Safety profile of over-the-counter naproxen sodium.

The safety of naproxen sodium for over-the-counter use was evaluated based on 48 randomized, double-blind, placebo-controlled clinical trials that evaluated naproxen/naproxen sodium (NAP) for indications appropriate to, and under, conditions common to, nonprescription analgesics. Of the 48 studies, 27 were single-dose studies and 21 were multiple-dose studies of 1 to 10 days' duration; 19 studies included ibuprofen and 9 included acetaminophen. A total of 4138 patients received naproxen or naproxen sodium (3589 patients received naproxen 187.5 to 400 mg and 549 received naproxen sodium 220 to 440 mg), 2423 received placebo, 1574 received ibuprofen (200 or 400 mg), and 671 received acetaminophen (500 to 1000 mg). Adverse-event rates were examined in three sets of comparisons: NAP versus placebo (48 studies); NAP versus ibuprofen and placebo (19 studies); and NAP versus acetaminophen and placebo (9 studies). Across all 48 studies, 83% of both the NAP- and placebo-treated patients reported no adverse events. The incidence rates were similar between NAP and placebo, with headache (4.8% NAP, 6.4% placebo), nausea (3.4% NAP, 3.1% placebo), and somnolence (2.7% NAP, 1.9% placebo) the most commonly reported events. Rates of adverse events with NAP, ibuprofen, and acetaminophen were similar.

Anti-inflammatory pharmacology and mechanism of the orally active capsaicin analogs, NE-19550 and NE-28345.

We have evaluated the properties of a new class of anti-inflammatory agents derived from capsaicin, using the analogs NE-19550 (N-vanillyloleamide) and NE-28345 (N-oleyl-homovanillamide) as examples. This class displayed an atypical profile in the assays utilized, including 1) anti-edema and antileukocyte migration activity in the rat carrageenan pleurisy assay without suppression of pleural prostanoid synthesis, 2) blockade of human platelet aggregation induced by arachidonate or PAF but not that induced by the PGH2 analog U-46619, without equivalent inhibition in vitro of mammalian cyclooxygenase or thromboxane synthetase preparations, 3) greater potency and efficacy in the rat implanted sponge assay than in the adjuvant arthritis assay, without inhibition of LTB4 or 15-HETE synthesis in vitro, 4) stronger topical activity in the mouse croton oil inflamed ear assay than the guinea pig UV erythema assay, and 5) oral activity in the rat carrageenan paw edema assay and mouse phenylquinone abdominal constriction rest combined with failure to induce gastric erosion in rats at therapeutic doses. We conclude that NE-19550 and NE-28345 do not act like conventional NSAIDs via suppression of arachidonic acid metabolism.

Evaluation of olestra in short-term genotoxicity assays.

Olestra, a mixture of hexa-, hepta- and octa-esters formed from the reaction of sucrose with long-chain fatty acids, was evaluated for its genotoxic potential in the Salmonella/mammalian microsome test, the L5178Y thymidine kinase (TK+/-) mouse lymphoma assay, an unscheduled DNA synthesis assay in primary rat hepatocytes, and an in vitro cytogenetic assay in Chinese hamster ovary cells. The results indicated that olestra was non-genotoxic in these assays.

Biliary metabolites of all-trans-retinoic acid in the rat.

Biliary metabolites from physiological doses of all-trans-[10-3H]retinoic acid were examined in normal and vitamin A-deficient rats. The bile from normal and vitamin A-deficient rats contained approximately 60% of the administered dose following a 24-h collection period. However, vitamin A-deficient rats show a 6-h delay in the excretion of radioactivity compared to normal rats. Retinoyl-beta-glucuronide excretion was particularly sensitive to the vitamin A status of the rats. In normal rats, retinoyl-beta-glucuronide reached a maximum concentration of 235 pmol/ml of bile 2 h following the dose and then rapidly declined. Vitamin A-deficient rats show a relatively constant concentration of this metabolite (100-150 pmol/ml of bile) over a 10-h collection period. Retinoic acid excretion was low in both normal and deficient rats. The concentration of retinotaurine, a recently identified biliary metabolite, was approximately equal to retinoyl-beta-glucuronide in normal rats and appeared in the bile 2 h later than the glucuronide.

The biological activity of retinotaurine.

The ability of the biliary metabolite retinotaurine to reverse the cornification of vaginal epithelial cells induced by vitamin A deficiency was assessed using a vaginal smear assay. Retinotaurine activity was examined following the intravaginal administration of 10(-12) mol to 10(-8) mol of this compound per vagina. This metabolite exhibited no detectable activity at any dose tested. These results show that retinotaurine cannot be more than 1% as active as all-trans-retinoic acid since retinoic acid shows a response at concentrations of 10(-10) mol per vagina. The low biological activity of this recently identified biliary metabolite suggests that it represents an excretory form of retinoic acid.

Biliary metabolites of all-trans-retinoic acid in the rat: isolation and identification of a novel polar metabolite.

The biliary metabolites from normal rats dosed with either pharmacological or physiological doses of all-trans-[11,12-3H2]retinoic acid were investigated. Biliary metabolites excreted during the first 24 h account for approximately 60-65% of the radiolabeled dose. A major polar metabolite was purified to homogeneity by using Sephadex LH-20 chromatography and several high-performance liquid chromatographic procedures. This metabolite was negatively charged as revealed by high-performance liquid chromatography on ion-exchange columns and accounts for 10% of the total biliary radioactivity (6% of the dose). The polar compound was positively identified by using Fourier transform proton nuclear magnetic resonance spectroscopy, high- and low-resolution mass spectrometry, fast atom bombardment mass spectrometry, ultraviolet absorption spectrophotometry, Fourier transform infrared spectroscopy, amino acid analysis, and chemical derivatization as 2-[8-[6-(hydroxymethyl)-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl]-2,6- dimethyl-5,7-octadienamido]ethanesulfonic acid. The metabolic transformations required for the generation of this metabolite from all-trans-retinoic acid are the following: (1) allylic oxidation at carbon 4 of the cyclohexene ring to produce a 4-keto group, (2) hydroxylation of one of the methyl groups at carbon 1 of the cyclohexene ring, (3) saturation of the two terminal double bonds in the side chain, (4) loss of the terminal carboxyl group of the side chain via decarboxylation, and (5) conjugation of the resulting retinoid with taurine. To our knowledge, this metabolite represents the first taurine conjugate of a fat-soluble vitamin to be identified.