Mast cell inhibitors

Although mild, the adverse reactions associated with the mast cell inhibitors include headache, rhinitis, unpleasant taste, asthma, and cold/flu symptoms. These drug may also cause ocular burning or irritation, dry eye, eye redness, foreign body sensation, and ocular discomfort. 

Azelastine is a selective Hi antagonist mast cell inhibitor. Azelastine also decreases eosinophil chemotaxis and activation. 

It is known that cyclic AMP inhibits the release of a chemical mediator firm the mast cell. So when cyclic AMP phosphodiesterase is inhibited by some inhibitor the concentration of cyclic AMP is increased to inhibit the release of die chemical mediator from the mast cell. Inhibitors against cyclic AMP phosphodiesterase may be useful in the therapy for allergic diseases. In addition, by the presence of 5-lipoxygenase, free arachidonic acid is converted to leukotrienes, which is one of the chemical mediators known as a slow reacting substance of anaphylaxis. Therefore, specific inhibitors of 5-lipoxygenase may be useful in the therapy for allergic diseases. 

Slowing down the destruction of sensitized mast cells is the scientific rationale for administering Cromolyn, a mast cell inhibitor given to prevent asthma attacks. 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

Along with the bronchodilators, several types of dragp are effective in Hie treatment of asthma. These include corticosteroids, leukotriene formation inhibitors, leukotriene receptor agonists, and mast cell stabilizers. 

Akin C. Brockow K. D Ambrosio C. et al Effects of tyrosine kinase inhibitor SXI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hem-atol 2003 31 686-692. 

Ketotifen Hrreceptor antagonist, mast cell stabilizer, eosinophil inhibitor, platelet-activating factor inhibitor May inhibit eosinophil chemotaxis... 

He SH, Xie H, Zhang XJ, Wang XJ. Inhibition of histamine release from human mast cells by natural chymase inhibitors. Acta Pharmacol Sin. 2004 25 822-826. 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Atopic dermatitis has been proposed to be the cutaneous manifestation of IgE-mediated hypersensitive reaction to allergenic substances [29]. Conceptually, antagonizing IgE emerges as a logical therapeutic option. Systemic treatment with omalizumab, however, appears to be less efficacious in the skin than in the airway mucosa [23]. It is possible that small molecule Syk inhibitors may offer a more suitable mode to reach and prevent activation of sensitized dermal mast cells and dendritic cells. 

Stimulation by thrombin does not lead to the generation of leukotriene C4 or B4, whereas stimulation of the same mast cells by the calcium ionophore, A23187, does. The secretory response elicited by thrombin is prevented by preincubation with AT-III, a plasma inhibitor of thrombin, or by hirudin, a thrombin inhibitor derived from the leech [135],... 

While these observations clearly point to protein phosphorylation in the mast cell as an important aspect of stimulus-response coupling, how this may fit into the overall picture is unclear. It would be of interest to know, for example, whether activators of protein kinase C (for example, 1,2-diacylglycerol) will promote a similar pattern of phosphorylation or whether inhibitors of G protein involvement (for example, Pertussis toxin) alter the pattern of phosphorylation in response to peptide or immunologic stimulation. 

CysLTs) are proinflammatory molecules synthesized primarily by basophils, neutrophils, and mast cells and are potent mediators of airway inflammation and bronchoconstriction (77,78). There are two classifications of drugs in this category that can regulate the effects of CysLTs inhibitors of the 5-lipoxygenase enzyme, such as zileuton, and CysLT receptor antagonists, such as montelukast and zafirlukast. 

Inhibitors of histamine release One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the release of histamine from mast cells (p. 72, 326). Both agents are applied topically. Release of mast cell mediators can also be inhibited by some Hi antihistamines, e.g., oxatomide and ketotifen, which are used systemically. 

A number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

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