Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8392855 | Role of the endothelial cell in osteoclast control: new perspectives. | 1993 Mar | The osteoclast is of central importance in the process of bone remodeling. Its function is regulated by hormones and locally produced factors. Endothelial cells occur in close proximity to the osteoclast. Some endothelial cell-derived products, including endothelins, nitric oxide, and reactive oxygen species, have been recently implicated as modulators of osteoclast function. Endothelins inhibit bone resorption and osteoclast margin ruffling (quiescence or Q effect) at concentrations similar to those effective for their primary vasoconstrictive action. Contrary to expectations, however, it has been shown that endothelin action on the osteoclast is not mediated through an elevation of cytosolic Ca2+. Nitric oxide (NO) produces marked cell retraction (retraction or R effect), but its detailed mode of action is unknown. However, it is clear that the effects of this autocoid are not due to enhanced cyclic guanosine monophosphate (cGMP) production, a transduction system commonly used by NO. Finally, the reactive oxygen species H2O2 has been shown recently to enhance osteoclastic activity. Thus, the reported effects of the endothelial cell-derived products on the osteoclast are generally consistent with a regulatory role for endothelial cells in osteoclast control and suggest the existence of unique activation pathways, well worth exploring further. Unravelling the responsible mechanisms may also help understand the pathophysiology of a range of bone and joint diseases. For example, in rheumatoid arthritis, there is increased H2O2 production from activated neutrophils, and bone resorption is a major pathophysiological feature. | |
| 8313934 | Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. | 1993 | AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 8105849 | Recombinant fusion toxins--a new class of targeted biologic therapeutics. | 1993 | The design and construction of a new class of recombinant therapeutic agents, receptor-specific cytotoxins, has occurred within the last 5 years. Development of a number of receptor-targeted fusion toxins has been based on a detailed understanding of the structure-function relationships of both diphtheria toxin and Pseudomonas exotoxin A, and availability of the nucleic acid sequences of each structural gene. A variety of fusion toxins in which the native receptor-binding domain of either diphtheria toxin or Pseudomonas exotoxin A has been genetically replaced with either a polypeptide hormone or growth factor have been constructed. These fusion toxins selectively intoxicate receptor-bearing cells in vitro and are active in a variety of animal model systems. DAB486IL-2, and IL-2 receptor targeted cytotoxin, is the first fusion toxin to be evaluated in patients. Phase I/II clinical trials have been performed in refractory leukemia/lymphoma, severe rheumatoid arthritis, and Type 1 diabetes. DAB486IL-2 has been administered to more than 200 patients, has been well tolerated, and has shown encouraging signs of potential efficacy in all three clinical indications. Thus, DAB486IL-2 represents a new class of targeted biological therapeutic response modifiers whose mode of action is based on selective elimination of target cells. | |
| 1481224 | The cortisone era: aspects of its impact. Some contributions of the Merck Laboratories. | 1992 Dec | The announcement in 1949, by Hench at the Mayo Clinic, that cortisone had a dramatic beneficial effect on bed-ridden patients suffering from rheumatoid arthritis ushered in the cortisone era. This medical landmark was made possible by the prior steroid research of distinguished chemists and biologists in several countries. The first partial synthesis of cortisone by Sarett was the culmination of a worldwide chemical effort. This work ultimately enabled the process research department at Merck, under the direction of Max Tishler, to perform the 37-step conversion of deoxycholic acid to cortisone on a scale that made the initial clinical trials possible. In spite of the enormity of the project, and the fact that neither of two closely related analogs of cortisone had shown any interesting biological activity. Merck elected to embark on this synthetically challenging project. The clinical results reported in 1949, combined with the complexity of the partial synthesis, stimulated highly innovative research to discover new routes to cortisone and to cortisol, the active hormone. This research, particularly in the