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ID PMID Title PublicationDate abstract
8796985 Potential of tetracyclines to modify cartilage breakdown in osteoarthritis. 1996 May For several decades, it has been recognized that an imbalance between activated matrix metalloproteinases, generated locally by both infiltrating and resident cells, and their endogenous inhibitors may play a role in the pathologic breakdown of the joint extracellular matrix in osteoarthritis. This understanding has stimulated the search for a number of synthetic matrix metalloproteinase inhibitors that could serve as potential therapeutic agents. Tetracycline analogues are currently on the threshold of approval as anti-matrix metalloproteinases for another extracellular matrix-destructive disease, periodontitis, and this application could be extended to osteoarthritis and rheumatoid arthritis therapy. In this regard, specially formulated low-dose regimens of a commercially available tetracycline, doxycycline, have been used in long-term clinical trials and were found to reduce extracellular matrix breakdown, including bone loss, in adult periodontitis. Matrix metalloproteinase inhibition by tetracycline analogues is now recognized as complex, and multiple mechanisms have been proposed. A series of recently discovered nonantimicrobial chemically modified tetracyclines are potent inhibitors of several classes of matrix metalloproteinases, preventing collagen breakdown and bone loss in a variety of animal models, although these analogues have not yet been approved for human use. Various tetracyclines have reduced the severity of osteoarthritis in animal models, indicating therapeutic potential for this class of compounds in the future.
8536384 The influence of tetracyclines on T cell activation. 1995 Dec Minocycline has been shown to have an anti-inflammatory effect in patients with rheumatoid arthritis (RA). Since there is evidence that RA is a T cell-mediated disease, we investigated the effect of minocycline on human T cell clones derived from the synovium of an RA patient. The T cells, when activated via the T cell receptor (TCR)/CD3 complex, were suppressed functionally by minocycline, resulting in a dose-dependent inhibition of T cell proliferation and reduction in production of IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). Besides an inhibition of IL-2 production, minocycline exerted its effect on T cell proliferation by induction of a decreased IL-2 responsiveness. We showed that the chelating capacity of minocycline plays a crucial role in the inhibitory effect on T cell function, since the inhibitory effect on T cell proliferation could be annulled by addition of exogenous Ca2+. However, minocycline did not markedly influence the typical TCR/CD3-induced intracellular Ca2+ mobilization. Taken together, the results clearly indicate that minocycline has immunomodulating effects on human T cells.
8545289 An audit of ANCA in routine clinical practice. 1995 Oct We have reviewed the medical records of 301/327 consecutive patients in whom anti-neutrophil cytoplasmic antibodies (ANCA) were detected by the Regional Immunology Laboratory in Northern Ireland between January 1988 and October 1991 (45 months). We have collected data for each patient regarding age, sex, smoking habit, area of residence, and details of any other autoantibody activity. Clinical diagnosis was established, with the number of organ systems involved and the evidence for that involvement (symptomatic, biochemical, radiological, and histological). Diagnoses were divided into four groups according to their recognised vasculitic features and these were related to the pattern of immunofluorescence and maximum ANCA titre detected. The most frequent diagnosis was rheumatoid arthritis (18.2% of patients) and the connective tissue disorders as a whole accounted for 27.9% of patients. ANCA were also detected in a wide range of clinical conditions which are not associated with vasculitis and these patients were an important source of 'false-positives'. The positive predictive value (PPV) of ANCA of all patterns and titres for vasculitic conditions was 27%, however, the detection of a classical ANCA pattern at high titre (> or = 1:640) was associated with an increased PPV of 75%. The coexistence of an antinuclear antibody (ANA) reduces the PPV of both classical and perinuclear ANCA, although perinuclear ANCA with antimyeloperoxidase specificity had an improved PPV. We conclude that ANCA testing should not be used as the only screening investigation for vasculitis but should be included in a rational investigative scheme. The interpretation of a positive ANCA result must take into account the presence of other autoantibodies and the full range of non-vasculitic conditions when the clinical situation is not typical of vasculitis.
