Medicinal plants in Sabah (North Borneo) exhibit antipancreatic lipase, anti-amylase, and antioxidant properties

Medicinal plants have been widely used for their notable health benefits and help in disease prevention for generations. In recent years, obesity has become among the risk factors of hyperglycemia and oxidation stress. This study aims to investigate the potential of plants in Sabah, North Borneo to inhibit the key enzymes involved in obesity, hyperglycemia and oxidative stress. A total of 46 plant extracts were subjected to anti-pancreatic lipase, α-amylase inhibition and antioxidant assays. It was observed that S43 (Lantana camara) exhibited the greatest IC50 of anti-pancreatic lipase activity (mean of IC50 (±S.D.) = 0.20 mg mL-1 ± 0.010). Cinnamomum sp. (S42) has the most substantial α-amylase activity with a mean IC50 (±S.D.) = 2.68 mg mL-1 ± 0.471. S19 (Glochidion rubrum) was the most effective antioxidants (mean of IC50 (±S.D.) = 0.011 mg mL-1 ± 0.004) among all the investigated samples. Interestingly, three plant extracts were found (S6-Buchanania sp.; S22-Vitex negundo and S42-Cinnamomum sp.) to exhibit inhibition activity in ant pancreatic lipase, α-amylase and antioxidant assays. The bioactivities of plant extracts have been closely related to the content of phytochemicals, as in earlier studies. Thus, plants have the potential to serve as supplements and nutraceuticals for obesity and other related complications

Design of Effisayil™ 2: A randomized, double-blind, placebo-controlled study of spesolimab in preventing flares in patients with generalized pustular psoriasis

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by flares of widespread erythema with sterile pustules, and can be relapsing with recurrent flares, or persistent with intermittent flares. Spesolimab, a humanized anti-interleukin-36 (IL-36) receptor monoclonal antibody, targets the key IL-36 pathogenetic pathway in GPP. A previous study showed that spesolimab treatment led to rapid pustular and skin clearance in patients with GPP flares, which was sustained for up to 12 weeks. This study investigates the long-term effects of spesolimab on GPP flares, for which no specific treatments are currently available. The Effisayil™ 2 study will assess whether maintenance treatment with subcutaneous spesolimab prevents the occurrence of GPP flares and determine the optimal dosing regimen to achieve this aim. METHODS: Patients will have a documented history of GPP with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear) at screening and randomization. Patients will be randomized 1:1:1:1 to three groups receiving a 600-mg subcutaneous loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 or 12 weeks, or a 300-mg loading dose followed by a 150-mg maintenance dose administered every 12 weeks, and one group receiving placebo, for 48 weeks. The primary endpoint is time to first GPP flare. If a patient experiences a GPP flare during the randomized maintenance treatment period, an open-label intravenous dose of 900-mg spesolimab will be administered, with an option for a second intravenous dose after 1 week. CONCLUSIONS: Effisayil™ 2 is the first placebo-controlled study in patients with GPP to investigate whether maintenance treatment with spesolimab can prevent flares and provide sustained disease control. This study will provide valuable insights on the long-term management of patients with this potentially life-threatening skin disease. TRIAL REGISTRATION NUMBER: NCT04399837

