No abstract

The current etiology of uveitis in Japan was elucidated by means of a multi-center prospective survey. Conducting such surveys on a periodic basis may help clinicians in their management of uveitis.

AimsTwo multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD).Methods and resultsPatients with ACS (n = 241) or high-risk CAD (n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in ‘any’ TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was >90% with 100 and 200 mg E5555, and 20–60% with 50 mg E5555.ConclusionE5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.

Peritoneal exudate cells (PEC) incubated with antigen in the presence of transforming growth factor-(TGF)-beta 2 selectively suppress delayed hypersensitivity and IgG2a antibody production when injected intravenously into naive syngeneic recipients. In this study, we have examined in vitro the effects of TGF-beta 2 on the antigen presenting abilities of PEC to activate DO11.10 T cells that express a transgenic T cell receptor that recognizes ovalbumin peptide fragment 323-339 in the context of I-Ad. PEC were pretreated overnight with TGF-beta 2, washed extensively, then co-cultured with DO11.10 T cells in the presence of native OVA or P323-339. We found that TGF-beta 2-treated PEC induced the production of the T helper type 2 (Th2) cytokine, interleukin-4 (IL-4), but unlike untreated PEC, were unable to stimulate the Th1 cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, TGF-beta 2 was produced in an autocrine fashion by TGF-beta 2-treated PEC and was responsible for this shift to a Th2 response. This conclusion was supported by the following results. First, TGF-beta 2-treated PEC were found to express much more TGF-beta 1 and TGF-beta 2 mRNA than untreated PEC. Second, TGF-beta 2-treated PEC secreted large amounts of TGF-beta including its mature form. Third, addition of neutralizing anti-TGF-beta 2 antibodies, but not neutralizing anti-TGF-beta 1 antibodies, restored the ability of antigen-pulsed, TGF-beta 2-pretreated PEC to stimulate DO11.10 T cells to secrete IL-2 and IFN-gamma. These results indicate that antigen-presenting cells that encounter antigen in a TGF-beta-enriched environment (e.g., in the eye) shift responding native T cells toward Th2 responses by producing TGF-beta during antigen presentation.