Chinese researchers symptoms and conditions

Our son started taking Singulair when he was 2 for severe allergic rhinitis and cough variant asthma (in addition to Zyrtec, which didn’t control all of his symptoms). He is 5 now. For the last three years, he has been an increasingly violent, difficult, defiant, argumentative, volatile child who has intense mood swings--one minute he’s laughing uncontrollably, the next he’s weeping over nothing. His doctor and therapist recommended that we see a psychiatrist to have him evaluated for bipolar disorder, which used to be unknown in children. Because he has such chronic sleep problems, the doctor also suggested we take him off Singulair (and increase his Zyrtec dose) to see if it improved his sleep issues. Within a week, he was sleeping much better and was a calmer, happier, gentler boy. He suddenly could take “no” for an answer without flipping out and trying to hurt me. We thought that we were just in an unusual, calm window that would shift either to mania or intense sadness or both, any minute. We also thought that his behavior change might be due to sleeping better. We were enjoying the rare reprieve. Over the last weekend, his springtime allergies really flared up. We gave him Singulair on Monday and by noon, he was completely out of control. I had to strap him into his car seat at one point to keep him from hurting either me or himself. It finally occurred to me that Singulair might be causing his “bipolar” disorder. Of course, we stopped the Singulair. After two days he was a new boy. Yesterday, I Googled “Singulair bipolar children” and got a few hits. I am stunned to read how similar other families’ experiences have been to ours and I feel sick that we gave this drug to our child for three years.

Neurological problems and the effects of Singulair should be investigated. The Chinese researchers demonstrated that the CysLT1 receptor (singulair inhibits this receptor) does exist in the human brain. In the rat brain, they demonstrated that there is a link between this receptor and the astrocyte.

There are many researchers/doctors interested in excitotoxicity and damage to neurons.

http://www.jpands.org/vol9no2/blaylock.pdf

I would like to know how Singulair affects the astrocyte numbers and function. I would also like to know if there is a link between metabolism and the cysLT1 receptors in gastro-intestinal mucosa. Does Singulair affect the metabolic process?

So many parents are complaining of ADD/ADHD symptoms? The paper that I gave you the link correlates the immune response and excitotoxicity. That is very interesting. How many asthma and allergy patients also suffer from potential excitotoxicity? Does Singulair cause it in some patients or just make it worse in some patients? None the less--there is a possible link.

Why the brain function is impaired due to Singulair????? Maybe.

Here is the last chapter in a theoretical reason why Singulair affects brain function thus causing anxiety, depression, agitation, aggression, ADD/ADHD, and in extreme situations maybe seizures. I presented the study of the Chinese researchers that show a direct link between the cysLT1 receptor and the astrocyte in the brain. We don't really know how the cysLT1 receptor interacts with receptors that control astrocytes under all circumstances. We just know that there is an important link.

So last night, I had a dream about astrocytes. I don't really have anything to do but sit on an island, look at the Caribbean and fish so mental stimulation is actually welcome.

The last part of the "chain reaction" is probably the astrocytes role in glyconeogenesis. In other words, when the brain does not get proper nutrition, it sends signals to the liver to do something about the problem. The liver in turn releases glycogen which is turned into glucose to be released into the blood stream. A very unhappy brain becomes a very relieved brain. Obviously, we can't be eating all day long to keep our blood sugar up so the liver has to store energy and release it at the correct time.

Here is a diagram of that. Astrocytes are the only cell that produce the proper chemicals for this process to happen.

http://www.nature.com/jcbfm/journal/v27/n2/fig_tab/9600343f5.html
FIGURE
Quote: All credit to the authors, of course.

Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis
Leif Hertz, Liang Peng and Gerald A Dienel

BACK TO ARTICLEFigure 5.
Next figure | Previous figure | Figure and tables index

Glucose utilization pathways that provide or consume ATP. (A) Schematic of key aspects of the glycolytic pathway of glucose utilization for energy metabolism and major branch points that can divert carbon for other uses, including NADPH generation, storage of glucosyl units in glycogen, neuromodulator, and amino acid and nucleotide biosynthesis. The most important reactions for generation of energy are glycolysis (pyruvate/lactate formation from glucose), shown in light brown and occurring in all cell types, and glycogenolysis (pyruvate/lactate formation from glycogen), shown in light green, which occurs only in astrocytes, due to the astrocyte-specific expression of the enzyme glycogen phosphorylase, which releases a glucosyl unit from glycogen as G1P. The energetically most important biosynthetic reactions are synthesis of glycogen from glucose (glycogenesis) shown in brown and green and from pyruvate/lactate (gluconeogenesis) shown in pink, brown, and green. Gluconeogenesis is also astrocyte-specific, because only astrocytes express fructose-1, 6-bisphosphatase, which generates F6P from fructose-1, 6-bisphosphate (F1, 6P) and PC, which generates oxaloacetate (OAA) from pyruvate. The latter reaction is followed by formation of phosphoenolpyruvate (PEP) by decarboxylation of OAA; this sequence is necessary to form PEP from pyruvate, an energetically unfavorable reaction. Biosynthesis of serine/glycine (shown in olive) is also an astrocyte-specific process due to preferential expression of 3-phosphoglycerate dehydrogenase (Yamasaki et al., 2001). Both neurons and astrocytes form alanine and ribose-5-phosphate (R5P), the latter in the pentose shunt pathway (upper left corner), linked to NADPH production needed for operation of glutathione peroxidase and oxidation of monoamine transmitters. The MAS, indicated by red, transfers malate formed in the cytosol from oxaloacetate during conversion of NADH to NAD+ into mitochondria. PDH-mediated formation of acetyl CoA, which is also shown in red, initiates oxidative degradation of pyruvate in the mitochondria. Red and blue text for ATP indicates energy production and utilization, respectively. (B) Major reactions and net ATP yields or net ATP consumption of major pathways derived from the glycolytic pathway are indicated in color-coded boxes that correspond to the color-coded pathways in panel A. For simplicity, the scheme indicates the energy yields (ATP) and NAD(P)H production or utilization based on metabolism of 1 glucose to form one ribulose-5-P, two lactate/pyruvate, or 2 serine; a similar representation illustrates the energy and cofactors required for gluconeogenic conversion of two moles of lactate into one free (G6P) or glycogen-bound glucosyl unit. Glc, glucose; P, phosphate; G6P, glucose-6-P; 6PG, 6-P-gluconate; R5P, ribulose-5-P; GSH, reduced form of glutathione; GSSG, oxidized form of glutathione; F6P, fructose-6-P; F1, 6-P, fructose-1, 6-bisphosphate; GAP, glyceraldehyde-3-P; DHAP, dihydroxyacetone-P; 3PG, 3-P-glycerate; 2PG, 2-P-glycerate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Lac, lactate; Ala, alanine; OAA, oxaloacetate; 3P-HyPyr, 3-P-hydoxypyruvate; Glu, glutamate; KG, -ketoglutarate; 3P-L-Ser, 3P-L-serine; L-ser, L-serine; D-ser, D-serine; Gly, glycine; C1, one carbon fragment used for methyl donor reactions.

This is quite interesting because should the connection between the cysLT1 receptor and astrocyte be established and explained, it shows that there is a very direct link between the immune system and metabolism. That should be intuitive because when we get seriously sick, then we are laying in bed and the body should try to conserve energy so that we don't just waste away.

So what happens if we cause changes in the cysLT1 receptor to cause the astrocytes to believe that we are sick, the normal connection between the brain and glyconeogenesis then doesn't exist. We would have to be causing some kind of periods of extreme stress on the brain because we are out moving around and doing not home sick in bed.

Maybe we should award the Chinese researchers the nobel prize? Maybe they established the connection between the immune system and metabolism? Is there also a link between the immune system of some individuals and depression? Some how, this makes perfect sense. So we have to find out and help as many people as we can.

I think that it is time to call the lawyer-biochemists to find out if this can be proven to be true and if Merck knew or not.

Singulair does interact with the astrocyte in the brain.

The role of the cysLT1 receptor (Singulair blocks this receptor) and the astrocyte in the brain has been studied. For anyone from Merck to say that there are no mechanisms by which Singulair can affect the
brain is ludicrous. If the Chinese researchers are correct, then Singulair very clearly affects the brain. Certainly, we don't know exactly how or when the effect would be good or bad. Under what circumstances would it be beneficial and under what circumstances would it be harmful.

