Search PubMed⌕ Search

Biomedical subjects

L S Simon

Publications and source records attributed to L S Simon.

At least 19 recordsLinked to original sources
PubMed2004

Randomized controlled trials in systemic lupus erythematosus: what has been done and what do we need to do?

The study of systemic lupus erythematosus (SLE) is a challenging undertaking. It is difficult to assess outcomes in SLE randomized controlled trials (RCTs), and this is illustrated by the lack of new therapies approved for use in lupus. In a disease that is waxing and waning, and requires constantly changing medications, identifying treatment effects of new therapies may be difficult, and the use of potentially toxic therapies requires a rigorous understanding of the benefit to risk ratio. Some issues that need to be considered by the investigator in designing these studies include: 1) should the trial focus on patients with active or inactive disease; 2) which of the measures of disease activity should be used or should prevention of flares be examined; 3) should the study focus on defined organ specific endpoints or utilize one of the available disease activity indices to identify changes in disease activity; 4) should the trial be a superiority trial or an equivalence trial. This review summarizes the critical issues involving the design of studies in lupus and provides the reader with suggestions and recommendations for consideration before embarking on trials in this area.

Humans↗
PubMed2001

Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors.

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation but are frequently associated with gastrointestinal side effects, including life-threatening bleeding or perforation of gastroduodenal ulcers. Conventional NSAIDs are nonselective inhibitors of two isoforms of cyclooxygenase (COX): COX-1 and COX-2. The inhibition of COX-1 is believed to be responsible for inducing mucosal injury primarily by impairing prostaglandin-dependent mucosal protective mechanisms. The latest development in reducing the incidence of ulcers and ulcer complications associated with conventional NSAIDs is the use of recently approved COX-2-specific inhibitors (CSIs). This article critically reviews the data on gastrointestinal toxic side effects for conventional NSAIDs without as well as with prevention therapy. In addition, we compare these data with those for the CSIs, namely, celecoxib and rofecoxib. Finally, we offer recommendations on the clinical use of these drugs, emphasizing the need to balance clinical effectiveness with the avoidance of potential gastrointestinal side effects.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

COX-2 inhibitors. Are they nonsteroidal anti-inflammatory drugs with a better safety profile?

In the treatment of arthritis, NSAIDs are some of the most commonly used drugs, although the prescription of such drugs has been questioned due to their inherent risks for gastrointestinal compromise, platelet effects, and the potential for renal toxicity with long-term use. With the availability of celecoxib and rofecoxib, 2 cyclooxygenase (COX-2) inhibitors (or COX-1 sparing agents) as new forms of NSAIDs, these issues have become magnified not only in the context of risk-to-benefit ratios but also interms of pharmacoeconomics because they have been proven to be equally efficacious as the nonselective NSAIDs, with an improved safety profile particularly within the gastrointestinal tract, but at a significantly increased cost.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. MAIN OUTCOME MEASURES: Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. RESULTS: For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255

Aged↗
PubMed2000

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.

Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

Animals↗
PubMed2000

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.

In summary, COX-2 is a highly regulated gene product that catalyzes the local production of PGs in pathologic and physiologic situations (Figure 1). It is clear that COX-2 is the isoform responsible for production of the PGs that mediate inflammation, pain, and fever. However, the role for COX-2 in normal physiology is still being defined. Specific COX-2 inhibitors represent a significant conceptual advance in therapy for patients with arthritis. Although there is no expectation of superior efficacy, clinical trials suggest that efficacy will be comparable with that of nonselective NSAIDs. Clinical trials demonstrate the potential for clinically meaningful reductions in the incidence of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer, perforation, and GI bleeding. Over the next several years, treatment of large numbers of patients with specific COX-2 inhibitors will help to define the biology of COX-2. The magnitude of this advance in the therapy of rheumatic diseases is yet to be accurately determined, but the development of specific COX-2 inhibitors may afford significant new treatment options for many patients.

