Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity

Abstract

The methyl and some other esters of acetylsalicylic and salicylic acids and their derivatives were found to have much lower gastric ulcerogenic activity (when assayed in the stress-sensitized rat) compared with their corresponding acids. There was little or no loss in therapeutic potencies of these salicylate esters as determined by assessment of anti-inflammatory activity (against the carrageenan-induced oedema) and antipyretic activity (against yeast-induced fever in rats. The methyl ester of acetylsalicylic acid (=AME) was almost devoid of gastric irritancy/ulcerogenicity (as observed with acetylsalicylic acid) when given orally to pigs for 10 days. AME had appreciable anti-inflammatory activity in the adjuvant-arthritis model and at high doses (200 mg/kg t.i.d.) was without the lethal effects seen with acetylsalicylic acid. Moreover, no toxic effects were seen after long-term administration of 100-1000 mg/kg/day AME for 3-4 months. The results provide further evidence for the hypothesis that the carboxylic acid moiety of salicylates is a major factor in the gastric ulcerogenic activity of these drugs. The methyl esters of these salicylates may be considered as models for the development of pro-drugs and in some cases may be therapeutic alternatives to acetylsalicylic acid or salicylate.

Bio-distribution in rats of some salicylates with low gastric ulcerogenicity

“…through formaldehyde production, see Ref. [31]), actually decreases the toxic effects of ASA seen at high doses of the latter [32]. Also, the effects of AME on renal clearance and on excretion appear to be the same as ASA [33].…”

Development of Candidate Chemical Simulant List: The Evaluation of Candidate Chemical Simulants Which May Be Used in Chemically Hazardous Operations

“…In the same study, oral administration of methyl salicylate was also notably more effective than salicylic acid in significantly reducing fever induced in rats by subcutaneous injection of 2 g/kg dried Brewer's yeast in saline (Rainsford and Whitehouse, 1980;Whitehouse and Rainsford, 1980). Administration of 0.6-4.7 g/kg methyl salicylate by intubation into the stomach and duodenum of 4 dogs caused nausea, vomiting, diarrhea, intense hyperpnea, excitation of the central nervous system and death in two animals at 8 and 18 hours, respectively.…”

Gastrointestinal Adaptation, Regulation of Eicosanoids, and Mucosal Protection from NSAIDs

“…However, there is another subtlety concerning the gastric mucosal effects of these NO-NSAIDs that has escaped the proponents developing these drugs and which is as yet unresolved. This relates to the fact that it is well known that alkyl and other esters of NSAIDs have lower ulcerogenicity than the parent acid carboxyl acids, by virtue of the protection of the carboxyl group from its interactions with the gastric mucosa [33][34][35]. Thus, it is not possible to tell whether the purported low ulcerogenicity of the nitroxybutyl and other so-called nitric oxide donor esters of the NSAIDs is due to the release of nitrate or to the protective nature of the nitroxybutyl group in reducing the carboxyl interactions with the gastric mucosa.…”