109-731: Ketotifen is an antihistamine medication and a mast cell stabilizer used to treat allergic conditions such as conjunctivitis , asthma , and urticaria (hives). Ketotifen is available in ophthalmic (eye drops or drug-eluting contact lenses) and oral (tablets or syrup) forms: the ophthalmic form relieves eye itchiness and irritation associated with seasonal allergies , while the oral form helps prevent systemic conditions such as asthma attacks and allergic reactions. In addition to treating allergies, ketotifen has shown efficacy in managing systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), which involve abnormal accumulation or activation of mast cells throughout
218-694: A mast cell activation syndrome due to the presence of a not yet defined quorum sensing molecule (basal histamine itself?). Those patients are prone to food intolerance driven by another less specific path than the IgE receptor path: certainly the MRGPRX2 route. These patients also show cyclical skin pathergy and dermographism, every time the bacteria exits its hidden intracellular location. Mast cells are activated in response to infection by pathogenic parasites, such as certain helminths and protozoa , through IgE signaling. Mast cell activation disorders ( MCAD ) are
327-506: A phosphodiesterase inhibitor that regulates blood vessel dilation. While well-tolerated, ketotifen can have side effects, including drowsiness, weight gain, dry mouth, irritability, increased nosebleeds when taken orally, and temporary burning or stinging sensations in the eyes when used in the ophthalmic form. Ketotifen has contraindications for individuals with certain medical conditions, such as acute porphyrias or epilepsy . Controversies surrounding ketotifen include its classification as
436-543: A plasma half-life of about 12 hours. Ketotifen is extensively metabolized in the liver by oxidation and conjugation, and the metabolites are excreted in the urine and feces. The bioavailability of oral ketotifen is about 50% due to hepatic first-pass metabolism. Peak plasma concentration is reached in about 2 to 4 hours. The pharmacokinetics of ketotifen are not significantly affected by age, gender, or renal impairment, but may be altered by hepatic impairment or concomitant use of other drugs. Ketotifen, like other antihistamines,
545-450: A 4-month-old boy that led to growth retardation and mental deterioration. In systemic (oral) administration, ketotifen has the potential to enhance the effects of sedatives, hypnotics, antihistamines, and alcohol. Interactions have been observed between oral ketotifen and oral hypoglycemic agents , antihistamines, and medications with sedative properties. Oral ketotifen may interact with amphetamine and benzphetamine , which may decrease
654-449: A calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast and zafirlukast ) block the action of leukotriene mediators and are being used increasingly in allergic diseases. Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride. The secretory process can be divided into
763-446: A chemical resemblance to pizotifen , a substance known for its appetite-stimulating properties. One proposed mechanism of the increase in appetite involves the inhibitory effect of ketotifen on the production of TNF-α , which is a cytokine that plays a role in regulating energy metabolism. TNF-α can act directly on adipocytes (fat cells) to regulate the release of leptin . Leptin is a hormone produced by adipose tissue and acts as
872-436: A combination of medications targeting different aspects of mast cell activation along with lifestyle modifications to minimize triggers. The maximum antihistamine and mast cell stabilizing effect of oral ketotifen is achieved on long-term administration, and a period of at least 6-12 weeks is necessary for a maximum therapeutic effect to start. The sedation side effect decreases over time during such long-term administration, but
981-607: A common precursor in bone marrow expressing the CD34 molecule. Basophils leave the bone marrow already mature, whereas the mast cell circulates in an immature form, only maturing once in a tissue site. The site an immature mast cell settles in probably determines its precise characteristics. The first in vitro differentiation and growth of a pure population of mouse mast cells has been carried out using conditioned medium derived from concanavalin A-stimulated splenocytes. Later, it
1090-445: A decrease in serotonin levels due to this regulatory influence. As a result, the decrease in serotonin function may lead to increased food intake tendencies and heightened appetite. Still, these potential mechanisms have been hypothesized based on limited evidence. Studies on mice suggest that caffeine or citrus aurantifolia oil may prevent weight-gain induced by ketotifen, but, this has not been confirmed on human subjects. Ketotifen
1199-401: A distinct set of mediators ( β-Hexosaminidase , cytokines , chemokines , PGD2 , leukotrienes , and eoxins ). FcεR1 is a high affinity IgE-receptor that is expressed on the surface of the mast cell. FcεR1 is a tetramer made of one alpha (α) chain, one beta (β) chain, and two identical, disulfide-linked gamma (γ) chains. The binding site for IgE is formed by the extracellular portion of
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#17327867215481308-411: A dual mode of action as an antihistamine and a mast cell stabilizer , which makes it effective in the prophylaxis and treatment of various allergic and respiratory conditions, such as asthma, allergic rhinitis, conjunctivitis, dermatitis, urticaria, and anaphylaxis. Ketotifen can also reduce the bronchial hyperreactivity and airway inflammation that are characteristic of chronic asthma . Ketotifen has
1417-400: A fairly fundamental role in innate immunity : They are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNF-α; they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens; and mice without mast cells seem to be much more susceptible to a variety of infections. Mast cell granules carry
1526-465: A first-generation or second-generation antihistamine due to varying criteria of classification. Ketotifen, an antihistamine medication and a mast cell stabilizer, is most commonly sold as a salt with fumaric acid , ketotifen fumarate, and is available in two forms: Ketotifen ophthalmic solution (eye drops) relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies . It starts working within minutes after administering
