Norketotifen

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Norketotifen
Norketotifen.svg
Identifiers
3D model (JSmol)
PubChem CID
  • C1CNCCC1=C2C3=C(C(=O)CC4=CC=CC=C42)SC=C3
Properties
C18H17NOS
Molar mass 295.4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Norketotifen is a pharmaceutical medication which is not yet approved for use and is undergoing clinical trials. It is a biologically active demethylated metabolite of ketotifen and has a similar potency as ketotifen as an antihistamine H1 medication and a mast cell stabilizer, yet is devoid of severe sedative effects of ketotifen, potentially allowing for higher doses to be administered without sedation as a limiting factor. [1] Norketotifen is researched for its potential anti-inflammatory activity caused by dose-dependent inhibition of the release of the pro-inflammatory cytokine TNF-α, [1] and for its other potential properties. [2]

Pharmaceutical properties

A prodrug of norketotifen is ketotifen which was patented in 1970 by Sandoz Pharmaceuticals (currently a part of Novartis), a Swiss company, [3] [4] [5] and came into medical use in 1976. [5] Ketotifen can be considered a sedating (sleepiness-causing) prodrug that is converted to norketotifen, a nonsedating metabolite with anti-inflammatory properties, when used as an anti-inflammatory medication. [5]

Research directions

Influenza

The potential future applications of norketotifen, including a treatment for non-complicated influenza are researched by Emergo Therapeutics, a US company. [6] [7] [8] [9] [10]

Malaria

Norketotifen, the de-methylated metabolite of ketotifen, has shown promising potential as an antimalarial drug, but the research is in the very early stage. [2] Norketotifen has been found to be a more potent antimalarial in vitro compared to ketotifen, and it exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. [2] After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s (half-minimal inhibitory concentration) of the compounds against Plasmodium falciparum in vitro. [2] This suggests that the antimalarial activity of ketotifen in mice is mediated through norketotifen. [2] Given these findings, future research could focus on further understanding the pharmacokinetics and metabolism of norketotifen, as well as its mechanism of action against Plasmodium falciparum. [2] It would also be beneficial to investigate the drug's efficacy against other strains of Plasmodium and in different animal models. [2] If norketotifen continues to show promising results in future studies, it could potentially be developed into a new antimalarial drug. This could be particularly valuable given the increasing resistance of malaria parasites to existing drugs. [2]

Sedation

Both ketotifen and its active metabolite norketotifen exist as optically active atropisomers. They both have antihistaminic and anti-inflammatory properties. However, the S-atropisomer of norketotifen (SN) causes less sedation than ketotifen and the R-atropisomer of norketotifen (RN) in rodents. The lower sedative effect of SN in rodents is probably due to a combination of a lower uptake of norketotifen than ketotifen into the brain and less affinity of SN for histamine H1 receptors in the central nervous system. This research direction could potentially lead to the development of antihistamines with reduced sedative effects. [11]

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects vertebrates and Anopheles mosquitoes. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria. The mosquito vector is itself harmed by Plasmodium infections, causing reduced lifespan.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<span class="mw-page-title-main">Loratadine</span> Antihistamine medication

Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in which it is combined with pseudoephedrine, a nasal decongestant. It is taken orally.

<span class="mw-page-title-main">Artemisinin</span> Group of drugs used against malaria

Artemisinin and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua an herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant.

<span class="mw-page-title-main">Hydroxyzine</span> Antihistamine drug

Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, insomnia, and nausea. It is used either by mouth or injection into a muscle.

<span class="mw-page-title-main">Cetirizine</span> Antihistamine medication

Cetirizine is a second-generation antihistamine used to treat allergic rhinitis, dermatitis, and urticaria (hives). It is taken by mouth. Effects generally begin within thirty minutes and last for about a day. The degree of benefit is similar to other antihistamines such as diphenhydramine, which is a first-generation antihistamine.

<span class="mw-page-title-main">Promethazine</span> Sedating antihistamine

Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious, an effect that has led to some recreational use. Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).

<span class="mw-page-title-main">Artemether</span> Chemical compound

Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine.

<span class="mw-page-title-main">Artesunate</span> Chemical compound

Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of malaria. Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.

