Benzydamine

Last updated
Benzydamine
Benzydamine-2D-skeletal.png
Clinical data
Trade names Maxtra Gargle, Difflam, Tantum verde
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:B2
Routes of
administration 		Oral, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding <20%
Elimination half-life 13 hours
Excretion Kidney
Identifiers
  • 3-(1-benzyl-1H-indazol-3-yloxy)-N,N-dimethylpropan-1-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.010.354 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H23N3O
Molar mass 309.413 g·mol−1
3D model (JSmol)
  • n2c(OCCCN(C)C)c1ccccc1n2Cc3ccccc3
  • InChI=1S/C19H23N3O/c1-21(2)13-8-14-23-19-17-11-6-7-12-18(17)22(20-19)15-16-9-4-3-5-10-16/h3-7,9-12H,8,13-15H2,1-2H3 Yes check.svgY
  • Key:CNBGNNVCVSKAQZ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Benzydamine (also known as Tantum Verde and branded in some countries as Maxtra Gargle, Difflam and Septabene), available as the hydrochloride salt, is a locally acting nonsteroidal anti-inflammatory drug (NSAID) with local anaesthetic and analgesic properties for pain relief and anti-inflammatory treatment of inflammatory conditions of the mouth and throat. [2] It falls under class of chemicals known as indazole.

Contents

History

It was synthesized in Italy in 1964 and marketed in 1966. [3]

Uses

Medical

It may be used alone or as an adjunct to other therapy giving the possibility of increased therapeutic effect with little risk of interaction.

In some markets, the drug is supplied as an over-the-counter cream (Lonol in Mexico from Boehringer Ingelheim) used for topical treatment of musculoskeletal system disorders: sprains, strains, bursitis, tendinitis, synovitis, myalgia, periarthritis.

Recreational

Benzydamine has been used recreationally. In overdosages it acts as a deliriant and CNS stimulant. [4] Such use, particularly among teenagers, has been reported in Brazil, [5] [6] Poland, [4] Romania, and Turkey.[ citation needed ]

Contraindications

There are no contraindications to the use of benzydamine except for known hypersensitivity.

Side effects

Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur, as well as itching, a skin rash, skin swelling or redness, difficulty breathing and wheezing.

Pharmacology

It selectively binds to inflamed tissues (Prostaglandin synthetase inhibitor) and is normally free of adverse systemic effects. Unlike other NSAIDs, it does not inhibit cyclooxygenase or lipooxygenase, and is not ulcerogenic. [4] [7]

It is described as having powerful reinforcing effects in animals and showing cross-sensitization with drugs of misuse such as heroin and cocaine. It is hypothesized that it has cannabinoid agonistic activity and this may account for its recreational and hallucinogenic effects. [8] However, it has also been theorized that, based on structural similarity to lysergic acid diethylamide (LSD) and descriptions of its visual hallucinatory effects, benzydamine might be acting as a serotonin 5-HT2A receptor agonist and hence as a serotonergic psychedelic. [9] [10] More research is needed to determine the mechanism of action of the effects of benzydamine as a drug of misuse. [9] [10]

Pharmacokinetic

Benzydamine is poorly absorbed through skin [11] and vagina. [12]

Synthesis

Benzydamine synthesis: Benzydamine synthesis.svg
Benzydamine synthesis:

Synthesis starts with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give the N-nitroso derivative. Reduction by means of sodium thiosulfate leads to the transient hydrazine (3), which undergoes spontaneous internal hydrazide formation. Treatment of the enolate of this amide with 3-chloro-1-dimethylamino propane gives benzydamine (5). Please note there is an error in this section: US3318905 states that the nitroso derivative is reduced with sodium hydrosulfite (sodium dithionite) and not with sodium hyposulfite (sodium thiosulfate), as shown in the above scheme and stated in text.

Benzydamine synthesis 2.svg

An interesting alternative synthesis of this substance starts by sequential reaction of N-benzylaniline with phosgene, and then with sodium azide to product the corresponding carbonyl azide. On heating, nitrogen is evolved and a separatable mixture of nitrene insertion product and the desired ketoindazole # results. The latter reaction appears to be a Curtius rearrangement type product to produce an N-isocyanate #, which then cyclizes. Alkylation of the enol with sodium methoxide and 3-dimethylaminopropyl chloride gives benzydamine.

Alternatively, use of chloroacetamide in the alkylation step followed by acid hydrolysis produces bendazac instead.

