Gene type 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

Since HTML is not allowed...need you to find the links to the following:

"whether an oral contraceptive (OC) containing drospirenone (DRSP) (3 mg) + ethinyl estradiol (EE) (30 μg) (DRSP + EE) could modify psychological symptoms and whether it could modify steroids interfering with the γ-aminobutyric acid (GABA)-A receptors.

Conclusion(s): The results suggest beneficial effects of DRSP + EE on psychological symptoms by

decreasing DHEAS."

Beneficial to lower the levels of DHEAS?!

"Women With Higher Levels Of DHEAS Have Better Cognitive Function"

"dehydroepiandrosterone sulfate (DHEAS), inhibit the production of TNF in vitro and in vivo."

Who is at greater risk?

Those who have the HLA-DR gene type and already have allergies/asthma.

Adrenergically blockaded conditions = AdBCs include the following: respiratory allergies, skin allergies, and asthma.

IgE will go thru the roof. Allergic reaction. Th2 pathway.

""It has also been shown that young women exposed to intensive stress situations,

with low plasma of dehydroepiandrosterone
sulfate (DHEA-S),

and a recent use of contraceptive pills are most at risk for

onset of autoimmune disease."

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

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