. I personally don't see how a review of their data is going to make any difference at all. But, if there are experts who can propose a model of the pathways of cell signalling that include the possibility that these symptoms can occur (and under what circumstance), then maybe the problem will look like something much more than statistics.

This is not my field. But I tried to follow the possible pathways to see if I could identify a possible area of concern. Then I looked for someone who had written in the area and read their abstract. A place to start may be to get an opinion from those who know something about "normal homeostasis of the mast cell." Singular blocks the cysteinyl leukotriene receptor 1 which is a site on the outer membrane of the mast cell (other cells also). The mast cell which is produced in the bone marrow is released in a immature state and matures after it arrives at it's destination. The mast cell does not become active unless it's receptor sites come in contact with the activating agent. So, what happens when a receptor site on the mast cell is suppressed by Singular, a receptor antagonist.

You see, I don't have a clue what the signals are that tell the bone marrow to make mast cells (or what the signals are that tell them where to go after they are made in the bone marrow). Does Singular interfere with something that tells the bone marrow what to do? If Singular does interfere with that process, then what is happening and what period of time does it take to happen? Could we wonder whether Singular is interfering with the NUMBER of mast cells that are produced over time? And, of course, maybe there is some OTHER kind of explanation for why the adverse drug reactions are happening. But, at this level, I got lost and can't go any further.

Maybe this group would be interested in the Singulair problems or could suggest somebody else?

http://www.edata-center.com/journals/2ff21abf44b19838,0a1257122f661a7e,0d8ee7116ef23452.html

I apologize if this lead doesn't produce any results but at least it could be a place to start.