1635-410: A fluoride-activation step and a calcium-induced secretory step. It was observed that the fluoride-activation step is accompanied by an elevation of cyclic adenosine monophosphate (cAMP) levels within the cells. The attained high levels of cAMP persist during histamine release. It was further found that catecholamines do not markedly alter the fluoride-induced histamine release. It was also confirmed that
1744-556: A high-affinity receptor ( FcεRI ) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is in essence irreversible. As a result, mast cells are coated with IgE, which is produced by plasma cells (the antibody-producing cells of the immune system). IgE antibodies are typically specific to one particular antigen . In allergic reactions, mast cells remain inactive until an allergen binds to IgE already coated upon
1853-457: A key role in the recognition of pathogen associated molecular patterns (PAMPs) and initiating an antibacterial response. MRGPRX2 is able to bind to competence stimulating peptide (CSP) 1 - a quorum sensing molecule (QSM) produced by Gram-positive bacteria. This leads to signal transduction to a G protein and activation of the mast cell. Mast cell activation induces the release of antibacterial mediators including ROS, TNF-α and PRGD2 which institute
1962-463: A less sedating antihistamine, was synthesized in 1951, and hydroxyzine (Atarax, Vistaril), an antihistamine used specifically as a sedative and tranquilizer, was developed in 1956. The first non-sedating antihistamine was terfenadine (Seldane) and was developed in 1973. Subsequently, other non-sedating antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) were developed and introduced. The introduction of
2071-416: A mast cell stabilizer by preventing the degranulation and release of histamine and other inflammatory mediators, such as leukotrienes , prostaglandins , and cytokines , from mast cells . Ketotifen also inhibits the activation and migration of eosinophils , basophils , and neutrophils , which are involved in the inflammatory response and tissue damage in allergic and respiratory diseases. Ketotifen has
2180-515: A mast cell stabilizer to treat MCAS, oral ketotifen prevents the release of histamine and other inflammatory substances from mast cells , which are immune cells that react to allergens. Therefore, ketotifen, by blocking a calcium channel essential for mast cell activation, helps reduce symptoms of allergic conditions. These allergic conditions include asthma, hay fever, and conjunctivitis caused by mast cell activation. Calcium channels are proteins in mast cell membranes that allow calcium ions to enter
2289-420: A medical professional is recommended for those who intend to take antihistamines for longer-term use. Although the general public typically uses the word "antihistamine" to describe drugs for treating allergies, physicians and scientists use the term to describe a class of drug that opposes the activity of histamine receptors in the body. In this sense of the word, antihistamines are subclassified according to
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#17327867215482398-470: A neutral receptor antagonist or an inverse agonist at histamine receptors. Only a few currently marketed H 1 -antihistamines are known to function as antagonists. Histamine makes blood vessels more permeable ( vascular permeability ), causing fluid to escape from capillaries into tissues , which leads to the classic symptoms of an allergic reaction —a runny nose and watery eyes. Histamine also promotes angiogenesis . Antihistamines suppress
2507-587: A number of structures that mediate visceral sensory (e.g. pain) or neuroendocrine functions or that are located along the blood–cerebrospinal fluid barrier , including the pituitary stalk , pineal gland , thalamus , and hypothalamus , area postrema , choroid plexus , and in the dural layer of the meninges near meningeal nociceptors . Mast cells serve the same general functions in the body and central nervous system, such as effecting or regulating allergic responses, innate and adaptive immunity, autoimmunity , and inflammation. Across systems, mast cells serve as
2616-634: A part of Novartis ), a Swiss company. Ketotifen was approved for medical use in Canada in December 1990. Ketotifen was approved for medical use in the United States in July 1999. TA contact lens with ketotifen was approved for medical use in the United States in 2022. In 2021, it was the 301st most commonly prescribed medication in the United States, with more than 400 000 prescriptions. Ketotifen
2725-399: A prescription and provides relief from nasal congestion , sneezing , or hives caused by pollen , dust mites , or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma , sinusitis , and lower respiratory tract infection . Consultation of
2834-424: A role in the prevention of accumulation of eosinophils, which are white blood cells that become active during allergic reactions and infections; as such, ketotifen helps in reducing inflammation this way. In addition, ketotifen has weak anticholinergic (K i = 204 nM for mACh Tooltip muscarinic acetylcholine receptor ) and antiserotonergic (K i = 38.9 nM for 5-HT 2A ) activity. However, at
2943-426: A satiety signal by binding to receptors in the hypothalamus , where it inhibits appetite. By reducing TNF-α production, ketotifen may lead to decreased leptin levels, reducing appetite control inhibition. Furthermore, ketotifen's influence on serotonin regulation could be involved in central serotonin disinhibition . Serotonin is known to have suppressant effects on appetite. It is suggested that ketotifen might cause
3052-518: A sedating prodrug that converts to NK, a nonsedating metabolite with anti-inflammatory properties, when used as an anti-inflammatory medication. The potential future applications of norketotifen are researched by Emergo Therapeutics, a US company. The underlying mechanisms of why ketotifen (similarly to other antihistamine drugs such as astemizole , azelastine ) may increase appetite and lead to weight gain in some people, are not fully understood. Different studies have shown conflicting results about
3161-615: A signal amplifying kinase activity due to the fact that it targets multiple proteins and causes their activation. This antigen stimulated phosphorylation causes the activation of other proteins in the FcεR1-mediated signaling cascade. An important adaptor protein activated by the Syk phosphorylation step is the linker for activation of T cells (LAT). LAT can be modified by phosphorylation to create novel binding sites. Phospholipase C gamma (PLCγ) becomes phosphorylated once bound to LAT, and
