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Is It Time to Revisit the Role of Interleukin-1 Inhibitors in Osteoarthritis?
No full textThere remains a huge unmet need for new osteoarthritis (OA) therapies. A putative reason for the failure of some therapies has been the absence of well-defined phenotypes, which might be more appropriate for specific targeted treatment. Interleukin-1 (IL-1) plays a key role in the development of OA, but the results of clinical trials targeting IL-1 in OA have to date been disappointing.This narrative review is based on a literature search for publications describing interventions with direct Il-1 pathway inhibitors in patients with knee OA and substantiated by a description of key pre-clinical observations.Randomized controlled studies using IL-1 inhibition as treatment approach to knee OA have read out negatively, although trends for an improvement in pain and impact on biomarkers could be observed. However, in a post-hoc analysis of the large CANTOS trial data (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) testing an anti-IL-1 monoclonal antibody for the secondary prevention of cardiovascular events treatment arms receiving canakinumab demonstrated a substantial reduction in the incidence rate of joint replacement compared to those receiving placebo. Similar results have been reported from a post-hoc analysis of another cardiovascular risk reduction study, the low-dose colchicine 2 (LoDoCo 2) trial, raising the possibility of a beneficial effect of IL-1 inhibition in the subset of patients with metabolic phenotype.Based on the above results, it seems timely to revisit the role of IL-1 in OA, its relationship with chronic low-grade inflammation and its relevance in the subset of metabolic OA
Benchmarking quantum chemical methods with X-ray structures via structure-specific bond-distance/angle restraints
No full textThere is a need for fast, efficient, and accurate solid-state structure optimization for property prediction in the pharmaceutical industry. Optimizing structures of organic non-polymeric molecules including salts, solvates and cocrystals by efficient “molecule-in-cluster” (MIC) computations (Dittrich, Chan, et al., 2020) is therefore further investigated. The accuracy in reproducing experimental structure by semiempirical quantum mechanical (SQM) or quantum mechanical (QM) methods is evaluated by comparison to 22 very low-temperature high-resolution small-molecule crystal structures after aspherical-atom refinement. MIC GFN2-XTB, QM:MM (molecular mechanics), MO:MO (molecular orbital) were assessed and compared to full-periodic computations. Individual differences in bond distances between experiment and theory frequently exceed 0.005 Å. Since a bond-specific statistical analysis would require a much larger data set of structures, evaluating QM method performance was achieved by enforcing computed restraints in crystallographic least-squares refinements, followed by comparing the magnitude of root mean square Cartesian displacements (RMSCD) of computed and experimental structures. Analysis shows that MIC computations are a computationally efficient and accurate tool for solid-state structure optimization. Disagreements between experiment and high-level theory raise questions about their origin. Concerning practical application of structure-specific restraints, augmenting structural quality from comparably inaccurate experimental structures, e.g. from low-resolution refinement, 3D electron or powder diffraction, becomes possible. Augmenting such experimental results can then provide similar structural quality than low-temperature high-resolution single-crystal X-ray diffraction. For these applications, further improving efficiency and accuracy of optimization for providing restraints remains desirable
Genomic crosstalk between carbachol, a muscarinic receptor agonist, and indacaterol, a long-acting, β2-adrenoceptor agonist, in human airway epithelial cells
No full textMany patients with chronic obstructive pulmonary disease (COPD) are susceptible to recurrent exacerbations. Long-acting, muscarinic receptor antagonists protect against exacerbations suggesting that endogenous acetylcholine (ACh) could be a pro-inflammatory mediator. This idea was explored by determining if carbachol (CCh), a stable ACh analog, was a genomic stimulus in BEAS-2B bronchial epithelial cells. The ability of CCh to interact with indacaterol (Ind), a long-acting, β2-adrenoceptor agonists (LABA), was also assessed because sympathomimetic bronchodilators can promote the expression of adverse-effect genes in airway structural cells that are often regulated by the same transcription factors. Checkerboard assays using BEAS-2B cells expressing a cAMP response element luciferase reporter determined that CCh was a weak stimulus but interacted with Ind in a supra-additive manner. Likewise, mRNA-seq revealed that CCh regulated only 20 genes in BEAS-2B cells whereas Ind and Ind+CCh were powerful genomic stimuli affecting 869 and 1027 unique mRNAs, respectively. Of those, 39 genes were induced by Ind+CCh in a supra-additive manner; for the remainder, the interaction was either additive or infra-additive. Functional annotation of the Ind-regulated transcriptome identified transcription and signaling as dominant themes with gene ontology (GO) terms associated with inflammation and immune processes being highly represented. A comparable GO signature was obtained in the presence of CCh; however, the number, magnitude and duration of gene expression changes were markedly enhanced. If genomic interactions occur between a LABA and ACh in vivo, then this may lead to the expression of adverse-effect genes that, paradoxically, could maintain features of lung pathology in COPD
Harnessing Open-Source Solutions: Insights From the First Open Systems Pharmacology (OSP) Community Conference.