7554381 Chloroquine inhibits T cell proliferation by interfering with IL-2 production and responsi 1995 Oct Chloroquine (Chl) is an anti-rheumatic drug that is widely used in the treatment of rheumatoid arthritis (RA). It seems that T cells are important in the pathogenesis of RA, but it is not known whether Chl acts via inhibition of T cell function. We here present evidence that Chl, just like cyclosporine A (CsA), inhibits T cell proliferation as induced with immobilized alpha CD3 MoAb in a concentration-dependent manner, at least partly through interfering with the production of IL-2 protein and the induction of IL-2 mRNA. Furthermore, Chl impedes the responsiveness of T cell clones to IL-2 since (1) the inhibition of alpha CD3 MoAb-induced proliferation by Chl could not be reversed by rIL-2 and (2) Chl directly blocks IL-2-driven proliferation of cloned T cells. Chl appeared to interfere with the internalization (50% inhibition) and degradation (total blockade) of rIL-2. Finally, the combination of Chl and CsA synergistically inhibited T cell proliferation. We conclude that Chl may inhibit functional properties of human T cells, although the drug is 100- to 1000-fold less potent than CsA in inhibiting T cell proliferation and IL-2 production, respectively. It is speculated that the in vitro effects of Chl might be relevant in explaining the anti-rheumatic effect of this drug in patients with RA.
7487437 Employment after rehabilitation for musculoskeletal impairments: the impact of vocational 1995 Oct OBJECTIVE: To investigate to what extent vocational rehabilitation and working on a trial basis have an impact on employment after rehabilitation. DESIGN: Follow-up survey, conducted in 1991, among all patients, aged 14 to 64, who were treated between 1984 and 1987. SETTING: An out-clinic department of a rehabilitation center in the west of The Netherlands. SUBJECTS: 395 patients (59% of the original sample) participated in the study. They suffer from musculoskeletal impairments due to back pain (41%), brain injury (20%), neurological disorder (12%), trauma to the upper and/or lower extremities (8%), rheumatoid arthritis (7%), or other disorders (12%). No differences were found between those who did and those who did not respond with regard to age, gender, marital status, disorder, work experience, and participation in vocational rehabilitation. MAIN OUTCOME MEASURE: Odds ratio of having a paid job after rehabilitation. RESULTS: Participation in vocational rehabilitation and working on a trial basis depends on age, gender, work experience, and disorder. When statistically controlled for these variables vocational rehabilitation (odds ratio 1.96; 95% confidence interval 1.12 to 3.42) and working on a trial basis (odds ratio 3.26; 95% confidence interval 1.74 to 6.11) proved to have a significant impact on employment after rehabilitation. CONCLUSIONS: The findings suggest that rehabilitation programs that aim specifically at promoting employment for people with disabilities are effective, in particular when they take place in both a laboratory and a natural setting. The validity of this suggestion must be further tested by means of an experimental design.
7763103 Characterisation of anticytoplasmic antibodies and their clinical associations. 1995 Apr OBJECTIVES: To characterise the cytoplasmic staining patterns identified by indirect immunofluorescence (IF) of human epithelial (HEp-2) cells and the antigens recognised using additional serological techniques. To define the disease associations of anticytoplasmic antibodies. METHODS: Sera from 1173 patients were screened for cytoplasmic IF staining on HEp-2 cells and the patterns characterised. The presence of antimitochondrial antibodies (AMA) was evaluated by a sensitive anti-pyruvate dehydrogenase complex enzyme linked immunosorbent assay (ELISA) (IgG) and by immunoblotting. Detection of antibodies to extractable nuclear antigens (ENA) was performed by double immunodiffusion and the presence of anti-ribosomal P antibodies was determined by immunoblotting. RESULTS: Cytoplasmic IF staining was demonstrated in 75 sera (6.4%). Six different patterns were recognised: coarse granular filamentous speckles (AMA, n = 9); condensed large speckles (anti-golgi apparatus antibodies, n = 3); cytoskeletal (n = 9); centriolar (n = 4); diffuse coarse speckles (n = 33); and fine speckles (n = 17). Of the nine sera with an AMA pattern, the presence of these antibodies was confirmed in seven by the ELISA (n = 6) and on immunoblotting (n = 7). One of the seven patients had primary biliary cirrhosis, and two had scleroderma. Two patients with anti-golgi antibodies had rheumatoid arthritis and two with anticentriolar antibodies had scleroderma. Of 33 sera that had cytoplasmic staining and were ANA negative, three were positive for anti-Ro and two were positive for anti-Jo-1 antibodies. CONCLUSIONS: In general, defined cytoplasmic IF patterns have no specific disease associations. However, the finding of cytoplasmic fluorescence should not be ignored, as it may indicate the presence of antibodies to ENA in the absence of nuclear staining.
