Comparison of the upper gastrointestinal safety of Arthrotec 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers.

A 6-week, multicenter, double-masked, placebo-controlled, parallel-group study compared the upper gastrointestinal (UGI) safety of Arthrotec 75 (diclofenac sodium 75 mg-misoprostol 200 microg; G.D. Searle & Co., Skokie, Illinois) administered twice daily with that of nabumetone 1500 mg administered once daily in 1203 patients with symptomatic osteoarthritis (OA) of the hip or knee. All patients had a documented clinical history of endoscopically confirmed gastric, pyloric-channel, or duodenal ulcer or > or = 10 erosions in the stomach or duodenum. UGI endoscopy was performed at baseline and again at week 6 or early withdrawal. Treatment with Arthrotec 75 resulted in a significantly lower combined incidence of endoscopically confirmed gastric and duodenal ulcers compared with nabumetone (4% vs 11%), and its rate of endoscopically confirmed ulceration was equivalent to that of placebo. The incidence of gastric ulcers alone was also significantly lower with Arthrotec 75 than with nabumetone (1% vs 9%). The incidence of duodenal ulcer with Arthrotec 75 was not significantly different from that with nabumetone (4% vs 3%). Types of adverse events were similar for all treatment groups, with GI adverse events predominating. Arthrotec 75 was well tolerated by the majority of patients. The results of this study demonstrate that Arthrotec 75 has a superior UGI safety profile, causing significantly fewer UGI ulcers, in comparison with nabumetone in patients with symptomatic OA and a documented history of ulcers or > or = 10 erosions.

Health-related quality-of-life effects of oxaprozin and nabumetone in patients with osteoarthritis of the knee.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of signs and symptoms of osteoarthritis (OA). Nabumetone and oxaprozin are 2 of the newer NSAIDs and have been shown to have similar safety and efficacy profiles. Nabumetone 1000 mg to 1500 mg once a day (QD) and oxaprozin 1200 mg QD are commonly recommended doses. This study compared the health-related quality of life (HRQOL) of patients receiving oxaprozin 1200 mg QD with that of patients receiving nabumetone 1000 mg QD or nabumetone 1500 mg QD for the treatment of signs and symptoms of OA of the knee. Two similarly designed, independent, randomized, double-masked, placebo-controlled clinical trials were conducted. In trial 1, patients were randomized to receive oxaprozin 1200 mg QD (n = 109), nabumetone 1000 mg QD (n = 110), or placebo (n = 109); in trial 2, patients received oxaprozin 1200 mg QD (n = 116), nabumetone 1500 mg QD (n = 115), or placebo (n = 116). HRQOL was measured by the Medical Outcomes Study Short-Form-36 Health Survey (1-week recall period) at baseline and weeks 2 and 6. Data from the 2 trials were combined to assess differences across the 4 groups in 8 domains and 2 summary scores at baseline, and changes in HRQOL scores at weeks 2 and 6. At week 2, the oxaprozin group showed significantly greater improvement than the placebo group in role physical, vitality, and mental component summary (MCS) scores (P < 0.05), and in physical functioning, bodily pain, social functioning, and physical component summary (PCS) scores (P < 0.01). The nabumetone 1500-mg group showed significantly greater improvement than the placebo group in bodily pain and social functioning (P < 0.05), and in vitality and MCS score (P < 0.01). No significant differences were observed between the nabumetone 1000-mg and placebo groups. At week 2, the oxaprozin group showed a greater change than the nabumetone 1000-mg group in PCS score (P < 0.05). At week 6, oxaprozin treatment resulted in significantly greater improvement than placebo in physical functioning, role physical, and bodily pain (P < 0.05); social functioning, role emotional, and mental health (P < 0.01); and vitality and MCS score (P < 0.001). The nabumetone 1500-mg group showed significantly greater responses than the placebo group in vitality (P < 0.05), mental health (P < 0.01), and MCS score (P < 0.001). The oxaprozin group had significantly better scores than the nabumetone 1500-mg group in the PCS (P < 0.05), and it showed significantly greater improvement than the nabumetone 1000 mg group in role physical and PCS score (P < 0.01) and in role emotional (P < 0.05). No statistically significant differences were found between placebo and nabumetone 1000 mg at week 6. Results of this study suggest that oxaprozin 1200 mg QD has a significant positive impact on the HRQOL of patients with OA of the knee compared with nabumetone 1000 mg QD and placebo.

