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Pizotifen

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Pizotifen
Clinical data
Trade namesSandomigran, Mosegor, Litec, others
Other namesPizotyline; BC-105
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: B1
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability78%
Protein binding91%
MetabolismGlucuronidation (main route). N-glucuronide accounts for >50% of plasma and 60–70% of urinary excreted drug
Elimination half-life23 hours
Excretion18% feces, 55% urine (both as metabolites)
Identifiers
  • 4-(1-methyl-4-piperidylidine)-9,10-dihydro -4H-benzo-[4,5]cyclohepta[1,2]-thiophene
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.036.014 Edit this at Wikidata
Chemical and physical data
FormulaC19H21NS
Molar mass295.44 g·mol−1
3D model (JSmol)
  • s1c3c(cc1)C(\c2c(cccc2)CC3)=C4/CCN(C)CC4
  • InChI=1S/C19H21NS/c1-20-11-8-15(9-12-20)19-16-5-3-2-4-14(16)6-7-18-17(19)10-13-21-18/h2-5,10,13H,6-9,11-12H2,1H3 checkY
  • Key:FIADGNVRKBPQEU-UHFFFAOYSA-N checkY
  (verify)

Pizotifen, also known as pizotyline and sold under the brand names Sandomigran and Mosegor among others, is an antimigraine agent of the tricyclic group which is used primarily as a preventative to reduce the frequency of recurrent migraine headaches.[1]

Medical uses

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Migraine headaches

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The main medical use for pizotifen is for the prevention of migraine and cluster headache. Pizotifen is one of a range of medications used for this purpose, other options include propranolol, topiramate, valproic acid, cyproheptadine and amitriptyline. While pizotifen is effective in adults,[2] evidence of efficacy in children is limited,[3] and its use is limited by side effects, principally drowsiness and weight gain, and it is usually not the first choice medicine for preventing migraines, instead being used as an alternative when other drugs have failed to be effective.[4] It is not effective in relieving migraine attacks once in progress.

Other uses

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Pizotifen has also been reported as highly effective in a severe case of erythromelalgia, a rare neurovascular disease that is sometimes refractory to the other drugs named above.[5]

Other applications for which pizotifen may be used include as an antidepressant, or for the treatment of anxiety or social phobia.[6][7] Animal studies also suggest that pizotyline could be used in the treatment of serotonin syndrome or MDMA overdose[8] in a similar manner to the closely related antihistamine/antiserotonin medication cyproheptadine.

Pizotifen might be useful as a hallucinogen antidote or "trip killer" in blocking the effects of serotonergic psychedelics like psilocybin.[9] It might also be useful in the treatment of MDMA overdose.[10]

Contraindications

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Caution is required in patients having closed angle glaucoma and in patients with a predisposition to urinary retention as the medication exhibits a relatively small anticholinergic effect. Dose adjustment is required in people who have chronic kidney disease. Liver injury has also been reported. Pizotifen treatment should be discontinued if there is any clinical evidence of liver dysfunction during treatment. Caution is advised in patients having a history of epilepsy. Withdrawal symptoms like depression, tremor, nausea, anxiety, malaise, dizziness, sleep disorder and weight decrease have been reported following abrupt cessation of pizotifen.[11]

Pizotifen is contraindicated in patients who suffer from hypersensitivity to any of its components, also Pizotifen is contraindicated in gastric outlet obstruction, pregnancy, angle-closure glaucoma and difficulty urinating.[12]

Adverse effects

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Side effects include sedation, dry mouth, drowsiness, increased appetite and weight gain.[13] Occasionally it may cause nausea, headaches, or dizziness. In rare cases, anxiety, aggression and depression may also occur.

Pharmacology

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Pharmacodynamics

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Pizotifen activities
Target Affinity (Ki, nM) Species
5-HT1A 200–270 Human
5-HT1B 1415 Human
5-HT1D 770 Human
5-HT1E 820 Human
5-HT2A 2.0 Human
5-HT2B 2.0–2.3 Human
5-HT2C 8.4 Human
5-HT3 95 Human
5-HT4 ND Human
5-HT5A 110 Human
5-HT6 74 Human
5-HT7 17–25 Human
D1 3.5 Human
D2 2.4–87 Human
D3 ND ND
D4 64 Human
D5 50 Human
α1A 65 Human
α1B >10000 Human
α2A 660 Human
α2B 225 Human
α2C 390 Human
β1 >10000 Human
β2 >10000 Human
H1 1.9 Human
H2 1.4 Human
M1 67 Human
M2 34 Human
M3 29 Human
M4 130 Human
M5 6.8 Human
I1 receptor 121 Human
σ1 receptor >10000 Guinea pig
σ2 receptor 6450 Rat
SERTTooltip Serotonin transporter >10000 Human
NETTooltip Norepinephrine transporter 710 Human
DATTooltip Dopamine transporter >10000 Human
Note: The smaller the value, the more avidly the compound binds to or activates the site. Refs: [14][15][16][10][17]

Pizotifen is a serotonin antagonist acting mainly at the 5-HT2A and 5-HT2C receptors. It also has some activity as an antihistamine as well as some anticholinergic activity.[18] The drug binds non-selectivey to many targets, including serotonin, dopamine, adrenergic, histamine, and muscarinic acetylcholine receptors.[10]

Pizotifen is able to dose-dependently and fully antagonize the discriminative stimulus effects of the serotonin–norepinephrine–dopamine releasing agent and serotonin 5-HT2 receptor agonist MDMA in rodent drug discrimination tests.[10] Conversely, the related drug cyproheptadine was only partially effective and clozapine was ineffective.[10] All three of these agents, pizotifen, cyproheptadine, and clozapine act as non-selective monoamine receptor antagonists.[10] Pizotifen also fully blocks the effects of serotonergic psychedelics, including LSD, mescaline, 5-MeO-DMT, and DOM, in drug discrimination tests.[10]

Chemistry

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Pizotifen is a tricyclic compound and is specifically a benzocycloheptene.[19][20]

Close analogues of pizotifen include ketotifen and cyproheptadine, among others.

