ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Bovine and normal human articular chondrocytes in suspension culture were treated with misoprostol (an analog of prostaglandin E1[PGE1]), alone and in combination with interleukin-1 (IL-1) and/or diclofenac sodium, to study effects on proteoglycan metabolism. At concentrations of 50 ng ml-1and above, misoprostol suppressed synthesis of proteoglycans but did not affect their rate of catabolism. The mild inhibitory effect of misoprostol on proteoglycan synthesis was additive to that of IL-1, especially in chondrocytes from the superficial zone of bovine articular cartilage. In IL-1-treated cultures, diclofenac Na caused a modest improvement in proteoglycan synthesis, but this beneficial effect was diminished by the simultaneous addition of misoprostol. Cartilage or chondrocyte cultures treated with IL-1, in which proteoglycan synthesis is suppressed, serve as model systems in which to study metabolic responses of chondrocytes to potential therapeutic agents, but in these experiments, no chondroprotective effects of misoprostol were observed in IL-1-activated chondrocytes.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

To compare the modulatory effects of different prostaglandins on collagen gene expression in human chondrocytes, PGE2, PGE1, misoprostol (PGE1analog), and PGF2a(10, 50, and 100 ng ml-1) were added to human chondrocytes with or without interleukin-1β (1L-1β) in the presence of indomethacin to inhibit endogenous prostaglandin synthesis and the effects evaluated on chondrocyte morphology, collagen synthesis, and procollagen mRNA levels. The effects of prostaglandins on the expression of collagen gene regulatory sequences were examined using transient transfection assays of reporter gene constructs in human chondrocytes and BALB/c3T3 fibroblasts. PGE1, misoprostol, and PGF2a, similar to PGE2, inhibited type I collagen gene expression in fibroblasts and promoted type II collagen gene expression in chondrocytes. PGE2, the major inflammatory prostaglandin produced by IL-1-activated chondrocytes and fibroblasts, and PGF2awere somewhat more potent than the anti-inflammatory prostaglandins PGE1and misoprostol in counteracting the IL-1-induced suppression of type II collagen gene expression by chondrocytes and stimulation of type I collagen gene expression by fibroblasts. Rather than promoting degradation of the cartilage matrix in joint diseases, prostaglandins may be somewhat protective, suppressing fibrosis, and maintaining or promoting appropriate cartilage repair.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The ability of misoprostol to reverse the deleterious changes induced in cartilage by sodium salicylate was tested using osteoarthritic canine cartilage and chondrocytes. Adult mongrel dogs were subjected to anterior cruciate ligament transection and dosed with either misoprostol, salicylate, or misoprostol plus salicylate. No significant differences were noted among the three groups in either gross and histological changes or general biochemical changes. This approach was abandoned since the levels of misoprostol attained by oral dosing were much lower than those required for domonstration of misoprostol effectsin vitro.Next, chondrocytes were isolated from the osteoarthritic and contralateral knee joint cartilage of dogs 12 weeks after anterior cruciate ligament transection and cultured in alginate beads. The cultures were incubated with3H-proline and both the genetic types of collagen synthesized and the net synthesis of3H-hydroxyproline were determined. No drug or combination of drugs affected the genetic types of collagen synthesized. Total protein and collagen synthesis by chondrocytes was reduced in the presence of salicylate and increased in the presence of misoprostol. When osteoarthritic chondrocytes were incubated with both agents, the salicylate effect was reversed by misoprostol. Collagen synthesis by the chondrocytes from the contralateral knee was also suppressed by salicylate, but addition of misoprostol failed to restore synthesis. In summary, misoprostol, even at very high doses, has limited chondroprotective activity in canine cartilage, as judged from collagen synthetic activity.