Pyrithyldione is a central nervous system (CNS) depressant drug developed in 1949 as a nonbarbiturate sedative-hypnotic. It was marketed under various trade names, including Presidon, Persedon, Benedorm, Didropyridine, Dihydroprylone, Tetridin, and Tetridine. An improved method of manufacture was patented by Hoffmann-La Roche in 1959.[1]

Pharmacology

Chemical class and analogues

Chemically classified among lactams and ketones, specifically a 2,4-dioxotetrahydropyridine derivative, pyrithyldione shares structural and pharmacological similarities with glutethimide (another CYP2D6 inducer, albeit more potent)[2] and methyprylon, both indicated as sedative-hypnotics. All of these compounds, including pyrithyldione, were developed as alternatives to barbiturates, aiming for reduced toxicity and dependence liability.[3]

Mechanism of action and metabolism

Acting as a GABAA receptor positive allosteric modulator, pyrithyldione was indicated as a hypnotic and sedative in the 1950s.[4] A CYP2D6 inducer, albeit weaker than its analogue glutethimide, in studies it increased the O-demethylation of codeine by ~20%.[5]

Adverse effects and toxicity

Agranulocytosis was reported in some patients.[6][7]

Early reports[clarification needed] suggested it was less toxic than barbiturates.[8]

History

Pyrithyldione was first described in medical literature in April 1949.[9] Roche patented an improved synthesis method in 1959.[10]

Martindale: The Complete Drug Reference and USP drug directories list it as marketed under several trade names, including Presidon, Persedon, Benedorm, Didropyridine, Dihydroprylone, Tetridin, and Tetridine.[11][12] Spelling variants result from INN and USAN, thus resulting in the same molecule being spelt Pyridion, Pyridione, and Pyrithyldion depnending upon the source. These are transliterations, but not distinct brand names.[12]

The drug was voluntarily discontinued by its manufacturers and subsequently recognized as a withdrawn drug in compendia.[11] Similar to other nonbarbiturate CNS depressants such as ethinamate, chlorphenesin carbamate, and ethchlorvynol, it is not a controlled substance and does not appear on lists of legally banned medications. Its withdrawal was attributed to safety concerns, particularly reports of agranulocytosis.[13][14]

References

  1. ↑ US patent 3019230, Hinderling R, Lutz AH, Schnider O, "Method for the preparation of 2,4-dioxo-tetrahydropyridines", issued 1962-01-30, assigned to Hoffmann-La Roche
  2. ↑ [Is pyrithyldione (Benedorm) an enzyme inducer (author's transl)] Pharmazie. 1982 Jan;37(1):69.
  3. ↑ Pribilla, O. (1956). "Zur Toxikologie des Persedons". Archiv für Toxikologie. 16 (1): 34–49. doi:10.1007/BF00577351. S2CID 38210598.
  4. ↑ Becker EL, Fabing HD, Hawkins JR (April 1949). "Presidon; a new sedative-hypnotic". Christ Hospital Medical Bulletin. 2 (4): 80–4. PMID 18144514.
  5. ↑ [Is pyrithyldione (Benedorm) an enzyme inducer (author's transl)] Pharmazie. 1982 Jan;37(1):69.
  6. ↑ Ibáñez L, Ballarín E, Pérez E, Vidal X, Capellà D, Laporte JR (January 2000). "Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug". European Journal of Clinical Pharmacology. 55 (10): 761–4. doi:10.1007/s002280050011. PMID 10663456. S2CID 25595314.
  7. ↑ Covner AH, Halpern SL (January 1950). "Fatal agranulocytosis following therapy with presidon (3,3-diethyl-2,4-dioxotetrahydropyrididine) a new sedative hypnotic agent". The New England Journal of Medicine. 242 (2): 49–52. doi:10.1056/NEJM195001122420203. PMID 15399031.
  8. ↑ Pribilla, O. (1956). "Zur Toxikologie des Persedons". Archiv für Toxikologie. 16 (1): 34–49. doi:10.1007/BF00577351. S2CID 38210598.
  9. ↑ Becker EL, Fabing HD, Hawkins JR (April 1949). "Presidon; a new sedative-hypnotic". Christ Hospital Medical Bulletin. 2 (4): 80–4. PMID 18144514.
  10. ↑ US patent 3019230, Hinderling R, Lutz AH, Schnider O, "Method for the preparation of 2,4-dioxo-tetrahydropyridines", issued 1962-01-30, assigned to Hoffmann-La Roche
  11. 1 2 Martindale: The Complete Drug Reference (36th ed.). Pharmaceutical Press. 2009. ISBN 9780853698401.
  12. 1 2 USP Dictionary of USAN and International Drug Names. United States Pharmacopeia. 2006. ISBN 9781889788382. {{cite book}}: Check |isbn= value: checksum (help)
  13. ↑ Ibáñez L, Ballarín E, Pérez E, Vidal X, Capellà D, Laporte JR (January 2000). "Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug". European Journal of Clinical Pharmacology. 55 (10): 761–4. doi:10.1007/s002280050011. PMID 10663456. S2CID 25595314.
  14. ↑ Covner AH, Halpern SL (January 1950). "Fatal agranulocytosis following therapy with presidon (3,3-diethyl-2,4-dioxotetrahydropyridine) a new sedative hypnotic agent". The New England Journal of Medicine. 242 (2): 49–52. doi:10.1056/NEJM195001122420203. PMID 15399031.

See also

source: https://en.wikipedia.org/wiki/Pyrithyldione