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Physician Centricity in the Deployment of Digital Solutions for Neurological Conditions
No full textNo abstract [article is 1,000 word letter to editor
Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.
No full textNovel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity
Selectivity Arising from Synergy Between Two Metals and Aqueous Micelle: Nickel-Palladium Bimetallic Nanoparticles for Facile and Highly Selective 1,4-Reduction of Chalcones
No full textBy harnessing the synergy between Ni(0), Pd(0), and an aqueous micelle of proline-derived PS-750-M amphiphile, phosphine ligand-free ultrasmall nanoparticles (NPs) of Ni(0)-Pd(0) are developed for highly selective 1,4-reductions of enones. In the NP, Ni(0)-bound Pd(0) atoms are found to only react with the most electron-deficient double bond due to the electron enriching character of Pd and fine-tuning of the bimetallic NP’s d-band. Most notably, NPs containing a minimal amount of Pd (Ni:Pd = 25:1) were highly selective for 1,4-reductions of enones without affecting different types of N-and O-benzyl, aldehyde, nitrile, and nitro functional groups. The catalytic selectivity is investigated on a broad range of substrates, including a gram-scale reaction. Control experiments reveal Ni, Pd, and a micelle of PS-750-M are required for higher selectivity. Evidence of the metal-micelle binding was supported by a surface-enhanced Raman spectroscopy (SERS) study of the NPs and their components. Optical imaging, high-resolution transmission electron microscopy (HRTEM), and energy-dispersive X-ray spectroscopy (EDX) analyses were performed to reveal the formation of NP-containing micelles or vesicles, NP morphology, particle size distribution, and chemical composition, while X-ray photoelectron spectroscopy (XPS) measurements unveiled the oxidation state of each metal in the bimetallic NPs
Nanoparticules and their impact in the chemistry of interface-rich aqueous systems
No full textThis review highlights the recent development of nanocatalyst enabled chemical transformations in water, leveraging the nanomicelle/surfactant chemistry and related technology. Various types of chemical reactions including the most frequently used transformations in pharmaceutical industry are discussed herein. A potential implementation of such nano-technology in large scale synthesis in industry level is also briefed touched
Hot melt extruded PLGA implants loaded with ibuprofen: How heat exposure alters the physical drug state
No full textHot melt extrusion offers an interesting potential for the manufacturing of poly(lactic-co-glycolic acid) (PLGA)-based implants. However, the heat treatment might substantially alter the polymer, drug and degree of drug-polymer mixing. The aim of this study was to better understand the impact of varying the exposure time to 105 °C in the case of ibuprofen-loaded PLGA implants. In vitro drug release was measured in phosphate buffer pH 7.4. Optical and scanning electron microscopy, DSC, GPC, X-ray diffraction as well as gravimetric analysis were used to monitor dynamic changes of the implants’ morphology, dry & wet mass and average polymer molecular weight. Interestingly, increasing the exposure time from 3 to 15 min led to a decrease in the amount of crystalline drug present in the system, resulting in a slight decrease in the initial burst release. The average PLGA molecular weight also slightly decreased during the heat treatment. In contrast, the relatively rapid penetration of water into the implant and subsequent polymer degradation throughout the device did not seem to be affected to a noteworthy extent. Also the onset of substantial implant swelling after about 1 week and the subsequent beginning of the final rapid drug release phase (accounting for about 80% of the total drug dose) were not significantly altered. Thus, in this study, the changes in the physical state of the drug in the implant induced by prolonged heat exposure had only a limited impact on system performance. However, for different drugs and polymers, changes in their physical state as a function of the heat exposure time might have more importance consequences. Careful monitoring of these kinetic aspects is recommended to assure desired product quality
Contribution of MATE1 to Dofetilide-Induced Proarrhythmia
No full textDofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predisposes to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as an efflux transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window
High-Throughput Screen for Inhibitors of Klebsiella pneumoniae Virulence Using a Tetrahymena pyriformis Co-Culture Surrogate Host Model.
No full textThe continuing emergence of antibacterial resistance reduces the effectiveness of antibiotics and drives an ongoing search for effective replacements. Screening compound libraries for antibacterial activity in standard growth media has been extensively explored and may be showing diminishing returns. Inhibition of bacterial targets that are selectively important under in vivo (infection) conditions and, therefore, would be missed by conventional in vitro screens might be an alternative. Surrogate host models of infection, however, are often not suitable for high-throughput screens. Here, we adapted a medium-throughput Tetrahymena pyriformis surrogate host model that was successfully used to identify inhibitors of a hyperviscous Klebsiella pneumoniae strain to a high-throughput format and screened circa 1.2 million compounds. The screen was robust and identified confirmed hits from different chemical classes with potent inhibition of K. pneumoniae growth in the presence of T. pyriformis that lacked any appreciable direct antibacterial activity. Several of these appeared to inhibit capsule/mucoidy, which are key virulence factors in hypervirulent K. pneumoniae. A weakly antibacterial inhibitor of LpxC (essential for the synthesis of the lipid A moiety of lipopolysaccharides) also appeared to be more active in the presence of T. pyriformis, which is consistent with the role of LPS in virulence as well as viability in K. pneumoniae
Ligelizumab impairs IgE-binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN-α production and FOXP3+ Treg generation.
No full textLigelizumab is an anti-IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE-mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN-α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab.pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53-79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE-FcεRI crosslinking and Toll-like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen-specific model of resensitization and IgE-crosslinking was also performed.The levels of serum total free IgE show a non-linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9-L-induced IFN-α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab.The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti-IgE treatments in different IgE-mediated diseases
People of TM: Video of Slivana Libertini
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featuring stories of people in TM. No IP related content
Scientific and Regulatory Policy Committee Best Practices: Recommended ("Best") Practices for Informed (Non-blinded) Versus Masked (Blinded) Microscopic Evaluation in Animal Toxicity Studies.
No full textThis article describes the Society of Toxicologic Pathology's (STP) five recommended ("best") practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds ("no observed adverse effect level" and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination