Endothelial 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

Is there a potential explanation for the adverse psychiatric side effects of montelukast?

In my opinion, there are at least some very good clues based upon the work of the Chinese researchers.

A 2006 report indicated that they had localized (meaning found it was there) the CystLT1 receptor (same as the receptor that montelukast
Singulair blocks) in the neurons of the brain tissue of rats. In order to do that, they injected rat brain's with NMDA to cause a chemically induced state of excitotoxicity. Excitotoxicity is a common factor in Central Nervous System disease. They concluded that both 5-LOX and CystLT1 were upregulated by the excitotoxicity that they artificially created
with the NMDA. Therefore, there would be a potential link between neuron activity and CystLT1. Nerve cells are damaged by excitotoxicity. These researchers used NMDA to cause nerve damage which caused the CystLT1 to show up. NMDA was often used in human behavior studies to cause brain damage. They would then try to observe whether behavior was compromised to conclude what areas of the brain determined what behavioral response.

So I was thinking about the Chinese researchers as I was reading other posts. One post interested me particularly regarding the mother who described behavior that seemed like hypoglycemics when their snack doesn't arrive on time. So a light bulb went on. Glutamate, another excitotoxin, can build up in the brain to a level that is damaging if humans become excessively hypoglycemic. If glutamate concentration around the synaptic cleft reaches too high a level then neurons die. Clinically, it really does seem that many people experience things that sound like the effects of hypoglycemia. It could be only a coincidence. But then again, maybe not.

The Chinese researchers found the CystLT1 receptor in the rat brain neuron after brain damage. They found the CystLT1 receptor in the normal human brain in the microvascular endothelial cells and in neuron and glial-appearing cells in brain trauma or tumors.

What role does the CystLT1 play in brain function? If it exists in brain tissue, we can assume that it does have a function. If it plays a role in preventing or repairing neuron damage due to excitotoxins, then there would be a very direct link between Singulair and adverse psychiatric side effects.

http://www.chinaphar.com/1671-4083/27/1526.htm

The bottom line is that Merck owes people who take Singulair further research regarding it's effect on the brain.

(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.