Pizotifen

Last updated

Pizotifen
Pizotifen structure.svg
Clinical data
Trade names Sandomigran, Mosegor, Litec, others
Other namesPizotyline; BC-105
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:B1
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 78%
Protein binding 91%
Metabolism Glucuronidation (main route). N-glucuronide accounts for >50% of plasma and 60–70% of urinary excreted drug
Elimination half-life 23 hours
Excretion 18% 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 InfoCard 100.036.014 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H21NS
Molar mass 295.44 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 Yes check.svgY
  • Key:FIADGNVRKBPQEU-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

Medical uses

Migraine headaches

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

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/anti-serotonin 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

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 or have gastric outlet obstruction, angle-closure glaucoma, and difficulty urinating. [12] In addition, women who are pregnant should not take pizotifen. [12]

Adverse effects

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

Pharmacodynamics

Pizotifen activities
Target Affinity (Ki, nM)Species
5-HT1A 39–270 (Ki)
535 (EC50 Tooltip half-maximal effective concentration)
60% (Emax Tooltip maximal efficacy)		Human
Human
Human
5-HT1B 1,415Human
5-HT1D 770Human
5-HT1E 820Human
5-HT2A 2.0Human
5-HT2B 2.0–2.3Human
5-HT2C 8.4Human
5-HT3 95Human
5-HT4 NDHuman
5-HT5A 110Human
5-HT6 74Human
5-HT7 17–25Human
D1 3.5Human
D2 2.4–87Human
D3 NDND
D4 64Human
D5 50Human
α1A 65Human
α1B >10,000Human
α2A 660Human
α2B 225Human
α2C 390Human
β1 >10,000Human
β2 >10,000Human
H1 1.9Human
H2 1.4Human
M1 67Human
M2 34Human
M3 29Human
M4 130Human
M5 6.8Human
I1 receptor 121Human
σ1 receptor >10,000Guinea pig
σ2 receptor 6,450Rat
SERT Tooltip Serotonin transporter>10,000Human
NET Tooltip Norepinephrine transporter710Human
DAT Tooltip Dopamine transporter>10,000Human
Note: The smaller the value, the more avidly the compound binds to or activates the site. Refs: [14] [15] [16] [10] [17] [18]

Pizotifen is a serotonin antagonist acting mainly at the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It also has some activity as an antihistamine as well as some anticholinergic activity. [19] The drug binds non-selectively to many targets, including serotonin, dopamine, adrenergic, histamine, and muscarinic acetylcholine receptors. [10] Besides its serotonin 5-HT2 receptor antagonism, pizotifen is a low-potency moderate-efficacy partial agonist of the serotonin 5-HT1A receptor. [18]

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]

The antimigraine activity of pizotifen might be specifically due to serotonin 5-HT2B receptor blockade. [20]

Chemistry

Pizotifen is a tricyclic compound and is specifically a benzocycloheptene. [21] [22]

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

History

Pizotifen was first described in the literature by 1964. [21]

Society and culture

Names

Pizotifen is the generic name of the drug and its INN Tooltip International Nonproprietary Name and BAN Tooltip British Approved Name, while pizotyline is its USAN Tooltip United States Adopted Name. [21] [22] [23] Brand names of pizotifen include Sandomigran, Mosegor, and Litec, among others. [21] [22] [23] [24]

Availability

Pizotifen is available widely throughout the world, including in Europe. [22] [24]

References

  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.{{cite journal}}: CS1 maint: article number as page number (link)
  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. 1 2 3 4 5 6 7 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. 1 2 "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. 1 2 Newman-Tancredi A, Conte C, Chaput C, Verrièle L, Audinot-Bouchez V, Lochon S, Lavielle G, Millan MJ (June 1997). "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn Schmiedebergs Arch Pharmacol. 355 (6): 682–688. doi:10.1007/pl00005000. PMID   9205951.
  19. ↑ 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.
  20. ↑ Segelcke D, Messlinger K (April 2017). "Putative role of 5-HT2B receptors in migraine pathophysiology". Cephalalgia. 37 (4): 365–371. doi:10.1177/0333102416646760. PMID   27127104.
  21. 1 2 3 4 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.
  22. 1 2 3 4 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 992. ISBN   978-3-88763-101-7 . Retrieved 24 November 2024.
  23. 1 2 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.
  24. 1 2 "Pizotifen (International database)". Drugs.com. 3 November 2024. Retrieved 24 November 2024.
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