3270-512: A spectrum of immune disorders that are unrelated to pathogenic infection and involve similar symptoms that arise from secreted mast cell intermediates, but differ slightly in their pathophysiology , treatment approach, and distinguishing symptoms. The classification of mast cell activation disorders was laid out in 2010. Allergies are mediated through IgE signaling which triggers mast cell degranulation. Recently, IgE-independent " pseudo-allergic " reactions are thought to also be mediated via
3379-542: A typical duration for the second generation of the class. Ketotifen is a tricyclic , benzocycloheptene -based compound with chemical structures similar to first-generation antihistamines such as azatadine , cyproheptadine , chlorpheniramine , and diphenhydramine , and other compounds with antihistamine properties such as pizotifen . The sedative effects of ketotifen are also a reason for differences in classification. First-generation antihistamines are well known for their sedating side effects due to their ability to penetrate
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3488-399: A variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and neurons in a process of transgranulation via mast cell pseudopodia . Unlike other hematopoietic cells of the immune system , mast cells naturally occur in the human brain where they interact with the neuroimmune system . In the brain, mast cells are located in
3597-483: Is 12 hours. Besides its anti-histaminic activity, it is also a functional leukotriene antagonist (a medication that blocks the action of leukotrienes, which are chemicals that cause inflammation and narrowing of the airways in some allergic and respiratory conditions) and a phosphodiesterase inhibitor (a medication that blocks the enzymes that regulate the levels of cAMP and cGMP , which are molecules that control blood vessel dilation and smooth muscle relaxation in
3706-436: Is a selective antihistamine – that is, an inverse agonist of the histamine H 1 receptor (K i = 0.166 nM) – and mast cell stabilizer . By preventing the degranulation of mast cells, ketotifen inhibits the release of inflammatory mediators such as histamine and leukotrienes , which are implicated in allergic reactions. Ketotifen action is also based on its inhibition of serotonin release. Ketotifen also plays
3815-450: Is a common side effect of H 1 -antihistamines that readily cross the blood–brain barrier ; some of these drugs, such as diphenhydramine and doxylamine , may therefore be used to treat insomnia . H 1 -antihistamines can also reduce inflammation, since the expression of NF-κB , the transcription factor the regulates inflammatory processes, is promoted by both the receptor's constitutive activity and agonist (i.e., histamine ) binding at
3924-453: Is a part of the immune and neuroimmune systems. Mast cells were discovered by Friedrich von Recklinghausen and later rediscovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis , mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis , immune tolerance , defense against pathogens , and vascular permeability in brain tumors. The mast cell
4033-540: Is associated with higher risk for cognitive decline and dementia in older people. Also, most of the research has been on caucasians and other ethnic groups are not as represented in the research. The evidence does not report how antihistamines affect women differently than men. Different studies have reported on antihistamine use in children, with various studies finding evidence that certain antihistamines could be used by children 2 years of age, and other drugs being safer for younger or older children. Research regarding
4142-552: Is associated with the cytoplasmic end of the FcεR1 β chain. The antigen cross-links the FcεR1 molecules, and Lyn tyrosine kinase phosphorylates the ITAMs in the FcεR1 β and γ chain in the cytoplasm. Upon the phosphorylation , the Syk tyrosine kinase gets recruited to the ITAMs located on the γ chains. This causes activation of the Syk tyrosine kinase, causing it to phosphorylate. Syk functions as
4251-424: Is currently researched in context of a possible link between abnormalities in intestinal mast cells and irritable bowel syndrome , but there are no solid results yet. Antihistamine Antihistamines are drugs which treat allergic rhinitis , common cold , influenza , and other allergies . Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without
4360-525: Is dependent on antibodies and complement components. Mastocytosis is a rare clonal mast cell disorder involving the presence of too many mast cells ( mastocytes ) and CD34 + mast cell precursors. Mutations in c-Kit are associated with mastocytosis. More specifically, the majority of patients with mastocytosis have a mutation at codon 816 in the kinase domain of KIT, known as the KIT D816V mutation. The most commonly affected organs in mastocytosis are
4469-556: Is diagnosed based upon four sets of criteria involving treatment response, symptoms, a differential diagnosis , and biomarkers of mast cell degranulation. Mast cells were first described by Paul Ehrlich in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules also led him to the incorrect belief that they existed to nourish the surrounding tissue, so he named them Mastzellen (from German Mast 'fattening', as of animals). They are now considered to be part of
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4578-423: Is higher in children, especially those with a history of epilepsy or febrile seizures . The risk of coma and death is higher in adults, especially those with pre-existing medical conditions or concomitant use of other drugs that cause sedation or lower the seizure threshold. In children, ketotifen overdose may lead to toxic encephalopathy with lifelong health consequences. There was a reported case of an overdose in
4687-459: Is mainly metabolized by the cytochrome P450 (CYP) enzymes , especially CYP3A4 in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolites norketotifen and 10-hydroxyketotifen . Norketotifen is pharmacologically active and has a similar potency as ketotifen, while 10-hydroxyketotifen is inactive. The metabolites are then conjugated with glucuronic acid or sulfate and excreted in
