Quinoline symptoms and conditions

I have stated many times that I am not an expert. I just post what I find. This has been a mind boggling journey for me. This is way over my head but I struggle to read and understand. Finding answers to why children are suffering from neuro-psychiatric side effects is worth the effort.

I have made the following observations.

1. Some quinoline are known to be able to cross the blood brain barrier.
2. Molecules that ionize are known to be more likely to be able to cross cell membranes. So if montelukast ionizes as a result of change in blood pH to sufficient acid conditions that it ionizes, then it could be possible or maybe like that it does in fact cross the blood brain barrier.
3. We know that there are cysLT1 receptors in the brain.
4. We know that researchers believe that montelukast may bind at the arginine of the cysLT1 receptor.
5. We know that arginine contains four nitrogens. And montelukast contains one.
6. We don't know what happens to those nitrogens.
7. We do know what macrophages create nitric oxide as I posted.
8. We do know that if something cause excessive nitric oxide to build in the brain that there would be damage to the neurons.

Some people may remember when I got stuck at the astrocytes, the cysLT1 receptors and glutamate. I keep looking for research reports that may shed more light on this.

Titre du document / Document title
Nitric oxide causes glutamate release from brain synaptosomes
Auteur(s) / Author(s)
MCNAUGHT K. S. P. (1) ; BROWN G. C. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Biochemistry, University of Cambridge, Cambridge, ROYAUME-UNI
Résumé / Abstract
We determined the ability of pathological levels of nitric oxide (NO) to cause glutamate release from isolated rat brain nerve terminals using a fluorometric assay. It was found that NO (0.7 and 2 μM) produced (4 and 10 nmol/mg of synaptosomal protein) Ca2+-independent glutamate release from synaptosomes (after 1 min of exposure). Spermine/NO complex (spermine NONOate; a slow NO donor) and potassium cyanide (an inhibitor of cytochrome oxidase) also caused Ca2+-independent glutamate release. Preincubation of synaptosomes with 5 μM 1H- oxadiazole quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) had no effect on NO-induced Ca2+-independent glutamate release. Ca2+-independent glutamate release produced by NO was greater in a low-oxygen medium. NO, spermine NONOate, and potassium cyanide inhibited synaptosomal respiration with a similar order of potency with respect to their ability to cause glutamate release. Because NO has been shown previously to inhibit reversibly cytochrome oxidase in competition with oxygen, our findings in this study suggest that NO (and cyanide) causes glutamate release following inhibition of mitochondrial respiration at the level of cytochrome oxidase. Thus, elevated NO production leading to mitochondrial dysfunction, glutamate release, and excitotoxicty may contribute to neuronal death in neurological diseases.
Revue / Journal Title
Journal of neurochemistry ISSN 0022-3042 CODEN JONRA9
Source / Source
1998, vol. 70, no4, pp. 1541-1546 (29 ref.)

INIST-CNRS, Cote INIST : 4037, 35400007527188.0230

The example that I am posting below is not the only patent for an aminoquinoline derivative that is proposed for the treatment of neuro-psychiatric disorders. Even though we are not comparing exact chemical structures, it is certainly worth considering how the quinolines relate to this receptor.

It is also worth considering why montelukast, a quinoline, seems to be causing some of the problems that this owners of this particular patent think that they can treat.

As I mentioned before, I have no answers. Regardless of how small Merck believes the population of Singulair patients who suffer neuro-psychiatric disorders is, I do not believe that any patient should be ignored. It also seems that many companies have studied this area in depth and more than one company knows a lot more than we know about why it is possible for these side effects to happen.

" The compounds of formula I have a good activity on the 5-HT.sub.5A receptor. Therefore, the invention further provides methods for the treatment of depression (which term includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorders and dysthymia, depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion), anxiety disorders, (which includes generalized anxiety and social anxiety disorder, panic disorders, agoraphobia, social phobia, obsessive compulsive disorders, post-traumatic stress disorders, psychotic disorders (which includes schizophrenia, schizoaffective disorders, bipolar disease, mania, psychotic depression, and other psychoses involving paranoia and delusions), pain (particularly neuropathic pain), memory disorders (including dementia, amnesic disorders and age-associated memory impairment), disorders of eating behaviors (including nervosa and bulimia nervosa), sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs (such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin, morphine, sedative hypnotic, amphetamine or amphetamine-related drugs), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders and gastrointestinal disorders such as irritable bowel syndrome (WO 2004/096771). "

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hi, im not sure what to do. my 3 1/2 year old daughter was today given the prescription for singulair. i voiced my concerns to the doctor after my friend telling me its no good due to the side effects.she said that there are risks and side effects with any drug you take but for some reason i don't feel right about this. don't doctors know better than this. anyway Would like to know if all the people who take singulair suffer some sort of side affects or is it minimal? or going by this side it looks like its probably best not to give it to her at all.

I had made the point that Merck had looked at structures other than quinolines. I am not making a reference at the time frame just that they looked at other structures. I didn't have the proof of that then so I am posting that now.

L-733,321 a pyridyl analog of montelukast was an alternative leukotriene receptor antagonist.( L-733,560 is Merck's anti-fungal drug Cancidas.)

Bioorg Med Chem Lett. 1998 Mar 3;8(5):453-8. Links
A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair

Guay D, Gauthier JY, Dufresne C, Jones TR, McAuliffe M, McFarlane C, Metters KM, Prasit P, Rochette C, Roy P, Sawyer N, Zamboni R.
Merck Frosst Center for Therapeutic Research, Québec, Canada.

