Mechanistic insights into hydride transfer for catalytic hydrogenation of CO(2) with cobalt complexes.

The catalytic hydrogenation of CO2 to formate by Co(dmpe)2H can proceed via direct hydride transfer or via CO2 coordination to Co followed by reductive elimination of formate. The different nature of the rate-determining step in the two mechanisms may provide new insights into designing catalysts with improved performance.

Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis.

OBJECTIVE: A double blind, randomised, placebo controlled study to evaluate the safety and efficacy of etanercept to treat adult patients with ankylosing spondylitis (AS). METHODS: Adult patients with AS at 14 European sites were randomly assigned to 25 mg injections of etanercept or placebo twice weekly for 12 weeks. The primary efficacy end point was an improvement of at least 20% in patient reported symptoms, based on the multicomponent Assessments in Ankylosing Spondylitis (ASAS) response criteria (ASAS 20). Secondary end points included ASAS 50 and ASAS 70 responses and improved scores on individual components of ASAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), acute phase reactants, and spinal mobility tests. Safety was evaluated during scheduled visits. RESULTS: Of 84 patients enrolled, 45 received etanercept and 39 received placebo. Significantly more etanercept patients than placebo patients responded at the ASAS 20 level as early as week 2, and sustained differences were evident up to week 12. Significantly more etanercept patients reported ASAS 50 responses at all times and ASAS 70 responses at weeks 2, 4, and 8; reported lower composite and fatigue BASDAI scores; had lower acute phase reactant levels; and had improved spinal flexion. Etanercept was well tolerated. Most adverse events were mild to moderate; the only between-group difference was injection site reactions, which occurred significantly more often in etanercept patients. CONCLUSIONS: Etanercept is a well tolerated and effective treatment for reducing clinical symptoms and signs of AS.

Prosthesis-associated pseudomembrane-induced bone resorption.

A pseudomembranous structure invariably develops at the cement-bone interface of implanted prostheses in association with aseptic loosening. The tissue has histological characteristics of a foreign body reaction presumably initiated by repetitive microtrauma-associated release of methacrylate cement and polyethylene wear debris. Explant cultures of pseudomembrane and synovial tissue derived from osteoarthritic patients undergoing revision for cemented hip implant failure have been shown to produce interleukin-1, tumour necrosis factor and prostaglandin E2, recognized mediators of bone resorption. Further, the conditioned media obtained from pseudomembrane cultures could directly effect bone resorption by inducing 45Ca release from prelabelled limb bone rudiments. Results implicate the prosthesis-associated pseudomembrane in the pathogenesis of the bone resorptive process responsible for prosthesis failure.

Polymethylmethacrylate-induced release of bone-resorbing factors.

A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

In vitro effect of select nonsteroidal antiinflammatory drugs on the synthesis and activity of anabolic regulatory factors produced by osteoarthritic and rheumatoid synovial tissue.

Nutriment replenished conditioned media derived from cultures of osteoarthritic and rheumatoid synovial tissue contain factors of variable molecular weight, independent of prostaglandin activity, which are capable of reversibly down-regulating cartilage matrix proteoglycan synthesis. Piroxicam significantly reduced anabolic suppressant factor production on an apparent selective basis. It could be shown to partially modify the chromatographic profile of newly synthesized osteoarthritic synovial tissue protein fractions containing suppressant activity. Dependent on experimental design, piroxicam also partially blocked inhibitory activity at a chondrocyte level. Indomethacin and sodium salicylate were essentially without effect.

Modulation of cartilage proteoglycan synthesis by osteoarthritic synovium.

Conditioned media derived from explant cultures of human osteoarthritic synovial tissue have been shown to contain preformed and newly synthesized factors of variable molecular weight which are capable on a concentration dependent basis of modulating cartilage proteoglycan metabolism. Anabolic inhibitory and stimulatory activity often appeared to coexist, a reversible down-regulation usually dominating in unfractionated preparations. The size of newly synthesized proteoglycan aggregates and monomers and the length of glycosaminoglycan chains produced in the presence of conditioned media were normal. The pattern of anabolic response did not necessarily correlate with the presence of catabolic inducing activity.

Immunologic modulation of cartilage metabolism.

Preservation of the structural integrity of cartilage requires that metabolic homeostasis be maintained between chondrocyte anabolic and catabolic functions. This critical balance is perturbed in osteoarthritis (OA) in which synovial tissue and subchondral intratrabecular marrow often contain a focal and at times more diffuse mononuclear cell infiltration. Cytokines derived from T lymphocytes and monocytes have a capacity to: a) cause qualitative changes in and reversibly suppress chondrocyte proteoglycan, collagen, and non-collagen protein synthesis, and b) induce the synthesis and release of chondrocyte proteinases. Factors having comparable metabolic regulatory activity are produced by synovial tissue derived from idiopathic and secondary forms of OA.

