Benzydamine

It was synthesized in Italy in 1964 and marketed in 1966.{{cite web|url=https://flipper.diff.org/app/items/info/6989|title=DEXTROMETHORPHAN AND BENZYDAMINE'S USE AND MISUSE|website=Flipper.diff.org|access-date=25 June 2022}}

• Odontostomatology: gingivitis, stomatitis, glossitis, aphthous ulcers, dental surgery and oral ulceration due to radiation therapy.
• Otorhinolaryngology: glandular fever, pharyngitis, tonsillitis, post-tonsillectomy, radiation or intubation mucositis.

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.

Benzydamine has been used recreationally. If taken in excess amounts, it acts as a deliriant and CNS stimulant. Such use, particularly among teenagers, has been reported in Brazil,{{cite journal | vauthors = Opaleye ES, Noto AR, Sanchez Z, Moura YG, Galduróz JC, Carlini EA | title = Recreational use of benzydamine as a hallucinogen among street youth in Brazil | journal = Revista Brasileira de Psiquiatria | volume = 31 | issue = 3 | pages = 208–13 | date = September 2009 | pmid = 19784487 | doi = 10.1590/S1516-44462009000300005 | doi-access = free}}{{cite journal | vauthors = Mota DM, Costa AA, Teixeira C, Bastos AA, Dias MF | title =Use abusive of benzydamine in Brazil: an overview in pharmacovigilance | language = pt | journal = Ciencia & Saude Coletiva | volume = 15 | issue = 3 | pages = 717–24 | date = May 2010 | pmid = 20464184 | doi = 10.1590/S1413-81232010000300014 | doi-access = free}} Poland, Romania, and Turkey.{{citation needed|date=February 2023}}

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

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.

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.{{cite journal |vauthors=Anand JS, Glebocka ML, Korolkiewicz RP |title=Recreational abuse with benzydamine hydrochloride (tantum rosa) |journal=Clinical Toxicology |volume=45 |issue=2 |pages=198–9 |year=2007 |pmid=17364645 |doi=10.1080/15563650600981210 |doi-access=free}}{{cite journal |vauthors=Müller-Peddinghaus R |title=New pharmacologic and biochemical findings on the mechanism of action of the non-steroidal antiphlogistic, benzydamine. A synopsis |language=German |journal=Arzneimittel-Forschung |volume=37 |issue=5A |pages=635–45 |date=May 1987 |pmid=3304305}}

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. 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-HT_2A receptor agonist and hence as a serotonergic psychedelic.{{cite journal | vauthors = Ősz BE, Jîtcă G, Sălcudean A, Rusz CM, Vari CE | title = Benzydamine-An Affordable Over-the-Counter Drug with Psychoactive Properties-From Chemical Structure to Possible Pharmacological Properties | journal = Pharmaceuticals (Basel) | volume = 16 | issue = 4 | date = April 2023 | page = 566 | pmid = 37111323 | pmc = 10144213 | doi = 10.3390/ph16040566 | doi-access = free | url = }}{{cite journal | vauthors = Chiappini S, Miuli A, Mosca A, Pettorruso M, Guirguis A, John MC, Martinotti G, Di Giannantonio M, Schifano F | title = The Benzydamine Experience: A Systematic Review of Benzydamine Abuse | journal = Curr Neuropharmacol | volume = 19 | issue = 10 | pages = 1728–1737 | date = October 2021 | pmid = 33441070 | pmc = 8977632 | doi = 10.2174/1570159X19666210113151136 | url = }} More research is needed to determine the mechanism of action of the effects of benzydamine as a drug of misuse.

Benzydamine is poorly absorbed through skin{{cite journal |vauthors=Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B |title=Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects |journal=Biopharmaceutics & Drug Disposition |volume=12 |issue=7 |pages=481–92 |date=October 1991 |pmid=1932611 |doi=10.1002/bdd.2510120702|s2cid=42167110 }} and vagina.{{cite journal |vauthors=Maamer M, Aurousseau M, Colau JC |title=Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study |journal=International Journal of Tissue Reactions |volume=9 |issue=2 |pages=135–45 |date=1987 |pmid=3610512}}

File:Benzydamine synthesis.svg

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.

File: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.

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.{{cite journal | vauthors = Fanaki NH, el-Nakeeb MA | title = Antimicrobial activity of benzydamine, a non-steroid anti-inflammatory agent | journal = Journal of Chemotherapy | volume = 4 | issue = 6 | pages = 347–52 | date = December 1992 | pmid = 1287137 | doi = 10.1080/1120009X.1992.11739190 }}{{cite journal | vauthors = Fanaki NH, El-Nakeeb MA | title = Antibacterial activity of benzydamine and antibiotic-benzydamine combinations against multifold resistant clinical isolates | journal = Arzneimittel-Forschung | volume = 46 | issue = 3 | pages = 320–3 | date = March 1996 | pmid = 8901158 }}

It also has some cannabinoid activity in rats but has not been tested in humans.{{cite journal |vauthors=Avvisati R, Meringolo M, Stendardo E, Malavasi E, Marinelli S, Badiani A |title=Intravenous self-administration of benzydamine, a non-steroidal anti-inflammatory drug with a central cannabinoidergic mechanism of action |journal=Addiction Biology |volume=23 |issue=2 |pages=610–619 |date=March 2018 |pmid=28429885 |doi=10.1111/adb.12516 |s2cid=206970991 |url=http://sro.sussex.ac.uk/id/eprint/67500/1/__smbhome.uscs.susx.ac.uk_ellenaj_Desktop_SRO_Avvisati_BZY_R2.pdf}} It is also hypothesized to act on 5-HT2A receptors due to its structural similarity with serotonin.

• AB-FUBINACA
• Pravadoline
• GW-405,833
• Bendazac

{{Reflist}}

• {{ cite web

| url = http://www.medicinenet.com/benzydamine-oral_rinse/article.htm

| title = Benzydamine oral rinse

| publisher = Medicinenet

}}

• {{ cite web

| url = http://www.netdoctor.co.uk/medicines/100003456.html

| title = Difflam spray (benzydamine)

| date = 8 March 2020

| publisher = Net Doctor, UK

}}

• {{cite web

|url=http://tantumverde.ie/

|title=Tantum Verde (benzydamine)

|publisher=Carysfort Healthcare Limited, Ireland

|url-status=dead

|archive-url=https://web.archive.org/web/20151125211741/http://tantumverde.ie/

|archive-date=2015-11-25

}}

{{Stomatological preparations}}

{{Anti-inflammatory and antirheumatic products}}

{{Topical products for joint and muscular pain}}

{{Stimulants}}

{{Prolactin inhibitors and anti-inflammatory products for vaginal administration}}

{{Hallucinogens}}

{{Muscarinic acetylcholine receptor modulators}}

{{Authority control}}

Category:Nonsteroidal anti-inflammatory drugs

Category:Indazoles

Category:Dimethylamino compounds

Category:Dental drugs

Category:Benzyl compounds

Category:Muscarinic antagonists

Category:Aromatic ethers