7882511 Immunoprecipitation assay for autoantibodies to steroid 21-hydroxylase in autoimmune adren 1995 Mar Adrenal autoantibodies characteristic of autoimmune Addison disease are directed towards steroid 21-hydroxylase (21-OH; EC 1.14.99.10). We describe a new assay to measure 21-OH autoantibodies (21-OH Abs), based on immunoprecipitation by the antibodies of 35S-labeled human 21-OH. Using this immunoprecipitation assay (IPA), we detected 21-OH Abs in 42 of 64 (66%) patients with Addison disease and in 14 of 19 (74%) patients with autoimmune polyendocrine syndromes type I and type II. No 21-OH Abs were detected by the IPA in any patients with Addison disease attributable to tuberculosis (n = 9) or adrenoleukodystrophy (n = 9) or in patients with autoimmune thyroid disease (n = 28), systemic lupus erythematosus (n = 10), myasthenia gravis (n = 10), rheumatoid arthritis (n = 10), or insulin-dependent diabetes mellitus (n = 12). None of the 26 sera from healthy normal blood donors was positive for 21-OH Abs by the assay. We found good agreement between 21-OH Abs measured by IPA and by Western blotting (r = 0.83, n = 123, P < 0.001). The inter- and intraassay CVs for IPA were well < 10% at high, medium, and low concentrations of 21-OH Abs. Overall, our studies indicate that the IPA provides a specific, sensitive, and convenient system for measuring 21-OH Abs.
20470522 [Alloplasty of the shoulder joint - introduction to the problem.]. 1995 The authors present a review of contemporary views on the problem of alloplasty of the shoulder joint. In the historical introduction they mention the development of surgery of the shoulder joint with the gradual transition from resection or interposition arthroplasties to endoprostheses of varying design which according to the principle of internal constraint can be divided into three groups, i. e. not compressed, semi-constrained and fully-constrained implants. Development revealed that the best results with the least number of complications are achieved with non-constrained implants which predominate nowadays in the production of most firms. The authors describe separately indications for hemiarthroplasties (which implies always implantation of the humeral component) and total replacement of the shoulder joint. Both indication groups overlap to a considerable extent. The spectrum of indications was extended considerably, from the original oncological indications, in particular by degenerative diseases (osteoarthritis, rheumatoid arthritis, systemic diseases etc.) and with regard to the rising number and complexity of fractures of the proximal end of the humerus (or scapula) also by traumatological indications (comminuted dislocated and luxation fractures, poorly healed fractures and fractures of severely osteoporotic bones etc.). Contraindications include nervous lesions with paralysis of the deltoid muscle or the rotator muscles, previous infection, an irreparable defect of bone tissue and a mentally labile, not collaborating patient. During the rehabilitation period a three-stage programme elaborated by Hughes and Neer proved useful. The authors emphasize early positioning of the operated extremity in maximal elevation. In the subsequent part the authors analyze complications associated with surgery of endoprostheses of the shoulder joint. In general it may be stated that the number of complications increases with the degree of constraint of the implant and fully-constrained implants are practically no longer used because of the large number of complications. The most frequent complications are a restricted mobility of the shoulder joint, instability - luxation of the endoprosthesis, impingement syndrome, lack of incorporation of protuberances, pseudoarthroses, infections, loosening of the implants, fractures, nervous and vascular lesions, heterotopic ossifications and permanent postoperative pain. In the conclusion the authors emphasize that replacement of the shoulder joint is not a simple operation and should be carried out by surgeons with great experience with surgery of the shoulder in departments adequately equipped for surgery and rehabilitation. Key words: alloplasty, endoprosthesis, shoulder joint.