4796-436: Is mostly short-term studies or studies which look at too few people to make general assumptions. Another gap in the research is in information reporting the health effects for individuals with long-term allergies who take antihistamines for a long period of time. Newer antihistamines have been demonstrated to be effective in treating hives. However, there is no research comparing the relative efficacy of these drugs. In 2020,
4905-441: Is released through degranulation following the activation of cell surface receptors on mast cells. Examples of mediators that are released into the extracellular environment during mast cell degranulation include: Histamine dilates post-capillary venules, activates the endothelium , and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to
5014-466: Is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against parasites and bacteria. A unique, stimulus-specific set of mast cell mediators
5123-399: Is sold under various brand names worldwide, depending on country and formulation, with over 200 different names used. In the United States, ketotifen fumarate ophthalmic solution is marketed under brand name Zaditor, which is owned by Alcon Inc. , a Swiss-American pharmaceutical company. There was a litigation related to ketotifen. In 2021, the plaintiff, Edward C. Hanks, brought an action in
5232-414: Is then used to catalyze phosphatidylinositol bisphosphate breakdown to yield inositol trisphosphate (IP3) and diacyglycerol (DAG). IP3 elevates calcium levels, and DAG activates protein kinase C (PKC). This is not the only way that PKC is made. The tyrosine kinase FYN phosphorylates Grb2-associated-binding protein 2 (Gab2), which binds to phosphoinositide 3-kinase , which activates PKC. PKC leads to
5341-432: Is used to treat asthma, allergic rhinitis , allergic conjunctivitis , atopic dermatitis , chronic urticaria (hives), cold-induced urticaria, cholinergic urticaria , exercise-induced urticaria , systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), as well as allergic and nonallergic anaphylaxis . Ketotifen has also shown efficacy in managing angioedema and food allergies. As
5450-399: Is very similar in both appearance and function to the basophil , another type of white blood cell . Although mast cells were once thought to be tissue-resident basophils, it has been shown that the two cells develop from different hematopoietic lineages and thus cannot be the same cells. Mast cells are very similar to basophil granulocytes (a class of white blood cells ) in blood , in
5559-465: The H 4 receptor antagonists . Most people who use an H 1 receptor antagonist to treat allergies use a second-generation drug. The United States government removed two second generation antihistamines, terfenadine and astemizole , from the market based on evidence that they could cause heart problems. Not much published research exists which compares the efficacy and safety of the various antihistamines available. The research which does exist
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#17327867215485668-767: The National Institute of Child Health and Human Development advises to apply pressure on the tear duct near the corner of the eye for at least one minute and remove any excess solution with a tissue. Ketotifen safety when taken via the oral route (tablets or syrup) during pregnancy and lactation remains unknown; therefore, it is not recommended to use ketotifen orally during these periods until sufficient safety data becomes available. Common side effects of ophthalmic use are eye redness and swelling . Less common are eye discharge , eye discomfort, eye pain, hives , increased itching of eyes, and rash. Ophthalmic use of ketotifen may also cause burning, stinging, or itching of
5777-694: The United States District Court for the Central District of Illinois against the defendants, Ned Hubbard and others, alleging that they violated his rights under the Eighth Amendment to the United States Constitution by acting with deliberate indifference to his serious medical needs. The plaintiff claimed that he suffered from a chronic eye condition that required medical attention and that
5886-521: The blood–brain barrier to a much lesser extent than the first-generation antihistamines. They minimize sedatory effects due to their focused effect on peripheral histamine receptors. However, upon high doses second-generation antihistamines will begin to act on the central nervous system and thus can induce drowsiness when ingested in higher quantity. H 2 -antihistamines, like H 1 -antihistamines, exist as inverse agonists and neutral antagonists . They act on H 2 histamine receptors found mainly in
5995-456: The blood–brain barrier . While ketotifen has some sedative properties, it is generally considered to have a milder sedative effect compared to traditional first-generation antihistamines, so this reduced sedation is one of the reasons why ketotifen is sometimes classified as a second-generation antihistamine. Ketotifen was patented in 1970 and came into medical use in 1976. Ketotifen was developed and patented by Sandoz Pharmaceuticals (currently
6104-438: The histamine receptor that they act upon. The two largest classes of antihistamines are H 1 -antihistamines and H 2 -antihistamines . H 1 -antihistamines work by binding to histamine H 1 receptors in mast cells , smooth muscle , and endothelium in the body as well as in the tuberomammillary nucleus in the brain. Antihistamines that target the histamine H 1 -receptor are used to treat allergic reactions in
6213-459: The immune system . Research into an immunological contribution to autism suggests that autism spectrum disorder (ASD) children may present with "allergic-like" problems in the absence of elevated serum IgE and chronic urticaria , suggesting non-allergic mast cell activation in response to environmental and stress triggers. This mast cell activation could contribute to brain inflammation and neurodevelopmental problems. Toluidine blue : one of
6322-464: The parietal cells of the gastric mucosa, which are part of the endogenous signaling pathway for gastric acid secretion. Normally, histamine acts on H 2 to stimulate acid secretion; drugs that inhibit H 2 signaling thus reduce the secretion of gastric acid. H 2 -antihistamines are among first-line therapy to treat gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease . Some formulations are available over
