Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE).

OBJECTIVES: To compare the pharmacokinetic parameters and safety of the progestagen, Org 30659, (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), and ethinyl estradiol (EE) in Caucasian and Japanese women after single and multiple doses. METHODS: This was an open-label parallel design of a single dose followed by a multiple dose period in healthy young Japanese and Caucasian subjects. RESULTS: The area under the curve (AUC) of Org 30659 after single dosing was increased by a factor of 1.75 [90% confidence interval (CI): 1.48-2.08] in Japanese women compared to Caucasian women. At steady state, this difference increased to a factor of 1.90 (90% CI: 1.60-2.25). The AUC of EE after single dosing was similar in Caucasian and Japanese women, but at steady state it was increased by a factor 1.38 (90% CI: 1.15-1.64) in the Japanese group. Weight normalization reduced, but did not remove, all the observed differences. Sex hormone binding globulin played no significant role in the differences between Caucasian and Japanese subjects. Both the single- and multiple-dose treatments with Org 30659/EE were generally well tolerated by all subjects. The Japanese population reported more and different treatment-related adverse events than the Caucasian population. CONCLUSIONS: The peak concentration and extent of exposure of Org 30659, and to a lesser extent of EE, in Japanese women are higher than in Caucasian women. Furthermore, the peak concentration and extent of exposure at steady state of Org 30659, and to a lesser extent of EE, are higher than would be predicted assuming linear pharmacokinetics over time. No major safety issues were observed.

Cellular immune response to human cartilage glycoprotein-39 (HC gp-39)-derived peptides in rheumatoid arthritis and other inflammatory conditions.

OBJECTIVE: To study the specificity of the peripheral blood mononuclear cell (PBMC) response to peptides derived from human cartilage glycoprotein-39 (HC gp-39) in patients with rheumatoid arthritis (RA) and the correlation between this response and disease activity. METHODS: RA patients, patients with systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) or osteoarthritis (OA) and healthy controls were studied. All individuals were typed for HLA-DRB1 and their disease activity score was documented. Proliferation of PBMC was measured following incubation with five different HC gp-39-derived peptides, selected by the use of a DR4 (DRB1*0401) binding motif. RESULTS: A proliferative response to one of the five peptides (peptide 259-271 at 10 microg/ml) was more often observed in RA patients than in healthy controls (P=0.001). RA patients who expressed DRB1*0401 more often showed a response against this peptide than RA patients who did not express this RA-associated haplotype. This response was not RA-specific since patients with IBD or OA also showed a response significantly more frequently than healthy controls (P:=0.02 and P=0.03 respectively). However, the level of the response against peptide 259-271 correlated with disease activity in RA patients but not in patients with IBD or SLE. Increased responses to HC gp-39 263-275 were found in patients with IBD or OA; a trend towards such a response failed to reach significance in RA patients in this study. CONCLUSION: In RA patients as well as in patients with other inflammatory conditions, HC gp-39-derived peptides may be targets of the T-cell-mediated immune response. In the RA patient group the immune response to HC gp-39-derived peptide 259-271 correlated with disease activity.

A high dose (up to 200 mg) tolerance and efficacy study of intra-articular rimexolone (Org 6216) in rheumatoid synovitis of the knee.

Twenty patients with classical or definite rheumatoid arthritis received one intra-articular injection of 40, 80, 120, 160 or 200 mg rimexolone (Org 6216) into one knee joint. Rimexolone was well tolerated and the incidence of side-effects was low. A beneficial effect was sustained over the study period of 94 days and a long-lasting effect was observed in 84% of the patients after one year and in 79% after 2 years. Safety parameters remained unaffected. Individual changes in adrenal response to ACTH and morning cortisol levels did not correlate with the dose or with serum levels of rimexolone. Rimexolone showed linear kinetics. The mean residence time in the intra-articular depot was 44 days (SD +/- 53) with a median of 26 days. Ninety percent was absorbed after 4 months. Outside the intra-articular depot the mean residence time was less than 0.1 days.

Pharmacokinetics of rimexolone after intra-articular administration.

The pharmacokinetics of rimexolone were investigated after intra-articular injection into the knee joints of patients with rheumatoid arthritis. After a single dose of 40 mg rimexolone the drug could be detected in plasma over 3 months. The suspension dissolves in the synovia very slowly and provides a sustained release of the steroid in the joint. Pharmacokinetic analysis was performed on the assumption that the disposition of rimexolone after intra-articular administration is absorption limited ("flip-flop-case"). Dose linearity was studied in a range from 40 to 200 mg. Total body clearance averaged 106 L/h and was independent of dose. The mean residence time of rimexolone in the knee joint is very long and averaged 25 days. It could be shown that the mean residence time of different glucocorticoids correlates well with the duration of their clinical effectiveness.

Intra-articular rimexolone in the rheumatoid knee: a placebo-controlled, double-blind, multicentre trial of three doses.

One-hundred and thirty-seven patients with classical or definite rheumatoid arthritis, involving at least one knee joint, were randomly allocated to a single intra-articular injection of 10, 20 or 40 mg of rimexolone (Org 6216) or placebo. The follow-up period was 84 days, during which clinical and laboratory assessments were done. Clinical improvement of the treated knee joint was measured by the following variables: pain, tenderness, morning stiffness, swelling, range of movement and walking ability. Placebo response was considerable. However, clinical improvement with rimexolone at 20 mg and 40 mg was significantly superior to placebo for most of the variables, whilst with the 10 mg dose only reduction of tenderness was significantly superior. The duration of improvement was longest with 40 mg of rimexolone. One single, intra-articular injection of this dose into the affected knee joint provided significant reduction in pain, tenderness and stiffness and improved the range of movement and walking ability for a period of 8 to 12 weeks.