7750287 Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. 1995 Jan Tripterygium wilfordii Hook f. is a medicinal plant which possesses anti-fertility activity in males and has been used in China for the treatment of rheumatoid arthritis, chronic nephritis and other pulmonary diseases for years. The effect of Tripterygium wilfordii extract on in vitro development in day 9 and day 10 mouse embryos was examined. The embryotoxicity of T. wilfordii extract was obvious on day 9 and day 10 embryos at doses of 50 and 100 micrograms/ml, respectively. The embryonic abnormalities produced included abnormal branchial apparatus, open cranial neural tube and absence of forelimb bud in day 9 embryos. In day 10 embryos, the abnormality appeared first in the branchial apparatus. At higher doses, additional abnormalities appeared: abnormal optic and otic vesicles and twisted body axis in day 9 embryos; microcephaly, hematoma in cranial region and absence of hindlimb buds in day 10 embryos. There were reductions in final somite number, yolk sac surface area and axial length. Dead cells were present all over the embryo. The blood circulation of the visceral yolk sac of the abnormal embryos became defective. Ultrastructural analysis of the visceral yolk sac revealed abnormalities including decrease in the amount of microvilli, reduction in the number of storage vesicles, appearance of large vacant vacuoles and decrease in the number of pinocytotic invaginations on the apical surface of the yolk sac epithelium. The embryotoxic effect of T. wilfordii extract was, however, destroyed by heat treatment of the extract at 80 degrees C for 6 hours.
7992105 Photosensitizers in photodynamic therapy. 1994 Dec Photodynamic therapy (PDT) is based on the use of light-sensitive molecules called photosensitizers. Photoactivation causes the formation of singlet oxygen, which produces peroxidative reactions that can cause cell damage and death. Porfimer sodium (Photofrin, manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, BC, Canada) is the photosensitizer that has been studied most extensively. Patients generally have to be hospitalized for 2 days prior to light treatment after administration of porfimer sodium; it takes approximately 48 hours after injection to reach optimal concentration in tumor tissue. The tumoricidal capacity of PDT with porfimer sodium is determined in part by the maximum depth of penetration of light having a wavelength of 630 nm. Porfimer sodium causes cutaneous photosensitivity that may last for up to 6 weeks. Benzoporphyrin derivative (BPD verteporfin; BPD-Quadra Logic Technologies, Inc, Vancouver, BC, Canada), another photosensitizer, accumulates more rapidly in tumor tissue, permitting optimal PDT 30 to 150 minutes following intravenous administration. It is rapidly cleared from the body, and skin photosensitivity does not extend beyond a few days. The primary mechanism of action of PDT is related to the selective accumulation of photosensitizers in cancer tissue. Photodynamic therapy also shows promise in the treatment of a number of nonneoplastic conditions, including psoriasis, macular degeneration of the retina, atherosclerotic plaque and restenosis, bone marrow purging for treatment of leukemias with autologous bone marrow transplantation, inactivation of viruses in blood or blood products, and several autoimmune conditions, including rheumatoid arthritis. Physiologic characteristics shared by this disparate group of diseases, and the mechanisms by which they may mediate photoactivation, are discussed.
7727689 Interleukin-1, tumor necrosis factor and their specific inhibitors. 1994 Nov It has become evident during the past years that interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), mainly produced by monocyte-macrophages, are the principal mediators of tissue destruction in many immuno-inflammatory diseases such as rheumatoid arthritis (RA). However, the discovery of a biologically active monokine of approximately 17 kD preceded the isolation of IL-1 and TNF-alpha as well as their cloning by more than 16 years. The two latter cytokines induce in synergy the production of high levels of matrix metalloproteinases (MMP) by fibroblasts, synovial cells and chondrocytes. The biological activity of MMP is controlled by tissue inhibitor of MMP (TIMP) which also depends on the presence of cytokines in the microenvironment. One of the principal stimuli of the production of IL-1 and TNF-alpha is the direct contact between the membranes of activated lymphocytes and monocyte-macrophages. Several glycoproteins expressed on the surface of activated lymphocytes (CD11, CD69) are implicated in this activation process and can be partially blocked by their respective antibodies. These prompt the decrease of cytokines and proteases in the lymphocyte/monocyte interaction. In the past few years, two pathways for inhibiting the activation of macrophages, fibroblasts and synovial cells have been elucidated. One of them is due to the action of anti-inflammatory cytokines such as IL-4 and IL-10 which considerably decrease production of IL-1, TNF-alpha and metalloproteases. In contrast to IL-4, IL-10 is also capable of stimulating the production of TIMP.(ABSTRACT TRUNCATED AT 250 WORDS)
7945411 Effects of tenidap on Ca(2+)- and protein kinase C-mediated protein phosphorylation, activ 1994 Sep 15 Tenidap is a novel antirheumatic drug which combines non-steroidal antiinflammatory drug-like cyclooxygenase inhibition with cytokine modulating qualities in rheumatoid arthritis. We show herein that tenidap (5-20 microM) inhibited protein kinase C-mediated signalling leading to release of arachidonate in mouse macrophages by interfering with the up-regulation of the 85 kDa arachidonate-mobilizing phospholipase A2, although it did not inhibit this enzyme directly. The Ca(2+)-mediated activation of arachidonate mobilization was inhibited only at higher concentrations (20-40 microM). Studies of protein phosphorylation indicated that tenidap in itself was capable of inducing the phosphorylation of several protein bands through interaction with intracellular protein kinases and/or phosphatases. Importantly, tenidap inhibited both arachidonate release and the increase in intracellular protein phosphorylation when the cells were stimulated with zymosan. We propose that the main inhibitory influence of tenidap on the macrophage signalling investigated here is exerted at some level between protein kinase C and the 85 kDa phospholipase A2 and quite possibly also at the receptor-linked activation of phospholipase C.