Maritime threat response

This report was prepared by Systems Engineering and Analysis Cohort Nine (SEA-9) Maritime Threat Response, (MTR) team members.Background: The 2006 Naval Postgraduate School (NPS) Cross-Campus Integrated Study, titled “Maritime Threat Response” involved the combined effort of 7 NPS Systems Engineering students, 7 Singaporean Temasek Defense Systems Institute (TDSI) students, 12 students from the Total Ship Systems Engineering (TSSE) curriculum, and numerous NPS faculty members from different NPS departments. After receiving tasking provided by the Wayne E. Meyer Institute of Systems Engineering at NPS in support of the Office of the Assistant Secretary of Defense for Homeland Defense, the study examined ways to validate intelligence and respond to maritime terrorist attacks against United States coastal harbors and ports. Through assessment of likely harbors and waterways to base the study upon, the San Francisco Bay was selected as a representative test-bed for the integrated study. The NPS Systems Engineering and Analysis Cohort 9 (SEA-9) Maritime Threat Response (MTR) team, in conjunction with the TDSI students, used the Systems Engineering Lifecycle Process (SELP) [shown in Figure ES-1, p. xxiii ] as a systems engineering framework to conduct the multi-disciplinary study. While not actually fabricating any hardware, such a process was well-suited for tailoring to the team’s research efforts and project focus. The SELP was an iterative process used to bound and scope the MTR problem, determine needs, requirements, functions, and to design architecture alternatives to satisfy stakeholder needs and desires. The SoS approach taken [shown in Figure ES-2, p. xxiv ]enabled the team to apply a systematic approach to problem definition, needs analysis, requirements, analysis, functional analysis, and then architecture development and assessment.In the twenty-first century, the threat of asymmetric warfare in the form of terrorism is one of the most likely direct threats to the United States homeland. It has been recognized that perhaps the key element in protecting the continental United States from terrorist threats is obtaining intelligence of impending attacks in advance. Enormous amounts of resources are currently allocated to obtaining and parsing such intelligence. However, it remains a difficult problem to deal with such attacks once intelligence is obtained. In this context, the Maritime Threat Response Project has applied Systems Engineering processes to propose different cost-effective System of Systems (SoS) architecture solutions to surface-based terrorist threats emanating from the maritime domain. The project applied a five-year time horizon to provide near-term solutions to the prospective decision makers and take maximum advantage of commercial off-the-shelf (COTS) solutions and emphasize new Concepts of Operations (CONOPS) for existing systems. Results provided insight into requirements for interagency interactions in support of Maritime Security and demonstrated the criticality of timely and accurate intelligence in support of counterterror operations.This report was prepared for the Office of the Assistant Secretary of Defense for Homeland DefenseApproved for public release; distribution is unlimited

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.</p

Inhibition of the interleukin-36 pathway for the treatment of generalized pustular psoriasis

No abstract available

Spesolimab treatment for the prevention of flares in people with generalized pustular psoriasis (GPP): a plain language summary of the Effisayil ™ 2 study

What is this study about?: Generalized pustular psoriasis (shortened to GPP) is a rare, potentially life-threatening disease in which pus-filled blisters or pustules may suddenly form all over the body. The drug spesolimab has been approved to treat worsening GPP (known as flares) in many countries. However, it was not known if spesolimab could prevent the symptoms of GPP. This summary reports the results from a clinical study called Effisayil™ 2, that was done to understand if spesolimab was a safe and effective way to prevent flares in people with GPP. In the study, 123 participants, recruited in 20 different countries, were given one of three different doses of spesolimab (low, medium, or high) or a non-active medicine (placebo) over 48 weeks. What were the results?: Participants who received spesolimab had fewer GPP flares over the course of the 48-week study. Different doses of the drug were tested and compared to placebo, and a high dose of spesolimab worked better than low and medium doses. Using spesolimab also reduced the chance of developing skin symptoms, such as redness or pustules, and prevented quality of life getting worse over 48 weeks. While some participants experienced unwanted effects, they were mostly mild or moderate and most did not appear to be caused by spesolimab, or the dose at which it was given. What do the results of the study mean?: The results indicate that a high dose of spesolimab works well to prevent GPP flares and stop the disease getting worse. Health authorities are looking at the results of this study to decide if spesolimab can also be prescribed for the prevention of GPP flares

Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare

Introduction: Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare. Methods and analysis: At least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated. Ethics and dissemination: The study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal. Trial registration details: ClinicalTrials.gov identifier: NCT03782792; Pre-results

The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score: online assessment and validation study of a specific measure of GPP disease activity

No abstract available

Trial of spesolimab for generalized pustular psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti–interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity. RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P&lt;0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P=0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.