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.
History
It was synthesized in Italy in 1964 and marketed in 1966.[3]
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 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
Benzydamine is poorly absorbed through skin[9] and vagina.[10]
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.
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.
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]
^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.
PMID3304305.
^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.
PMID3610512.
^
abPalazzo 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.
PMID5958958.
^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.
PMID1287137.
^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.
PMID8901158.