8060250 Serum hyaluronic acid and interleukin-6 as possible markers of carpal tunnel syndrome in c 1994 Jun To elucidate the precise mechanism of carpal tunnel syndrome (CTS), serum hyaluronic acid (HA), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were measured in 71 chronic hemodialysis patients with or without CTS and/or shoulder pain. Patients were divided into two groups: Group 1 (n = 40) was the control group, and Group 2 (n = 31) patients had carpal tunnel syndrome, shoulder pain, or both. None of the patients had liver disease, rheumatoid arthritis, other inflammatory disease, or cancer. Serum HA concentrations in Groups 1 and 2 were 106.0 +/- 77.5 and 442.6 +/- 564.7 ng/dl (mean +/- SD), respectively. The difference between the groups was significant (p < 0.01). The serum concentrations of IL-6 in Group 1 were significantly lower than in Group 2 (p < 0.05); however, there was no significant difference in serum IL-1 beta and TNF-alpha levels. The mechanisms regulating in vivo synthesis of HA was obscure; however, in vitro studies suggest that inflammatory cytokines may stimulate an increased production of HA. In this study, CTS might be associated with increased serum concentrations of HA, and HA production might be mediated by IL-6.
8119667 T-T cell interactions in patients with endocrine autoimmunity. Definition of antiergotypic 1993 Dec T-T cell interactions are known to be of importance in the generation of immune responses and have been postulated to play a role in autoimmunity. Antiergotypic T lymphocytes are cells, which react with other activated T cells, which they may consecutively neutralize. Antiergotypic T cells have been described to play a role in animal models of autoimmunity and have been found in patients with rheumatoid arthritis. It was the aim of the present study to analyse, whether antiergotypic T cells were also present in the blood of patients with endocrine autoimmunity and to characterize them in vitro. We found that peripheral blood mononuclear cells from patients with Graves' disease, Hashimoto's thyroiditis and Diabetes mellitus show a pronounced proliferative response, when stimulated with autologous T cell lines. This response is dependent on the state of activation of the stimulator cell population, but is independent of its phenotype and is not MHC restricted. In contrast to normal control cells PBMC from patients with endocrine autoimmune disorders respond better to autologous T lymphocytes, than to allogeneic T cells and to autologous E- monocytic cells. T cells responsive to activated autologous T cell lines can also be expanded from PBMC. They may be CD4+ or CD8+ and recognize autologous T cells in the presence of autologous PBMC as feeder cells. These results suggest the presence of a T-T cell network in patients with endocrine autoimmune disease, which may have an important regulatory role in the disease process.
8225562 Elevated levels of xanthine oxidase in serum of patients with inflammatory and autoimmune 1993 Oct Sera of patients with various inflammatory and autoimmune rheumatic diseases were screened for the presence of xanthine oxidase (XOD) and compared to sera from healthy donors and patients with nonrheumatic diseases including AIDS, internal diseases, and different carcinomas. Up to 50-fold higher levels of XOD were detected in rheumatic sera (P < 0.001). In addition, serum sulfhydryls (SH) were determined as sensitive markers of oxidative stress. The SH status in rheumatic patients was diminished by 45-75% (P < 0.001) and inversely correlated to the concentration of serum XOD (R = 0.73), suggesting a causal interrelation. The depletion of serum sulfhydryls by the oxyradical-producing XOD/acetaldehyde system was mimicked successfully ex vivo in human serum from healthy donors. Cortisone treatment of patients suffering from systemic lupus erythematosus and rheumatoid arthritis impressively normalized elevated XOD concentrations in rheumatic sera to those of healthy controls. The participation of xanthine oxidase in the depletion of serum antioxidants in rheumatic patients is discussed in the light of substrate availability and Km values.