6431-640: The H 1 receptor. A combination of these effects, and in some cases metabolic ones as well, lead to most first-generation antihistamines having analgesic-sparing (potentiating) effects on opioid analgesics and to some extent with non-opioid ones as well. The most common antihistamines utilized for this purpose include hydroxyzine , promethazine (enzyme induction especially helps with codeine and similar prodrug opioids), phenyltoloxamine , orphenadrine , and tripelennamine ; some may also have intrinsic analgesic properties of their own, orphenadrine being an example. Second-generation antihistamines cross
6540-495: The MRGPRX2 receptor activation of mast cells (e.g. drugs such as muscle relaxants , opioids , Icatibant and fluoroquinolones ). Many forms of cutaneous and mucosal allergy are mediated in large part by mast cells; they play a central role in asthma , eczema , itch (from various causes), allergic rhinitis and allergic conjunctivitis . Antihistamine drugs act by blocking histamine action on nerve endings. Cromoglicate -based drugs (sodium cromoglicate, nedocromil) block
6649-747: The UK National Health Service wrote that "[m]ost people can safely take antihistamines" but that "[s]ome antihistamines may not be suitable" for young children, the pregnant or breastfeeding, for those taking other medicines, or people with conditions "such as heart disease, liver disease, kidney disease or epilepsy". Most studies of antihistamines reported on people who are younger, so the effects on people over age 65 are not as well understood. Older people are more likely to experience drowsiness from antihistamine use than younger people. Continuous and/or cumulative use of anticholinergic medications, including first-generation antihistamines,
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#17327867215486758-636: The US for people who are at least three years of age. In the EU, ketotifen oral formulatios (syrup, tables and capsules) are approved by the European Medicines Agency for adult use. In the UK, ketotifen is available as tables and elixir (liquid). Oral ketotifen can be used as a long-term control medication for asthma and wheeze in children, and it has been shown to improve the control of asthma by reducing
6867-644: The activation of myosin light-chain phosphorylation granule movements, which disassembles the actin–myosin complexes to allow granules to come into contact with the plasma membrane. The mast cell granule can now fuse with the plasma membrane. Soluble N-ethylmaleimide sensitive fusion attachment protein receptor SNARE complex mediates this process. Different SNARE proteins interact to form different complexes that catalyze fusion. Rab3 guanosine triphosphatases and Rab-associated kinases and phosphatases regulate granule membrane fusion in resting mast cells. Human mast-cell-specific G-protein-coupled receptor MRGPRX2 plays
6976-480: The activities of ketotifen. The concomitant use of oral ketotifen with amifampridine , bupropion , donepezil , and pitolisant is not recommended. In rare instances, patients who have been administered oral ketotifen with oral antidiabetic agents have exhibited a reversible decrease in thrombocyte count. As such, it is recommended to monitor thrombocyte counts in patients who are concurrently taking oral antidiabetic agents. Systemic use of ketotifen may decrease
7085-411: The activity of the H 1 receptor . Since the H 1 receptor exhibits constitutive activity , H 1 -antihistamines can be either neutral receptor antagonists or inverse agonists . Normally, histamine binds to the H 1 receptor and heightens the receptor's activity; the receptor antagonists work by binding to the receptor and blocking the activation of the receptor by histamine; by comparison,
7194-514: The activity of the H 4 receptor . Examples include: Inhibit the action of histidine decarboxylase : Mast cell stabilizers are drugs which prevent mast cell degranulation . Examples include: The first H 1 receptor antagonists were discovered in the 1930s and were marketed in the 1940s. Piperoxan was discovered in 1933 and was the first compound with antihistamine effects to be identified. Piperoxan and its analogues were too toxic to be used in humans. Phenbenzamine (Antergan)
7303-725: The affected system of the body. The cardiovascular effects of ketotifen overdose may include tachycardia, hypotension, arrhythmias, and cardiac arrest . The respiratory effects may include respiratory depression, sleep apnea , and pulmonary edema . The gastrointestinal effects may include nausea, vomiting, abdominal pain, diarrhea, and pancreatitis . The renal effects may include acute renal failure and urinary retention . The hepatic effects may include hepatitis and jaundice . The hematologic effects may include anemia , leukopenia , thrombocytopenia , and coagulopathy . The neurologic effects of ketotifen overdose may include convulsions , hyperexcitability, coma , and death. The risk of seizures
7412-447: The amount of weight gain caused by ketotifen. In one study ( postmarketing surveillance ), it was found that around 1 to 2 out of every 100 people who took the drug experienced weight gain, with adults gaining about 1 kilogram (2.2 lb) and children over the age of one gaining 2.8–3.3 kilograms (6.2–7.3 lb). However, in another study, adults gained a higher amount of weight: 5.0–5.4 kilograms (11.0–11.9 lb). Ketotifen exhibits
7521-473: The antihistamine and mast cell stabilizing properties persist even if administered for 12 months or longer. Oral ketotifen is available at compounding pharmacies in the United States with a prescription requirement, still, the use of oral ketotifen is only approved by the Food and Drug Administration (FDA) for adults and older children with asthma or allergic conditions. However, ketotifen eye drops are approved in
7630-468: The body). The eye drops are contraindicated for individuals who have a known hypersensitivity to ketotifen or any other ingredient in the formulation, whereas drug-eluting contact lenses are contraindicated for those who experience irritation from wearing contact lenses. Eye drops are not recommended for use in children under three years of age, whereas drug-eluting contact lenses are not recommended for children under eleven years of age. For oral ketotifen,
7739-483: The body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock . Histamine is a vasodilatory substance released during anaphylaxis. Mast cells may be implicated in the pathology associated with autoimmune, inflammatory disorders of the joints. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g., rheumatoid arthritis ) and skin (e.g., bullous pemphigoid ), and this activity