pharmaceutical industry in the United States, Mexico, and Europe, demonstrated, among other things, the value of microbial transformations in synthetic sequences. The recognition that the chronic administration of cortisol produces several unexpected side effects stimulated an intensive effort in many countries to discover an analog with an improved therapeutic index. This led to more novel chemistry and many analogs were discovered that proved to be more potent than cortisol. Prednisolone, discovered at the Schering Corporation, was the first compound that combined a high level of anti-inflammatory activity with reduced salt retention. Derek Barton contributed greatly to steroid research during the 1950s by applying creative structural thinking to systematize a host of seemingly unrelated chemical and biological observations. The cortisone era had a profound impact on drug discovery also, since it led to the logical application of steric and electronic concepts to medicinal chemistry. Last, but not least, the cortisone era taught medicinal chemists many important lessons about drug-receptor interactions. | |
| 1516334 | Alumina versus polyethylene in total knee arthroplasty. | 1992 Sep | The cementless alumina total knee prosthesis, which uses alumina in the portions coming in contact with the bone and a combination of alumina and ultra-high molecular-weight polyethylene (UHMWPE) in the sliding portions, is referred to as a total condylar. Alumina total knee arthroplasty was performed on 137 patients, including 103 rheumatoid arthritis (RA) and 34 osteoarthrosis (OA) patients, from January 1982 to February 1985. The follow-up period was seven years 11 months and four years ten months, respectively. At follow-up evaluation, 108 patients were available for clinical and roentgenographic examinations, amounting to a 79% follow-up rate. At follow-up examination, 67 joints (62%) were completely pain free and 28 joints (26%) caused slight pain on bearing weight. Walking ability was recovered moderately in RA and markedly in OA. In RA, 14 of 84 knees were cemented and one knee was treated with loosening. Of 72 cementless implantations, 55 sustained displacing distally and one sustained loosening in the tibia, whereas 31 sustained displacing proximally and six sustained loosening in the femur. In OA, 21 cementless knees had 17 displacings in the tibia, and ten displacings and two loosenings in the femur. Scanning electron microscopy (SEM) observation of the UHMWPE surface in tibial plates revealed smoothing and burnishing. Alumina is far superior to metal for the sliding part, although it is not always best for the portion in contact with the bone. To resolve these problems, for cementless fixation, anchoring portions of Ti alloy and alumina implants were covered with beads and coated with hydroxyapatite. For cement fixation, "the interface bioactive bone cement technique" interposing hydroxyapatite granules between bone and cement was performed. | |
| 1400901 | Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases | 1992 May | Anti-pyruvate dehydrogenase (PDH) antibodies were determined in 1451 sera of patients with primary biliary cirrhosis (PBC) and several autoimmune rheumatic conditions by ELISA and immunoblotting. They were detected in sera of 93% of the patients with PBC (179 of 192 patients) in 60 of 277 (22%) patients with Sjogren's syndrome (SjS), 34 of 437 (8%) patients with scleroderma, 33 of 191 patients with SLE (17%), and 5 of 55 (10%) patients with rheumatoid arthritis (RA) but in none of the patients with polymyositis or the antiphospholipid syndrome. The ELISA studies were confirmed by immunoblots showing binding of autoimmune rheumatic sera to the same epitope (74 kd) of mitochondria that the PBC sera reacted with. The identical binding characteristics were also confirmed by protein competition assays with purified PDH. In 4 of 53 patients with SjS who were positive for anti-PDH, high titers as in PBC were detected. The anti-PDH antibodies in Sjogren's patients were associated with deranged liver function tests and extraglandular features but did not correlate with any other non-organ-specific antibody. Follow-up studies confirmed the association of the emergence of anti-PDH antibodies with defects in liver function tests. The antibodies were more prevalent in SLE and RA when they were associated with Sjogren's syndrome (30 and 18.8%, respectively). Among patients with different forms of scleroderma, anti-PDH antibodies were noted in subjects with systemic sclerosis, morphea, and Raynaud's phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 1555361 | Risk factors of avascular necrosis of the femoral head in patients with systemic lupus ery | 1992 Apr | A prospective study of systemic lupus erythematosus (SLE) patients under high doses of corticosteroid therapy (greater than 30 mg/day prednisolone) for a five-year period elucidated some risk factors of avascular necrosis of the femoral head (ANFH). A complete survey was performed on 62 patients, of whom nine patients developed ANFH during the period of study. The risk factors in the causation of ANFH were ascertained on the basis of characteristic clinical features of SLE, a typical pattern of laboratory data at the onset of ANFH, and the mode of glucocorticosteroid administration observed from a statistical point of view. The risk factors include stomatitis, drug-induced lupus, lupus erythematosus cell positive rheumatoid arthritis, interstitial pneumonitis, and thrombocytopenic purpura (characteristic clinical features); increased total cholesterol, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase, red blood cell, hemoglobin, and albumin/globulin; advanced renal failure (pattern abnormality of laboratory data); and a rash introduction of high-dose corticosteroid therapy (greater than or equal to 30 mg/day prednisolone) without corticosteroid preloading (mode of administration). | |
| 1567788 | Induction of human hsp60 expression in monocytic cell lines. | 1992 Mar | Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells. | |
| 11859380 | T-Cell Derived Lymphokines as Regulators of Chronic Inflammation: Potential Targets for Im | 1996 Feb | In recent years, compelling evidence has accumulated that inflammation results from a cascade of events that are orchestrated by cytokines. Cytokines are products of nonimmune and immune cells which regulate the recruitment, differentiation, and proliferation of inflammatory cells. Although there is redundancy in cytokine production and function, major pathways of cytokines have been identified. Besides macrophages, T cells represent important sources of pro- and anti-inflammatory cytokines. In support of a critical regulatory role of T cells in inflammation, two T cell subtypes characterized by different cytokine profiles have been described. TH1 cells produce interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and are prone to interact with macrophages. TH2 cells are producers of IL-4, IL-5, and IL-10 and are capable of supporting B cells and eosinophils. Here, we are providing evidence that different human inflammatory diseases are characterized by distinct in situ cytokine patterns. Giant cell vasculitis represents a typical TH1-like disease, whereas TH2 helper cells appear to be more important in rheumatoid arthritis. Given the association of different diseases with cytokine profiles, the question arises how the microenvironment influences cytokine pattern and thus disease and whether mediators produced at the site of inflammation could serve as therapeutic targets to modulate the cytokine cascade. Prostaglandin E(2) (PGE(2)) is an important inflammatory mediator. We have examined the influence of PGE(2) and the PGE analog misoprostol on T-cell function and T-cell cytokine production. Here, we describe that IL-2 and IFN-gamma production are sensitive to PGE(2) and misoprostol, whereas IL-4 and IL-5 are unaffected. Thus, in the presence of PGE(2), TH0 cells acquire a TH2-like function, whereas TH1-like aspects are suppressed. We suggest that PGE(2) and misoprostol might represent useful modulators of the cytokine network. | |
| 22823240 | Stromelysin (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase (TIMP-1 | 1995 | Scleritis is a severe and destructive inflammatory eye disease characterized by extensive extracellular matrix degradation. As in rheumatoid arthritis (RA), tissue destruction in scleritis may be mediated in part by matrix metalloproteinases such as collagenase (MMP-1) and stromelysin (MMP-3) which are normally kept in balance by endogenous inhibitors, such as tissue inhibitor of metalloproteinase (TIMP-1). To test this hypothesis, in situ hybridization was used to localize MMP-1, MMP-3 and TIMP-1 mRNA in diseased and normal scleral tissue using digoxigenin labelled probes. Strong expression of MMP-3 and TIMP-1 mRNA, but not MMP-1, was observed in the diseased scleral tissue. Infiltrating inflammatory cells such as macrophages and scleral fibroblasts were the primary source of MMP-3 and TIMP-1 expression. There was also relatively less TIMP-1 compared with MMP-3 mRNA expression in the inflammatory cells in