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

Abstract

The distribution of three radioactively labelled salicylate derivatives with low ulcerogenic activity was compared with that of acetylsalicylic acid (ASA) and salicylic acid using whole body autoradiography and liquid scintillation counting techniques in rats. The methyl ester of ASA (AME) was distributed in vivo very similarly to that observed with ASA and salicylic acid. AME is rapidly demethylated following absorption from the stomach and is subsequently converted to ASA and salicylate. Salicylate is the main metabolite produced from both AME and ASA, which specifically accumulates in inflamed tissues. The 3-methyl- and 6-methyl-substituted salicylic acids are not as rapidly absorbed as either ASA or salicylic acid and do not pass readily into the brain or bone marrow. These results show that the methyl (ester) group of AME (which adequately protects the gastric mucosa from damage caused by ASA itself) does not impair the quantity of pharmacologically active form of drug (salicylate and ASA) generated in vivo. However, insertion of the methyl group at the 3- and 6-position of salicylic acid markedly affects both absorption, distribution and pharmaco-activity of these acids.

Dual effects of acetylsalicylic acid on mast cell degranulation, expression of cyclooxygenase-2 and release of pro-inflammatory cytokines

“…Serum concentrations have been reported to be as high as 2 mM in patients treated for chronic inflammatory diseases [34]. Moreover, the acidic nature of ASA results in accumulation in acidic body compartments, such as inflamed tissues, because of the increased lipophilicity of ASA under these conditions [35,36].…”

“…preceded by phosphorylation of two serine residues (Ser 32 and Ser 36 ) and subsequent ubiquitination [4,21]. To address the mechanism involved in the stabilization of IkB-a by ASA, we examined phosphorylation of IkB-a by Western blot analysis.…”

“…NF-kB is activated by a wide variety of agents, including phorbol esters, IL-1b, TNF-a, lipopolysaccharide (LPS), double-stranded RNA, cAMP, bacteria, and viral transactivators [4,5]. Upon cell stimulation, the signal-responsive kinases IKKa and b are activated which directly phosphorylate Ser 32 and Ser 36 in IkB-a, triggering ubiquitination at Lys 21 and Lys…”

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

“…in respect of anti-oedemic, anti-pyretic and anti-platelet aggregating activities [22] as well as being an inhibitor of prostaglandin synthesis comparable to that of the parent drug in vivo [22]; but clearly showing negligible gastric ulcerogenic activity. Furthermore, the ready liberation of salicylate in vivo following oral administration of aspirin methyl ester [23] indicates that the pharmacological effectiveness of this compound must be due to the generation of both aspirin and salicylate following passage through the gastric mucosa. The methyl esters of some halo-aspirin derivatives may also show similar advantages to those of aspirin methyl ester.…”

2H-[1]Benzopyrano[3,4-b]pyridines. Synthesis and activity at central monoamine receptors

“…First the required 3-chromanones are often difficult to prepare and relatively unstable, possessing a marked tendency to dimerize.12 Second the formation of the vinylogous amide 8 fails when X is methoxy, presumably because of steric compression in the transition state necessary for the cyclization of the enamine 7. (7) Boyar, W. C.; Wood, P. L.; Hutchison, A.; Altar, C. A. Soc.…”