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Crystalline Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
As mentioned previously, gout flares are driven by activation of the NLRP3 inflammasome, which leads to upregulation of IL-1 and the inflammatory cascade (see Figure 4.2). Although therapies that indirectly affect this cascade are currently used to treat gout flares, for patients with intolerance or contraindications to traditional medications, a new oral NLRP3 inflammasome blocker has had success in phase 2 trials. This orally active small molecule, dapansutrile, is a β-sulfonyl nitrile compound that selectively inhibits the NLRP3 inflammasome in neutrophils and macrophages.50 In a recent open-label phase 2a trial, thirty-four patients with a monoarticular, crystal-proven gout flare were split into four groups to receive either 100 mg, 300 mg, 1,000 mg, or 2,000 mg daily doses of dapansutrile for seven days. Patients had a decrease in pain and inflammatory markers at days 3 and 7, as well as a decrease in plasma IL-6 levels. Gastrointestinal discomfort was seen in 22.2% of patients, similar to that found with colchicine use, and one patient in the 1,000-mg-per-day group had an MI eighteen days after the final dose of dapansutrile.51 Future studies will assess how effective this medication will be in treating flares, and eventually, in flare prophylaxis, adding to our growing anti-inflammatory armamentarium.52
The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Dorsa Sohaei, Morley Hollenberg, Sok-Ja Janket, Eleftherios P. Diamandis, Gennady Poda, Ioannis Prassas
NLRP3 activation results in the maturation of pro-inflammatory cytokines IL1β and IL18 that subsequently increase tissue factor (TF), fibrin levels, endothelial cell permeability, and formation of neutrophil extracellular traps (NETs). Inhibition of inflammasome activation is a common target for many chronic inflammatory conditions, therefore many compounds are already in production that can be repurposed for COVID-19 treatment [113–117]. NLRP3 inflammasome inhibitors include Carvedilol from Roche (launched in 1991, angina pectoris), a popular sleep supplement Melatonin from Neurim Pharmaceuticals (launched in 2007), and Dapansutrile from Olatec Therapeutics (Phase II, myocardial infarction). Phase II clinical trials are testing the efficacy of direct NLRP3 inhibition with either mild or severe COVID-19 infection (Novartis, NCT04382053; Olatec Therapeutics, NCT04540120). Indirect inhibition of NLRP3 is also being explored with the use of colchicine and metformin. Colchicine, a medication classically used to treat gout, inhibits tubulin polymerization leading to anti-inflammatory effects, including attenuation of the NLRP3 inflammasome pathway. A small RCT demonstrated the ability of colchicine to reduce oxygen requirements and hospitalization in moderate to severe COVIV-19 patients [118]. Metformin, a first-line antidiabetic agent, regulates the AMPK/mTOR pathway to inhibit the NLRP3 inflammasome. SARS-CoV-2 animal models have demonstrated that metformin was shown to inhibit NLRP3 and reduce lung inflammation, which supports the observed association of metformin with reduced mortality in COVID-19 patients [119,120].
Regulation of crystal induced inflammation: current understandings and clinical implications
Published in Expert Review of Clinical Immunology, 2021
Paola Galozzi, Sara Bindoli, Roberto Luisetto, Paolo Sfriso, Roberta Ramonda, Anna Scanu, Francesca Oliviero
Moreover, CY-09 is able to block ATP, MSU, and nigericin-induced activation of caspase-1, resulting in a decrease of IL-1β production. OLT177 or Dapansutrile (a β-sulfonyl nitrile compound) was proved to have favorable outcomes in gouty arthritis, by directly binding NLPR3 and blocking its ATPase activity. Results from an open-label phase II, a clinical trial (EU Clinical Trials Register, EudraCT 2016–000943-14), proved the efficacy and safety of oral Dapansutrile in reducing neutrophils and monocyte infiltration in joints of gouty subjects [144]. By now, many other natural compounds, which can be commonly found in plants and other natural substances, have been evaluated in murine and in vitro models since they can potentially represent a treatment option or at least support the current available treatments. In this context, it is worth mentioning oridonin, the main component of a herbal plant Rabdosia rubescens; it was reported to interact with NACHT domain of NLPR3, exhibiting significant preventive and therapeutic effects on crystal-induced inflammation [145]. Loganin, an iridoid glycoside derived from seeds of Loganiaceae family and present in several herbs, was proved to inhibit in vitro NLRP3 in bone-marrow-derived primary mouse macrophages (BMDMs), by preventing the cleavage of procaspase- 1 to caspase-1 and the degradation of pro-IL-1β to mature IL-1β. In addition, the oral administration of loganin could alleviate MSU crystal-induced inflammatory symptoms and NLRP3 inflammasome activation in a mouse gouty model [146]. Similarly, Baeckein E (BF-2), isolated from Baeckea frutescens L., is known to have anti-inflammatory properties since it can hamper NLRP3 assembly, by binding to ASC and caspase I. Moreover, the inhibition of MAPK and NFkb pathways and the suppression of pyroptosis were proposed as mechanisms of IL-1β blockade. The administration of BF2 was evaluated as a possible treatment for gout since it was associated with a reduction in ankle swelling, in murine models [147].