No abstract

The Freund's adjuvant‐injected rat shares a number of features with the arthritis patient, viz the presence of a proliferative synovitis, joint swelling, and cartilage and bone erosion. Naproxen, a prostaglandin synthetase inhibitor which is an effective antiinflammatory agent in laboratory animals and humans, was evaluated as an inhibitor of connective tissue destruction in this model by use of radiologic and histopathologic analyses. Sixteen days after rats were injected with Freund's complete adjuvant, marked joint swelling was noted. On day 17, vehicle or naproxen, 7 mg/kg/day, was administered orally. Twenty‐eight days later, vehicle‐treated animals demonstrated the following pathologic changes in their hindpaws: swelling, cartilage loss, large amounts of pannus within the joint spaces, osteoporosis, bone erosions, periosteal new bone formation, heterotopic ossification, and bony ankylosis. Rats treated 28 days with naproxen had significantly milder disease than the vehicle controls. The incidence of severe juxtaarticular bone destruction was 10/10 in the vehicle controls versus 2/10 of the drug‐treated group (P < 0.01). A comparable reduction in cartilage erosion, incidence of pannus, and new bone formation was noted in the drug‐treated group. These effects may relate to an inhibition of prostaglandin biosynthesis; prostaglandins have been shown to: 1) stimulate collagenase secretion from macrophages, 2) stimulate bone resorption in vivo and in vitro, and 3) diminish proteoglycan synthesis in cartilage.

Flunisolide (6 alpha-fluoro-11 beta,16 alpha,17 alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide) is a potent corticoid used clinically in topical formulations. Three men were given single 2-mg intravenous and oral doses of 14C-labeled flunisolide and plasma and urine concentrations of flunisolide and a major metabolite, 6 beta,11 beta,16 alpha,17 alpha,21-penta-hydroxypregna-1,4-diene-3,20-dione 16,17-acetonide (6 beta-OH metabolite) were determined. Oral flunisolide was metabolized rapidly and extensively to the 6 beta-OH metabolite and to conjugates; comparison in the intravenous dose kinetics suggested significant first-pass metabolism. In a separate study in 12 normal subjects, flunisolide in plasma was quantitated by radioimmunoassay (RIA); average systemic availability was 20%. The apparent volume of distribution (Vd beta) of flunisolide was large and systemic clearance and apparent oral clearance values were high. The 6 beta-OH metabolite had corticoid activities no more than 3 times that of hydrocortisone in rats as measured by thymolytic, anti-inflammatory, and adrenal-suppressive assays, whereas flunisolide had 180 to 550 times the activity of hydrocortisone. These data offer a metabolic explanation for the clinical observation that flunisolide can be administered intranasally and by inhalation in therapeutically effective doses without causing significant reduction in adrenal function.

No abstract

A series of xanthone-2-carboxylic acids, substituted mainly with electron-withdrawing groups, has been synthesized and assayed for antiallergic activity, using the passive cutaneous anaphylaxis (PCA) reaction in the rat. The effect of substituent type and substitution pattern on PCA neutralizing capacity is presented.