7848-500: The body. Ketotifen is also used for other allergic-type conditions like atopic dermatitis ( eczema ) and food allergies . Ketotifen acts by blocking the H 1 histamine receptors , which are found on various cells in the body, such as smooth muscle , endothelium , and nerve cells . This blocking prevents the binding of histamine to these receptors and thus reduces the symptoms of histamine-mediated reactions, such as itching, sneezing, wheezing, and swelling. Ketotifen also prevents
7957-459: The boundaries between the outside world and the internal milieu, such as the skin , mucosa of the lungs , and digestive tract , as well as the mouth , conjunctiva , and nose . Mast cells play a key role in the inflammatory process. When activated, a mast cell can either selectively release ( piecemeal degranulation ) or rapidly release ( anaphylactic degranulation ) "mediators", or compounds that induce inflammation, from storage granules into
8066-672: The cell, triggering the release of histamine and other inflammatory substances. When these channels open, calcium floods into the cells, causing them to degranulate. By blocking these channels, ketotifen prevents this process, reducing allergic reactions. In Canada, Europe, and Mexico, oral ketotifen is commonly prescribed for these indications (asthma, hay fever, and conjunctivitis caused by mast cell activation). In patients with MCAS, ketotifen reduces episodes of flushing , gastrointestinal symptoms (such as abdominal pain, diarrhea), respiratory symptoms (such as wheezing), and other systemic manifestations. Still, treatment plans for MCAS typically involve
8175-423: The cell. Other membrane activation events can either prime mast cells for subsequent degranulation or act in synergy with FcεRI signal transduction. In general, allergens are proteins or polysaccharides . The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking)
8284-449: The co-transfected β and γ chains mask the ER retention and allows the α β γ complex to be exported to the golgi apparatus to the plasma membrane in rats. In humans, only the γ complex is needed to counterbalance the α chain ER retention. Allergen-mediated FcεR1 cross-linking signals are very similar to the signaling event resulting in antigen binding to lymphocytes . The Lyn tyrosine kinase
8393-439: The contraindication is for known hypersensitivity to any component of the product. Caution should be taken on the following conditions: The use of ketotifen eye drops during pregnancy and lactation is considered safe, as absorption through the eye is limited. It is unlikely to cause any adverse effects in breastfeeding infants after maternal use. To minimize the amount of medication transferred to breast milk when using eye drops,
8502-486: The counter. Most side effects are due to cross-reactivity with unintended receptors. Cimetidine, for example, is notorious for antagonizing androgenic testosterone and DHT receptors at high doses. Examples include: An H 3 -antihistamine is a classification of drugs used to inhibit the action of histamine at the H 3 receptor . H 3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate
8611-615: The defendant's motion to dismiss, finding that the plaintiff failed to state a claim upon which relief could be granted. The plaintiff appealed to the United States Court of Appeals for the Seventh Circuit , which affirmed the district court's judgment on 7 February 2022. Research directions for ketotifen include the investigation of norketotifen (NK), a metabolite of ketotifen. In vitro studies using human liver microsomes and hepatocytes suggest that NK may be
8720-434: The defendant, Dr. Hubbard, prescribed him ketotifen. The plaintiff further claimed that the ketotifen eye drops caused him adverse reactions, such as severe pain, burning, and blurred vision, and that the defendant, Dr. Hubbard, failed to offer him an alternative medication or refer him to an ophthalmologist. The plaintiff also claimed that he sustained permanent eye damage as a result of the ketotifen. The district court granted
8829-517: The dosages in which it is typically used clinically, both the anticholinergic and antiserotonergic activity of ketotifen are said not to be appreciable. Ketotifen is a lipophilic compound that can cross the blood–brain barrier and exert central nervous system effects, such as sedation, weight gain, and anticonvulsant activity. Ketotifen also has peripheral effects, such as inhibition of platelet aggregation, modulation of cytokine production, and enhancement of mucociliary clearance . Ketotifen acts as
8938-561: The drops. Ketotifen in the form of eye drops has not been studied in children under three years old, whereas drug-eluting contact lenses have not been studied in children under eleven years old. Drug-eluting contact lenses, which release ketotifen medication, are used to help prevent itchy eyes caused by allergies. The lenses can also correct vision problems like nearsightedness and farsightedness. These lenses are meant for people who don't have red eyes, can comfortably wear contact lenses, and have less than 1 degree of astigmatism. Oral ketotifen
9047-418: The ear and even tinnitus . Itching , sneezing , and inflammatory responses are suppressed by antihistamines that act on H1-receptors . In 2014, antihistamines such as desloratadine were found to be effective to complement standardized treatment of acne due to their anti-inflammatory properties and their ability to suppress sebum production. H 1 -antihistamines refer to compounds that inhibit
9156-507: The effectiveness of benzylpenicilloyl polylysine as a diagnostic agent. Ketotifen may affect the results of some laboratory tests, such as skin tests for allergies or blood glucose levels. Ketotifen may interfere with the skin test reactions by suppressing the histamine response, leading to false-negative results. Ophthalmic use of ketotifen may interact with contact lenses, as the eye drops may contain preservatives that can be absorbed by soft contact lenses and cause eye irritation. Ketotifen