The structure-activity relationship of a series of styrylpyridine analogs of MK-0476 (montelukast, Singulair) is described. This work has led to the identification of a number of potent and orally active cysLT1 receptor (LTD4 receptor) antagonists including 2ab (L-733,321) as an optimized candidate.

PMID: 9871597

An element of the side effects of Singulair that are listed here are musculo-skeletal symptoms. Quinolones such as levaquin are known to cause those issues. Singulair is a quinoline, while not the exact same category, their roots are similar. It makes the possibility that the symptoms have a common cause worth pursuing.

Here is an example of some poor rats in Tokyo that were selected to prove that the symptoms in humans were real. Maybe we should tell the levaquin board that at least some of their problems have been known since 1997.

1: Toxicol Pathol. 1997 Nov-Dec;25(6):635-43.Links
Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats.Kashida Y, Kato M.
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. JDN07402@niftyserve.or.jp

Quinolone antibacterial agents have adverse effects on the musculoskeletal system in humans, consisting mainly of myalgia and arthralgia, and additionally of tendon disorders and rhabdomyolysis. The present study was conducted to examine the toxic effects of quinolones on the musculoskeletal system in juvenile rats using light microscopy, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and electron microscopy. Single oral administration of 900 mg/kg pefloxacin (PFLX) or levofloxacin (LVFX) was found to induce lesions in the muscle + fascia, tendon + sheath, and synovial membrane, in addition to articular cartilage in the fore- and hindlimbs. Articular cartilage lesions were not necessarily associated with changes in the muscle, tendon, and synovial membrane, or the reverse. Among all lesions, the ankle and elbow showed the highest incidence and severity. Changes were more severe in the PFLX than in the LVFX group. Lesions in the muscle + fascia, tendon + sheath, and synovial membrane were similar and characterized by edema and increased number of mononuclear cells, many of which were positively stained with BrdU, as well as vascular endothelial cells in the Achilles tendon sheath and synovial membrane in the ankle. Electron microscopic examination revealed an increased number of fibroblasts and macrophages and collagen deposition in the matrix of the synovial membrane and tendon sheath. Capillary endothelial cells were hypertrophied, increased in number, and stratified. These results suggest that quinolones have toxic potentials in the muscle, tendon, and synovial membrane in addition to articular cartilage, and that local vascular hyperpermeability may contribute to the development of these lesions.

PMID: 9437810

Sorry, I can't just walk away.

When you find patents or patent applications for certain purposes, then you know that your ideas are well founded. There are several patents for using an anti-malaria drug for asthma. I would bet that somebody had that idea all the way back to the 1960's. So it is very possibly no coincidence at all that a chloroquinoline or other quinoline ring would be part of montelukast's chemical structure.

Here is one of the patents.

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It is well known that quinoline rings can be toxic to some people even very rapidly. As in this very extreme example.
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PEDIATRICS Vol. 27 No. 1 January 1961, pp. 95-102 This Article

FATAL ACUTE CHLOROQUINE POISONING IN CHILDREN
Howard M. Cann M.D.1 and Henry L. Verhulst M.S.1

1 National Clearinghouse for Poison Control Centers, Accident Prevention Program, Public Health Service, U. S. Department of Health, Education, and Welfare
Four cases of acute chloroquine poisoning in children are presented. In three instances death occurred within 2 hours of ingestion of larger than therapeutic amounts of the drug. The rapid occurrence of death in acute chloroquine poisoning is probably explained by complete and rapid absorption of the drug from the gastrointestinal tract resulting in high blood concentrations which depress vasomotor function and respiration. Cardiac arrest follows and may be caused by the direct myocardial action of chloroquine, to anoxia, or to both. The similarity of the manifestations of acute chloroquine poisoning and those of acute quinine and quinidine poisoning suggests that acute toxicity may be attributed to the quinoline ring portion of these drugs.

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I don't think that we are seeing extreme examples. But we may be seeing less extreme immediate reactions or reactions where the toxicity builds up over time.

Quinoline rings are know to cause neurotoxicity. There are theories about how that happens. One of the theories is about blocking connexins which are gap junction proteins in the brains.

I don't know how montelukast could be breaking up so that it causes toxicity. Or if the problem is the how rapidly the liver enzymes can metabolize it. But there is plenty, plenty, plenty of clinical evidence that there is a quinoline ring culprit somewhere in the picture. Or some by-product of that causing problems.

Somehow it was decided that montelukast did not have the safety issues that the other drugs in the same category have. See this.

"The starting point in the development of montelukast appears to be a quinoline-containing structure, likely identified as a weak random screening lead (Figure 3). The Merck group hypothesized that this molecule was mimicking the olefin backbone of cysLTs, and that the addition of mimics for the acid and peptide regions of LTD4, might improve its potency. As a first step, the dithioacetal linkage first seen in some SmithKline compounds was incorporated; this led to a compound with greatly increased in vitro potency but poor oral bioavailability. When one of the carboxylic acids was replaced by an amide, forming MK-571, the new antagonist had even greater potency and good efficacy following oral administration. The enantiomers were resolved to yield MK-679 (verlukast), a compound with better clinical effects than MK-571, but whose clinical development was stopped for safety reasons. Further structure-activity relationship studies led to the development of montelukast (16), an antagonist that appears free of the safety concerns plaguing earlier members of this series."

If we can find out why the earlier versions were not safe and how they thought fixed it, then maybe we can find out what is going on with the quinoline ring in some people.

I would be very surprised if the FDA will address our concerns. Why does it always seem like they wait for enough people to die like in Vioxx? Wasn't Vioxx responsible for thousands of deaths?