8104799 Chimaeric anti-CD4 monoclonal antibody cross-linked by monocyte Fc gamma receptor mediates 1993 Oct Previous studies have shown that murine anti-CD4 monoclonal antibody, cross-linked by rabbit anti-mouse immunoglobulin, could mediate apoptosis of murine CD4+ lymphocytes when they were stimulated by T cell receptor antibody. In this study, we have shown that the murine anti-CD4 monoclonal antibody, OKT4, can induce apoptosis in human CD4+ T cells stimulated by the recall antigen tuberculin purified protein derivative (PPD) only when cross-linked by rabbit anti-mouse immunoglobulin. The chimeric anti-CD4 monoclonal antibody, cM-T412 whose Fc fragment is human, was able to cause apoptosis without cross-linking by a second antibody. Similarly, abolition of PPD-induced proliferation of peripheral blood mononuclear cells by cM-T412 did not require cross-linking with rabbit anti-human immunoglobulin. Inhibition of proliferation by cM-T412 could be reduced by pre-treating monocytes with heat-aggregated human IgG. This suggested that monocyte Fc gamma receptors might be cross-linking the human Fc of cM-T412. Propidium iodide staining together with immunofluorescence showed that the apoptotic cells were indeed CD4+ lymphocytes. It is proposed that during treatment with cM-T412 in autoimmune disease such as rheumatoid arthritis, cM-T412-coated CD4 T cells, when they are subsequently stimulated by the unknown arthritogenic antigen, may undergo apoptotic cell death through cross-linking of cM-T412 on Fc gamma receptor-positive cells within the joint.
7689347 Molecular characterization of the GM 4672 human lymphoblastoid cell line and analysis of i 1993 Jul The GM 4672 lymphoblastoid cell line has been used in cell hybridization experiments with peripheral blood lymphocytes (PBLs) in order to generate human-human hybridomas that secrete immunoglobulins directed against a number of different autoantigens. The GM 4672 cells were fused with PBLs isolated from patients with rheumatoid arthritis or systemic lupus erythematosus, or from normal individuals, and the resulting hybridomas were screened for reactivity to platelets, erythrocytes, DNA, cardiolipin, human IgG-Fc, phosphatidylethanolamine, and for lupus anticoagulant activity. This report analyzes the results from 149 fusion experiments completed over a period of nine years. Fifty to sixty-six percent of the fusion experiments resulted in immunoglobulin-secreting clones, with an average of 15 clones/fusion. The hybridoma antibodies were predominantly of the IgM heavy chain isotype, and 67% expressed kappa light chains. Although most hybridoma antibodies (78%) recognized a single autoantigen, 22% recognized more than one autoantigen and were considered polyreactive. In addition, the light and heavy chain variable regions of the antibody secreted by the GM 4672 cell line were amplified by the polymerase chain reaction technique and sequenced. The GM 4672 light chain was encoded by a VkI gene and used a Jk4 minigene. The GM 4672 heavy chain was derived for the rearrangement of a gene from the VH4 subgroup and used a JH4 minigene. The 8 amino acid long diversity region was generated by the fusion of the DK1 and DLR2 genes. The hybridomas generated in fusion experiments, when examined, did not appear to secrete antibodies using the immunoglobulin variable regions derived from the GM 4672 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
8353983 Multicenter study of the safety/efficacy of misoprostol in the prevention and treatment of 1993 May Gastrointestinal symptoms and lesions are often associated with the clinical use of non-steroidal antiinflammatory drugs (NSAIDs). An open-label, single arm multicenter Italian study evaluated if misoprostol, a prostaglandin E1 analogue with gastroduodenal mucosal protective activity, was effective in the prevention and treatment of NSAID-induced gastroduodenal lesions. Patients affected by rheumatoid arthritis (RA) or osteoarthritis (OA), in treatment with NSAIDs and suffering from gastric symptoms or gastroduodenal lesions related to NSAID use, were admitted to the study. Gastrointestinal and arthritic symptoms were assessed before and after 4 weeks co-administration of an NSAID (the most frequent was diclofenac, used in 35% of the RA and in 22% of the OA patients, followed