No full textIn 2017, the free and open-source software Open Systems Pharmacology (OSP) was launched. Since then, OSP has evolved from a small community into a diverse network of stakeholders committed to advancing open-source solutions for model-informed drug development (MIDD). In this context, the first OSP Community Conference was hosted by Novartis in Basel, Switzerland, on October 7-8, 2024, which gathered over 100 attendees from more than 40 institutions. This perspective synthesizes key insights from the conference
Ion-Pairing Hydrophilic Interaction Chromatography for Impurity Profiling of Therapeutic Phosphorothioated Oligonucleotides.
No full textTherapeutic oligonucleotides (ONs) may contain many closely related impurities. Using conventional liquid chromatography (LC) modes, the separation of impurities comprising the same number of nucleotides as the ON product remains a challenge. In this study, we investigated the performance of ion-pairing HILIC (IP-HILIC) as an alternative mass-spectrometry (MS)-compatible LC mode for ON impurity profiling. A fully phosphorothioated, N-acetylgalactosamine-conjugated 16-mer antisense ON (full-length product; FLP) served as a model compound, along with shortmer, longmer, PS-PO converted, deaminated (DA) and nonconjugated (NC) products, which are potential impurities. We describe the effect of ion-pairing reagent (IPR) hydrophobicity, eluent pH, and column temperature on IP-HILIC performance, with IPRs reducing the relative contribution of the phosphate moiety on retention, thereby increasing separation selectivity based on the nature of nucleobases and conjugated groups. For a poly(dT) ladder, the effective peak capacity was reduced from 35 to 22 when introducing triethylamine as IPR; however, improved separations were observed for PS ONs. By employing an eluent containing 25 mM triethylamine acetate (pH 6.3) and a column temperature of 80 °C, IP-HILIC successfully resolved the DA impurities from both the FLP and the NC-FLP. This is noteworthy, as current MS-compatible, one-dimensional LC methods cannot resolve the DA impurity from the FLP, and MS resolution is often insufficient to differentiate the FLP and DA due to a mass difference of less than 1 Da. The proposed IP-HILIC method shows the potential for ON impurity profiling
The Basel Modeling and Simulation Seminar: 20 Editions of Fostering Local Exchange in Pharmacometrics.
No full textThis year marks the 20th edition of the Basel Modeling and Simulation (M&S) Seminar, an initiative rooted in a commitment to promoting the exchange of the latest advancements in pharmacometrics and related disciplines in the region of Basel, Switzerland. This article provides insight into the history of this event, its operations to the present date, and a glimpse at the future
Implementation of GoDig-MS Technology for Spatial Proteomics: A Novel Approach for Efficient Method Developement and Sample Measurement in the Targeted Proteomics Space
No full textSpatial proteomics not only enables the identification of protein composition but also allows the mapping of their localization within cells or tissues. This analytical approach is supported by increasingly sensitive and advanced mass spectrometers, which have also led to the development of new acquisition methods. While already established and commonly used techniques do not always provide the required sensitivity and efficiency for the analysis of low-abundance analytes, GoDig technology promises deeper and multiplexed mass spectrometric analyses without the need for internal standards. To evaluate this method, GoDig was benchmarked against Real-time search and a conventional acquisition method using specifically concentrated myoglobin peptides. The myoglobin peptides as well as the generated background spectral library were labeled with TMTpro and analyzed using an Orbitrap Eclipse mass spectrometer. The results show that at higher concentrations, GoDig performs comparably to both reference methods. However, at lower concentrations, GoDig sensitively detects the target peptides at all levels, whereas the reference methods partially fail to detect any signals. Additionally, the cosine similarity scores of the GoDig method show values close to 1.0, indicating high spectral agreement. Further experiments are recommended to continue evaluating the limit of quantification of this method
Optical and Electrical Dual-Mode Detection of a Carcinogenic Substance Based on Synergy of Liquid Crystals and Ionic Liquids
No full textVisual, sensitive, and selective detection of carcinogenic substances is highly
desired in portable health protection and practical medicine production. However,
achieving this goal presents significant challenges with the traditional single-mode sensors
reported so far, as they have limited sensing mechanisms and provide only a single output
signal. Here, we report an effective optical and electrical dual-mode sensor for the visual,
sensitive, and selective detection of N-nitrosodiethylamine (NDEA), a typical volatile
carcinogenic substance, leveraging the synergy of ionic liquid-doped liquid crystals (ILLC).