Diclofenac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: a randomized, placebo controlled trial. Arthrotec Osteoarthritis Study Group.

OBJECTIVE: Gastric (GU) and duodenal ulcers (DU) are common adverse effects of nonsteroidal anti-inflammatory drugs (NSAID). Endoscopically diagnosed upper gastrointestinal (GI) ulceration occurs in about 24% of longterm NSAID users. Coadministration of misoprostol with the NSAID reduces the incidence of NSAID induced GU and DU and their complications. However, compliance is limited by the different dosing regimens of misoprostol and NSAID and GI symptoms associated with misoprostol at its recommended q.i.d. dose. We compared the efficacy, safety, and incidence of endoscopic upper GI ulceration associated with the administration of 2 combinations of diclofenac (50 or 75 mg) and misoprostol 200 microg (D50/M200 t.i.d., D75/M200 b.i.d.), diclofenac 75 mg b.i.d., and placebo in a 6 week, randomized, double blind study in patients with osteoarthritis (OA) of the knee or hip. METHODS: A total of 572 patients with symptomatic OA of the knee or hip and history of GU, DU. or 10 or more erosions were randomized to receive D50/M200 t.i.d., D75/M200 b.i.d., diclofenac 75 mg b.i.d., or placebo for 6 weeks. Arthritis assessments were performed at baseline, 2, and 6 weeks, and upper GI endoscopies at baseline and end of treatment. RESULTS: All active treatment groups were significantly better than placebo, at all visits, in improving OA symptoms. There were no significant differences in arthritis efficacy between the diclofenac/ misoprostol combinations and diclofenac. However, endoscopically diagnosed GU and/or DU were significantly less frequent in patients receiving D50/M200 t.i.d. (8%), D75/M200 b.i.d. (7%), and placebo (4%) compared to diclofenac 75 mg b.i.d. (17%). Adverse events were not different between the active treatment groups, except for higher incidences of flatulence with D75/M200 and diarrhea with D50/M200. CONCLUSION: Diclofenac 50 mg/misoprostol 200 microg t.i.d. and diclofenac 75 mg/misoprostol 200 microg b.i.d. are as efficacious as diclofenac 75 mg b.i.d. in the treatment of OA, but are associated with a significantly lower incidence of gastric and/or duodenal ulcers.

The efficacy, tolerability, and safety of 1200 mg/d of oxaprozin and 1500 mg/d of nabumetone in the treatment of patients with osteoarthritis of the knee.

This 6-week, multicenter, double-masked, placebo-controlled study compared the efficacy, tolerability, and safety of the recommended starting dose of oxaprozin (1200 mg/d) and a 1500-mg/d dose of nabumetone in the treatment of patients with moderate-to-severe osteoarthritis (OA) of the knee. A total of 347 patients with a mean age of 61.1 years were randomized to receive oxaprozin (116 patients), nabumetone (115 patients), or placebo (116 patients). Adults of either sex who were older than 18 years of age were eligible for entry into the study, if they had had OA of the knee for at least 6 months. Efficacy variables included knee pain on weight bearing, knee pain on motion, patients' and physicians' global assessments of OA, pain intensity as measured on a visual analog scale, and time to walk 50 feet as quickly as possible. Efficacy variables were assessed at baseline and at weeks 1, 2, 4, and 6. Between-group differences in efficacy variables were evident by week 1. Mean improvements were significantly greater with oxaprozin than with placebo for all efficacy variables at all time periods, except knee pain on motion at weeks 2 and 4 and time to walk 50 feet at weeks 1, 2, and 4. Mean improvements were significantly greater with nabumetone than with placebo for all efficacy variables at all time periods, except the following: knee pain on weight bearing at weeks 2, 4 and 6; knee pain on motion at weeks 2 and 4; patients' global assessment at week 4; and pain intensity as measured on a visual analog scale at weeks 2 and 4. There were, however, no significant differences between oxaprozin and nabumetone in any of these efficacy variables. Adverse events were reported by 83 (71.6%) patients who took oxaprozin, by 80 (69.6%) patients who took nabumetone, and by 57 (49.1%) patients who took placebo. Adverse events were reported for significantly more patients taking oxaprozin or nabumetone than placebo. However, adverse events tended to be mild or moderate and rarely resulted in patients withdrawing from the study. Combined with the results of an earlier study, the results of this study showed that a 1500-mg/d dose of nabumetone, which is higher than the recommended starting dose of 1000 mg/d, is required for efficacy equivalent to that of the recommended starting dose of oxaprozin, 1200 mg/d, in relieving the symptoms of OA. Thus nabumetone may require dosage titration from the recommended starting dose. Oxaprozin and nabumetone were found to have similar tolerability profiles, as shown by adverse-event monitoring and withdrawal rates, as well as clinically similar safety profiles, as demonstrated by physical examinations, hematologic and biochemical laboratory testing, hemoccult testing, and adverse-event monitoring and symptom assessment.