Modulation of cartilage destruction by select nonsteroidal antiinflammatory drugs. In vitro effect on the synthesis and activity of catabolism-inducing cytokines produced by osteoarthritic and rheumatoid synovial tissue.

Non-enzymatic factors produced by synovial tissue can potentially mediate cartilage destruction by inducing the synthesis and release of matrix-degrading proteinases from chondrocytes. Pharmacologic control of this process is of potential clinical relevance. The in vitro effect of therapeutic concentrations of select nonsteroidal antiinflammatory drugs on the synthesis and activity of catabolism-inducing cytokines produced by 6-day explant cultures of osteoarthritic and rheumatoid synovial tissue was studied. Piroxicam regularly suppressed such factor synthesis by both types of tissue without significantly affecting total protein synthesis. This did not occur using sodium salicylate or indomethacin in osteoarthritis tissue cultures and was observed only occasionally in rheumatoid arthritis cultures. None of the nonsteroidal antiinflammatory drugs studied consistently blocked catabolism-inducing activity in osteoarthritis tissue, whereas piroxicam more consistently inhibited activity produced by rheumatoid arthritis tissue. Results suggest that the catabolism-inducing factors produced by the 2 tissue sources may differ.

The in vitro effect of select classes of nonsteroidal antiinflammatory drugs on normal cartilage metabolism.

The in vitro effect of piroxicam, a newer nonsteroidal antiinflammatory drug (NSAID), on normal cartilage metabolism has been studied and response contrasted to indomethacin and sodium salicylate. Therapeutic levels of piroxicam has no effect on cartilage glycosaminoglycan (GAG), collagen or noncollagen protein synthesis by porcine weight bearing articular cartilage explants. Salicylate consistently suppressed GAG and protein synthesis, whereas indomethacin had no consistent effect on GAG production but suppressed protein synthesis. NSAID studied had no effect on proteoglycan catabolism. The potential significance of the effect of NSAID on cartilage metabolism is discussed and placed in perspective as regards selection of these agents for human use.

Cytokine modulation of chondrocyte metabolism--in vivo and in vitro effects of piroxicam.

Changes in the macromolecular proteolycan (PG) and collagen of the cartilage matrix may culminate in irreparable tissue destruction. Molecular modifications appear to result from: (A) exogenous proteinases, (B) endogenous chondrocyte proteinases whose synthesis and release is modulated by exogenous non-enzymatic cytokines (CKs) and (C) quantitative and/or qualitative alterations in chondrocyte PG and collagen synthesis which are potentially induced by exogenous CKs. Studies have recently been initiated to determine the effect of piroxicam on the synthesis and activity of such metabolic regulatory CKs in patients with rheumatoid arthritis and osteoarthritis, and in age-, sex-, and race-matched controls. Therapeutic doses of piroxicam alone had no effect on the anabolic or catabolic function of chondrocytes. Current studies concern the effect of piroxicam on: (a) spontaneous and lectin-driven production by peripheral blood monocytes and T-cells of trypsin-sensitive, heat-labile CKs (interleukin 1, lymphokine) which, in a protein- and RNA-synthesis-dependent manner, induce a concentration and duration of substrate exposure dependent release of chondrocyte PG- and collagen- degrading neutral proteinases in cartilage organ and chondrocyte suspension culture systems; (b) spontaneous and lectin-driven synthesis by peripheral blood T-cells of lymphokines capable of suppressing chondrocyte PG, glycosaminoglycan, protein, collagen and nucleic acid synthesis in a quantitatively reversible manner; (c) pathological synovial membrane synthesis of such catabolic-inducing and anabolic-modulatory CKs. These experimental model system are reviewed together with preliminary data on the effect of piroxicam.

Cytokine modulation of chondrocyte proteinase release.

Nonenzymatic, trypsin sensitive cytokines derived from lectin stimulated normal human mononuclear cells have been shown to induce release of proteoglycan and collagen degrading proteinase activity from chondrocytes in cartilage organ and isolated suspension culture systems. Active chondrocyte protein and RNA synthesis were required to induce activity. Cytokines responsible were of both monocyte and T cell origin. Direct monokine catabolic induction and monokine/lectin-triggered lymphokine inducing activity could be demonstrated. Cyclooxygenase inhibitors and direct or indirect modulation of mononuclear cell or chondrocyte cAMP levels had no effect on factor synthesis or activity. Hydrocortisone abrogated the effect. Cytokines responsible were heat labile, unaffected by reduction/alkylation or neuraminidase exposure, and stable over a pH range of 3-10.