For quite a while, researchers have been hypothesizing about the role of the astrocyte in brain function. If we go to look for theories, we will find them. Here is the theory of Dr. Dale Antanitus. I am no here to promote anyone's theory in particular but just to point out that they exist.

http://www.antanitus.com/hypothesis

We can see that the Chinese researchers have gone forward to look at potential links between the cysLT1 receptor (Singulair receptor) and inflammatory response in the brain. The 2008 study showed a link between the astrocyte and the cysLT1 receptor (Singulair receptor)

1: Glia. 2008 Jan 1;56(1):27-37. Links
Activation of CysLT receptors induces astrocyte proliferation and death after oxygen-glucose deprivation.

Huang XJ, Zhang WP, Li CT, Shi WZ, Fang SH, Lu YB, Chen Z, Wei EQ.
Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.

We recently found that 5-lipoxygenase (5-LOX) is activated to produce cysteinyl leukotrienes (CysLTs), and CysLTs may cause neuronal injury and astrocytosis through activation of CysLT(1) and CysLT(2) receptors in the brain after focal cerebral ischemia. However, the property of astrocyte responses to in vitro ischemic injury is not clear; whether 5-LOX, CysLTs, and their receptors are also involved in the responses of ischemic astrocytes remains unknown. In the present study, we performed oxygen-glucose deprivation (OGD) followed by recovery to induce ischemic-like injury in the cultured rat astrocytes. We found that 1-h OGD did not injure astrocytes (sub-lethal OGD) but induced astrocyte proliferation 48 and 72 h after recovery; whereas 4-h OGD moderately injured the cells (moderate OGD) and led to death 24-72 h after recovery. Inhibition of phospholipase A(2) and 5-LOX attenuated both the proliferation and death. Sub-lethal and moderate OGD enhanced the production of CysLTs that was inhibited by 5-LOX inhibitors. Sub-lethal OGD increased the expressions of CysLT(1) receptor mRNA and protein, while moderate OGD induced the expression of CysLT(2) receptor mRNA. Exogenously applied leukotriene D(4) (LTD(4)) induced astrocyte proliferation at 1-10 nM and astrocyte death at 100-1,000 nM. The CysLT(1) receptor antagonist montelukast attenuated astrocyte proliferation, the CysLT(2) receptor antagonist BAY cysLT2 reversed astrocyte death, and the dual CysLT receptor antagonist BAY u9773 exhibited both effects. In addition, LTD(4) (100 nM) increased the expression of CysLT(2) receptor mRNA. Thus, in vitro ischemia activates astrocyte 5-LOX to produce CysLTs, and CysLTs result in CysLT(1) receptor-mediated proliferation and CysLT(2) receptor-mediated death. (c) 2007 Wiley-Liss, Inc.

PMID: 17910051

The astrocyte has been studied to see how it functions in the brain. The astrocyte:

1. may perform a role in the physical structuring of the brain
2. may perform a role in providing neurons with nutrients
3. may perform a minor role in the maintenance of the blood brain barrier
4. may perform a role in neurotransmitters
5. may perform a role in the regulation of ion concentration in the extracellular spaces
6. may perform a role in neuronal regulation of blood flood
7. may perform a role in the protection and repair of neurons

TO LIE TO PEOPLE REGARDING THEIR HEALTH IS CRIMINAL AND SHOULD BE PROSECUTED. PEOPLE OUT THERE ARE GETTING SICKER IF THEY ARE EXPERIENCING SIDE EFFECTS BECAUSE MERCK IS LYING. SOME PEOPLE MAY NOT EXPERIENCE SIDE EFFECTS BUT WHY NOT TELL THE TRUTH AND SAY THAT THERE COULD BE SOME PEOPLE WHO HAVE PSYCHIATRIC SIDE EFFECTS BECAUSE THERE IS A PATHWAY FOR THAT TO HAPPEN.

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 just want to tell you another thing.

There are leukotriene receptors in the brain" That is the real quote from Dr. Bremner.

When I read that he said "unclear", I said, what?, are these Chinese researchers that have been saying since 2002 or maybe before just "cuckoo"?
So the media deliberately misquoted.

