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Biomedical subjects

L S Simon

Publications and source records attributed to L S Simon.

At least 37 records · Page 2Linked to original sources
PubMed1999

Osteoarthritis: a review.

In 1994, the Centers for Disease Control and Prevention reported that by the year 2020, arthritis will have the largest increase in numbers of new patients of any disease in the United States. The term arthritis refers to many diseases, the most common of which is osteoarthritis (OA). OA affects at least 16 million Americans, most of whom are older than 60 years. The disease is usually defined using radiologic criteria. More than 80% of people older than 75 years are symptomatic of OA. Considering cost of diagnosis, therapy (nonpharmacologic, pharmacologic, and surgical), side effects of therapy, and lost productivity, it is one of the more expensive and debilitating diseases in the United States. Given the large numbers of patients and the expense of the disease, it is not surprising that the diagnosis and care of patients with OA have come under scrutiny. The following article will provide some background on the disease and discuss management approaches that view the patient as a whole.

Humans↗
PubMed1999

The evolution of arthritis antiinflammatory care: where are we today?

Nonsteroidal antiinflammatory drugs (NSAID) are among the most commonly used drugs. Due to age-related changes in the gastrointestinal (GI) mucosa, the elderly are at increased risk of NSAID-induced gastropathy. Known risk factors include age > 60 years, concomitant glucocorticoid therapy, history of peptic ulcer disease or GI bleeding, and presence of significant comorbid conditions. Combinations of these risk factors substantially increase the likelihood of the development of a serious GI event in patients taking NSAID. The pathogenesis of NSAID-induced GI mucosal injury involves depletion of prostaglandins. Prostaglandin analog misoprostol is effective in preventing NSAID-induced gastric and duodenal ulcers and serious ulcer complications. The single tablet formulation of diclofenac and misoprostol is for patients at high risk of developing GI toxicity. This agent has been shown to provide antiinflammatory and analgesic activity equivalent to that of diclofenac, but with a significantly reduced incidence of GI ulceration compared with traditional NSAID. The finding that there are two isoforms of the enzyme prostaglandin synthase or cyclooxygenase (COX) has led to the search for compounds that inhibit only the isoform associated with the development of inflammation (COX-2), while sparing the isoform involved in normal physiologic processes. All NSAID inhibit both isoforms. Compounds specific for COX-2 promise to provide potent antiinflammatory and analgesic effects without the toxicity of NSAID, as well as having potential applications in other medical conditions.

Anti-Inflammatory Agents↗
PubMed1999

Arthritis: new agents herald more effective symptom management.

For physicians and patients alike, managing the symptoms of rheumatoid and osteoarthritis is an ongoing challenge. Myriad therapies are available, although virtually all provide only temporary relief and produce side effects that interrupt long-term use. New disease-modifying antirheumatic drugs, biologic response modifiers, and cyclooxygenase inhibitors offer the promise of more effective, longer lasting symptom management and, in some cases, reduced side effects. The population of older persons affected by arthritis continues to grow. Increased familiarity with these new treatments will aid primary care physicians in helping older patients better manage their arthritis during the next decade.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects.

OBJECTIVE: To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme. METHODS: Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function. RESULTS: The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo. CONCLUSION: SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.

Adult↗
PubMed1998

Biology and toxic effects of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) continue to be important therapeutically. The development of drugs that are highly COX-2 selective has led to interesting new findings about their effects and potential toxic reactions. This year there were interesting observations about the effects of individual NSAIDs on the gastrointestinal mucosa, risk factors for sustaining an NSAID-induced gastric or duodenal ulcer, and there has been progress in further understanding what may or may not work to prevent a toxic reaction. Furthermore, information has been gathered about the effects of NSAIDs on colorectal polyps and the development of cancers.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Cyclooxygenase in biology and disease.