scleritis tissue. In order to study regulation of metalloproteinase expression in ocular cells the authors established human scleral fibroblasts (HSF) in primary culture. Northern blot analysis was performed on total RNA extracted from HSF grown in serum free media. MMP-1 MMP-3 and TIMP-1 were constitutively expressed in these cells. Stimulation of HSF with pro-inflammatory cytokines likely to be present in scleritis, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), significantly induced MMP-3 and TIMP-1 mRNA expression. Using culture supernatants derived from the same cytokine stimulated scleral fibroblast the authors were able to detect MMP-3 protein production by Western blot analysis. They conclude that matrix metalloproteinase-3 mRNAs are present in scleritis tissue and may be induced by cytokines produced in the inflammatory process. | |
| 8896059 | Education for outpatients with rheumatic diseases. Evaluation of short-term and medium-ter | 1996 Jul | This prospective study was conducted to evaluate the short- and medium-term impact of the outpatient education sessions that have been available at the Cochin Teaching Hospital since 1992. Each patient was asked to complete a ten-item anonymous questionnaire at the beginning of the education session (evaluation 0), immediately after the session (evaluation 1), after six months (evaluation 2) and after 12 months (evaluation 3). Mean numbers of correct answers per patient were calculated. Eight education sessions were evaluated (osteoarthritis, osteoporosis, rheumatoid arthritis, back pain, conservative treatments, surgical treatments, low-calorie diets and high-calcium diets). One hundred twenty-four patients completed the first two questionnaires, 94 (75.80%) completed the six-month questionnaire and 75 (60.5%) completed the 12-month questionnaire. Mean numbers of correct answers were as follows: 5.7 before the session, 7.3 after the session (p = 0.0001), 7.2 after six months (p = 0.0001), and 7.9 after 12 months (p = 0.0001). These results demonstrate that the education sessions significantly improved patient knowledge in the short and medium term. Their impact on quality of life is being evaluated. | |
| 8841833 | The inhibitory effects of antirheumatic drugs on the activity of human leukocyte elastase | 1996 Jul | The serine proteinases elastase and cathepsin G from polymorphonuclear granulocytes play a critical role in articular cartilage degradation, not only as proteolytic enzymes able to degrade the extracellular matrix but also by additionally modulating the level of active matrix metalloproteinases, key enzymes of the proteolytic destruction of cartilage during rheumatoid arthritis. The aim of our study was to examine whether anti-inflammatory drugs and selected compounds inhibited elastase and cathepsin G, and also to determine whether it is necessary to use a highly purified elastase preparation to screen drugs for their ability to block the activity of this enzyme. Eglin C and the glycosaminoglycan-peptide complex DAK-16, at concentrations ranging from 10(-9) to 10(-4) M, dose-dependently inhibited elastase and cathepsin G while the nonsteroidal anti-inflammatory drugs oxyphenbutazone, phenylbutazone, sulfinpyrazone and diclofenac-Na required high concentrations to demonstrate some inhibitory effects on the activity of both enzymes. None of the other anti-inflammatory drugs tested at a concentration of 10(-4) M such as acetylsalicylic acid, dexamethasone, indomethacin, ketoprofen, naproxen, oxaceprol, pirprofen and tiaprofenic acid demonstrated any marked inhibitory activity on either of these proteinases. Only a few drugs, when dosed therapeutically, achieved synovial fluid concentrations sufficient to inhibit the activities of both proteinases. The antirheumatic drugs demonstrated similar inhibition profiles in purified or partially purified elastase preparations. Thus the leukocyte extract containing the partially purified elastase and cathepsin G which can be rapidly and easily prepared at low costs appears to be an efficient mean of screening potentially new therapeutic agents for their ability to inhibit leukocyte elastase and cathepsin G. | |