9265-749: The effects of commonly used medications upon certain cancer therapies has suggested that when consumed in conjunction with immune checkpoint inhibitors some may influence the response of subjects to that particular treatment whose T-cell functions were failing in anti-tumor activity. Upon study of records in mouse studies associated with 40 common medications ranging from antibiotics, antihistamines, aspirin, and hydrocortisone, that for subjects with melanoma and lung cancers, fexofenadine, one of three medications, along with loratadine, and cetirizine, that target histamine receptor H1 (HRH1), demonstrated significantly higher survival rates and had experienced restored T-cell anti-tumor activity, ultimately inhibiting tumor growth in
9374-707: The eyes, blurred vision, or increased sensitivity to light. Side effects of systemic (oral) use include drowsiness , weight gain (5.0–5.4 kilograms (11.0–11.9 lb)), dry mouth , irritability, and increased nosebleeds . Systemic use of ketotifen may also cause abdominal pain, nausea, vomiting, constipation, diarrhea, headache, dizziness, or fatigue. In rare cases, systemic use of ketotifen may cause serious side effects such as anaphylaxis , liver dysfunction, blood disorders, or seizures. Systemic use of ketotifen may interact with other drugs that cause sedation, such as alcohol , antihistamines, opioids , benzodiazepines , or antidepressants . Systemic use of ketotifen may affect
9483-465: The first-generation antihistamines marked the beginning of medical treatment of nasal allergies. Research into these drugs led to the discovery that they were H 1 receptor antagonists and also to the development of H 2 receptor antagonists , where H 1 -antihistamines affected the nose and the H 2 -antihistamines affected the stomach. This history has led to contemporary research into drugs which are H 3 receptor antagonists and which affect
9592-406: The histamine-induced wheal response (swelling) and flare response (vasodilation) by blocking the binding of histamine to its receptors or reducing histamine receptor activity on nerves , vascular smooth muscle , glandular cells, endothelium , and mast cells . Antihistamines can also help correct Eustachian Tube dysfunction , thereby helping correct problems such as muffled hearing, fullness in
9701-409: The inverse agonists bind to the receptor and both block the binding of histamine, and reduce its constitutive activity, an effect which is opposite to histamine's. Most antihistamines are inverse agonists at the H 1 receptor, but it was previously thought that they were antagonists. Clinically, H 1 -antihistamines are used to treat allergic reactions and mast cell -related disorders. Sedation
9810-668: The local microenvironment. Mast cells can be stimulated to degranulate by allergens through cross-linking with immunoglobulin E receptors (e.g., FcεRI ), physical injury through pattern recognition receptors for damage-associated molecular patterns (DAMPs), microbial pathogens through pattern recognition receptors for pathogen-associated molecular patterns (PAMPs), and various compounds through their associated G-protein coupled receptors (e.g., morphine through opioid receptors ) or ligand-gated ion channels . Complement proteins can activate membrane receptors on mast cells to exert various functions as well. Mast cells express
9919-874: The main effector cell through which pathogens can affect the gut–brain axis . In the gastrointestinal tract, mucosal mast cells are located in close proximity to sensory nerve fibres, which communicate bidirectionally. When these mast cells initially degranulate, they release mediators (e.g., histamine, tryptase, and serotonin) which activate, sensitize, and upregulate membrane expression of nociceptors (i.e., TRPV1 ) on visceral afferent neurons via their receptors (respectively, HRH1 , HRH2 , HRH3 , PAR2 , 5-HT3 ); in turn, neurogenic inflammation, visceral hypersensitivity , and intestinal dysmotility (i.e., impaired peristalsis ) result. Neuronal activation induces neuropeptide ( substance P and calcitonin gene-related peptide ) signaling to mast cells where they bind to their associated receptors and trigger degranulation of
10028-447: The major demethylated hepatic metabolite of ketotifen. Unlike ketotifen, NK does not seem to induce severe sedative effects, potentially allowing for higher doses to be administered without sedation as a limiting factor. Furthermore, NK may probably have potent and dose-dependent inhibition of the release of the pro-inflammatory cytokine TNF-α , suggesting potential anti-inflammatory activity. thus, ketotifen can probably be considered
10137-501: The most common stains for acid mucopolysaccharides and glycoaminoglycans , components of mast cells granules. Bismarck brown: stains mast cell granules brown. Surface markers: cell surface markers of mast cells were discussed in detail by Heneberg, claiming that mast cells may be inadvertently included in the stem or progenitor cell isolates, since part of them is positive for the CD34 antigen. The classical mast cell markers include
10246-427: The need for bronchodilators , decreasing symptoms, preventing exacerbations, and reducing the use of rescue oral steroids, ketotifen has also been found to be effective when used alone or in combination with other medications. Oral ketotifen is an alternative to inhaled therapy for asthma in children, especially for younger children who may have difficulty using inhalers. The mean elimination half-life of oral ketotifen
10355-620: The nose (e.g., itching, runny nose, and sneezing). In addition, they may be used to treat insomnia , motion sickness, or vertigo caused by problems with the inner ear . H 2 -antihistamines bind to histamine H 2 receptors in the upper gastrointestinal tract , primarily in the stomach . Antihistamines that target the histamine H 2 -receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux ). Other antihistamines also target H 3 receptors and H 4 receptors . Histamine receptors exhibit constitutive activity , so antihistamines can function as either
10464-517: The recruitment of other immune cells to inhibit bacterial growth and biofilm formation. The MRGPRX2 receptor is a possible therapeutic target and can be pharmacologically activated using the agonist compound 48/80 to control bacterial infection. It is also hypothesised that other QSMs and even Gram-negative bacterial signals can activate this receptor. This might particularly be the case during Bartonella chronic infections where it appears clearly in human symptomatology that these patients all have