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Endoprosthetic orthopedic implants may loosen over time. The mechanism of this loosening process remains poorly understood. Wear debris sloughed from bone cement (polymethylmethacrylate, PMMA) and orthopedic implant materials (metal, ultrahigh-molecular-weight polyethylene) may stimulate inflammatory responses in phagocytic cells which populate the bone-implant interface (synovial-like membrane). This investigation aimed to determine whether the prostaglandin-E1(PGE1) analog misoprostol might modulate PMMA-stimulated phagocytic cell degranulation and the release of interleukins such as IL-1. Lysozyme and IL-1 release from PMMA-stimulated neutrophilsin vitrowere measured as approximately 0.07 μg per 106cells per min and 4 pg per 106cells per min, respectively. These rates decreased to 0.03 μg per 106cells per min and 1.7 pg per 106cells per min, respectively, after the addition of 50 nM misoprostol to the incubation medium. Misoprostol inhibited degranulation and cytokine release in a dose-dependent manner. Consequently, misoprostol modulates PMMA-stimulated inflammatory responses. These responses appear to be mediated by prostanoids, and the regulation of prostanoids at the bone-implant interface may modulate the release of inflammatory osteolytic mediators (PGE2) which contribute to implant loosening.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Total hip arthroplasty (THA) has provided dramatic pain relief and improvement in function for millions of patients with end-stage arthritis; however, periprosthetic osteolysis following THA has become increasingly recognized as a major clinical problem in both cemented and cementless reconstructions. An aggressive granulomatous tissue (interfacial membrane) consisting predominantly of fibroblasts, aggregates of macrophages, and foreign body giant cells develops at the interface of bone/prostheses or bone/cement. It is believed that particulate wear debris from prosthetic materials and/or bone cement are phagocytized by histiocytic cells of interfacial membrane and then these cells produce inflammatory mediators and proteolytic enzymes to provoke a cascade of osteolytic events. In this paper, we studiedin vitroresponsiveness of various cell types to particulate wear debris. Although titanium and titanium alloys demonstrate excellent biocompatibility in bulk form, titanium in particulate form can provoke a variety of cellular responses. We have found that small-sized Ti particles of phagocytosable size, a commonly encountered particle species in the periprosthetic tissues of failed THAs, stimulate macrophages to secrete various mediators of bone resorption (prostaglandin E2, interleukin-1, interleukin-6, and tumor necrosis factor-α from macrophages and cause bone resorption in organ culture. In addition, we have shown that phagocytosable titanium particles stimulate fibroblasts to up-regulate the expression of matrix metalloproteinases (stromelysin and collagenase) without a substantial effect on the tissue inhibitor of these enzymes (TIMP). Titanium particulates also have a suppressive effect on procollagen synthesis by an osteoblast-like cell line. Thus, titanium particulates have the capacity to stimulate bone resorption and inhibit bone matrix formation. In this series of experiments, we have also shownin vitroinhibitory effect of certain pharmaceutical components (indomethacin, misoprostol) upon bone resorption in organ culture, which may indicate a potential therapeutic intervention to prevent or treat particulate-induced pathological bone resorption in total joint arthroplasties.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Immunization of BALB/c mice with a select group of cartilage proteoglycans induces progressive polyarthritis. The pathological mechanisms of proteoglycan-induced arthritis are based on autoimmune reactions developed against the mouse self-proteoglycan. This autoimmune inflammatory animal model, which shows many similarities to human rheumatoid arthritis, has close to 100% incidence in susceptible BALB/c mice and is an excellentin vivomodel for testing disease-modifying agents. The aim of this work was to study the regulatory mechanisms which control the autoimmune reactions in proteoglycan-induced arthritis, in association with the release of most important cytokines/mediators (interleukin 1 [IL-1], interleukin-2 [IL-2], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], and prostaglandin E2) which are believed to play key roles in inflammatory events and cartilage degradation. We have found relatively high levels of IL-1 in sera and synovial-cell culture supernatants of arthritic animals, whereas IL-1 was not detected in nonarthritic control animals. Serum autoantibody and IL-1 levels seemed to be sensitive indicators of the oncoming inflammatory events in the joints, whereas autoreactive T-cell responses to mouse proteoglycan became evident only after the onset of arthritis. As proteoglycan-specific T-cell responses were mainly restricted to the joint-draining lymph nodes during the arthritic process, it is likely that the autoantigen-driven mechanism of joint inflammation became local and self-sustaining during cartilage degradation. Thus, autoimmune mechanisms seem to be essential in the “organ specificity” of inflammatory reactions, as “arthritogenic” lymphocytes migrate to and accumulate in both the lymphoid organs and the synovium. IL-1 and IL-2 are among the most important mediators in proteoglycan-induced arthritis and are able to influence autoimmune reactions and the migration of lymphocytes to the synovium.