Nitric oxide symptoms and conditions

Hey, maybe those ancient people who invented yoga were on to something when they say to do "your o-o-h-h-m-m-s-s-." So hum those ohms every day and increase our resistance against nasal infection.

American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 144-145, (2002)
© 2002 American Thoracic Society

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Brief Communication

Humming Greatly Increases Nasal Nitric Oxide
Eddie Weitzberg and Jon O. N. Lundberg
Department of Anesthesiology and Intensive Care, Karolinska Hospital, and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Correspondence and requests for reprints should be addressed to Dr. E. Weitzberg, Department of Anesthesiology and Intensive Care, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: ******

The paranasal sinuses are major producers of nitric oxide (NO). We hypothesized that oscillating airflow produced by humming would enhance sinus ventilation and thereby increase nasal NO levels. Ten healthy subjects took part in the study. Nasal NO was measured with a chemiluminescence technique during humming and quiet single-breath exhalations at a fixed flow rate. NO increased 15-fold during humming compared with quiet exhalation. In a two-compartment model of the nose and sinus, oscillating airflow caused a dramatic increase in gas exchange between the cavities. Obstruction of the sinus ostium is a central event in the pathogenesis of sinusitis. Nasal NO measurements during humming may be a useful noninvasive test of sinus NO production and ostial patency. In addition, any therapeutic effects of the improved sinus ventilation caused by humming should be investigated.

Key Words: exhaled • sinus • sinusitis

Why does Singulair cause these symptoms? I am going to give my explanation which is only a HYPOTHESIS. This should not be categorized as any thing but an educated guess. This is not backed by scientific research because nobody will do any research that would appear to anger
Merck even if people are suffering in the thousands.

1. The original research that preceded the development of Singulair (montelukast) seemed to focus on the theory that asthma was caused by an unusual immune response to certain pathological stimulus. There are many references to the observation that a high percentage of asthma sufferers are people whose asthma is caused by fungus. Many people suffer from asthma and are told that they are allergic to dust mites. Dust mites can live only because the fungus aspergillus pre-digests the
food source that dust mites can then absorb. Other sources of fungus occur in the home due to dampness or problems with wood rot.

2. The body's immune system fights certain categories of pathogens such as bacteria and fungus by creating nitric oxide which kills them at the site where they try to enter the body. The mast cell is the immune cell that is responsible for the production of nitric oxide. Mast cells are found in the skin, airways, intestines etc. The mast cell is capable of many different types of biochemical functions that are designed to signal other cells or other chemical responses. When the mast cell knows that pathogens
are present and nitric oxide is NOT produced, then it signals other immune cells to be sent to the site of the infection. Thus in the case of asthma, it is known that excessive numbers of eosinophils appear in the airways and these cells create inflammation.

3. Singulair was developed for asthma and later allowed to be prescribed for other reasons. I believe that montelukast probably creates a source of nitric oxide that prevents the mast cell from signalling for other immune cells to arrive at the source of infection. I arrived at that conclusion from studying the chemical structure of montelukast, the chemical structure of the gene cysLT1 receptor, and the chemical structure of the cell wall of fungus which would be what the mast cell uses to determine "what to do in order to kill the fungus."

The researchers who invented montelukast first had to clone the gene-cysLT1 receptor meaning that they had to be able to identify the gene and replicate it. Then by trial and error they had a find a "chemical"
that would bind (connect chemically) to the cysLT1 receptor. The theory would be that montelukast would take the place of the fungus or other pathogen and thus prevent the gene from reacting to produce the
responses that the sick patient with asthma produced. Merck says in the literature that montelukast binds with the cysLT1 receptor in order to prevent the mast cell from signalling the eosinophils to arrive in excessive
numbers that cause inflammation. I believe that montelukast is also causing the production of an amount of nitric oxide that is actually killing the pathogens that are present. For one thing, I would think that it
would be dangerous to incapacitate the immune system in that way without providing a way to kill the pathogens. I don't believe that the asthma response is just allergies to something like dust. Pollen from trees and flowers is loaded with fungus spores.