10573-446: The release of histamine . Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H 1 receptors in the cerebral cortex . Consequently, unlike the H 1 -antihistamines which are sedating, H 3 -antihistamines have stimulant and cognition-modulating effects. Examples of selective H 3 -antihistamines include: H 4 -antihistamines inhibit
10682-400: The release of histamine and other inflammatory substances from immune cells (mast cells); this action helps reduce symptoms of conditions (including allergic conditions) by blocking the activation of these cells. In addition to its antihistaminic activity, ketotifen also functions as a leukotriene antagonist , which blocks inflammation-causing chemicals known as leukotrienes ; it also acts as
10791-1117: The results of some laboratory tests, such as skin tests for allergies or blood glucose levels. The symptoms of ketotifen overdose are dose-dependent and may vary from mild to severe. The onset of symptoms may be delayed for several hours after ingestion, and the duration of symptoms may last for more than 24 hours. The most common symptom of ketotifen overdose is significant sedation . Other symptoms may include confusion, disorientation, agitation, hallucinations , ataxia (impairment of voluntary muscle movement), tremor (involuntary regular muscle contraction), myoclonus (involuntary, irregular muscle twitch), nystagmus (dysfunction of eye movement), dysarthria (poor speech), and slurred speech . Other symptoms of ketotifen overdose may include tachycardia (fast, pounding, or irregular heartbeat or pulse), hypotension (low blood pressure), convulsions , hyperexcitability (particularly in children), reversible coma, unusual tiredness or weakness, blurred vision , dizziness or fainting, loss of consciousness. The symptoms of ketotifen overdose may be described according to
10900-560: The second, but not the first, step in sodium fluoride-induced histamine secretion is inhibited by theophylline. Vasodilation and increased permeability of capillaries are a result of both H1 and H2 receptor types. Stimulation of histamine activates a histamine (H2)-sensitive adenylate cyclase of oxyntic cells, and there is a rapid increase in cellular [cAMP] that is involved in activation of H+ transport and other associated changes of oxyntic cells. In anaphylaxis (a severe systemic reaction to allergens , such as nuts, bee stings, or drugs),
11009-547: The sense that both are granulated cells that contain histamine and heparin , an anticoagulant . Their nuclei differ in that the basophil nucleus is lobated while the mast cell nucleus is round. The Fc region of immunoglobulin E (IgE) becomes bound to mast cells and basophils, and when IgE's paratopes bind to an antigen, it causes the cells to release histamine and other inflammatory mediators. These similarities have led many to speculate that mast cells are basophils that have "homed in" on tissues. Furthermore, they share
11118-466: The site of release. It also depolarizes nerve endings (leading to itching or pain ). Cutaneous signs of histamine release are the "flare and wheal "-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen. The other physiologic activities of mast cells are much less-understood. Several lines of evidence suggest that mast cells may have
11227-519: The skin and bone marrow. Mastocytomas , or mast cell tumors, can secrete excessive quantities of degranulation products. They are often seen in dogs and cats. Other neoplastic disorders associated with mast cells include mast cell sarcoma and mast cell leukemia . Mast cell activation syndrome (MCAS) is an idiopathic immune disorder that involves recurrent and excessive mast cell degranulation and which produces symptoms that are similar to other mast cell activation disorders. The syndrome
11336-427: The subject animals. Such results encourage further study in order to see whether results in humans is similar in combating resistance to immunotherapy. Mast cell A mast cell (also known as a mastocyte or a labrocyte ) is a resident cell of connective tissue that contains many granules rich in histamine and heparin . Specifically, it is a type of granulocyte derived from the myeloid stem cell that
11445-654: The urine and feces. Ketotifen is a noncompetitive H 1 -antihistamine and mast cell stabilizer . There is no academic consensus on whether ketotifen should be classified as a medication belonging to the first or the second generations of antihistamine drugs; the classification can vary depending on the criteria used and the context of the study, and is primarily based on chemical structure, pharmacological properties, and side effect profiles of an antihistamine drug. First-generation H 1 antihistamines, such as diphenhydramine, reduce skin reactivity for up to 24 hours, whereas ketotifen suppresses skin reactivity for over five days,
11554-406: The α chain that contains two domains that are similar to Ig. One transmembrane domain contains an aspartic acid residue, and one contains a short cytoplasmic tail. The β chain contains, a single immunoreceptor tyrosine-based activation motif ITAM , in the cytoplasmic region. Each γ chain has one ITAM on the cytoplasmic region. The signaling cascade from the receptor is initiated when the ITAMs of
11663-404: The β and γ chains are phosphorylated by a tyrosine kinase. This signal is required for the activation of mast cells. Type 2 helper T cells,( Th2 ) and many other cell types lack the β chain, so signaling is mediated only by the γ chain. This is due to the α chain containing endoplasmic reticulum retention signals that causes the α-chains to remain degraded in the ER. The assembly of the α chain with
11772-501: Was discovered that T cell-derived interleukin 3 was the component present in the conditioned media that was required for mast cell differentiation and growth. Mast cells in rodents are classically divided into two subtypes: connective tissue -type mast cells and mucosal mast cells. The activities of the latter are dependent on T-cells . Mast cells are present in most tissues characteristically surrounding blood vessels, nerves and lymphatic vessels, and are especially prominent near
11881-433: Was the first clinically useful antihistamine and was introduced for medical use in 1942. Subsequently, many other antihistamines were developed and marketed. Diphenhydramine (Benadryl) was synthesized in 1943, tripelennamine (Pyribenzamine) was patented in 1946, and promethazine (Phenergan) was synthesized in 1947 and launched in 1949. By 1950, at least 20 antihistamines had been marketed. Chlorphenamine (Piriton),
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