Intra-articular rimexolone in the rheumatoid knee: a placebo-controlled, double-blind, multicentre trial of three doses.

One-hundred and thirty-seven patients with classical or definite rheumatoid arthritis, involving at least one knee joint, were randomly allocated to a single intra-articular injection of 10, 20 or 40 mg of rimexolone (Org 6216) or placebo. The follow-up period was 84 days, during which clinical and laboratory assessments were done. Clinical improvement of the treated knee joint was measured by the following variables: pain, tenderness, morning stiffness, swelling, range of movement and walking ability. Placebo response was considerable. However, clinical improvement with rimexolone at 20 mg and 40 mg was significantly superior to placebo for most of the variables, whilst with the 10 mg dose only reduction of tenderness was significantly superior. The duration of improvement was longest with 40 mg of rimexolone. One single, intra-articular injection of this dose into the affected knee joint provided significant reduction in pain, tenderness and stiffness and improved the range of movement and walking ability for a period of 8 to 12 weeks.

Effect of 16,16-dimethyl prostaglandin E2 on mucus glycoprotein biosynthesis in rat stomach and duodenal glands.

The present study describes the effect of 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) on mucus glycoprotein biosynthesis in rat stomach and duodenal glands. After in vivo treatment with 16,16-dmPGE2 (10 micrograms/kg subcutaneously) for 1 h, the incorporation rate of [3H]galactose, [3H]glucosamine, and [3H]serine in the ex vivo vascularly perfused stomach was determined by light microscopic autoradiography. As was previously found by us for the surface mucous cells in the fundus of 16,16-dmPGE2-treated rats, the incorporation of [3H]galactose and [3H]glucosamine (indicative of mucus glycoprotein synthesis) in the isthmus was increased two- to fourfold. Small if any increases were detected in the mucous cells near the base of the glands of the fundus (neck cells), the mucous cells in the antrum and the mucous cells in the duodenal glands. Total protein synthesis as measured by [3H]serine incorporation was not increased in any of these cells. We conclude that 16,16-dmPGE2 has different effects on mucus glycoprotein biosynthesis in various regions of the rat stomach. Increased biosynthesis in the fundus points to a role for mucus in the prostaglandin-induced protection of the gastric mucosa against injury.

Biosynthesis, processing and secretion of mucus glycoprotein in the rat stomach.

For the study of the biosynthesis, processing and secretion of mucus glycoproteins in rat gastric mucous cells, antibodies were raised against purified gastric mucus glycoproteins and against deglycosylated gastric mucus glycoproteins. Indirect immunofluorescence analysis of gastric mucosa sections revealed that both antibodies specifically labelled the mucus glycoprotein-synthesizing cells in the gastric mucosa. Stomach segments were pulse-labelled with [35S]cysteine and chased for various times. The radioactively labelled (glyco)proteins were quantitatively immunoprecipitated and analyzed by SDS-polyacrylamide gel electrophoresis. Less than 3% of the total radioactivity incorporated in protein was found to be present in mucus glycoproteins. Antibodies raised against native mucus glycoproteins recognized only high-molecular-weight mucus glycoproteins, while the antibodies against deglycosylated glycoproteins also bound to probable precursor forms. The synthesis of mature mucus glycoproteins (Mr greater than 300 000) required about 90 min. After 3 h of chase, only a small portion of the pulse-labelled mucus glycoproteins had been secreted; the majority of the radioactive glycoproteins at that time was still associated with the tissue. Immature (glyco)proteins were not secreted into the medium.

Quantitative aspects of mucus glycoprotein biosynthesis in rat gastric mucosa.

The synthesis of the polypeptide backbone of mucus glycoproteins in rat stomach was studied. CsCl centrifugation of the homogenate of [3H]serine pulse-chase labelled stomach or mucosal scrapings showed that [3H]serine was mainly incorporated into molecules having a density identical to that of proteins and that only 8-12% was incorporated into macromolecules with the density of mucus glycoproteins. [3H]-Galactose, however, was almost exclusively incorporated into macromolecules with a density identical to that of mucus glycoproteins. Electrophoretic analysis of the CsCl fraction containing the mucus glycoprotein revealed that 78% of the [3H]serine-labelled macromolecules had an electrophoretic behaviour identical to that of mucus glycoproteins. Thus, only a small portion (about 6-10%) of incorporated [3H]serine was present in the backbone of the mucus glycoprotein. Translation in a wheat germ cell-free system of total RNA derived from both whole stomach and superficial mucosal scrapings, using either [35S]methionine or [35S]cysteine as radioactive amino acid, yielded a wide range of proteins. On sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, one major translation product of whole stomach RNA had an apparent Mr (43000) identical to that of rat pepsinogen. As this polypeptide could not be found amongst the translation products of RNA from scrapings it probably was pepsinogen. The present data provide strong evidence that the backbone polypeptide of mucus glycoproteins only accounts for a small part of the proteins synthesized by mucus-producing cells.

16,16-Dimethyl prostaglandin E2 stimulates galactose and glucosamine but not serine incorporation in rat gastric mucous cells.

It has been suggested that the cytoprotective effect of prostaglandins could be mediated by an increased mucus glycoprotein secretion in the stomach. In the rat we studied the mucus glycoprotein synthesis after an in vivo treatment with 16,16-dimethyl prostaglandin E2 (10 micrograms/kg X day subcutaneously) for 1 h or 7 days. The incorporation rate of [3H]galactose, [3H]glucosamine, and [3H]serine was determined by light microscopic autoradiography in the ex vivo vascularly perfused stomach. Prostaglandin increased the rate of [3H]galactose and [3H]glucosamine incorporation twofold to fourfold in the fundic surface mucous cells; but the total protein synthesis as measured by [3H]serine incorporation was not increased. Analyses of purified mucus glycoprotein did not show an effect on carbohydrate composition, oligosaccharide chain size, nor on buoyant density, after prostaglandin treatment. The present study reveals that 16,16-dimethyl prostaglandin E2 stimulates the mucus glycoprotein synthesis in the fundic mucous cells. This effect may well be one of the mechanisms by which prostaglandin protects the stomach against noxious agents.

Lymphokine-mediated stimulation of eosinophil migration in the guinea-pig.

Guinea-pig lymphokines were shown to stimulate the migration of eosinophils from capillary tubes. Eosinophil migration stimulatory activity was produced by Freund's complete adjuvant (FCA)-sensitized lymph node or peritoneal exudate lymphocytes in the presence of purified protein derivative (PPD), as well as by Con A-stimulated lymph node lymphocytes. Like murine and human eosinophil-stimulation promoter lymphokine (ESP), the guinea-pig lymphokine activity is T cell-derived, non-dialysable and resistant to heating at 56 degrees. In contrast to the migration inhibition factor (MIF) which could be adsorbed by macrophages, eosinophil migration stimulatory activity could not be removed by pre-adsorption to macrophages or eosinophils.