4. IF, IF, IF, montelukast does actually produce nitric oxide, then it does so by binding with the gene. Any place in the body where a molecule of montelukast encounters the cysLT1 receptor (a gene) then the corresponding molecules of nitric oxide are produced before the liver enzymes break the montelukast molecules up. Nitric oxide is TOXIC and
INFLAMMATORY. So let's look at the symptoms in regard to the location of the cysLT1 receptors. The location of these symptoms would not be places in the body where the mast cells normally encounter fungus or bacteria. The cysLT1 also has other functions in that it communicates with the cysLT2 receptors. Obviously, nitric oxide
should not be produced in these locations because of the signalling effect of nitric oxide on other physiological functions.

a. intestinal pain - the cysLT1 receptors are located in the small intestines
b. leg pain actually caused by vasculitis - cysLT1 receptors are found inside blood vessels- consistent with the fact that montelukast causes
Churg-Strauss
c. some people who didn't have asthma develop asthma - the cysLT1 receptors are in the airways
d. nightmares, depression, neurological damage - when montelukast penetrates the blood brain barrier probably due to unusual conditions of blood pH or electrolyte imbalance then nitric oxide in the brain causes neuron damage and excitoxicity

5. Why do some patients not experience side effects? Probably because genetically they are completely compatible with the model that researchers created when they cloned the cysLT1 receptor gene. I didn't not find any information about whether researchers knew that there are many different variations of this gene.

6. IF, my theory is even close to being correct, then why doesn't Merck do anything about researching these side effects. Maybe because nobody in the company knows how this drug works but the researchers who created it. All of the Merck literature is very vague about any biochemical information.

Again, this is just speculation and hypothesis. I have made an attempt to put this in simplistic language and therefore sacrifice scientific accuracy. But, I think that you will get the point.

SINGULAIR IS VERY DANGEROUS TO PATIENTS WHO EXPERIENCE NEGATIVE SIDE EFFECTS. DOCTORS SHOULD JUST REALIZE THAT
THOSE PATIENTS ARE NOT COMPATIBLE WITH THE MODEL FOR THE DRUG.

I don't have any conclusions to report because I have recruited friends to help me. I got over my head as far as my understanding of this type of chemistry. I am particularly interested in what happens to the quinoline nitrogen during the metabolic break down of montelukast. Nitric oxide is an important molecule to the human body. BUT, however, in excess it is very toxic. The year of this study 1998, some medical researchers got the Nobel prize for their work on nitric oxide.

http://nobelprize.org/nobel_prizes/medicine/laureates/1998/press.html

So I am now working with friends to try to further understand the Merck report on the metabolism of montelukast. I found a Japanese researchers opinion of the connections of montelukast and the cysLT1 receptor showing the nitrogen as a key factor. I was also able to find some work done on mold spores that might give some clues because DPA - 2,6 pyridine dicarboxylic acid in the spore case might yield something about the receptor and/or quinolinic acid 2,3 pyridinedicarboxylic acid. I haven't concluded anything about Fenton reactions as of yet but that is always something to think about.

If anyone has any chemist friends, we could use some real experts in this field not just someone like me, CC, who can read and collect research.

J Med Chem. 1998 Apr 23;41(9):1439-45. Links
Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.Zwaagstra ME, Schoenmakers SH, Nederkoorn PH, Gelens E, Timmerman H, Zhang MQ.
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.

This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'- flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.

PMID: 9554877

I must have an angel watching over me, because for the life of me I do not know how I came across this website. I have been taking lisinopril 20mg with HCTZ12.5 for about 2 years. I have felt like I was going to have a heart attach, the bloating is driving me nuts, tired because lack of sleep and some times just plain can't sleep at night, leg cramps and now my vision seems to be getting worse. I have had all the symptoms at one time or another. I am going to be 57 years old in October and I am about 30-35 over weight. But I do walk and ride my bike and do other exercises. We just did a very small job landscaping and I could hardly walk or lift my arms for about 4 days. Muscles were so sore. And I didn't do that much to have that my muscles ache that badly. On both sides of my ankles are like little fat pockets, the doctor said it was not water retention, I now have swelling under my eyes. ??? Thank you to everyone for being posting. I need to talk to my doctor and get off this stuff. I recently forgot to take my medication on a 3 day vacation and when I got home I feeling pretty darn good, as soon as I started taking the meds for 2 or so days I was back to feeling that yuky feeling