作者: Otani, Naoyuki ; Kuranari, Masae ; Uemura, Naoto ; Furuie, Hidetoshi ; Nagabukuro, Hiroshi ; Higashi, Toshinori ; Kudo, Hideo ; Tanaka, Akira ; Wakuda, Hirokazu ; Kuniyeda, Kanako ; Ando, Haruhi

Abstract:

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad‐spectrum anti‐inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART‐648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole‐blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART‐648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide‐induced TNFα release in ex vivo whole‐blood assay. In the single rising dose study, ART‐648 was safe and well tolerated with a dose‐proportional increase in exposures up to 4 mg. Single doses of ART‐648 demonstrated dose‐dependent PD response, indicating target engagement at 2‐8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART‐648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

2021-01-01·Dermatologic therapy

The beneficial effect of a PDE4 inhibitor in a patient with juvenile‐onset intractable pityriasis rubra pilaris without CARD14 mutation

Letter

作者: Inoue, Emi ; Hanaoka, Yuma ; Tanemura, Atsushi ; Fujimoto, Manabu ; Arase, Noriko

Juvenile is the counterpart of classical adult and more favorable in children.The phosphodiesterase 4 inhibitor, a premilast has been used to treat adult-onset PRP.It could be an effective treatment for patients with juvenile.

2012-12-01·Journal of cellular biochemistry3区 · 生物学

Role of yessotoxin in calcium and cAMP‐crosstalks in primary and K‐562 human lymphocytes: The effect is mediated by Anchor kinase a mitochondrial proteins

3区 · 生物学

Article

作者: Araceli Tobío ; Amparo Alfonso ; Luis M. Botana ; Andrea Fernández-Araujo

Abstract:

Yessotoxin (YTX) is a marine polyether toxin previously described as a phosphodiesterase (PDE) activator in fresh human lymphocytes. This toxin induces a decrease of adenosine 3′,5′‐cyclic monophosphate (cAMP) levels in fresh human lymphocytes in a medium with calcium (Ca2+), whereas the contrary effect has been observed in a Ca2+‐free medium. In the present article, the effect of YTX in K‐562 lymphocytes cell line has been analysed. Surprisingly, results obtained in K‐562 cell line are completely opposite than in fresh human lymphocytes, since in K‐562 cells YTX induces an increase of cAMP levels. YTX cytotoxicity was also studied in both K‐562 cell line and fresh human lymphocytes. Results demonstrate that YTX does not modify fresh human lymphocytes viability, whereas in K‐562 cells, YTX has a highly cytotoxic effect. It has been described in a previous study that YTX induces a small cytosolic Ca2+ increase in fresh human lymphocytes but no effect was observed on Ca2+ pools depletion in these cells. However, our results show that, in K‐562 cells, YTX has no effect on cytosolic Ca2+ levels in a medium with Ca2+ and induces an increase on Ca2+ pools depletion followed by a Ca2+ influx. As far as Ca2+ modulation is concerned these results demonstrate that YTX has a clear opposite effect in tumoural and fresh human lymphocytes. In addition, intracellular Ca2+ reservoirs affected by YTX are different than thapsigargin‐sensible pools. Furthermore, YTX‐dependent Ca2+ pools depletion was abolished by cAMP analogue (dibutyryl cAMP), phosphodiesterase‐4 (PDE4) inhibitor (rolipram), protein kinase A inhibitor (H89) and oxidative phosphorylation uncoupler carbonyl cyanide p‐(trifluoromethoxy) (FCCP) treatments. This evidences the crosstalks between Ca2+, YTX and cAMP pathways. Also, results obtain demonstrate that YTX‐dependent Ca2+ influx was only abolished by FCCP pre‐treatment, which indicates a link between YTX and mitochondria in K‐562 cell line. Cytosolic expression of A‐kinase anchor proteins (AKAPs), the proteins which integrates phosphodiesterases (PDEs) and PKA to the mitochondria, was determined in both cell models. On the one hand, in human fresh lymphocytes, YTX increases AKAP149 cytosolic expression. This fact is accompanied with a decrease in cAMP levels, and therefore PDEs activation, which finally leads to cell survival. On the other hand, in tumoural lymphocytes, YTX has an opposite effect since decreases AKAP149 cytosolic expression and increase cAMP levels which leads to cell death. This is the first time that YTX and mitochondrial AKAPs proteins relationship is characterised. J. Cell. Biochem. 113: 3752–3761, 2012. © 2012 Wiley Periodicals, Inc.

