The antipyretic effect of dipyrone differs from that of indomethacin in that it does not depend on AVP release or inhibition of PG synthesis.

No abstract

BackgroundIn osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA.MethodsqMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher’s exact, Wilcoxon Mann–Whitney, and Student’s t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population.ResultsIn the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib –8.1 % ± 4.2, CS –6.3 % ± 3.2; p = 0.018) and medial condyle (–7.7 % ± 4.7, –5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib –5.6 % ± 3.0, CS –4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib –8.4 % ± 4.2, CS –6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib –8.1 % ± 4.7, CS –5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS –0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs.ConclusionThis study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients.Trial registrationClinicalTrials.gov NCT01354145. Registered 13 May 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1149-0) contains supplementary material, which is available to authorized users.

Human osteoblasts produce PGD 2 , which acts on the DP receptor to decrease osteoprotegerin production and on the CRTH2 receptor to decrease RANKL expression and to induce osteoblast chemotaxis. These results indicate that activation of CRTH2 may lead to an anabolic response in bone.Introduction: Whereas the actions of prostaglandin (PG)E 2 as a modulator of bone and osteoblast function are relatively well characterized, little is known about PGD 2 and bone metabolism. The objectives of this study were to determine if human osteoblasts can produce PGD 2 , which prostaglandin D 2 synthases are implicated in this synthesis, to identify the PGD 2 receptors (DP and CRTH2) on these cells and to characterize the biological effects resulting from their activation. Materials and Methods:RT-PCR analysis and immunohistochemistry were used to detect PGD 2 receptor and synthases in cultured human osteoblasts. Immunohistochemistry was used to identify the synthases and receptors in human bone tissue. Intracellular cAMP and calcium levels were determined to verify receptor activation. The cells were stimulated with PGD 2 or the specific agonists BW 245C (DP) and DK-PGD 2 (CRTH2), and the resulting effects on osteoprotegerin (OPG) secretion, RANKL expression, and chemotaxis were determined. Osteoblast production of PGD 2 was evaluated by measuring PGD 2 in the culture supernatants after stimulation with interleukin (IL)-1, TNF-␣, PTH, vascular endothelial growth factor (VEGF), and insulin-like growth factor I (IGF-I). Results: Human osteoblasts in culture generated PGD 2 when stimulated. Both osteoblasts in culture and in situ present the lipocalin-type PGD 2 synthase only. Both DP and CRTH2 receptors were present in human osteoblasts in culture and in situ. Stimulation of DP resulted in an increase in cAMP, whereas CRTH2 increased the intracellular calcium level. OPG production was reduced by 60% after DP receptor stimulation, whereas CRTH2 receptor stimulation decreased RANKL expression on human osteoblasts. As reported for other cell types, CRTH2 was a potent inducer of chemotaxis for human osteoblasts in culture. Conclusions: Human osteoblasts in culture produce PGD 2 under biologically relevant stimuli through the lipocalin-type PGD 2 synthase (L-PGDS) pathway. As an autacoid, PGD 2 can act on DP and CRTH2 receptors, both present on these cells. Specific activation of CRTH2 could lead directly and indirectly to an anabolic response in bone.

No abstract

Prostaglandin D 2 is the most abundant prostaglandin in the brain. It has long been described as a modulator of the neuroinflammatory process, but little is known regarding the role of its Gα s -coupled receptor, DP1. Therefore, in this study, the effect of the DP1 receptor on the outcome of cerebral ischemia in wildtype (WT) and DP1 knockout (DP1 −/− ) C57Bl/6 mice was investigated. Ischemiareperfusion injury was produced by a 90-min occlusion of the right middle cerebral artery followed by a 4-day reperfusion. Infarct size was 49.0 ± 11.0% larger in DP1 −/− mice (n = 11; P < 0.01) than in WT mice (n = 9 per group). However, no differences were detected in the relative cerebral blood flow (CBF) or any of the physiological parameters measured (n = 5 per group) or in the large blood vessel anatomy (n = 3 per group). To further address whether the DP1 protective role in the brain could be extended to neurons, mouse primary corticostriatal neuronal cultures were exposed to the DP1-selective agonist, BW245C, which provided dose-dependent protection against excitotoxicity induced by glutamate. Protection was significant at a dose as low as 0.05 μm. The results indicate that the DP1 receptor is neuroprotective in both in vivo and in vitro paradigms. Development of drugs to stimulate the DP1 receptor in brain could provide a new therapeutic strategy against cerebral ischemia and potentially other neurological conditions.

Objective. To compare the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) from patients with osteoarthritis (OA) to that of PBMCs from self-reported normal individuals. Methods.PBMCs from 140 patients with OA and 45 healthy donors were assayed for CD14؉ expression and induced to differentiate into osteoclasts over 3 weeks in vitro. We assessed the number of osteoclasts, their resorptive activity, osteoclast apoptosis, and expression of the following cytokine receptors: RANK, interleukin-1 receptor type I (IL-1RI), and IL-1RII. A ridge logistic regression classifier was developed to discriminate OA patients from controls.Results. PBMCs from OA patients gave rise to more osteoclasts that resorbed more bone surface than did PBMCs from controls. The number of CD14؉ precursors was comparable in both groups, but there was less apoptosis in osteoclasts obtained from OA patients. Although no correlation was found between osteoclastogenic capacity and clinical or radiographic scores, levels of IL-1RI were significantly lower in cultures from patients with OA than in cultures from controls. Osteoclast apoptosis and expression levels of IL-1RI and IL-1RII were used to build a multivariate predictive model for OA.Conclusion. During 3 weeks of culture under identical conditions, monocytes from patients with OA display enhanced capacity to generate osteoclasts compared to cells from controls. Enhanced osteoclastogenesis is accompanied by increased resorptive activity, reduced osteoclast apoptosis, and diminished IL-1RI expression. These findings support the possibility that generalized changes in bone metabolism affecting osteoclasts participate in the pathophysiology of OA. (83330) Drs. Komarova, Manolson, Harrison, Dixon, Sims, Kurgan, Boire, and de Brum-Fernandes are named inventors on a patent application for a diagnostic method and prognostic tool for osteoarthritis and the uses thereof. Dr. Boire has received consulting fees, speaking fees, and/or honoraria from Warner Chilcott, Merck, Pfizer, Supported by a New Emerging Team Grant

No abstract