Cyclooxygenase (COX), the key enzyme required for the conversion of arachidonic acid to prostaglandins was first identified over 20 years ago. Drugs, like aspirin, that inhibit cyclooxygenase activity have been available to the public for about 100 years. In the past decade, however, more progress has been made in understanding the role of cyclooxygenase enzymes in biology and disease than at any other time in history. Two cyclooxygenase isoforms have been identified and are referred to as COX-1 and COX-2. Under many circumstances the COX-1 enzyme is produced constitutively (i.e., gastric mucosa) whereas COX-2 is inducible (i.e., sites of inflammation). Here, we summarize the current understanding of the role of cyclooxygenase-1 and -2 in different physiological situations and disease processes ranging from inflammation to cancer. We have attempted to include all of the most relevant material in the field, but due to the rapid progress in this area of research we apologize that certain recent findings may have been left out.

Animals↗
PubMed1998

The classification of cyclooxygenase inhibitors.

In summary, precise classification of COX inhibitors has important clinical implications for efficacy and toxicity. However, classification of these agents clinically is difficult because there are insufficient data to predict correlations between biochemical and pharmacologic properties and the clinical effect of a given agent. In any case, specific COX-2 inhibitors are expected to show antiinflammatory and analgesic activities equivalent to those of NSAID, as well as significant reductions in the incidence of the life threatening side effects (i.e., GI bleeding) associated with COX-1 inhibition. The advantages of preferential COX-2 inhibitors may be more subtle and therefore more difficult to verify in clinical trials.

Animals↗
PubMed1997

Biologic effects of nonsteroidal anti-inflammatory drugs.

The nonsteroidal antiinflammatory drugs (NSAIDs) continue to be important therapeutic interventions for the treatment of pain and inflammation. Investigators continue to produce new information about their biologic effects, including their actions as well as their toxic effects and methods to decrease the potential side effects associated with their use. This year many papers have been published speculating about those NSAIDs that are reported to selectively inhibit the isoform of the cyclooxygenase enzyme that is induced in inflammatory conditions (Cox-2) rather than that associated with normal physiologic function (Cox-1). Reports have shown that the more Cox-2-selective NSAIDs (from three- to 10-fold more selective for Cox-2 over Cox-1) seem to have less gastrointestinal toxicity associated with their use; however, little evidence has yet emerged from phase I, II, or III studies about the clinical effects of the highly selective Cox-2 inhibitors (300-fold or more selective for Cox-2 over Cox-1). In addition, intriguing animal studies have shown the effects of knockout of the genes controlling the activities of either Cox-1 or Cox-2 in mice.

Animals↗
PubMed1997

NSAIDs and the elderly. Toxicity and economic implications.

Despite their propensity to cause toxicity, nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed for older patients for painful musculoskeletal conditions, many of which are noninflammatory in nature. In some settings, simple analgesia with paracetamol (acetaminophen) or tramadol may be just as effective as NSAIDs. The benefits of therapy with NSAIDs must be weighed against their potential risks. With the anticipated growth of the elderly population, the economic implications of NSAID use in older patients are staggering. Estimates of the total cost of prescribing NSAIDs to the elderly must include the additional costs of gastroprotective agents, prophylaxis, laboratory monitoring, physician evaluations and interventions for adverse effects. Misoprostol may be cost effective as primary prophylaxis of NSAID-induced ulcer disease in some elderly patients. NSAIDs may reduce disability and improve quality of life, thereby offsetting their costs. To date, the direct, indirect and intangible cost of NSAIDs and cost offsets have not been systematically evaluated in the elderly. At this juncture, NSAIDs may be used judiciously in older patients, and misoprostol should be considered in high risk patients. Further studies to assess the economics of NSAIDs in the elderly population are warranted.