项与 PDE4 inhibitors (inflammatory disease/COPD)(NCATS) 相关的新闻（医药）

2024-09-20

·PRNewswire

UNION therapeutics to present orismilast Phase 2b results in atopic dermatitis as a late-breaking oral presentation at the EADV Congress 2024

ADESOS Phase 2b results with orismilast in atopic dermatitis (AD) selected as late-breaking oral presentation Additionally, two posters on data from the pioneering use of tape stripping for biomarker analysis in the ADESOS study and additional ADESOS Phase 2b results Orismilast is a next generation, high potency PDE4 B/D selective inhibitor with reported positive results from a Phase 2b study in psoriasis and Phase 2, IIT, study in hidradenitis suppurativa (HS); orismilast is currently being evaluated in an ongoing Phase 2, IIT study in ulcerative colitis (UC) UNION plan to progress orismilast to Phase 3 development in AD HELLERUP, Denmark, Sept. 20, 2024 /PRNewswire/ -- UNION therapeutics A/S (UNION), a privately held, clinical stage, pharmaceutical development company focused on immunology, today announced ADESOS Phase 2b results selected as a late-breaking oral presentation at the European Academy of Dermatology and Venerology (EADV) Congress 2024 on September 25-28, 2024, in Amsterdam, Holland. New data from the ADESOS Phase 2b study of orismilast in AD will be presented by Prof. Dr. Eric Simpson. The efficacy and safety results of orismilast from the Phase 2b ADESOS trial will also be presented as an poster. Additionally, one poster on the molecular effects in the skin of AD patients after oral orismilast treatment will be presented. "Despite the current developments of new treatments in AD, there is a clear need for safe and efficacious oral treatments. Impact on patients' experience of itch and pain along with lesional improvements are key to determine the relevance of a treatment", says Prof. Dr. Eric Simpson. "I am excited to present the results from the Phase 2b ADESOS study at the EADV Congress 2024, showing that orismilast offers the promise as a novel treatment option in AD with early impact on patients' burden of disease, including significant itch reduction from 1 week of treatment." "We are pleased that the Phase 2b results from the ADESOS study have been selected as a late-breaking oral presentation at the EADV Congress 2024", adds Kim Kjøller, Co-CEO of UNION. "Additionally, we appreciate the opportunity to present two posters on ADESOS Phase 2b results and the molecular effects in the skin after treatment with orismilast, following the pioneering use of tape strips to analyze the effect on relevant disease biomarkers. We look forward to being at the conference and discuss the results with leading experts within the field as we are progressing orismilast in Phase 3 development in atopic dermatitis." Presentation details for the late-breaking presentation Presentation: Orismilast efficacy in adults with moderate-to-severe atopic dermatitis in a phase 2b trial: early impact on itch and patient-reported outcomes Session code: D1T01.1 Presenter: Prof. Dr. Eric Simpson, Professor of Dermatology, School of Medicine, Frances J. Storrs, M.D. Medical Dermatology Professor, Dermatology, School of Medicine Date and time: Wednesday September 25, 2024, at 2:30-2:45 PM GMT Details for the posters Poster title: Molecular effects in the skin of atopic dermatitis after oral treatment with orismilast ID: 5905 Poster number: P3569 Poster title: Efficacy and safety of orismilast, a potent PDE4B/D inhibitor, in adults with moderate-to-severe atopic dermatitis: a Phase 2b randomized, double-blinded, placebo-controlled clinical trial (ADESOS) ID: 4256 Poster number: P0598 About orismilast Orismilast is a next generation, high potency PDE4 inhibitor targeting the PDE4B/D subtypes linked to inflammation, demonstrating potent inhibition of Th1, Th2 and Th17 pathways. It acts early in the inflammation cascade, inducing a broad range of anti-inflammatory effects across multiple cytokines involved in many dermatological and immunological diseases.1) UNION is developing orismilast as an oral treatment across immunology. Based on the well-known safety profile of the PDE4 class, initially targeting best-in-class or first-in-class positions in atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis and ulcerative colitis (UC). The FDA has cleared UNION's Investigational New Drug (IND) application for orismilast and granted Fast Track designation for orismilast for the treatment of moderate to severe AD as well as for the treatment of moderate to severe HS. Sources Blauvelt A et al., Dermatology and Therapy 2023: Next Generation PDE4 Inhibitors that Selectively Target PDE4B/D Subtypes: A Narrative Review - PubMed (nih.gov) & Silverberg J.I. et al., JEADV 2022: & Warren R.B. et al., JEADV 2022: Contacts Morten Boesen, Chief Financial Officer, UNION therapeutics A/S +45 2381 5487 [email protected] Sarah Toft-Jørgensen, Director of Communications and IR, UNION therapeutics A/S +45 5385 3044 [email protected] About UNION therapeutics UNION therapeutics is a privately held, clinical stage, pharmaceutical development company focused on immunology. UNION's lead asset is orismilast, a next generation, high potency PDE4 B/D inhibitor, for a range of immunological diseases e.g., atopic dermatitis (AD) and hidradenitis suppurativa. Orismilast holds the potential to become the first safe oral treatment in AD. UNION is headquartered in Hellerup, Denmark, and led by an international team combining biotech entrepreneurs and seasoned pharma executives, with a track record of developing and launching more than fifteen marketed drugs. Read more at This information was brought to you by Cision WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床2期快速通道临床结果

100 项与 PDE4 inhibitors (inflammatory disease/COPD)(NCATS) 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
炎症	药物发现	美国	National Center for Advancing Translational Sciences	2008-04-17
炎症	药物发现	美国	National Institutes of Health	2008-04-17
慢性阻塞性肺疾病	药物发现	美国	National Institutes of Health	2008-04-17
慢性阻塞性肺疾病	药物发现	美国	National Center for Advancing Translational Sciences	2008-04-17