Die Rolle von Stickoxid (NO) bei der basalen synaptischen Transmission im visuellen Cortex der Ratte

Stickoxid (NO) fungiert als Neurotransmitter im Zentralnervensystem, wobei es vor allem eine Rolle als retrogrades Signalmolekül bei der aktivitätsabhängigen synaptischen Transmission spielt. In der vorliegenden Arbeit wurde der Einfluss von NO auf die basale, d.h. aktivitätsunabhängige, Transmission mittels patch-clamp-Ableitungen an Hirnschnitten des visuellen Cortex untersucht. Dabei wurden NO-abhängige Signalkaskaden pharmakologisch unterbrochen. Es wurde gezeigt, dass NO einen komplexen modulierenden Einfluss auf die basale synaptische Transmission im visuellen Cortex hat. NMDA-Rezeptor vermittelte Antworten wurden durch die Hemmung der NO-Signalkaskaden vermindert, während AMPA-Rezeptor vermittelte Antworten überwiegend potenziert wurden. Demnach wird die basale synaptische Transmission durch mehrere NO-abhängige Signalkaskaden beeinflusst

Izokibep for the treatment of moderate-to-severe plaque psoriasis : a phase II, randomized, placebo-controlled, double-blind, dose-finding multicentre study including long-term treatment

Background:  Monoclonal antibodies to interleukin (IL)-17 have shown strong efficacy in patients with psoriasis. Izokibep is a unique IL-17A inhibitor with a small molecular size and favourable distribution to sites of inflammation.Objectives To evaluate the dose response, efficacy and safety of izokibep in patients with plaque psoriasis. Methods: In this double-blind, randomized, phase II dose-finding study (AFFIRM-35) in adults with moderate-to-severe plaque psoriasis and inadequate response to two or more standard therapies, patients were randomized (1:1:1:1:1) to placebo or izokibep 2, 20, 80 or 160 mg every 2 weeks for 12 weeks. During the remainder of the 52-week core study, patients given placebo were switched to izokibep 80 mg, and dosing intervals were adapted based on Psoriasis Area and Severity Index (PASI) scores for all patients. The core study was followed by two optional consecutive 1-year extension periods for a total duration of 3 years. The primary endpoint was a 90% reduction in PASI score (PASI 90) at week 12. Additional efficacy outcomes and adverse event (AE) rates were evaluated.Results In total, 109 patients were randomized [safety set, n = 108 (one exclusion criteria failure); full analysis set, n = 106]. At week 12, PASI 90 response rates were 0%, 5%, 19%, 71% and 59% for the placebo, 2-, 20-, 80- and 160-mg izokibep groups, respectively. Rapid dose-dependent improvements were also observed across other efficacy outcomes. During the placebo-controlled period, AEs in the izokibep groups were similar to placebo except for mild injection site reactions. AEs were generally mild to moderate and the drug was well tolerated. Izokibep maintained efficacy at the higher dosage groups for up to 3 years, with no new safety signals. Conclusions: Data from this phase II study indicate that izokibep is well tolerated and efficacious in the treatment of plaque psoriasis. Higher doses or more frequent dosing could be explored to further enhance response rates. We conducted a randomized, placebo-controlled, dose-finding, phase II study of izokibep, a novel small-molecule triple-helical protein that inhibits the interleukin-17A homodimer, in patients with moderate-to-severe plaque psoriasis. Subcutaneous izokibep at 80 or 160 mg every 2 weeks showed a high level of efficacy in reducing psoriasis symptoms vs. placebo, and was safe and well-tolerated up to 3 years