Research

Studies indicate that benzydamine has notable in vitro antibacterial activity and also shows synergism in combination with other antibiotics, especially tetracyclines, against antibiotic-resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa. [16] [17]

It also has some cannabinoid activity in rats but has not been tested in humans. [8] It is also hypothesized to act on 5-HT2A receptors due to its structural similarity with serotonin. [3]

See also

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ Turnbull RS (February 1995). "Benzydamine Hydrochloride (Tantum) in the management of oral inflammatory conditions". Journal. 61 (2): 127–34. PMID   7600413.
  3. 1 2 "DEXTROMETHORPHAN AND BENZYDAMINE'S USE AND MISUSE". Flipper.diff.org. Retrieved 25 June 2022.
  4. 1 2 3 Anand JS, Glebocka ML, Korolkiewicz RP (2007). "Recreational abuse with benzydamine hydrochloride (tantum rosa)". Clinical Toxicology. 45 (2): 198–9. doi: 10.1080/15563650600981210 . PMID   17364645.
  5. ↑ Opaleye ES, Noto AR, Sanchez Z, Moura YG, Galduróz JC, Carlini EA (September 2009). "Recreational use of benzydamine as a hallucinogen among street youth in Brazil". Revista Brasileira de Psiquiatria. 31 (3): 208–13. doi: 10.1590/S1516-44462009000300005 . PMID   19784487.
  6. ↑ Mota DM, Costa AA, Teixeira C, Bastos AA, Dias MF (May 2010). "Use abusive of benzydamine in Brazil: an overview in pharmacovigilance". Ciencia & Saude Coletiva (in Portuguese). 15 (3): 717–24. doi: 10.1590/S1413-81232010000300014 . PMID   20464184.
  7. ↑ Müller-Peddinghaus R (May 1987). "New pharmacologic and biochemical findings on the mechanism of action of the non-steroidal antiphlogistic, benzydamine. A synopsis". Arzneimittel-Forschung (in German). 37 (5A): 635–45. PMID   3304305.
  8. 1 2 Avvisati R, Meringolo M, Stendardo E, Malavasi E, Marinelli S, Badiani A (March 2018). "Intravenous self-administration of benzydamine, a non-steroidal anti-inflammatory drug with a central cannabinoidergic mechanism of action" (PDF). Addiction Biology . 23 (2): 610–619. doi:10.1111/adb.12516. PMID   28429885. S2CID   206970991.
  9. 1 2 Ősz BE, Jîtcă G, Sălcudean A, Rusz CM, Vari CE (April 2023). "Benzydamine-An Affordable Over-the-Counter Drug with Psychoactive Properties-From Chemical Structure to Possible Pharmacological Properties". Pharmaceuticals (Basel). 16 (4): 566. doi: 10.3390/ph16040566 . PMC   10144213 . PMID   37111323.
  10. 1 2 Chiappini S, Miuli A, Mosca A, Pettorruso M, Guirguis A, John MC, Martinotti G, Di Giannantonio M, Schifano F (October 2021). "The Benzydamine Experience: A Systematic Review of Benzydamine Abuse". Curr Neuropharmacol. 19 (10): 1728–1737. doi:10.2174/1570159X19666210113151136. PMC   8977632 . PMID   33441070.
  11. ↑ Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B (October 1991). "Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects". Biopharmaceutics & Drug Disposition . 12 (7): 481–92. doi:10.1002/bdd.2510120702. PMID   1932611. S2CID   42167110.
  12. ↑ Maamer M, Aurousseau M, Colau JC (1987). "Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study". International Journal of Tissue Reactions . 9 (2): 135–45. PMID   3610512.
  13. 1 2 Palazzo G, Corsi G, Baiocchi L, Silvestrini B (January 1966). "Synthesis and pharmacological properties of 1-substituted 3-dimethylaminoalkoxy-1H-indazoles". Journal of Medicinal Chemistry. 9 (1): 38–41. doi:10.1021/jm00319a009. PMID   5958958.
  14. ↑ FR 1382855 ; Palazzo, U.S. patent 3,318,905 (1964, 1967 both to Angelini Francesco).
  15. ↑ Baiocchi L, Corsi G, Palazzo G (1965). "Ricerche nel campo degli indazoli.—Nota 1. Sulla ciclizzazione termica di azidi di acidi N-aril-N-benzil-carbamici". Annali di Chimica. 55: 116–25.
  16. ↑ Fanaki NH, el-Nakeeb MA (December 1992). "Antimicrobial activity of benzydamine, a non-steroid anti-inflammatory agent". Journal of Chemotherapy. 4 (6): 347–52. doi:10.1080/1120009X.1992.11739190. PMID   1287137.
  17. ↑ Fanaki NH, El-Nakeeb MA (March 1996). "Antibacterial activity of benzydamine and antibiotic-benzydamine combinations against multifold resistant clinical isolates". Arzneimittel-Forschung. 46 (3): 320–3. PMID   8901158.
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