Smooth muscle cells symptoms and conditions

Researchers have been doing studies for many years regarding trying to determine the role of genetic factors in patients response to Singulair (Montelukast).

This study from Spain identified the following gene variations hypothesize to be related to leukotriene pathway response. Sixty one patients with asthma were studied. Three gene types were identified:

type 1. Thirty-two patients (52.5%) were homozygous for the five repeats allele;
type 2. 17 (27.9%) were heterozygous (4/5 repeats)
type 3. 12 (19.7%) were homozygous for 4/4 repeats.

The study showed that montelukast was effective for types 1 and 2 but not effective for type 3. Type 3 represented approximately 20% of the group study.

"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."

So it seems logical that if it can be identified that montelukast is not effective for certain gene type variations, then montelukast could cause adverse side effects in certain gene type variations.

It is interesting that 20% of this group does not respond positively to montelukast. That is the exact same number that even Merck says gets a headache from montelukast. Headache is the highest incidence of adverse side effects that has been reported. That comparison, however, is just a coincidence because it has not been studied and proven. Maybe.

Where are the studies that pertain to gene type variations and adverse side effects? You would think that somebody could do them.

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. ******

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

CysLT1 receptor (the one that Singulair blocks) is also expressed (shows up) in the spleen. I have not seen anything yet that says what it does in the spleen. The spleen has important immune system functions especially in children. It contains B-lymphocytes that fight infection.

: Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:587-97.Links
Cysteinyl leukotriene receptors.Evans JF.
Department of Pharmacology, Merck Research Laboratories, Merck & Co., West Point, PA 19486, USA. jilly_evans@merck.com

The cysteinyl leukotrienes, leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), activate contractile and inflammatory processes via specific interaction with putative seven transmembrane-spanning receptors that couple to G proteins and subsequent intracellular signaling pathways. Pharmacological characterizations identified at least two subtypes of cysteinyl leukotriene (CysLT) receptor based on agonist and antagonist potency for biological responses. The rank potency of agonist activation for the CysLT1 receptor is LTD4 > LTC4 > LTE4 and for the CysLT2 receptor is LTC4 = LTD4 > LTE4. CysLT1 selective receptor antagonists are efficacious in the treatment of asthma. No selective CysLT2 receptor antagonists have been described. Molecular identification of the human and mouse CysLT1 and CysLT2 receptors has confirmed their structure as putative seven transmembrane domain G protein-coupled receptors and largely confirmed the previous pharmacological characterizations. The CysLT1 receptor is most highly expressed in spleen, peripheral blood leukocytes including eosinophils, and lung smooth muscle cells and interstitial lung macrophages. The CysLT2 receptor is most highly expressed in the heart, adrenal medulla, placenta and peripheral blood leukocytes. The molecular identification of the mouse CysLT1 and CysLT2 receptors show similar but not identical profiles to the orthologous human receptors.

PMID: 12432945