Cyclooxygenase 2↗
PubMed2000

New and future drug therapies for rheumatoid arthritis.

Several new drugs have recently been introduced for the treatment of rheumatoid arthritis (RA). These include the cyclooxygenase-2 inhibitor, celecoxib, the anti-tumour necrosis factor agents, etanercept and infliximab, and the new disease-modifying anti-rheumatic drug (DMARD), leflunomide. In clinical trials, celecoxib has been shown to be effective for palliation of the signs and symptoms of RA and to have fewer gastrointestinal side-effects than conventional non-steroidal anti-inflammatory drugs. Etanercept and infliximab are indicated for reduction of the signs and symptoms of RA in patients who have failed to respond adequately to previous DMARDs. The clinical success rate in etanercept-treated patients is significantly better than in placebo-treated patients for up to 18 months. Leflunomide is a DMARD with a novel mechanism of action that has been approved as a first-line treatment for RA. Treatment with leflunomide results in significantly greater improvement of the signs and symptoms of RA than placebo for up to 2 yr and slows radiographically assessed disease progression. Agents are currently in development that will be targeted against components of the immune activation and co-stimulatory pathways. These include antibodies directed against the interleukin-2 receptor and blockers of the CD28 and CD40 co-stimulatory pathways. Continuing research into the pathogenesis of RA will undoubtedly identify even more effective therapeutic approaches for the management of this disease in the future.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Are the biologic and clinical effects of the COX-2-specific inhibitors an advance compared with the effects of traditional NSAIDs?

This has been an unusual year for the accumulation of evidence regarding the clinical effects of inhibition of cyclooxygenase (COX)-1 and COX-2. This article reviews the available data regarding the clinical effects of the new COX-2-specific inhibitors, and speculates about the importance of the data as they relate to the treatment of patients with chronic pain and/or inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

DMARDs in the treatment of rheumatoid arthritis: current agents and future developments.

The purpose of this paper is to review the benefits and limitations of current disease-modifying antirheumatic drugs (DMARDs) used for the treatment of rheumatoid arthritis (RA). Literature about DMARD use in RA, both as monotherapy and in combination therapy, is reviewed. The efficacy and safety of methotrexate, antimalarials, gold-containing compounds, sulphasalazine, D-penicillamine, azathioprine and cyclosporin, as well as several new antirheumatic agents are considered. Controlled short-term clinical studies demonstrate that DMARDs are superior to placebo. Early and continuous use of DMARDs is necessary to slow joint damage and improve long-term outcomes. Unfortunately, long-term treatment with these drugs is frequently limited by loss of response and/or onset of serious adverse events. The efficacy of combination DMARD therapy has also been tested, but with mixed success, and the goals of combination DMARD therapy have yet to be fully realised. New DMARDs that have recently been introduced offer promise for future RA management.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.

CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Adult↗
PubMed1999

Role and regulation of cyclooxygenase-2 during inflammation.

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes. COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process. All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2-specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.

Animals↗
PubMed1999

Osteoarthritis.

Explore the source record for details and available documents.

Aged↗
PubMed1999

Viscosupplementation therapy with intra-articular hyaluronic acid. Fact or fantasy?

Pharmacologic therapy for osteoarthritis is presently only palliative and is based on the use of analgesic or anti-inflammatory agents. Simple analgesics, however, do not provide enough of an effect to satisfy the needs of many OA patients, and anti-inflammatory drugs that are currently available do not have favorable risk-to-benefit ratio in typical patients with OA. A need remains, therefore, for therapies that will be analgesic, appropriately anti-inflammatory when necessary, and that may favorably alter the natural history of the disease. The development of intra-articular hyaluronic acid (HA) supplementation was thought to fulfill these criteria. This therapy has been shown to modulate pain in OA of the knee and investigators have attempted to show that it have positive effects on articular cartilage biology. This article considers these claims for HA supplementation as an important therapy for the treatment of OA.

Animals↗