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Studies have focused on control of expression and the relative importance of basic fibroblast growth factor (bFGF) in a purported autocrine/paracrine regulatory network functioning in the modulation of cartilage metabolic and structural homeostasis. Preformed and newly synthesized bFGF and concurrent antagonist activity could be identified by bioassay in cell/pericellular matrix extracts of normal bovine articular chondrocytes maintained in suspension culture. Specificity was determined using antibody neutralization. Prostanoids (PGE1, PGE2) enhanced chondrocyte expression of the putative inhibitor. The antagonist, recognized in the presence of suboptimally triggered bFGF receptors, was active against both endogenously produced and recombinant bFGF. Chondrocyte expression of bFGF was significantly altered following exposure to conditioned medium obtained from explant cultures of osteoarthritic synovial tissue. Response pattern, that is, an upregulation or downregulation of growth factor expression, was dependent on medium concentration and the duration of chondrocyte exposure. Synovium-conditioned medium generated in the presence of PGE1appeared to attenuate suppressive responses seen with naive conditioned medium. Promotion of expression of bFGF inhibitory activity within the milieu of the diseased joint may negate potential detrimental pathophysiologic effects of this competence factor on cartilage, synovial tissue, and bone metabolism and repair.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Extracts of Ginkgo biloba (EGb) are among the most prescribed drugs in France and Germany. EGb is claimed to be effective in peripheral arterial disorders and in “cerebral insufficiency.” The mechanism of action is not yet well understood. Three of the ingredients of the extract have been isolated and found to be pharmacologically active, but which one alone or in combination is responsible for clinical effects is unknown. The recommended daily dose (3 x 40 mg extract) is based more on empirical data than on clinical dose-finding studies. However, despite these, according to double-blind, placebo-controlled clinical trials, EGb has therapeutic effects, at least, on the diagnostic entity of “cerebral insufficiency,” which is used in Europe as synonymous with early dementia. To determine whether EGb has significant pharmacological effects on the human brain, a pharmacodynamic study was conducted using the Quantitative Pharmacoelectroencephalogram (QPEEG8) method. It was established that the pharmacological effects (based on a predetermined 7.5–13.0-Hz alpha frequency band in a computer-analyzed electroencephalogram = CEEG8) of EGb on the central nervous system (CNS) are significantly different than placebo, and the high and low doses could be discriminated from each other. The 120-mg, but particularly the 240-mg, single doses showed the most consistent CNS effects with an earlier onset (1 h) and longer duration (7 h). Furthermore, it was established that the electrophysiological effects of EGb in CNS are similar to those of well-known cognitive activators such as “nootropics” as well as tacrine, the only marketed “antidementia” drug currently available in the United States.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

TheN-acetylation phenotyping of isoniazid (INH) was studied in 434 unrelated Japanese pulmonary tuberculosis patients. The frequency of slow acetylators was determined using three methods based on the urinary levels of INH and AcINH: percentage acetylisoniazid (%AcINH), the inactivation index or acetylation index (AcINH/INH), and the molar metabolic ratio (INH/AcINH) in urine. Frequency histograms and probit plots were constructed with the data obtained from each method. Using %AcINH with the conventional antimode of 70%, the number of slow acetylator was 12.7%. Using AcINH/INH, the number of slow acetylator was 52% according to the conventional antimode of 6.0. The molar metabolic ratio INH/AcINH showed explicitly the best bimodality and a clear-cut antimode among these three methods. From probit plots of INH/AcINH, an antimode of 0.45 can be suggested for the 434 Japanese patients; 377 patients (86.9%) as rapid acetylator and 57 patients (13.1%) as slow acetylator.

ISSN:1075-2765    

出版商:OVID    

年代:1996

数据来源: OVID