by piroxicam and tenoxicam respectively) + misoprostol (200 mcg two times daily in 58% of the cases, 200 mcg three times daily in 39%, 200 mcg four times daily in 3%). On admission and after 4 weeks of therapy a gastrointestinal endoscopy was performed to evaluate the condition of the gastroduodenal mucosa. Final results showed that: (i) NSAID-related gastric lesions were more frequent than duodenal lesions; (ii) when patients were given misoprostol and NSAIDs, 96% of them did not develop gastric lesions and 97% did not develop duodenal lesions; (iii) even when NSAID therapy was continued, gastric or duodenal lesions induced by NSAIDs healed or in any case did not worsen in 92% and 91% respectively of the cases; (iv) during the period of coadministration of NSAIDs+misoprostol, NSAID-related UGI symptoms disappeared or improved in 77% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)
8466865 Effects of isotype and Fc region on in vitro function of a mouse/human chimeric CD4 antibo 1993 Mar Murine CD4 mAbs have shown potential for the treatment of allograft rejection and autoimmune disorders including rheumatoid arthritis. Clinical usefulness of the murine mAbs has been limited by immunogenicity and a short circulating half-life. Mouse/human chimeric antibodies have been constructed, composed of the variable region of M-T412 (a murine G2a mAb specific for the human CD4 molecule) and human G1 (cM-T412 G1) or G4 (cM-T412 G4) Fc regions. F(ab')2 and F(ab) fragments of the murine G2a and chimeric G1 mAbs were generated by enzymatic digestion. The chimeric mAbs and all fragments retained the avidity and specificity of the murine M-T412 and were evaluated in in vitro assays measuring Ig production by pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC), sIL-2R produced by phytohemagglutinin-stimulated PBMC, and proliferation in response to tetanus toxoid, CD3 mAb plus IL-2, and mixed lymphocyte response (MLR). When PBMC were stimulated with tetanus toxoid, 10 ng/ml of cM-T412 G1 inhibited proliferation by 90%, while neither the cM-T412 G4, M-T412 G2a, nor any mAb fragment produced > 65% inhibition, even at 1000-fold higher concentrations. A similar pattern of inhibition was observed in MLR assays. In contrast, the F(ab')2 fragment of the cM-T412 G1 was as effective as the whole antibody in inhibiting PWM-stimulated IgM synthesis and PBMC proliferation in response to stimulation by a CD3 mAb plus IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)
8447695 6-Thioguanine nucleotide accumulation in erythrocytes during azathioprine treatment for sy 1993 Feb BACKGROUND: Owing to adverse pharmacokinetics, azathioprine treatment may fail to induce a satisfactory clinical response in systemic connective tissue diseases. The major intracellular cytotoxic metabolites of azathioprine are 6-thioguanine nucleotides (6TGNs). METHODS: To assess whether the erythrocyte accumulation of 6TGN is a clinically applicable index for monitoring azathioprine treatment, erythrocyte accumulation of 6TGN was measured in patients with rheumatoid arthritis (n = 12), systemic lupus erythematosus (n = 7), polyarteritis nodosa (n = 2), myositis (n = 1), or leukocytoclastic vasculitis (n = 1). Ages ranged from 28 to 75 (median 58) years. RESULTS: Erythrocyte accumulation of 6TGN varied among the patients from 20 to 303 (median value 95) nmol/mmol haemoglobin. No significant correlation was found between erythrocyte accumulation of 6TGN and the dose of azathioprine/kg body weight, the age of the patients, the duration of treatment, or the presence of myelotoxicity or hepatotoxicity. The interindividual coefficient of variation (CV) in the erythrocyte accumulation of 6TGN/mg azathioprine/kg body weight was 0.65. The median intraindividual CV in erythrocyte accumulation of 6TGN at an unchanged dose of azathioprine was 0.09 (19 patients; range 0.03-0.27). CONCLUSIONS: The low intraindividual variation compared with the high interpatient variation in erythrocyte accumulation of 6TGN implies that erythrocyte accumulation of 6TGN may be clinically applicable for monitoring azathioprine treatment. Prospective studies are needed to clarify the relation between the erythrocyte accumulation of 6TGN and the clinical response to treatment, and to establish recommendations for dose modifications.