Ketotifen fumarate Chemical Properties

Melting point:

192 C

storage temp. 

2-8°C

solubility 

Sparingly soluble in water, slightly soluble in methanol, very slightly soluble in acetonitrile.

form 

Solid

color 

White to Pale Beige

PH

pH (10g/l, 25℃) : 3.0～4.0

Water Solubility 

Soluble in water (10 mg/ml), DMSO (100 mM), and methanol.

λmax

297nm(MeOH)(lit.)

Merck 

14,5307

InChIKey

YNQQEYBLVYAWNX-WLHGVMLRSA-N

CAS DataBase Reference

34580-14-8(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn,T

Risk Statements 

22-36/37/38-23/24/25

Safety Statements 

36-45-36/37/39-26

WGK Germany 

3

RTECS 

DE8260000

HS Code 

29349990

Toxicity

child,TDLo,oral,200ug/kg (0.2mg/kg),Drug Safety. Vol. 7, Pg. 387, 1992.

MSDS

• Language:English Provider:SigmaAldrich

Ketotifen fumarate Usage And Synthesis

Anti-allergic drugs

Ketotifen fumarate is a kind of strong anti-allergic drugs containing simultaneously of both tricyclic structure as well as piperidine structure. It is characterized by both a strong antagonism effect on histamine H1 receptor and inhibitory effect of the release of the mediator of allergic reaction. It can inhibit the release various kinds of mediators of mast cells, basophils and macrophages, including the release of slow reacting substances and other active substances. It also has antagonism effect on the calcium ion; can inhibit the activity of phosphodiesterase; increase the intracellular cAMP level inside mast cells. Moreover, it can also inhibiting the chemotaxis and inflammation of neutrophil with an effect 10 times as strong as that of chlorpheniramine, and it also has a long duration time which is better compared with sodium cromolyn. Ketotifen fumarate has therapeutic effect on both Ⅰ and Ⅲ type of allergic reaction. Its peak blood concentrations can sustain for 2 to 3 hours with a half-life of 22 hours during which 60% goes through urinary excretion, 40% goes through the fecal excretion. Children usually have a faster excretion rate of it than adults. Long-term treatment will not cause resistance. No rebound phenomenon will occur with interruption of treatment.

Chemical Properties

This product is white (or light-yellow) crystalline powder, and is odorless with bitter taste. It is slightly soluble in water and ethanol, and easily soluble in methanol but very slightly soluble in chloroform and acetone.

Indications

Dermatology applies it to the treatment of allergic diseases such as urticaria, pruritus, eczema, atopic dermatitis, and neurodermatitis; it is recently reported that it is also effective in the treatment of scleroderma. For medicine, it has a good efficacy in treating asthma, especially with a significant effect on treating allergic asthma, followed by mixed asthma, and being effective in half of cases for infecting type. It can also be used for the prevention of asthma.

Pharmacological effects

The pharmacological effect of ketotifen fumarate is very complicated. It has achieved a certain efficacy in the prevention and treatment of asthma and childhood asthma. But the detailed mechanism of its pharmacology remains to be unclear. From the current research information, the pharmacological mechanisms of ketotifen fumarate in treating asthma and childhood asthma include the following several aspects:
1. Antagonizing effect on inflammatory mediators: Clinical studies have already demonstrated that ketotifen fumarate can effectively inhibit the histamine-induced bronchospasm with its intensity being comparable to Azelastine, suggesting that ketotifen fumarate has strong histamine antagonistic effect. Modern studies have shown that ketotifen fumarate may also other inflammatory mediators such as antagonize leukotrienes and platelet activating factor. From this perspective, it is considered that ketotifen is a drug which can antagonize a variety of inflammatory mediators. This may be the primary mechanism for its prevention and treatment of asthma as well as childhood asthma.
2. The membrane protective effect of mast cells/basophils: the related pharmacological studies of ketotifen fumarate have confirmed that it can inhibit mast cell /basophil cells to release inflammatory mediators such as histamine, leukotrienes and platelet activating factor, suggesting that it has a strong membrane protective effects on mast cells/basophils membrane. This may be the major mechanism underlying the dual property of ketotifen fumarate for being able to both prevent and treat the asthma and childhood asthma.
3. The inhibition of airway inflammatory cell infiltration: fumarate ketotifen can inhibit the infiltration of the airways of eosinophil and neutrophil. However, the mechanism remains to be unclear.
4. Regulation of T cell activity: ketotifen fumarate can inhibit the biosynthesis of intracellular lgE through regulating the release activity of CD4 + and CD8 + lymphocytes. The mechanisms of inhibition of the biosynthesis of lgE and the above two mechanisms determines the airway anti-inflammatory effects of ketotifen fumarate.
5. Other effects: Some studies have suggested that ketotifen fumarate can reverse the low-regulation of β2-receptor caused by the long-term administration of β2-receptor agonist and also increase the density of airway β2-receptor as well as enhance the effect of β2-receptor. Some studies have also suggested that ketotifen fumarate also having blocking effect on the calcium channels.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Clinical application

