Inflammatory mediators symptoms and conditions

If anyone has any access to databases that can describe the history of drug licensing in other countries and whether Merck had to amend product statements, this is worth investigating. I do know that montelukast was at least not initially licensed for seasonal allergies in the United Kingdom when the FDA granted approval in the US. As of 2006, seasonal allergies were not on the approved listed in the UK.

More to add to the files:

Safety of leukotriene antagonists
United Kingdom — The Medicines Control Agency
has published a review of adverse drug reactions to
a new class of asthma drugs, leukotriene antagonists.
Zafirlukast and moltelukast, competitive cysteinyl
leukotriene type-1 receptor antagonists, were
both marketed for the first time in 1998.
Cysteinyl leukotrienes are inflammatory mediators
and potent constrictors of bronchial smooth muscle
that attract human eosinophils and cause airway
oedema, mucus hypersecretion and reduced
mucociliary clearance. By blocking this action, leukotriene
antagonists can improve respiratory function
and lessen symptoms in patients with asthma.
The pharmacological action of leukotrienes is quite
complex and varying side effects have been
reported. Zafirlukast inhibits the hepatic cytochrome
P4502C9, and interacts with warfarin, theophyllin,
terfenadine, acetylsalicylic acid and erythromycin.
Montelukast is metabolized by hepatic cytochrome
P450CYP3A4 and co-administration of such drugs
as phenytoin, phenobarbitone and rifampicin, which
induce this enzyme, result in a marked reduction in
plasma levels.
Side-effects identified during clinical trials were
headache, abdominal pain, nausea, diarrhoea,
gastro-enteritis, influenza, pharyngitis, sinusitis,
cough, nasal congestion, dizziness, fatigue and insomnia.
Since marketing of montelukast, 173 reports
of 317 suspected adverse drug reactions
have been received in the United Kingdom. These
include oedema (50), psychiatric reactions, including
including agitation/restlessness (15), allergy, including
anaphylaxis, angioedema and urticaria (10), chest
pain (7), tremor (5), mouth dryness (5), vertigo (4)
and arthralgia (3).
Reference: Current Problems in Pharmacovigilance,
Volume 24, August 1998.
https://www.who.ch/druginformation/vol12/12-4.pdf

Here is another who might know how to help.

I got stuck on trying to understand IgE. Here is somebody else who might know something.

Immunol Res. 2007;37(1):1-16.Links
Decoding IgE Fc receptors.Zhang M, Murphy RF, Agrawal DK.
Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.

Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases by interacting with two membrane receptors: high-affinity FcepsilonRI and low-affinity FcepsilonRII (CD23). Allergeninduced IgE-occupied FcepsilonRI aggregation on the mast cell or basophil cell surface leads to the activation of intracellular signaling events and eventually the release of pre-formed and de novo synthesized inflammatory mediators. The role of FcepsilonRII in allergic diseases has been proposed to include regulation of IgE synthesis, enhanced histamine release from basophils, and a contribution to Ag-IgE complex presentation but the exact function of CD23 remains poorly understood. This review summarizes some new developments in IgE Fc-receptor studies with an emphasis on regulation of FcepsilonRI expression and signal transduction, including monomeric IgE, lipid raft segregation, and some recently identified negative regulators. A better understanding of signaling events following IgE FcR aggregation will shed new light on how allergy patients might be treated more safely and effectively.

I know that many here would like the FDA to take a very serious took at the problem. I personally don't see how a review of their data is going to make any difference at all. But, if there are experts who can propose a model of the pathways of cell signalling that include the possibility that these symptoms can occur (and under what circumstance), then maybe the problem will look like something much more than statistics.

This is not my field. But I tried to follow the possible pathways to see if I could identify a possible area of concern. Then I looked for someone who had written in the area and read their abstract. A place to start may be to get an opinion from those who know something about "normal homeostasis of the mast cell." Singular blocks the cysteinyl leukotriene receptor 1 which is a site on the outer membrane of the mast cell (other cells also). The mast cell which is produced in the bone marrow is released in a immature state and matures after it arrives at it's destination. The mast cell does not become active unless it's receptor sites come in contact with the activating agent. So, what happens when a receptor site on the mast cell is suppressed by Singular, a receptor antagonist.

You see, I don't have a clue what the signals are that tell the bone marrow to make mast cells (or what the signals are that tell them where to go after they are made in the bone marrow). Does Singular interfere with something that tells the bone marrow what to do? If Singular does interfere with that process, then what is happening and what period of time does it take to happen? Could we wonder whether Singular is interfering with the NUMBER of mast cells that are produced over time? And, of course, maybe there is some OTHER kind of explanation for why the adverse drug reactions are happening. But, at this level, I got lost and can't go any further.

Maybe this group would be interested in the Singulair problems or could suggest somebody else?

http://www.edata-center.com/journals/2ff21abf44b19838,0a1257122f661a7e,0d8ee7116ef23452.html

I apologize if this lead doesn't produce any results but at least it could be a place to start.

From Canada:

Leukotriene receptor antagonists: suspected adverse reactions

The cysteinyl leukotrienes are inflammatory mediators that bind to cysteinyl leukotriene receptors found in the human airway and cause a number of airway actions including bronchoconstriction, mucous secretion, vascular permeability and eosinophil recruitment.1 Zafirlukast (Accolate®) and montelukast sodium (Singulair®), marketed in Canada since November 1997 and August 1998 respectively, are competitive cysteinyl leukotriene receptor antagonists. Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in patients 12 years of age and older.2 Montelukast is indicated for the prophylaxis and chronic treatment of asthma, the treatment of asthma in ASA-sensitive patients and the prevention of exercise-induced bronchoconstriction in pediatric patients 6-14 years of age and adults 15 years of age and older.1

As of June 1, 1999, the CADRMP has received 41 reports of suspected adverse drug reactions associated with the use of zafirlukast and 22 associated with the use of montelukast. This article will discuss a serious and rare adverse reaction associated with the use of these agents, drug-drug interactions and unexpected adverse reactions that have been reported to the CADRMP.

http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v9n4_e.html

Conditions are discussed in the article.