Update about my post about the Chinese researchers who reported leukoteine receptors in the brain. There were a few people who misunderstood what I was trying to say to you. I was trying to say that yes it is possible or at least not impossible that Singulair does interfere with brain function in some people because at least one group of researchers found leukoteine receptors in the brain.

I located an article where a professor at Emory was quoted as saying that psychiatric side effects could be possible if leukoteine receptors exist in the brain. That is what I was trying to say without getting myself in trouble for giving misinformation. There is quite a bit more that I would like to say but I cannot find proof as of yet but I am working on it.

Merck’s Singulair likely to see prescription drop-off only in high-risk populations
By Beth Herskovits and Gayatri Iyer in New York

Published: March 28 2008 19:52 | Last updated: March 28 2008 19:52

This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
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Merck’s asthma and allergy drug Singulair may see a decline in prescriptions due to recent concerns about suicidality, but the drop will not be precipitous, physicians told Pharmawire.

The warning will likely cause the biggest prescription fall-off among patients with a personal or family history of depression, or patients with mild disease, they add. The drug is taken daily to prevent asthma attacks and allergies, or as needed for exercise-induced asthma.

”Both my kids are on Singulair - and I’m not going to take them off it,” said Dr Lawrence Ciesemier, an allergist and immunologist who practices Kirksville, Missouri. ”It was a surprise to me that this data came out.”

Dr Gregg Santilli, an allergist and immunologist in private practice at AirCare in Plano, Texas, noted that he has prescribed Singulair - a drug he helped launch - for 10 years without seeing any suicides. ”Apparently this is an extremely rare event,” he said. ”This drug has certainly not been linked in a causative way to this.”

”The real question is whether the is greater than what’s seen in the general population,” said Dr Jay Portnoy, president of the American College of Allergy, Asthma and Immunology. ”It’s still an extremely safe and effective medication.”

The FDA announced yesterday that it is ”considering” regulatory action after post-marketing reports seemed to link the asthma and allergy blockbuster to suicidal thoughts and action. Officials said in a statement that they are undertaking a nine-month review of Singulair and three other leukotriene modifying medications: AstraZeneca’s Accolate and Dey’s Zyflo and Zyflo CR.

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HERE IS THE PART ABOUT THE LEUKOTRIENE RECEPTORS IN THE BRAIN

Dr Douglas Bremner, director of Emory’s Clinical Neuroscience Research Unit, noted that drugs can cause psychiatric effects when the targeted receptor also exists in the brain. But he added that it’s unclear whether the brain has leukotriene receptors.

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He noted that despite the updated label, the side effects ”sort of flew below the radar.” However, he painted a grimmer picture of the effect on the market, saying this would affect Singular sales badly. People are likely to stop taking it, he added.

Over the past year, Merck has updated its safety label to include reports of tremors, depression, suicidality, and anxiousness, the FDA said.

But Dr George Philip, senior director in clinical research for Merck, noted that none of the reports of suicidality came out of clinical studies. He added that post-marketing reports can be ”sketchy” and ”not well-defined” - making it more difficult to determine whether the drug caused the change in behavior.

Asked about whether certain high-risk patients should avoid Singulair, he said, ”It may be part of the dialogue moving forward. These are still unanswered questions.”

He added that other allergy drugs have also been linked to suicide, including Pfizer’s Zyrtec.

Santilli noted that he would consider each patient’s individual risk factors - and the severity of their asthma - before making any treatment changes. GlaxoSmithKline’s Advair has a black box warning linking it to an increased risk of asthma-related death, he said, and Zyflo patients must be monitored for liver toxicity.

”Every drug has risks and benefits,” he said. ”Singulair seemed to be a very clean, very safe drug.”

Ciesemier agreed. ”I prescribe Singulair daily,” he said, but conceded that ”maybe this wouldn’t be the first choice” for patients with a history of suicidality.

Patients who are taking the drug for allergies, a less serious condition, might be more likely to switch to an antihistamine, Santilli noted.

Singulair earned USD 4.3bn last year, growing 19%, and is the bestselling respiratory product on the US market, according to the company. Merck has a market cap of USD 96.57bn.

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