The optical mode derived from LCs provides the sensor with a visual identification
recognizable by the naked eye, while the electrical mode derived from ILs offers a
quantitative detection capability. It is noteworthy that the synergistic effect of the IL and
LC enhances the performance of both optical and electrical modes. Unique sensing
mechanisms derived from the interaction between NDEA and IL-LC endow the sensor
with excellent selectivity. As a proof of concept, a portable kit based on a dual-mode sensor
has been developed for the real-time and on-site analysis of N-nitrosamine impurities in pharmaceuticals. This work provides
valuable insights and a theoretical foundation for developing portable multimode chemical sensors
Formulation and Characterization of Bevacizumab Encapsulated Poly (D, L-Lactide-co-glycolide) and Polycaprolactone microspheres
No full textAge-related macular degeneration (AMD) is one of the leading causes of central vision loss in the elderly population. Bevacizumab, a full-length humanized monoclonal anti-VEGF antibody, is commonly used off-label drug to treat AMD. However, the dosing regimen of bevacizumab and other anti-VEGF antibodies requires monthly intravitreal injections followed by regular intravitreal injections at 4–16-week intervals. In 2021, the FDA approved an innovative port delivery system of ranibizumab (Susvimo®) that can be implanted intravitreally to slowly release the active ingredient anti-VEGF antibody and reduce injection frequency to once every 6 months. An approach utilizing polymeric slow-release microspheres encapsulating a full-length antibody, such as bevacizumab, would be much more patient-friendly because it could be injected intravitreally, avoiding surgical implantation. While microsphere encapsulation is traditionally successful for small molecule hydrophobic drugs, we assessed two different polymers, namely Poly (D, L-Lactide-co-glycolide) [ PLGA] and Polycaprolactone [ PCL] and discovered the benefits of utilizing a slow degrading hydrophobic polymer such as PCL. Using traditional double emulsion fabrication techniques with PCL polymer, we could produce microspheres that encapsulate the full-length antibody bevacizumab, and in spite of the harsh fabrication conditions we demonstrate release of biologically active therapeutic agent over a period of 60 days
Cross-Electrophile Coupling to form Sterically Hindered C(sp2)-C(sp3) Bonds: Ni and Co Afford Complementary Reactivity
No full textThe formation of sterically hindered C(sp2)−C(sp3)
bonds could be a useful synthetic tool but has been understudied in
cross-electrophile coupling. Here, we report two methods that
couple secondary alkyl bromides with aryl halides that contain
sterically hindered C−X bonds: 1) ortho-substituted aryl bromides
with nickel catalysts and 2) di-ortho-substituted aryl iodides with
cobalt catalysts. Stoichiometric experiments and deuterium labeling
studies show that 1) [Co] is better than [Ni] for oxidative addition
of di-ortho-substituted Ar−I and 2) [Co] is better than [Ni] for
radical capture/reductive elimination steps with di-ortho-substituted arenes. For both metals, Ar−H side products observed in
reactions with low-yielding di-ortho-substituted aryl iodides appear to arise from Ar• formation and hydrogen-atom transfer from the
solvent. While the origins of the differences in scope are not yet understood, these studies demonstrate a previously unknown
complementarity between nickel and cobalt in cross-electrophile coupling