Histamine 1; SARS-CoV-2; Influenza virus

Ketotifen (0-100 μM; 2 or 4 days) inhibits SARS-CoV-2 with an EC50 of 48.9 μM; when co-administered with 25, 50, and 100 μM Indomethacin, respectively, increases the percentage inhibition of SARS-CoV-2 to 79%, 83%, and 93%[3].
Ketotifen (0-50 μM; 24 h) demonstrates comparatively low cytotoxicity in MDCK cells (EC50=291 μM) and has inhibitory activity against PR8, pH1N1, and H3N2 with EC50s of 5.9 μM, 33.7 μM, and 48.5 μM, respectively[4].

Ketotifen (80 mg/kg; orally for 3 days) lowers mortality and end organ damage in mice with influenza virus infection[4].
Ketotifen fumarate (0.4 mg/kg; intraperitoneal; daily for 10 days) lowers the incidence and severity of encephalomyelitis (EAE)[5].

Female C57BL/6 mice (4-6 weeks; intranasal infection with 1×10³ TCID50 of PR8 in 30 μL of DMEM)
80 mg/kg
i.g.; daily for 3 days

Absorption, Distribution and Excretion
Following oral administration, absorption is relatively quick (with a Tmax of ~3 hours) and nearly complete as judged by plasma concentrations and urinary excretion levels - despite this, oral bioavailability is only ~50% due to a significant first-pass effect in the liver.
More than 60% of an administered dose is excreted in the urine, primarily as metabolites - of this material, <1% is found as unchanged drug, while the glucuronide and pharmacologically active nor-ketotifen metabolites account for 50% and 10%, respectively.
Within 48 hours, urinary excretion amounts to 1% as unchanged drug and 60% to 70% as metabolites. Clearance is higher in children. /Ketotifen fumarate/
Following oral administration absorption is at least 60% ... The rate of absorption is rapid with an absorption half life of 1 hour. Bioavailability is about 50%, due to a large first pass effect. Bioavailability is not affected by the intake of food. /Ketotifen fumarate/
... A study conducted with 15 healthy volunteers dosed bilaterally with ketotifen fumarate ophthalmic solution twice daily for 14 days demonstrated plasma concentrations generally below the quantitation limit of assay (< 20 pg/mL). /Ketotifen fumarate/
It is not known whether ophthalmic ketotifen is absorbed in sufficient quantities to be distributed into human breast milk. However, it has been found in the milk of nursing rats following oral administration. /Ketotifen fumarate/
For more Absorption, Distribution and Excretion (Complete) data for KETOTIFEN (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Ketotifen is extensively metabolized in humans and three distinct metabolites have been detected in human urine. The main metabolite is the N-glucuronide, comprising roughly 50% of urinary drug product, with the N-demethylated nor-ketotifen and the 10-hydroxyl derivative comprising 2% and <1%, respectively. Nor-ketotifen appears to be equally as active as its parent drug, though the clinical relevance of this is unclear given the relatively small proportion in which nor-ketotifen is found in the plasma. Formation of the N-glucuronide metabolite is carried out by several UGT enzymes, including UGT1A3, UGT1A4, and UGT2B10.
The main metabolite found in both plasma and urine is the inactive ketotifen-N-glucuronide. Nor-ketotifen, the N-demethylated metabolite, and the 10-hydroxyl derivative are the only other metabolites detectable in human urine. Both the 10-hydroxyl derivative and N-glucuronide conjugate may reform the intact product by in vivo reversibility. The pattern of metabolism in children over the age of 3 years is the same as in adults, but the clearance is higher in children. /Ketotifen fumarate (systemic)/
Ketotifen has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[1-methyl-4-(8-oxo-6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-2-ylidene)piperidin-1-ium-1-yl]oxane-2-carboxylic acid and Ketotifen N-glucuronide.

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Biological Half-Life
Ketotifen clearance is biphasic - the half-life of the distribution phase is approximately 3-5 hours and the half-life of the elimination phase is 22 hours.
Distribution: 3 to 5 hours. Elimination: 21 hours. /Ketotifen fumarate (systemic)/
... The rate of absorption /following oral administration/ is rapid with an absorption half life of 1 hour.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because absorption from the eye is limited, ketotifen would not be expected to cause any adverse effects in breastfed infants after maternal use of ketotifen eye drops. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Ketotifen is 75% protein-bound in plasma, though the specific proteins to which it binds are unclear.

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Interactions
Concurrent use /of alcohol, antihistamines, hypnotics, or sedatives/ with /oral/ ketotifen may potentiate the CNS depressant effects of these medications. /Ketotifen fumarate/
Concomitant use /of oral antidiabetic agents/ with /oral/ ketotifen may result in reversible thrombocytopenia ... /Ketotifen fumarate/
... Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin.
...Ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate /in mice/.

[1]. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21.

[2]. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020;35(1):1322-1330.

[3]. In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2. Viruses. 2021 Mar 26;13(4):558.

[4]. Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity. Front Immunol. 2019 Jun 5;10:1097.

[5]. Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy? Neurotherapeutics. 2020 Jan;17(1):218-234.

Therapeutic Uses
Oral ketotifen is indicated as an add-on medication in the chronic treatment of mild atopic asthmatic children. Ketotifen is a prophylactic agent to be used on a continuous basis and is not effective in the acute prevention or treatment of acute asthma attacks. /Not commercially available in US/
Ophthalmic ketotifen is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis. /Included in US product labeling/

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Drug Warnings
Ketotifen should not be used to treat contact lens related irritation. /Ketotifen fumarate/
Pregnancy risk category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Symptoms of central nervous system stimulation, such as excitation, irritability, insomnia, and nervousness have been observed, particularly in children. /Ketotifen fumarate (systemic)/
For patients with diabetes: Recognizing that ketotifen syrup contains 4 g of carbohydrate in every 5 mL; glucose concentrations may be affected. /Ketotifen fumarate (systemic)/
For more Drug Warnings (Complete) data for KETOTIFEN (9 total), please visit the HSDB record page.

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Pharmacodynamics
Ketotifen is a non-competitive histamine antagonist and mast cell stabilizer. Administered orally, it functions as a non-bronchodilator antiasthmatic drug by inhibiting the effects of endogenous substances known to be inflammatory mediators. While effects can take 6 to 12 weeks to become apparent, the use of ketotifen has been demonstrated to reduce the frequency, severity, and duration of asthma symptoms, and may allow for a reduction in the use of other asthma therapies.

C23H23NO5S

425.5

425.129

C, 64.92; H, 5.45; N, 3.29; O, 18.80; S, 7.53

34580-14-8

Ketotifen-d3 fumarate; 1795138-23-6; Ketotifen; 34580-13-7

3827

White to off-white solid powder

0.968 g/mL at 25 °C(lit.)

250-263 °C(lit.)

-43°C

96-98°C/5mm

n20/D 1.522(lit.)

3.664

0

3

0

22

476

0

S1C([H])=C([H])C2=C1C(C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1/C/2=C1/C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C/1([H])[H])=O

YNQQEYBLVYAWNX-WLHGVMLRSA-N

InChI=1S/C19H19NOS.C4H4O4/c1-20-9-6-13(7-10-20)18-15-5-3-2-4-14(15)12-17(21)19-16(18)8-11-22-19;5-3(6)1-2-4(7)8/h2-5,8,11H,6-7,9-10,12H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1+

(E)-but-2-enedioic acid;2-(1-methylpiperidin-4-ylidene)-6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-8-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 37.5 mg/mL (88.13 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)