The use of methotrexate perioperatively in patients with rheumatoid arthritis undergoing major joint replacement surgery: will we ever have consensus about its use?

Whether methotrexate can be safely administered during the perioperative period to rheumatoid arthritis patients undergoing arthroplasties is an issue that has not been resolved to date. We are describing our attempt to conduct a case-controlled, multicenter study addressing this issue. The estimated sample size of approximately 140 patients proved to be difficult to recruit. Complications were all mild, but there tended to be more perioperative complications in the methotrexate-treated than in the placebotreated patients. Possible explanations for the failure to complete the study are discussed.

Hyperlipidemia, amyloidosis, sarcoidosis, iron storage disease, and Wilson's disease.

The objective of this review is to summarize the most recent developments related to this miscellaneous group of diseases. Emphasis has been placed on information that will help the practicing physician, such as clinical observations, improved diagnostic techniques, particularly ones that are noninvasive or minor, and new therapeutic approaches. An interesting animal study that helps in the understanding of the increased frequency of coronary artery disease in patients with long-standing systemic lupus erythematosus is described.

Clinical findings in symptomatic women with silicone breast implants.

We report the clinical findings in a series of women with silicone breast implants (SBI) and rheumatic disease. These findings represent the first 50 patients seen at the University of South Florida Medical Clinic between March 1977 and January 1991. The average age was 44 years with a range of 30 to 66 years. The most common clinical findings included chronic fatigue, muscle pain, joint pain, joint swelling, and lymphadenopathy. Seventeen women with an average Steinbrocker functional class of 1.8 decided not to remove the implants. An average of 14 months later, follow-up showed no change in their condition. Thirty-three women, with an average functional class of 2.5 underwent implant removal. Twelve of the 33 had documented implant rupture. During an average follow-up of 22 months after implant removal, 24 women improved clinically, 8 did not change, and 1 worsened. We believe this series supports a relationship between silicone breast implants and rheumatic disease signs and symptoms. Although this report is not a definitive epidemiological study, findings suggest that physicians should inform women about the possible benefit of implant removal.

Musculoskeletal syndromes in parasitic diseases.

Parasitic infestation can induce a variety of rheumatic syndromes as a result of infiltration of musculoskeletal structures by parasites or an immune mediated mechanism. Parasite-induced symptoms should be considered when arthritis, enthesitis, myositis, or vasculitis develop in patients residing in endemic areas and in certain subsets of the population of developed countries, for example, migrants, travelers, and immunocompromised individuals. Diagnosis is based on the demonstration of infection with a pathogenic parasite, lack of response to anti-inflammatory agents, and improvement following antiparasitic therapy. Treatment consists of erradication of the parasite.

Long-term safety and efficacy profile of simvastatin.

Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has been administered to approximately 2,400 patients with primary hypercholesterolemia with a mean follow-up of 1 year in controlled clinical studies and their open extensions. Approximately 10% of this population received simvastatin for a period of greater than or equal to 2 years. The population on whom this safety analysis is based had a mean age of 50 years; 62% were men and approximately 27% had preexisting coronary artery disease. Simvastatin was titrated to the maximal daily dose of 40 mg each evening in 56% of the study population (last recorded dose). The most frequently reported drug-related clinical adverse experiences were constipation (2.5%), abdominal pain (2.2%), flatulence (2.0%) and headaches (1%). Persistent elevations of serum transaminase levels greater than 3 times the upper limit of normal were observed in only 1% of this cohort with only 0.1% of the total population requiring discontinuation of therapy. There were no clinically apparent episodes of hepatitis. Discontinuation of therapy due to myopathy was extremely rare (0.08%). Only minimal increases in the frequency of lens opacities (1%) were observed from baseline to the last lens examination during follow-up, consistent with the expected increase in lens opacity development due to normal aging. Patients who were greater than or equal to 65 years old had a clinical and laboratory safety profile comparable to the nonelderly population.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol. A multicenter study. The Simvastatin Study Group.