It has been more than 20 years since ketotifen fumarate have been applied to the prevention and treatment of asthma and childhood asthma. It is a kind of drug with dual effect of both prevention and treatment in the prevention and treatment of asthma and childhood asthma. It should be particularly noted that ketotifen had ever taken as the long-term controlling drug of asthma and childhood long-term asthma and was subject to wide application in many countries. Since the early 1980s, ketotifen fumarate had already been applied in Western Europe, Asia, and China for the prevention and treatment of asthma and asthma in children. But since entering into 21st century, the annual applied amount has decreased year by year. Because of its side effect of inhibition of the central nervous system, its oral tablet currently has still not approved by the FDA and thus failing to enter the US market with only ketotifen fumarate eye drops (ZADITOR) had been approved by the FDA in 1999. Recent studies have also shown the effectiveness of ketotifen asthma still demands further studies. Moreover, ketotifen fumarate has several additional advantages. First, it can cause sleepiness of the schoolchildren and thus being able to affect their academic performance; second, it can also do harm to the mental development of infants and young children. Thirdly, it is also be able to affect the metabolism of sustained-release tea and thus negatively affecting its anti-inflammatory effects of theophylline. For all the above points, it is not recommended by the GINA (affiliated organization of WHO) to apply ketotifen fumarate for the treatment and prevention of asthma and childhood asthma. But from the perspective of clinical economics, ketotifen fumarate is a suitable anti-allergic drug for being applied in developing countries and rural areas for treating asthma and childhood asthma with certain efficacy due to its relative low price.

Side Effects

The most severe side effect of ketotifen fumarate is its inhibitory effect on central nerve system such as causing sleepiness or fatigue, weakness. This side effect is more significant in adults and is one of the major reasons for limiting its clinical application. The resulted sense of lethargy or fatigue, weakness may reduce the life quality of asthma patients as well as children with asthma. Usually, after continuous administration of 1-4 weeks, the side effect of suppression of the central nerve system can significantly reduce and even gradually disappear. Clinical observation has found that combination with theophylline can reduce the central nerve inhibitory effect of ketotifen fumarate as well as offset the stimulus effect on central nerve system of theophylline. But it still demands further observation to demonstrate whether there exist synergistic anti-inflammatory between them. Clinical observations have already confirmed children who administering ketotifen fumarate usually get no significant inhibition of the central nervous system and at most cause only the lower concentration of children’s mind. This is still true even the children subject to an adult dose. However, this mechanism is still unclear. In the clinical observation on the asthma adults patients as well as children patients who subject to 2-year continuous oral administration, wood et al have confirmed that long-term administration of ketotifen fumarate caused no other serious side effects without affecting the liver and kidney function as well as peripheral blood cell counts. It is also not easy to produce drug resistance issues. Usually after continuous oral administration of ketotifen fumarate for six weeks, we can begin to gradually withdraw or reduce the amount of bronchial spasm agent or corticosteroids. Discontinuation of treatment after long-term treatment has not resulted in rebound phenomenon. Therefore, the comprehensive evaluation of the drug is that: ketotifen fumarate is an anti-asthma drug with central nervous inhibition effect (this side effect can gradually adapt), but is relatively safe and effective with certain anti-inflammatory properties and being relatively inexpensive. However, because it has not approved by the FDA, it should be applied with caution in clinical practice.

Description

Ketotifen is a histamine H₁ receptor antagonist (K_i = 1.3 nM) and mast cell stabilizer. It is selective for H₁ receptors over H₂ and H₃ receptors (K_is = 987 and 2,500 nM, respectively). Ketotifen (50 and 100 μM) inhibits degranulation of rat peritoneal mast cells induced by compound 48/80 . It inhibits the passive cutaneous anaphylaxis (PCA) reaction in rats by 54.6% when administered orally at a dose of 20 mg/kg. Ketotifen (30 mg/kg) inhibits the quick phase airway response in a rat ovalbumin-induced immediate airway response model. Formulations containing ketotifen have been used in the treatment of itching associated with allergic conjunctivitis.

Chemical Properties

Off-White Solid

Uses

vasodilator

Uses

Ketotifen fumarate salt has been used: for mast cell product antagonism, as a positive control in β-hexosaminidase release assay, as mast cell stabilizer to treat pregnant dams added to ad libitum drinking water

Uses

Antiasthmatic; antiallergic.

Uses

Ketotifen, C19H19NOS, is also a piperidine derivative; like oxatomide, it has mast cell stabilizing actions besides its antihistamine properties.

brand name

Zaditor (Novartis).

General Description

Ketotifen fumarate, 4-(1-methyl-4-piperidylidene)-4Hbenzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one hydrogenfumarate (Zaditor), is a fine crystalline powder.Ketotifen is a ketothiophene isostere analog of the dibenzocycloheptaneantihistamines. The solution contains0.345 mg of ketotifen fumarate, which is equivalent to0.25 mg of ketotifen. The solution also contains the preservativebenzalkonium chloride (0.01%) as well as glycerol,sodium hydroxide and/or hydrochloric acid (to adjust pH),and purified water. It has a pH of 4.4 to 5.8 and an osmolalityof 210 to 300 mOsm/kg.
The recommended dose of ketotifen solution is 1 drop instilledinto each affected eye every 8 to 12 hours. The mostfrequently reported adverse reactions are conjunctival infection,headaches, and rhinitis. This drug product is for ocularadministration only and not for injection or oral use.Ketotifen solution should be used with caution during pregnancyor while nursing, because its safety has not been studiedunder these circumstances.

Biological Activity

An H 1 receptor antagonist.

storage

Store at RT

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