| 19078048 | Nonsteroidal antiinflammatory drugs and their effects. | 1996 Jun | New information about the mechanisms of action of nonsteroidal antiinflammatory drugs (NSAIDs) offers potential opportunities to minimize the complications of these commonly used drugs. Traditionally, the accepted mode of action of the NSAIDs has been the inhibition of prostaglandin synthesis through either reversible or irreversible binding to cyclooxygenase (COX). However, drugs that are weak prostaglandin synthesis inhibitors in vitro have been demonstrated to be equally as effective in vivo as other "stronger" COX inhibitors in treating inflammatory diseases, suggesting the importance of other actions of these drugs. Various NSAIDs have been used for years to palliate pain and inflammation in many different disease processes; unfortunately, they have not been demonstrated to alter the natural history of disease such as rheumatoid arthritis. Perhaps that is because prostaglandins do not play a large role in most inflammatory diseases; alternatively, it might be attributable to the inability of NSAIDs to exert their full effects because of their potential toxic reactions.An understanding of the effects of cyclooxygenase inhibition has been further complicated by the recently described second isoenzyme of prostaglandin synthase. One form of cyclooxygenase appears to be important in the maintenance of normal physiologic functions (COX-1), whereas the other form is induced primarily in sites of inflammation (COX-2). Even if inhibition of cyclooxygenase is only one mechanism of action for these drugs, with only some of the potential toxic effects modulated by the inhibition of prostaglandin synthesis such as inhibition of COX-1, an understanding of the actions of the two isoforms of cyclooxygenase is an important step in further delineating the inflammatory cascade. Ideally, the treatment of inflammation could be improved by inhibiting the effects of COX-2 without inhibiting COX-1 activity. Thus, some potential side effects of the NSAIDs might be alleviated. The presently available NSAIDs all affect both COX-1 and COX-2, although not equally. There are also data describing some of the NSAIDs as less toxic to the gastrointestinal mucosa because of their chemical composition. These data are typically based on in vitro experiments that use varying methodologies, making it difficult to compare the effects of any one NSAID between studies.This paper presents a brief review of several of the newly described effects of the NSAIDs and concentrates on the possible implications of the experimentally observed COX-2-selective effects of these clinically useful antiinflammatory agents. | |
| 8707778 | Hypopigmented skin lesions associated with atopic dermatitis in asthma. | 1996 | The association of vitiligo and other skin pigmentary disorders has been well shown with autoimmune diseases, i.e., systemic lupus erythematosus, rheumatoid arthritis. Furthermore, in certain diseases such as diabetes mellitus and adrenal insufficiency the incidence of pigmentation disorders is higher than in the general population. A total of 53 male and 46 female patients with a diagnosis of asthma, based on clinical findings and pulmonary function tests (PFT), were thoroughly examined for the presence of hypopigmented skin lesions and compared with 100 nonasthmatic controls with a similar demographic distribution. The patients were questioned regarding the history of steroid treatment in the past and present and subdivided into five groups based on the duration of therapy. Adrenal gland function was tested by 8:00 A.M. serum cortisol concentration in the group of patients with a history of steroid use as well as in some patients without this history. These patients were also tested for absolute lymphocyte and eosinophil count. Hypopigmented lesions were noted in 36.4% of asthmatic patients and in 11% nonasthmatic controls (p-value < 0.01). There were no differences in the location, but the size of lesions per patient was larger in the asthmatic than the control group. Twenty of 55 patients who had a history of steroid treatment in the past had hypopigmented skin lesions as compared to 16 of 42 patients who had no history of steroid treatment. We conclude that there is a higher coincidence of hypopigmented skin lesions, mainly vitiligo-type in asthmatic patients, compared to the general population, which is not related to a history of steroid treatment or incidence of adrenal insufficiency in these patients. | |
