Analysis of the anorectic efficacy of HMR1426 in rodents and its effects on gastric emptying in rats.

OBJECTIVES: Pharmacodynamics of HMR1426 in rodents. SUBJECTS: Male and female rats and male mice. MEASUREMENTS: 24 h feed consumption was measured. From the time curves IC(50) values of HMR1426 were calculated. Microanalysis of feeding behavior was determined. Macronutrient preference was measured, by offering rats three different diets. Gastric emptying was measured after liquid gastric loads or solid meals. In rats with gastric cannulas, milk consumption was measured with closed or open cannulas. Diabetes-related parameters and thyroid hormones were measured. RESULTS: HMR1426 inhibited feed consumption dose-dependently in rodents. Microstructural analysis of feeding after HMR1426 differed from central acting anorectics. HMR1426 inhibited consumption of fat- and carbohydrate-enriched diets. Gastric emptying was dose- and time-dependently delayed. Gastric emptying correlated with the time course of the anorectic effect. In sham-fed rats, HMR1426 had no anorectic effect with open cannulas. Anorectic effect occurred with closed cannulas. We proved that HMR1426 is not a CCK(A) agonist. CONCLUSION: The correlation between anorectic properties of HMR1426 and gastric emptying suggests that gastric emptying may cause the anorectic properties of HMR1426. The differences in microstructural feeding behavior between HMR1426 and centrally active anorectics makes it unlikely that HMR1426 acts via the CNS. Evidence for a peripheral mode of action is derived from sham-fed rats with open gastric fistula. When the milk fed was drained, HMR1426 was ineffective. HMR1426 is not a CCK(A) agonist. The molecular action of HMR1426 causing gastric emptying and its anorectic properties are under investigation.

Improved functional ability in patients with rheumatoid arthritis--longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group.

OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.

Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with leflunomide or sulfasalazine.

Radiographic disease progression with leflunomide and sulfasalazine treatment was assessed in rheumatoid arthritis patients in a double-blind trial that was placebo controlled for the first 6 months. Completers at 6 months opted to continue on 12- and 24-month double-blind extensions; patients in the placebo group were switched to sulfasalazine. Changes in Larsen scores were assessed in evaluable patient cohorts at 6 (n=228), 12 (n=136), and 24 (n=65) months. Changes in Larsen scores and erosive joint counts with leflunomide and sulfasalazine at 6 months showed significantly less radiographic progression than placebo. Sustained retardation of radiographic progression was seen in the 24-month intent-to-treat cohorts (delta Larsen scores: leflunomide -0.07, sulfasalazine -0.03). Changes in erosive joint counts within the 24-month leflunomide cohort suggest halting of disease progression for patients who continued in the study for 2 years (leflunomide -0.92, sulfasalazine 0.80). Leflunomide was well tolerated with no unexpected adverse events during the 2-year period. This study demonstrates that slowing of disease progression with leflunomide, observed as early as 6 months, is maintained long term in patients who complete 2 years of treatment.

Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers.

OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue. METHODS: In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1). RESULTS: Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.

A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.

OBJECTIVE: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. RESULTS: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. CONCLUSIONS: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.

Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group.

BACKGROUND: Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. METHODS: 358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat. FINDINGS: The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9.7, -4.3, and -8.1 for tender joint count; -7.2, -3.4, and -6.2 for swollen joint count; -1.1, -0.3, and -1.0 for physician's overall assessment; and -1.1, -0.4, and -1.1 for patient's overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0.0001 for joint counts; p<0.001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0.01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. INTERPRETATION: Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a disease-modifying antirheumatic drug.

Electromyography of lumbar erector spinae muscles--influence of posture, interelectrode distance, strength, and fatigue.

The aims of the study were to obtain information (1) on surface electromyograms (SEMG) from the lumbar erector spinae muscles at different interelectrode distances and postures during short isometric contractions with constant force, (2) on the relationships between SEMG and extension force at different postures, and (3) on changes in SEMG during fatiguing isometric contractions at different postures and strengths. Six male subjects developed target forces in prone postures without gravity confounding the measurement of the extension torque. The angles between the constantly horizontal upper trunk and thighs were 90 degrees (P1), 135 degrees (P2), 170 degrees (P3), and 190 degrees (P4). Standard deviations of the distribution of SEMG amplitudes (RMS values), autoregressive (AR) time series models of the 15th order and spectral densities, including mean power frequency (MPF), were computed. Smaller interelectrode distances accompanied smaller RMS values and higher MPF. At a constant extension torque of about 110 Nm, RMS values and MPF increased from P1 to P4. Changes of interelectrode distance were of relatively minor importance, compared with the variation in the posture. With increasing torque, the increase in RMS values was steeper at P3 than at P2. The AR structure and MPF did not exhibit distinct effects of force. During sustained contractions at P2 and P3, only the highest force (mean = 140 Nm) at P3 caused a significant decrease of the MPF at the very beginning of the contraction. Endurance at P2 was greater than at P3. Higher forces and/or shorter muscles (P3) induced more pronounced and earlier relative decreases of the MPF and residual variance of AR models. Up to the "failure point", RMS values increased slightly, but without significant differences.