A 12-week, randomized, double-blind, multicenter study was undertaken to compare the efficacy, tolerability, and safety of simvastatin and gemfibrozil in 290 patients with primary hypercholesterolemia. Patients in stratum I (initial low-density lipoprotein cholesterol level less than 195 mg/dl) received simvastatin 5 to 10 mg once every afternoon; patients in stratum II (initial low-density lipoprotein cholesterol level at least 195 mg/dl) received 10 to 20 mg once every afternoon. Gemfibrozil was given in a constant dosage of 600 mg twice daily in both strata. Simvastatin reduced low-density lipoprotein cholesterol levels by 26 and 34 percent in strata I and II, respectively. The corresponding reductions brought about by gemfibrozil were 18 and 17 percent. High-density lipoprotein cholesterol was increased by 7 and 9 percent by simvastatin and by 17 and 16 percent by gemfibrozil in strata I and II, respectively. Ratios of low-density to high-density lipoprotein cholesterol were reduced by approximately 25 percent by simvastatin 5 to 10 mg once every afternoon and gemfibrozil 600 mg twice daily, but were reduced by 37 percent by simvastatin 10 to 20 mg once every afternoon. Both drugs reduced plasma triglyceride levels, but gemfibrozil was much more effective. The short-term tolerability and safety of both drugs appeared to be good during the 12-week study. The results suggest that both drugs have useful but distinctly different lipid-modifying properties.

Brucellar arthritis: a study of 39 Peruvian families.

A study was conducted to characterise the articular manifestation of Brucella melitensis within a family in Peru. From January 1981 to June 1986, 39 families with 232 individuals were evaluated. Brucellosis was diagnosed in 118 family members (attack rate of 50.9%). A lower attack rate was observed in children less than 10 years' old compared with other age groups (p less than 0.02). Complete clinical data were available in 92 of the 118 affected members. Moderate and severe forms of the diseases were more prevalent in women than in men (41.8% v 13.5%; p less than 0.001). Twenty eight of the 92 patients developed some brucellar complications; the articular involvement was the most prevalent (23.9%). Arthritis was also more common in women than in men (34.5% v 8.1%; p less than 0.01). Children appeared to have less articular involvement. Overall, the following pattern was observed: peripheral arthritis (54.5%); unilateral sacroiliitis (23.0%); mixed arthritis (4.5%), and spondylitis (9.1%). Spondylitis was seen only in the elderly with chronic brucellosis. Four patients developed extra-articular rheumatism. Within members of family groups, brucellar arthritis occurred less frequently than in individual patients from the same hospital. This suggests that many family cases were diagnosed in the early stages.

HLA studies in brucellar spondylitis.

Among the clinical manifestations of brucellosis, arthritis may occur in over one-third of the patients. Different articular syndromes have been well recognized: some are definitely infectious in nature, whereas others appear to be reactive. The possibility that B27 and B7-CREG antigens could predispose to the occurrence of brucellar spondylitis was investigated in 14 mestizo Peruvian patients. No association was found. Since there is a low frequency of B27 and B7-CREG in the control population, the possibility that a "native" antigen could be the predisposing one remains to be elucidated.

Humoral immune abnormalities in human brucellosis.

Humoral immune responses were evaluated in a group of patients with acute brucellosis due to Brucella melitensis biotype I. Levels of immunoglobulins, C3 and C4, and the presence of antinuclear antibodies, rheumatoid factor and circulating immune complexes were sequentially studied in all brucellosis patients during the acute phase of the disease and following specific therapy. Elevated levels of all immunoglobulin classes, IgG, IgM and IgA and C3, C4, were found in the majority of patients. Antinuclear antibodies, rheumatoid factor and circulating immune complexes were found in circulation, particularly during the active stages. These findings provide support for the participation of the humoral immune system in the pathogenesis of human brucellosis.