Ibuprofen and diclofenac sodium in the treatment of osteoarthritis: a comparative trial of two once-daily sustained-release NSAID formulations.

An investigator-blind, parallel-group, multicentre study was undertaken to compare the efficacy and tolerability of once-daily, sustained-release (s-r) ibuprofen and diclofenac sodium in patients (mean age 59.8 years) suffering from painful osteoarthritis affecting chiefly the knee and/or hip. Patients attending eight Swiss centres received either two s-r tablets of ibuprofen (daily dose 1600 mg; n = 30) or a single s-r diclofenac 100 mg tablet (n = 31) each evening for 21 days. Clinical assessments were performed prior to initiating therapy and after 7 and 21 days of treatment. Both treatments were efficacious, but statistically significant differences in favour of s-r ibuprofen were observed for the principal measure of efficacy, the investigator's assessment of the overall change in clinical condition; by Day 21, 37% of ibuprofen-treated patients vs 10% of diclofenac-treated patients were 'much improved' (p = 0.04). Patients' assessments of the efficacy of their treatment also favoured s-r ibuprofen at Day 7 for the relief of night pain (p = 0.048), at Day 21 for alleviation of day pain (p = 0.006) and for the ability to carry out normal activities (p = 0.01), and at both Days 7 and 21 for quality of sleep (p = 0.04 and 0.03, respectively). The patients' overall opinion of treatment was also significantly in favour of s-r ibuprofen, which was rated 'good or excellent' by 80% (24/30), compared with only 38% of patients (11/29) receiving s-r diclofenac sodium (p = 0.002). Two patients (6%) receiving s-r diclofenac sodium ceased treatment owing to dizziness and severe diarrhoea, respectively; there were no withdrawals in the ibuprofen-treated group. Ten (32%) patients in the s-r diclofenac group reported a total of 12 adverse events (mostly gastrointestinal in nature), compared with three (10%) patients in the s-r ibuprofen group who reported only three events (abdominal pain, insomnia and constipation). In conclusion, although both NSAID treatments improved the clinical condition of patients with painful osteoarthritis, statistically significant differences in favour of once-daily s-r ibuprofen (1600 mg) were demonstrated in terms of efficacy, indicating a potential therapeutic advantage for this formulation. Ibuprofen was also better tolerated than diclofenac sodium (100 mg/day), the latter being associated with gastrointestinal side effects in a significant proportion of patients. Sustained-release ibuprofen (Brufen Retard) thus represents an important addition to the available therapeutic armamentarium of once-daily NSAID formulations.

Cytokeratin expression in bovine corpora lutea.

Cytokeratin (CK)-positive cells were obtained from bovine corpora lutea. When cultured, these cells behave like CK-positive endothelial cells obtained from bovine large blood vessels. The origin of CK-positive cells has now been studied in 45 bovine corpora lutea of different estrous cycle stages. Additionally, 7 corpora lutea of pregnant cows were examined. The tissues were grouped into early stage (days 2 to 4), secretory stage (days 5 to 17) and late stage (days 18 to 21) according to gross morphology, wet weight and total progesterone content. One portion of a corpus luteum was used for immunohistochemistry, and another for Western blot analysis. Twenty-six of the 45 corpora lutea showed CK expression, as confirmed by immunostaining and Western blotting. Cytokeratin expression was found in all corpora lutea from the early stage, in 14 of 26 corpora lutea from the secretory stage, and 3 of 10 from the late stage. Early stage corpora lutea displayed "zonation" such that a high number of CK-positive luteal cells occurred in the region of the previous granulosa layer and a very low number in the previous thecal layer. Secretory CK-positive corpora lutea showed uniformly distributed, predominantly large luteal cells. In secretory corpora lutea of group A, CK-positive cells and a distinct microvascular tree were seen, the latter visualized by factor VIII-related antigen immunolabelling of endothelial cells. Group B showed none or very few CK-positive cells. Corpora lutea of pregnant cows behaved like corpora lutea of group B. Roughly 1% of CK-positive cells closely associated with the capillary wall were sometimes reminiscent of endothelial cell sprouts.

Long-term co-culture of bovine granulosa cells with microvascular endothelial cells: effect on cell growth and cell death.

The intraovarian axis between granulosa cells and thecal cells is regulated by locally produced autocrine and paracrine factors. Until now, microvascular endothelial cells (MVEC) have not been included in such studies. Bovine granulosa cells from medium-sized antral follicles were plated at low density into the lower compartment of 24-well-culture plates on day 0. MVEC derived from bovine corpus luteum were seeded on appropriate inserts and placed as the upper compartment on day 1. Control granulosa cell cultures and MVEC co-cultures were maintained in serum-containing medium. On day 21, control cultures displayed an epithelioid monolayer and the coculture displayed a multilayer. Histochemical staining for 3 beta-HSD activity and for the lipid droplet stain with the fluorescent dye Nile Red were strong, suggesting augmented steroidogenesis in the multilayer. Yet the progesterone levels of supernants corrected for 10,000 cells were similar in monolayers and in multilayers. Co-cultures contained approximately three times more granulosa cells than control cultures as evaluated with a Coulter counter. Additionally, the occurrence of dead cells was quantified with the fluorescent DNA stain, ethidium homodimer, in 11-day-old control cultures and MVEC co-cultures which were deprived of serum, MVEC, or both for an additional 40 h. Serum and MVEC suppressed the occurrence of granulosa cell death. It is concluded that MVEC produce survival factors for the growth and maintenance of granulosa cells.

Bovine microvascular endothelial cells of separate morphology differ in growth and response to the action of interferon-gamma.

Five cell types recently isolated from the bovine corpus luteum differed in their epithelioid morphology and their cytoskeleton, but shared common criteria of microvascular endothelial cells. To give strong evidence for the separate entity, the growth rate of the 5 phenotypically different cells was studied. They were seeded at low density on day 0. Most of these cells were treated with 200 to 1000 U recombinant bovine interferon-gamma (IFN-gamma) for 3 days. The untreated remainder served as controls. Cell counts were made for all cultures on days 4, 7, 10 and 13. Morphology: 13 d after treatment with IFN-gamma senescent cells as well as intact cells occurred in cultures of cell types 1 to 4. Cultures of cell type 5 were apparently unchanged and resembled their untreated counterparts. Desmin-positive cells in cultures of cell type 2 developed cell processes. Growth rate: In the absence of IFN-gamma, the growth rate was high for cell types 3 and 4, moderate for cell type 1, and low for cell types 2 and 5. The presence of IFN-gamma caused anti-proliferative effects. These were higher for cell types 3 and 4 than for cell types 1 and 2. IFN-gamma could be cytotoxic on cell type 3. In contrast, the cytokine tended to support the cell growth of cell type 5. These findings substantiate the postulate that endothelial cells exhibiting separate morphology in culture also function differently.