Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain

Drugs, Journal Year: 2022, Volume and Issue: 82(4), P. 357 - 373

Published: March 1, 2022

Around 20% of the American population have chronic pain and estimates in other Western countries report similar numbers. This represents a major challenge for global health care systems. Additional problems treatment persistent are comparably low efficacy existing therapies, failure to translate effects observed preclinical models human patients related setbacks clinical trials from previous attempts develop novel analgesics. Drug repurposing offers an alternative approach identify analgesics as it can bypass various steps classical drug development. In recent years, several approved drugs were attributed analgesic properties. Here, we review available data discuss findings suggesting that minocycline, fingolimod, pioglitazone, nilotinib, telmisartan, others, which originally developed different pathologies, analgesic, antihyperalgesic, or neuroprotective inflammatory neuropathic pain. For our analysis, subdivide into substances target neuroinflammation act on peripheral sensory neurons, highlight proposed mechanisms. Finally, merits challenges development

Language: Английский

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Multi‐model averaging improves the performance of model‐guided infliximab dosing in patients with inflammatory bowel diseases

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2022, Volume and Issue: 11(8), P. 1045 - 1059

Published: June 15, 2022

Abstract Infliximab dosage de‐escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss response. A single‐model approach model‐informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in with inflammatory bowel diseases. We evaluated predictive performances two multi‐model approaches, a model selection algorithm averaging algorithm, using 18 published population pharmacokinetic models guiding de‐escalation. Data 54 Crohn’s disease ulcerative colitis who underwent after an earlier escalation were used. priori prediction (based solely on covariate data) maximum posteriori data trough concentrations) compared accuracy metrics classification concentration target 5.0 mg/L. was inaccurate imprecise, lowest accuracies irrespective (median 59%, interquartile range 59%–63%). Using prediction, had systematically better performance than or any model, regardless number data. Only single (preferably point care) sufficed accurate precise prediction. Predictive both single‐ approaches robust to lack Model four demonstrated similar five‐fold shorter computation time. This implemented TDMx software tool guide forthcoming prospective MODIFI study (NCT04982172).

Language: Английский

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Mycobiome and Inflammatory Bowel Disease: Role in Disease Pathogenesis, Current Approaches and Novel Nutritional-based Therapies

Inflammatory Bowel Diseases, Journal Year: 2022, Volume and Issue: 29(3), P. 470 - 479

Published: July 19, 2022

Abstract Inflammatory bowel disease (IBD), a disorder characterized by chronic inflammation of the gastrointestinal (GI) tract and range adverse health effects including diarrhea, abdominal pain, vomiting, bloody stools, affects nearly 3.1 million genetically susceptible adults in United States today. Although etiology IBD remains unclear, genetics, stress, diet, gut microbiota dysbiosis— especially immunocompromised individuals— have been identified as possible causes disease. previous research has largely focused on role bacteria pathogenesis, recently observed alterations fungal load biodiversity GI afflicted individuals suggest interkingdom interactions amongst different microbial communities, particularly between fungi. These discoveries point to potential utilization treatment approaches such antibiotics, antifungals, probiotics, postbiotics that target both fungi managing IBD. In this review, we discuss impact specific with focus highly virulent genus Candida how presence certain co-enzymes impacts its virulence. addition, evaluate current microbiome-based therapeutic intention better understanding mechanisms behind novel therapies.

Language: Английский

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Engineered therapeutic antibodies with mannose 6-phosphate analogues as a tool to degrade extracellular proteins

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: March 12, 2024

Inducing the degradation of pathological soluble antigens could be key to greatly enhancing efficacy therapeutic monoclonal antibodies (mAbs), extensively used in treatment autoimmune and inflammatory disorders or cancer. Lysosomal targeting has gained increasing interest recent years due its pharmaceutical applications far beyond lysosomal diseases, as a way address proteins lysosome for eventual degradation. Mannose 6-phosphonate derivatives (M6Pn), called AMFA, are unique glycovectors that can significantly enhance cellular internalization conjugated AMFA via cation-independent mannose 6-phosphate receptor (M6PR) pathway. engineering mAbs results generation bifunctional antibody is designed bind both antigen M6PR. The improvement potential by was investigated using two directed against antigens: infliximab (IFX), tumor necrosis factor α (TNF-α), bevacizumab (BVZ), vascular endothelial growth (VEGF). conjugations were performed either on oligosaccharidic chains lysine residues. Both controlled reproducible provided novel affinity M6PR without altering antigen. grafting mAb increased their uptake through an M6PR-dependent mechanism. also 2.6 5.7 times more internalized mAb-AMFA rapidly degraded cells. Additional cell culture studies proved higher IFX-AMFA BVZ-AMFA compared unconjugated counterparts inhibiting TNF-α VEGF activities. Finally, zebrafish embryo model angiogenesis xenografted chick embryos showed effective than BVZ reducing angiogenesis. These demonstrate induces significant increase efficacy. Engineering with analogues develop new class diseases.

Language: Английский

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At The Interface: Small-Molecule Inhibitors of Soluble Cytokines

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Cytokines are crucial regulators of the immune system that orchestrate interactions between cells and, when dysregulated, contribute to progression chronic inflammation, cancer, and autoimmunity. Numerous biologic-based clinical agents, mostly monoclonal antibodies, have validated cytokines as important targets now part standard care for a number diseases. These while impactful, still suffer from limitations including lack oral bioavailability, high cost production, immunogenicity. Small-molecule cytokine inhibitors attractive alternatives can address these limitations. Although targeting cytokine-cytokine receptor complexes with small molecules has been challenging research endeavor, multiple small-molecule identified, them undergoing evaluation. In this review, we highlight recent advancements in discovery development soluble cytokines. The strategies identifying novel ligands well structural mechanistic insights into their activity represent milestones tackling clinically protein-protein interactions.

Language: Английский

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