Aged↗
PubMed1996

Actions and toxicity of nonsteroidal anti-inflammatory drugs.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) continues to be an important therapeutic intervention throughout the world for patients with pain and inflammation. The six major classes of NSAIDs (including the salicylates) bear the common property of inhibiting cyclooxygenase, the enzyme that catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to yield prostaglandins. Anecdotal evidence has accumulated that the nonacetylated salicylates are as efficacious as the other NSAIDs, but there have been few controlled trials demonstrating that they are reasonable anti-inflammatory agents. This paper discusses the newest of the available clinical observations that nonacetylated salicylates are as efficacious as one of the newer NSAIDs in patients with rheumatoid arthritis. Because the nonacetylated salicylates are weak prostaglandin inhibitors, several other non-prostaglandin mediated mechanisms of action for the NSAIDs have been postulated and are described in this paper. In addition to papers describing NSAID effects on cartilage, this year several interesting papers described further effects of tenidap, a novel NSAID presently in development. Other papers reviewed attempts to develop NSAIDs with less severe gastrointestinal effects. Some reports discuss the use of topical NSAIDs, which are not clearly better than oral preparations. Data are also reviewed demonstrating that misoprostol effectively decreased significant poor gastrointestinal outcomes in patients who were treated with this NSAID for 6 months. New treatment regimens for decreasing misoprostol-induced toxicity are also reviewed. Finally, the effects of NSAID prophylaxis in preventing heterotopic bone formation in patients with osteoarthritis who undergo hip replacement surgery are noted.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels.

OBJECTIVE: To evaluate the acute toxicity, potential efficacy, and effects on the soluble interleukin 2 receptor (sIL-2R) of recombinant human interferon gamma (rIFN-gamma) in patients with systemic sclerosis (SSc). METHODS: A multicentered, pilot clinical trial of rIFN-gamma was performed on 20 patients (15 women, 5 men, mean age 45 years) with active cutaneous SSc (mean disease duration 36 months) to evaluate it potential as a novel therapy for this untreatable disorder. After one week of rIFN-gamma 0.01 mg/m2/day, subjects self-administered rIFN-gamma 0.1 mg/m2/day intramuscularly for a total of 18 weeks. The major outcome variable was a modified skin score (0 = normal skin, 3 = hidebound skin) measured and summed from 15 anatomic areas of the body. sIL-2R levels were measured by ELISA at entry and exit from the study. RESULTS: The clinical results were modest at best. Nine of 20 patients achieved at least a 20% reduction in skin score, with one patient showing almost total remission of all skin abnormalities. The mean skin score at entry for all subjects was 22.8 +/- 8.9 and over the course of the trial improved marginally compared to baseline (mean change -4.72 +/- 6.62; p = 0.008). However, 8 subjects did not change appreciably while in the trial. Antibodies to Scl-70 were observed in only 5 patients (all with diffuse scleroderma) and were not associated with either response to or complications from therapy. The adverse reactions were frequent and occasionally severe. Ten subjects were withdrawn because of exacerbation of Raynaud's symptoms (n = 5), constitutional symptoms (n = 2), development of renal crises (n = 2), and mild pancytopenia (n = 1). Minor laboratory abnormalities were common and included elevation of cholesterol, triglycerides, hepatic transaminases, and reduction in white blood cell count. Compared to controls, mean sIL-2R was markedly elevated at entry (1309 +/- 495 U/ml; p = 0.0001) and did not change appreciably at exit. Spearman correlation analysis showed a trend but no statistically significant association of skin score with sIL-2R (R = 0.408; p = 0.074). However, sIL-2R was significantly correlated with erythrocyte sedimentation rate (R = 0.542; p = 0.0165). A subset analysis revealed that skin score (p = 0.0001) and sIL-2R (p = 0.00170) were significantly higher at baseline for patients with diffuse scleroderma compared to patients with limited disease. CONCLUSION: rIFN-gamma may be beneficial for some patients with SSc, but the benefit appears marginal for most individuals and the side effects frequent. Although sIL-2R was elevated in many of the patients with SSc, it did not appear to be correlated with activity of cutaneous disease or response to therapy.

Adult↗
PubMed1996

Risk factors for serious nonsteroidal-induced gastrointestinal complications: regression analysis of the MUCOSA trial.

