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Benzydamine

January 01, 1970

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.

Benzydamine
Clinical data
Trade namesMaxtra Gargle, Difflam, Tantum
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: B2
Routes of
administration		Oral, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding<20%
Elimination half-life13 hours
ExcretionKidney
Identifiers
  • 3-(1-benzyl-1H-indazol-3-yloxy)-N,N-dimethylpropan-1-amine
CAS Number
  • 642-72-8 Y
PubChem CID
  • 12555
ChemSpider
  • 12036 Y
UNII
  • 4O21U048EF
KEGG
  • D07516 Y
ChEBI
  • CHEBI:94563 Y
ChEMBL
  • ChEMBL12610 Y
CompTox Dashboard (EPA)
  • DTXSID7047859
ECHA InfoCard100.010.354
Chemical and physical data
FormulaC19H23N3O
Molar mass309.413 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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 Y
  • Key:CNBGNNVCVSKAQZ-UHFFFAOYSA-N Y
  (verify)

History edit

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

Uses edit

Medical edit

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 edit

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 edit

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

Side effects edit

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 edit

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 has powerful reinforcing effect and has cross sensitization with drugs of abuse such as heroin and cocaine in animals. It is hypothesized that it has cannabinoid agonistic activity.[8]

Pharmacokinetic edit

Benzydamine is poorly absorbed through skin[9] and vagina.[10]

Synthesis edit

 
Benzydamine synthesis:[11][12]

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.

 
[11][13]

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 edit

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.[14][15]

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 edit

References edit

  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). 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. ^ a b "DEXTROMETHORPHAN AND BENZYDAMINE'S USE AND MISUSE". Flipper.diff.org. Retrieved 25 June 2022.
  4. ^ a b c 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. ^ a b 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. ^ 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.
  10. ^ 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.
  11. ^ a b 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.
  12. ^ FR 1382855 ; Palazzo, U.S. patent 3,318,905 (1964, 1967 both to Angelini Francesco).
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.

External links edit

  • "Benzydamine oral rinse". Medicinenet.
  • "Difflam spray (benzydamine)". Net Doctor, UK. 8 March 2020.
  • . Carysfort Healthcare Limited, Ireland. Archived from the original on 2015-11-25.

January 01, 1970
benzydamine, also, known, tantum, verde, branded, some, countries, maxtra, gargle, difflam, septabene, available, hydrochloride, salt, locally, acting, nonsteroidal, anti, inflammatory, drug, nsaid, with, local, anaesthetic, analgesic, properties, pain, relief. 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 BenzydamineClinical dataTrade namesMaxtra Gargle Difflam TantumAHFS Drugs comInternational Drug NamesPregnancycategoryAU B2Routes ofadministrationOral topicalATC codeA01AD02 WHO G02CC03 WHO M01AX07 WHO M02AA05 WHO R02AX03 WHO Legal statusLegal statusBR Class C1 Other controlled substances 1 UK General sales list GSL OTC EU OTCPharmacokinetic dataProtein binding lt 20 Elimination half life13 hoursExcretionKidneyIdentifiersIUPAC name 3 1 benzyl 1H indazol 3 yloxy N N dimethylpropan 1 amineCAS Number642 72 8 YPubChem CID12555ChemSpider12036 YUNII4O21U048EFKEGGD07516 YChEBICHEBI 94563 YChEMBLChEMBL12610 YCompTox Dashboard EPA DTXSID7047859ECHA InfoCard100 010 354Chemical and physical dataFormulaC 19H 23N 3OMolar mass309 413 g mol 13D model JSmol Interactive imageSMILES n2c OCCCN C C c1ccccc1n2Cc3ccccc3InChI 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 YKey CNBGNNVCVSKAQZ UHFFFAOYSA N Y verify Contents 1 History 2 Uses 2 1 Medical 2 2 Recreational 3 Contraindications 4 Side effects 5 Pharmacology 5 1 Pharmacokinetic 6 Synthesis 7 Research 8 See also 9 References 10 External linksHistory editIt was synthesized in Italy in 1964 and marketed in 1966 3 Uses editMedical edit 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 Recreational edit 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 editThere are no contraindications to the use of benzydamine except for known hypersensitivity Side effects editBenzydamine 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 editIt 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 has powerful reinforcing effect and has cross sensitization with drugs of abuse such as heroin and cocaine in animals It is hypothesized that it has cannabinoid agonistic activity 8 Pharmacokinetic edit Benzydamine is poorly absorbed through skin 9 and vagina 10 Synthesis edit nbsp Benzydamine synthesis 11 12 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 nbsp 11 13 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 editStudies 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 14 15 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 editAB FUBINACA Pravadoline GW 405 833 BendazacReferences edit Anvisa 2023 03 31 RDC Nº 784 Listas de Substancias Entorpecentes Psicotropicas 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 Diario Oficial da Uniao published 2023 04 04 Archived from the original on 2023 08 03 Retrieved 2023 08 16 Turnbull RS February 1995 Benzydamine Hydrochloride Tantum in the management of oral inflammatory conditions Journal 61 2 127 34 PMID 7600413 a b DEXTROMETHORPHAN AND BENZYDAMINE S USE AND MISUSE Flipper diff org Retrieved 25 June 2022 a b c 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 Opaleye ES Noto AR Sanchez Z Moura YG Galduroz 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 Mota DM Costa AA Teixeira C Bastos AA Dias MF May 2010 Use abusive of benzydamine in Brazil an overview in pharmacovigilance Ciencia amp Saude Coletiva in Portuguese 15 3 717 24 doi 10 1590 S1413 81232010000300014 PMID 20464184 Muller 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 a b 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 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 amp Drug Disposition 12 7 481 92 doi 10 1002 bdd 2510120702 PMID 1932611 S2CID 42167110 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 a b 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 FR 1382855 Palazzo U S patent 3 318 905 1964 1967 both to Angelini Francesco 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 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 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 External links edit Benzydamine oral rinse Medicinenet Difflam spray benzydamine Net Doctor UK 8 March 2020 Tantum Verde benzydamine Carysfort Healthcare Limited Ireland Archived from the original on 2015 11 25 Retrieved from https en wikipedia org w index php title Benzydamine amp oldid 1186635364, wikipedia, wiki, book, books, library,

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