| 8720080 | Glycosylation and biological activity of CAMPATH-1H expressed in different cell lines and | 1995 Dec | CAMPATH-1H (where CAMPATH is a trade mark of Wellcome group companies), a humanized IgG antibody used in the therapy of lymphoma, leukaemia and rheumatoid arthritis, has been expressed in Chinese hamster ovary, Y0 myeloma and NS0 myeloma cell lines. These engineered cell lines were grown under different culture conditions, and the antibody isolated and purified. N-Linked oligosaccharides, on the CH2 heavy chain region of the antibody, were isolated and analysed by hydrazinolysis, high-performance anion-exchange chromatography with pulsed amperometric detection, laser-desorption mass spectrometry and sequential exoglycosidase treatment. Both the glycosylation pattern and the biological activity of CAMPATH-1H, as measured by antibody-dependent cell-mediated cytotoxicity, were markedly affected by the cell line used to express the antibody. It is concluded that glycosylation of the antibody may be important in the clinical outcome of therapy. | |
| 8560604 | Renal amyloidosis in childhood. An overview of the topic with 25 years experience. | 1995 Oct | Amyloidosis is a heterogeneous group of diseases characterized by extracellular accumulation of an eosinophilic, hyalin and proteinaceous material containing mucopolysaccharide substance in various tissues and organs. Knowledge about the chemical structure of amyloid fibril proteins has led to the recognition of various forms of amyloidosis including Amyloid-A (AA), Amyloid-L (AL), hereditary, senile, dialysis-related, localized and cerebral amyloidosis. It is now recognized that all types of amyloid contain amyloid P (AP) component which is derived from the serum amyloid P component, a normal circulating glycoprotein and a member of the pentraxin family. A recent classification proposed by WHO-IUIS (Nomenciature Subcommittee) is based on the chemical nature of amyloid fibris rather than their clinical and pathologic features. The kidneys are frequently involved, and renal failure is the major cause of death. Childhood renal amyloidosis is almost always secondary (reactive, AA type) and usually associated with chronic inflammatory, infectious and heredofamilial diseases. In developed countries, rheumatoid arthritis is the most common cause of renal amyloidosis, while in developing countries patients with familial Mediterranean fever (FMF) (untreated) and chronic suppurative infections constitute a large proportion of renal amyloidosis cases. No specific therapy is currently available for amyloidosis. Once renal amyloidosis develops, progress to end-stage renal failure is almost inevitable within 2-13 years. The aim of treatment is to give effective supportive therapy and to control the underlying diseases by colchicine, alkylating agents and appropriate antibiotics. The prognosis of patients with end-stage renal failure can be improved by maintenance dialysis and renal transplantation. The growing knowledge about the pathogenesis and chemical nature of amyloid fibris may open up further avenues for the discovery of specific therapeutic modalities against amyloidosis. | |
| 7482575 | Comparative efficacy and toxicity of desferrioxamine, deferiprone and other iron and alumi | 1995 Oct | The efficacy and toxicity aspects of the iron and aluminium chelating drugs desferrioxamine and deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one), have been compared. Major emphasis was given in the use of these two and also of other chelators in conditions of iron overload, imbalance and toxicity, as well as the incidence and possible causes of toxic side effects in both animals and humans. The chemical basis of chelation and the interaction of these chelators with the iron pools are discussed within the context of clinical application in iron overload and other conditions such as renal dialysis, rheumatoid arthritis, cancer, heart disease, malaria, etc. The design and development of new orally active alpha-ketohydroxypyridine and other chelators are considered and compared with 14 other chelators which have been previously tested in man for the removal of iron, most of which, however, were later abandoned because of low efficacy or major toxicity. The design of new therapeutic protocols based on the pharmacological, toxicological and metabolic transformation properties of the chelating drugs is also being considered, within the context of maximising their efficacy and minimising their toxicity. Overall, oral deferiprone appears to be as effective as s.c. desferrioxamine in the removal of iron and aluminium in man and to have a similar but different toxicity profile from desferrioxamine in both animals and man. The low cost and oral activity of deferiprone will make it the drug of choice for the vast majority of patients, who are not currently being chelated either because they cannot afford the high cost of desferrioxamine therapy or are not complying or have toxic side effects with its s.c. administration. | |