OBJECTIVES: This analysis evaluated the clinical and demographic risk factors for a suspected, serious nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complication in everyday clinical practice and calculated the risk reduction associated with misoprostol therapy in these "at-risk" patients. METHODS: Using logistic regression analysis, the data set from a randomized, parallel, placebo-controlled trial of misoprostol in 8,843 rheumatoid arthritis patients taking NSAIDs (the Misoprostol Ulcer Complications Outcomes Safety Assessment trial) was modeled to identify risk factors for GI adverse events. The dependent variable was defined as a "suspected serious GI complication," and the independent variables included demographic features, level of functional disability, presence of co-morbid diseases, use of certain drugs, and treatment arm. RESULTS: Two hundred forty-two suspected serious GI complications were observed; 102 occurred in the misoprostol treatment group (risk: 2.32%) and 140 in the placebo group (risk: 3.15%). Overall risk reduction due to misoprostol therapy was 26.6% (confidence interval 5.5%-42.9%, P < .05). However, in patient groups with identified risk factors, misoprostol use decreased the risk for an adverse GI event by 38.3%-87.3%. Specifically, those who benefitted significantly from therapy with misoprostol were patients with a history of peptic ulcer disease (risk reduction 52.4%), history of previous GI bleeding (risk reduction 50%), history of significant cardiovascular disease (risk reduction 38.3%), significant functional disability (risk reduction 87.2%), and patients whose symptoms required concomitant antacid use (risk reduction 48.3%). CONCLUSION: We conclude that in everyday practice, patients who require chronic NSAID therapy and who have specific clinical risk factors may benefit from misoprostol co-therapy.

Aged↗
PubMed1995

Use of magnetic resonance imaging and positron emission tomography in the assessment of synovial volume and glucose metabolism in patients with rheumatoid arthritis.

OBJECTIVE: To measure the anatomic and physiologic changes in the synovium of patients with active rheumatoid arthritis (RA) before and after the initiation of treatment with low-dose systemic glucocorticoids and methotrexate (MTX). METHODS: Two patients with RA with active synovitis involving the carpus were evaluated by imaging parameters at baseline and again after 14 weeks (of treatment with low-dose prednisone and MTX). Standard clinical parameters, laboratory measurements, and contrast-enhanced magnetic resonance imaging (MRI) (synovial volume estimate) and positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (18-FDG) (synovial metabolism estimate) were performed. RESULTS: Compared with baseline, standard clinical parameters (i.e., joint count, joint index, morning stiffness, global assessments of arthritis activity, and erythrocyte sedimentation rate) improved dramatically in both patients after treatment with low-dose prednisone and MTX. In concert with this trend, the synovial volume of the affected wrist was reduced by 60%, and 76% and the metabolism of 18-FDG was reduced by 66% and 69% in the 2 patients. CONCLUSION: These preliminary observations indicate that a volumetric estimate of inflamed synovium (using contrast-enhanced MRI) and quantification of synovial deoxyglucose metabolism (using PET) are technically feasible and, in the 2 reported cases, correlate well with standard outcome measures. These imaging modalities may provide new objective parameters to determine RA disease activity and effectiveness of antirheumatic medications; however, the potential clinical utility of these measures remains to be defined.

Arthritis, Rheumatoid↗
PubMed1995

Actions and toxicity of nonsteroidal anti-inflammatory drugs.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) continues to grow, despite the known potential toxic risks associated with it, probably because these drugs palliate pain and inflammation and are relatively well tolerated. Unfortunately, NSAID use has not been shown to have long-term beneficial effects on the natural history of inflammatory diseases. Regardless, the NSAID market has reached the 2.2 billion dollar mark, with 73,000,000 prescriptions written yearly throughout the world. Although individual toxic events are relatively rare, the large number of NSAID prescriptions ensures that all the possible potential adverse events will likely be encountered by some patients. Over the past year, interesting additions to the literature have been made regarding the mechanisms of action as well as adverse reactions associated with NSAIDs.

Animals↗