Biomedical subjects
Publications and source records attributed to L F Sancilio.
A series of substituted derivatives of 2-amino-3-benzoylphenylacetic acid (amfenac) has been synthesized and evaluated for antiinflammatory, analgesic, and cyclooxygenase inhibiting activity. Several derivatives including 157 (4'-chloro), 158 (4'-bromo), and 182 (5-chloro, 4'-bromo) were more potent than indomethacin in these assays.
Several substituted 2-aminophenylacetic acid derivatives were prepared and tested for in vitro prostaglandin synthetase inhibition activity and for in vivo antiinflammatory activity. The 2-amino substituent is beneficial to potency in the inhibition of prostaglandin synthetase for the 3-phenoxy, 4-phenyl, and 3-benzoyl series, but only the 3-benzoyl series shows increased antiinflammatory potency in the in vivo assay.
The synthesis and antiinflammatory activity of 2-amino-3-benzoylphenylacetic acid are described. This compound was postulated to be an active metabolite of 7-benzoylindoline in order to explain the unexpected antiinflammatory activity of the latter compound. Metabolism studies on 14C-labeled 7-benzoylindoline did not confirm this hypothesis. Nevertheless, 2-amino-3-benzoylphenylacetic acid, its ethyl ester, and the sodium salt show potent antiinflammatory activity in pharmacological models.
A series of 1-benzoyl- and 1-phenylisoquinolineacetic acid derivatives was prepared and tested for antiinflammatory activity. The most potent compound synthesized, 1-(4-chlorophenyl)-3-isoquinolineacetamide, was as active as phenylbutazone in the Evans blue carrageenan-induced pleural effusion assay but inactive in the adjuvant-induced arthritis model of chronic inflammation.
Dogs respond to bradykinin (triacetate) by struggling, vocalizing, and/or biting. In 128 dogs used twice, the threshold dose of the peptide increased more than 2-fold, while its onset and duration of action were unchanged. In both trials, the frequency distribution of the threshold dose was not normal; struggling occurred alone or with vocalization and/or biting in 95% of the animals in the first trial and in 96% of the animals in the second trial. In assaying analgesic drugs for antibradykinin activity, multiples of the threshold dose of the peptide were given after oral administration to compensate for tachphylaxis. The oral ED50 values (95% confidence limits) were 0.80 (0.50--1.06) mg/kg for d-amphetamine, 1.20 (0.63--2.57) mg/kg for indomethacin, 1.90 (0.50--6.48) mg/kg for methadone, 15.0 (8.0--30.9) mg/kg for phenylbutazone and 50.0 (20.0--120.0) mg/kg for acetylsalicylic acid. ED50 values for d-proproxyphene, codeine, meperidine, pentazocine and ethoheptaxine by the oral route could not be determined. The intravenous ED50 (95% confidence limits) of meperidine was 0.80 (0.30--1.90 mg/kg. The antibradykinin model in dogs is sensitive to orally administered acetylsalicylic acid-type analgesic compounds which may be a reflection of their prostaglandinsynthetase inhibiting properties.
AHR-5850 is a non-steroidal anti-inflammatory compound possessing antipyretic and analgesic properties. AHR-5850 was 16.4 and 22.8 times more potent than phenylbutazone in suppressing acute (Evans blue-carrageenan pleural effusion) and chronic (adjuvant-induced arthritis) inflammation, respectively. The analgesic activity of AHR 5850 was 43 times that of acetylsalicylic acid in the Randall-Selitto assay, and 156 and 56.3 times more potent than phenylbutazone in the acetylcholine-induced abdominal constriction in mice and in the bradykinin-induced nociceptive response in dogs, respectively. Single-dose studies showed that AHR-5850 produced less gastric irritation than acetylsalicylic acid when applied topically to the exposed gastric mucosa of cats or when administered orally to rats and dogs. Upon subchronic oral administration to rats, the therapeutic ratio of AHR-5850 was twice that of phenylbutazone. This was based on the ratio of its potency relative to phenylbutazone in producing intestinal lesions to its anti-inflammatory potency relative to phenylbutazone in the adjuvant-induced arthritis.
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