History

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Pizotifen was first described in the literature by 1964.[19]

Society and culture

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Names

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Pizotifen is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while pizotyline is its USANTooltip United States Adopted Name.[19][20][21] Brand names of pizotifen include Sandomigran, Mosegor, and Litec, among others.[19][20][21][22]

Availability

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Pizotifen is available widely throughout the world, including in Europe.[20][22]

References

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  1. ^ Stark RJ, Valenti L, Miller GC (August 2007). "Management of migraine in Australian general practice". The Medical Journal of Australia. 187 (3): 142–146. doi:10.5694/j.1326-5377.2007.tb01170.x. PMID 17680738. S2CID 10357983.
  2. ^ Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, et al. (2015-07-14). "A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache". PLOS ONE. 10 (7): e0130733. Bibcode:2015PLoSO..1030733J. doi:10.1371/journal.pone.0130733. PMC 4501738. PMID 26172390.
  3. ^ Barnes N, Millman G (July 2004). "Do pizotifen or propranolol reduce the frequency of migraine headache?". Archives of Disease in Childhood. 89 (7): 684–685. doi:10.1136/adc.2004.054668. PMC 1719986. PMID 15210509.
  4. ^ Pierangeli G, Cevoli S, Sancisi E, Grimaldi D, Zanigni S, Montagna P, Cortelli P (May 2006). "Which therapy for which patient?". Neurological Sciences. 27 (Suppl 2): S153–S158. doi:10.1007/s10072-006-0592-0. PMID 16688621. S2CID 24217802.
  5. ^ Cohen JS (November 2000). "Erythromelalgia: new theories and new therapies". Journal of the American Academy of Dermatology. 43 (5 Pt 1): 841–847. doi:10.1067/mjd.2000.109301. PMID 11050591. S2CID 40807034.
  6. ^ Standal JE (October 1977). "Pizotifen as an antidepressant". Acta Psychiatrica Scandinavica. 56 (4): 276–279. doi:10.1111/j.1600-0447.1977.tb00228.x. PMID 335788. S2CID 6445059.
  7. ^ Banki CM (March 1978). "Clinical observations with pizotifene (Sandomigran) in the treatment of nonmigrainous depressed women". Archiv für Psychiatrie und Nervenkrankheiten. 225 (1): 67–72. doi:10.1007/bf00367352. PMID 348154. S2CID 13510725.
  8. ^ Young R, Khorana N, Bondareva T, Glennon RA (October 2005). "Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA)". Pharmacology, Biochemistry, and Behavior. 82 (2): 404–410. doi:10.1016/j.pbb.2005.09.010. PMID 16253319. S2CID 20885754.
  9. ^ Halman A, Kong G, Sarris J, Perkins D (January 2024). "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol. 38 (1): 3–18. doi:10.1177/02698811231211219. PMC 10851641. PMID 37982394.
  10. ^ a b c d e f g Young R, Khorana N, Bondareva T, Glennon RA (October 2005). "Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA)". Pharmacol Biochem Behav. 82 (2): 404–410. doi:10.1016/j.pbb.2005.09.010. PMID 16253319.
  11. ^ "SANDOMIGRAN® pizotifen 500 micrograms coated tablets" (PDF). AFT Pharmaceuticals Ltd. Medsafe: New Zealand Medicines and Medical Devices Safety. 21 June 2019.
  12. ^ "Pizotifen". Universal reference book of medicines – via Likarstwo.ru.
  13. ^ Crowder D, Maclay WP. Pizotifen once daily in the prophylaxis of migraine: results of a multi-centre general practice study. Current Medical Research and Opinion. 1984;9(4):280-5.
  14. ^ "PDSP Database". UNC (in Zulu). Retrieved 24 November 2024.
  15. ^ "PDSP Database". UNC (in Zulu). Retrieved 24 November 2024.
  16. ^ Liu T. "BindingDB BDBM82088 CAS_15574-96-6::NSC_27400::PIZOTIFEN". BindingDB. Retrieved 24 November 2024.
  17. ^ Moritomo A, Yamada H, Watanabe T, Itahana H, Akuzawa S, Okada M, Ohta M (December 2013). "Synthesis and structure-activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists". Bioorg Med Chem. 21 (24): 7841–7852. doi:10.1016/j.bmc.2013.10.010. PMID 24189186.
  18. ^ Dixon AK, Hill RC, Roemer D, Scholtysik G (1977). "Pharmacological properties of 4(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene hydrogen maleate (pizotifen)". Arzneimittel-Forschung. 27 (10): 1968–1979. PMID 411500.
  19. ^ a b c d Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1002. ISBN 978-1-4757-2085-3. Retrieved 24 November 2024.
  20. ^ a b c d Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 992. ISBN 978-3-88763-101-7. Retrieved 24 November 2024.
  21. ^ a b Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 225. ISBN 978-94-011-4439-1. Retrieved 24 November 2024.
  22. ^ a b "Pizotifen (International database)". Drugs.com. 3 November 2024. Retrieved 24 November 2024.
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