Background:Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management.Methods:The study is a narrative review conducted by collecting the most relevant and up-todate data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles.Results:Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDsexacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDsinduced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed.Conclusion:HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

2024-05-02·Rheumatology

Proteomics analyses of human plasma reveal triosephosphate isomerase as a potential blood marker of methotrexate resistance in rheumatoid arthritis

Article

作者: Coassy, Astrid ; Hodin, Sophie ; Escal, Jean ; Neel, Tiphany ; Delavenne, Xavier ; Marotte, Hubert ; Locrelle, Hervé ; Boussoualim, Karima ; Amouzougan, Adamah ; Thomas, Thierry

AbstractObjectiveThe objective of this study was to assess differentially expressed blood proteins between patients with active RA and patients in remission after MTX treatment, with the aim of identifying a biomarker of MTX resistance (MTXR).MethodsTwo populations of RA patients treated with a stable dose of s.c. MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n = 24) and active disease (DAS28 > 3.2; n = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment, which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach.ResultsUntargeted proteomics analysis revealed eight plasma proteins that were differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors in glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis.ConclusionA first step was achieved in the search for biomarkers of MTXR, with the identification of two actors in glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers.

2024-04-01·Future Medicinal Chemistry

Discovery of Novel Covalent Inhibitors of DJ-1 Through Hybrid Virtual Screening

Article

作者: Chen, Zhuo ; Li, Honglin ; Li, Shiliang ; Wang, Junyi ; Li, Shuang ; Shi, Xiayu ; Song, Yidan ; Ma, Yanyu ; Yuan, Zhen

Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC₅₀ value of 12.18 μM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.

项与 APN-501 series (Cleveland Clinic) 相关的新闻（医药）

2023-11-15

·GlobeNewswire-Health Care

NMD Pharma Raises €75 Million (~$80 million) in a Series B Financing

Proceeds will be used to complete three Phase 2 clinical studies of first-in-class ClC-1 molecule inhibitor NMD670 in myasthenia gravis, spinal muscular atrophy and Charcot-Marie-Tooth disease In addition, NMD Pharma will continue to mature and expand its pipeline of novel ClC-1 inhibitors, and pursue undisclosed targets for other neuromuscular diseases Aarhus, Denmark, 15 November 2023 – NMD Pharma A/S, a clinical-stage biotech dedicated to developing novel and improved treatments for patients living with neuromuscular diseases, today announces that it has raised €75 million (~$80 million) in a Series B financing. The financing was led by current investor Jeito Capital and includes investments from other current NMD Pharma investors: Novo Holdings, Lundbeckfonden BioCapital, INKEF Capital, and the Roche Venture Fund. NMD Pharma is developing first-in-class small molecule inhibitors of the skeletal muscle specific chloride ion channel (ClC-1) to enhance neuromuscular transmission with the potential to restore muscle function in a range of rare neuromuscular diseases. Proceeds from the financing will be used to complete three Phase 2 studies with NMD670, the Company’s lead ClC-1 inhibitor. The three studies will evaluate the novel mechanism of ClC-1 inhibition in AChR and MuSK antibody positive myasthenia gravis, spinal muscular atrophy, and Charcot-Marie-Tooth disease, respectively. Furthermore, NMD Pharma will continue to expand its pipeline of ClC-1 inhibitor molecules and pursue undisclosed targets for the treatment of other neuromuscular diseases. The new funds will also be used to expand NMD Pharma’s clinical and commercial operations in Denmark and in the US. “This funding will help NMD Pharma evolve significantly and enable us to become a late-stage clinical company with a pipeline of novel therapeutics in development for patients with neuromuscular diseases” said Thomas Holm Pedersen, Chief Executive Officer of NMD Pharma. “I would like to extend my thanks to my team for their work making NMD Pharma the company it is today and for the support and trust shown by our investors, and in particular to Jeito Capital, for leading this round.” “NMD Pharma has progressed its pipeline of first-in-class CIC-1 inhibitors from the laboratory to the clinic in several severe neuromuscular diseases. This financing round will be pivotal for the Company as we aim to deliver the next phase of growth to become a late-stage clinical company, supported by this new capital and expert investors who know us well and are experienced in building shareholder value.” remarked Mike Heffernan, Chairman of the Board at NMD Pharma. Sabine Dandiguian, Managing Partner at lead investor Jeito Capital, added: “Since we originally looked at NMD Pharma we have been impressed with the Company’s unique expertise in a very specialized area. The Company has matured and grown significantly since our initial investment last year and the recent positive clinical data has provided valuable validation. As such, we are very pleased to lead this new round and look forward to supporting Thomas Holm Pedersen, the CEO, and his talented team as they progress the NMD Pharma story to the next chapter with a joint ambition: provide patients with life transforming benefits.” -END- Contacts NMD Pharma A/SDan Brennan, SVP, Corporate and Commercial StrategyE-mail: contact@nmdpharma.com ICR ConsiliumMary-Jane Elliott / Ashley Tapp / Lindsey Neville E-mail: NMDPharma@consilium-comms.com Tel: +44 (0)20 3709 5700 About NMD PharmaNMD Pharma A/S is a clinical-stage biotech company developing a first-in-class platform of small molecule therapies selectively targeting the skeletal muscle chloride ion channel (ClC-1) for the treatment of severe neuromuscular disorders. The Company was incorporated as a spin-off from Aarhus University, Denmark in 2015 and was founded on more than 15 years of muscle physiology research with a focus on regulation of skeletal muscle excitability under physical activity. NMD Pharma has built a world-leading muscle electrophysiology platform leveraging the in-depth know-how of muscle physiology and muscular disorders, small molecule modulators, enabling technologies and tools as well as in vivo pharmacology models for discovering and developing proprietary modulators of neuromuscular function. NMD Pharma received initial seed financing in 2016 and has since raised ~€155 million from investors including Novo Holdings, Lundbeckfonden BioCapital, INKEF Capital, Roche Venture Fund, and Jeito Capital. Find out more about us online at http://www.nmdpharma.com/.

临床2期

100 项与 APN-501 series (Cleveland Clinic) 相关的药物交易

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