| 7657288 | Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug | 1995 Sep | Diclofenac is a nonsteroidal anti-inflammatory drug approved in the United States in 1988 for the treatment of patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis. To characterize the clinical, biochemical, and histological features and possible mechanisms of hepatic injury associated with its use, a retrospective analysis was undertaken of 180 patients whose cases were reported to the Food and Drug Administration from November 1988 through June 1991, as having had possible adverse reactions to diclofenac. Of the reported 180 cases, 79% were female, 71% were 60 years of age or older, and 77% had osteoarthritis. Sixty-seven percent of the cases were detected by symptoms and the remainder by abnormal laboratory tests. Seventy-five percent of the symptomatic patients (90 of 120) were jaundiced. Seven of the 90 icteric patients died. The biochemical pattern of injury was hepatocellular or mixed hepatocellular in 66% of cases. Only 8% had a pattern of cholestatic injury. The remainder, with modestly increased values of both transaminases and alkaline phosphatase, were considered "indeterminate," i.e., either mild hepatocellular or anicteric "cholestatic" injury. Sections of liver from 21 cases were available for study. Hepatic injury was apparent by 1 month after starting the drug in 24%, by 3 months in 63%, and by 6 months in 85% of cases. The latent period in 12% was 6 to 12 months, whereas in 3% it was greater than 12 months.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 8579904 | Modulation of osteoclast differentiation by local factors. | 1995 Aug | Bone-resorbing osteoclasts are of hemopoietic cell origin, probably of the CFU-M-derived monocyte-macrophage family. Bone marrow-derived osteoblastic stromal cells play an important role in modulating the differentiation of osteoclast progenitors in two different ways: one is the production of soluble factors, and the other is cell-to-cell recognition between osteoclast progenitors and osteoblastic stromal cells. M-CSF is probably the most important soluble factor, which appears to be necessary for not only proliferation of osteoclast progenitors, but also differentiation into mature osteoclasts and their survival. A number of local factors as well as systemic hormones induce osteoclast differentiation. They are classified into three categories in terms of the signal transduction: vitamin D receptor-mediated signals [1 alpha,25(OH)2D3]; protein kinase A-mediated signals (PTH, PTHrP, PGE2, and IL-1); and gp130-mediated signals (IL-6, IL-11, oncostatin M, and leukemia inhibitory factor). All of these osteoclast-inducing factors appear to act on osteoblastic cells to commonly induce osteoclast differentiation factor (ODF), which recognizes osteoclast progenitors and prepares them to differentiate into mature osteoclasts. This line of approach will undoubtedly produce new ways to treat several metabolic bone diseases caused by abnormal osteoclast recruitment such as osteoporosis, osteopetrosis, Paget's disease, rheumatoid arthritis, and periodontal disease. | |
| 7730639 | Tenidap-modulated proinflammatory cytokine activation of a monocyte cell line. | 1995 May 15 | Dysregulated cytokine production, in particular of the monokines IL-1, IL-6, and TNF, has been implicated in the inflammatory response in rheumatoid arthritis and in promoting the ensuing tissue destruction. The 3-substituted 2-oxindole tenidap has proven anti-inflammatory actions both in vivo and in vitro, among which is the inhibition of TNF and IL-1 production by monocytes following activation by LPS. We have investigated this ability to modulate cytokine activity by studying its effects on cytokine-monocyte interactions and in particular IL-6 production, with the THP-1 monocyte cell line. Tenidap inhibited IL-6 production in a dose-dependent manner when cells were stimulated with a combination of TNF-alpha and IFN-gamma. It also inhibited the priming effect of IFN-gamma, preventing the super-induction of IL-6 production following subsequent stimulation with TNF-alpha and IFN-gamma. These effects occurred under conditions in which the cells were not irreversibly altered with respect to their protein synthetic activity. IFN-gamma-induced up-regulation of HLA-DR was also inhibited by tenidap. Tenidap appears to affect some aspect of the IFN-gamma activation pathway, possibly the differentiation of these immature monocytes to a more mature phenotype. The data presented here indicate that tenidap has the potential to modulate the cytokine network in chronic disease. |