<span class="mw-page-title-main">Doxylamine</span> First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)

Doxylamine is an antihistamine medication used to treat insomnia and allergies, and—in combination with pyridoxine (vitamin B6)—to treat morning sickness in pregnant women. It is available over-the-counter and is typically sold under such brand names as Equate or Unisom, among others; and it is used in nighttime cold medicines (e.g., NyQuil) and pain medications containing acetaminophen and/or codeine to help with sleep. The medication is delivered chemically by the salt doxylamine succinate and is taken by mouth. Doxylamine and other first-generation antihistamines are the most widely used sleep medications in the world. Typical side effects of doxylamine (at recommended doses) include dizziness, drowsiness, grogginess, and dry mouth, among others.

<span class="mw-page-title-main">Clemastine</span> Allergy medication

Clemastine, also known as meclastin, is a first-generation H1 histamine antagonist (antihistamine) with anticholinergic properties (drying) and sedative side effects. Like all first-generation antihistamines, it is sedating.

<span class="mw-page-title-main">Proguanil</span> Chemical compound

Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistant malaria. It is taken by mouth.

<span class="mw-page-title-main">Methocarbamol</span> Medication for musculoskeletal pain

Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain. It may be used together with rest, physical therapy, and pain medication. It is less preferred in low back pain. It has limited use for rheumatoid arthritis and cerebral palsy. Effects generally begin within half an hour. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Ketotifen</span> Antihistamine medication

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 and oral 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 the body. Ketotifen is also used for other allergic-type conditions like atopic dermatitis (eczema) and food allergies.

Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by Plasmodium falciparum that is not treatable with chloroquine. It is not typically used to prevent malaria. It is taken by mouth.

<span class="mw-page-title-main">Amodiaquine</span> Chemical compound

Amodiaquine (ADQ) is a medication used to treat malaria, including Plasmodium falciparum malaria when uncomplicated. It is recommended to be given with artesunate to reduce the risk of resistance. Due to the risk of rare but serious side effects, it is not generally recommended to prevent malaria. Though, the World Health Organization (WHO) in 2013 recommended use for seasonal preventive in children at high risk in combination with sulfadoxine and pyrimethamine.

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without 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 a medical professional is recommended for those who intend to take antihistamines for longer-term use.

Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated Plasmodium falciparum malaria. It is taken by mouth.

<span class="mw-page-title-main">Arterolane</span> Chemical compound

Arterolane, also known as OZ277 or RBx 11160, is an antimalarial compound marketed by Ranbaxy Laboratories. It was discovered by US and European scientists coordinated by the Medicines for Malaria Venture (MMV). Its molecular structure is uncommon for pharmacological compounds in that it has both an ozonide (trioxolane) group and an adamantane substituent.

<span class="mw-page-title-main">10-Hydroxyketotifen</span> Chemical compound

10-Hydroxyketotifen (WR621365) is a biologically inactive metabolite of ketotifen. Despite the mainstream scientific consensus that 10-hydroxyketotifen is a biologically inactive compound, its pharmacological properties are not very well studied outside the context of ketotifen, therefore, 10-hydroxyketotifen may still possess biological activity similarly to norketotifen, another metabolite of ketotifen.

References

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  2. 1 2 3 4 5 6 7 8 Milner E, Sousa J, Pybus B, Auschwitz J, Caridha D, Gardner S, et al. (March 2012). "Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy". Eur J Drug Metab Pharmacokinet. 37 (1): 17–22. doi:10.1007/s13318-012-0080-2. PMID   22314893.
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  6. "A Phase 2b Double-blind, Randomized, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of Norketotifen (NKT) in the Treatment of Acute Uncomplicated Influenza-like Illness (ILI)". January 25, 2023. Archived from the original on April 13, 2024. Retrieved April 13, 2024.
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  8. "Efficacy and Safety of Norketotifen in Uncomplicated Influenza-like Illness". January 25, 2023. Archived from the original on April 20, 2024. Retrieved April 13, 2024.
  9. "Emergo finds midstage success in developing flu-fighter norketotifen + | Bioworld | BioWorld". Archived from the original on April 13, 2024. Retrieved April 13, 2024.
  10. "Norketotifen in Influenza -Like Illness - Clinical Trials Registry - ICH GCP". Archived from the original on April 13, 2024. Retrieved April 13, 2024.
  11. Feng F, Fawcett JP, Zhang H, Tucker IG (April 2020). "Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers". J Pharm Pharmacol. 72 (4): 507–518. doi:10.1111/jphp.13220. PMID   32030755.