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Fevipiprant has a low risk of influencing co-medication pharmacokinetics: Impact on simvastatin and rosuvastatin in different SLCO1B1 genotypes
No full textFevipiprant, a prostaglandin D2 receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of Ki values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450 mg QD on the pharmacokinetics of simvastatin 20 mg and rosuvastatin 20 mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450 mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450 mg QD has only minor liabilities as a perpetrator for DDI
The oxysterol synthesizing enzyme CH25H contributes to the development intestinal fibrosis
No full textIntestinal fibrosis and stenosis are common complications of Crohn’s disease [CD], frequently
requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, antifibrotic
therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with
important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H]
converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and
oxidative stress. In human intestinal samples from CD patients, we found a strong correlation
of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced
intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate
[DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of
intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of
hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed
in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the
pathogenesis of intestinal fibrosis
Evaluation of in vitro assays to assess the modulation of dendritic cells functions by therapeutic antibodies and aggregates
No full textTherapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to obtain human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analysing cytokine and chemokine production via mRNA and protein quantification, and identifying cell signalling pathways via protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1β, IL-6, IL-8, IL-12, TNFα, CCL3 and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signalling proteins Syk, ERK1/2 and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins
Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs
No full textTwo decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize molecules based on Ro5 parameters evolved into the introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examination of oral drug parameters approved before and after the original Ro5 analysis demonstrates that some parameters such as clogP and HBD remained constant while the cutoffs for parameters such as molecular weight and HBA have increased substantially over the past 20 years. The time dependent increase in the molecular weight of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that molecular weight is a "drug-like" property. This analysis does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist
Bridging the gap between transition metal and biocatalysis
No full textIn our quest to attain synergistic processes involving chemo- and bio-catalysis, it has been discovered that aqueous solutions containing 2 wt % of the designer surfactant TPGS-750-M not only is compatible with enzymes, but also enhances their activity. Indeed, the lipophilic core of the micelles is suspected to act as a reservoir for substrates/products, avoiding noncompetitive inhibition of the enzyme. Numerous examples of cross-coupling reactions followed by asymmetric ketone reductions mediated by alcohol dehydrogenases (ADH) are reported, all run in 1-pot under mild conditions. Various transition metal catalysts based on Pd, Cu, Rh, and Au proved to be innocuous towards enzymatic activity, making this process suitable for a broad range of tandem organic transformations
Continuous Amination of Aryl/Heteroaryl Halides Using Aqueous Ammonia in a Teflon AF-2400 Tube-in-Tube Micro-Flow Reactor
No full textThe annual production of primary (hetero)arylamines has exceeded 6 million tons and has been extensively employed in pharmaceutical, agrochemical, and material industries. Catalyst-free and protecting group free nucleophilic amination using ammonia represents a green and atom-economical method. However due to the innate reactivity, chemical compatibility issue and the safety hazardous property of ammonia gas, such transformation is still underused. By implementing the gas permeable Teflon AF-2400 tube-in-tube system, diffusion of NH3 from aqueous ammonia to reaction mixture for amination can be achieved in a continuous flow fashion. In this communication, we herein report the use of aqueous ammonia as NH3 source in amination of hetereoaryl chorides to generate primary heteroaryl amines, providing a protocol that is green, economical and safe
Mating suppresses alarm response in zebrafish
No full textMating and flight from threats are innate behaviors which enhance species survival. Stimuli to these behaviors often are contemporaneous and conflicting. How such conflicts are resolved, and where in the brain such decisions are made, both are poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses. For example, zebrafish manifest a stereotypical escape response when exposed to “alarm substance” released from injured conspecific skin. We found that mating zebrafish ignore alarm substance and that a significant part of this suppression is mimicked by water primed by the mating pair. Two-photon imaging of calcium transients in single telencephalic neurons revealed a specific telencephalic region, Dp, activated by alarm substance and another, Vs, is activated by mating water (in addition to overlapping responses in Dm and Dl). When mating water and alarm substance are applied simultaneously, the alarm-specific response in Dp is suppressed while the mating water-specific telencephalic response is retained. Thus, when presented with competing olfactory stimuli, zebrafish enact the stereotypical behaviors of mating over those for alarm and response to threat, and this choice is matched by suppression of activation in the alarm-specific region of the telencephalon. The choice made, for reproduction over escape, is different from mammals, suggesting that it correlates with different a different balance of species survival advantages
Sustainable ppm Level Palladium-Catalyzed Aminations Under Mild, Aqueous Nanomicellar Conditions
No full textA 1:1 Pd:L complex, [t-BuXPhos(Pd-p-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are mainly at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, compares very favorably vs. traditional amination conditions, and has been shown to successfully lead to key medicinal intermediates
Geroprotectors: A role in the treatment of frailty
No full textThe proportion of the population over the age of 65 is growing the most rapidly due to the longevity revolution. Frailty is prevalent in this age group and strongly associated with disability and hospitalization, having a significant impact on the costs of health and social care. New effective interventions to delay or reverse frailty are urgently required. Geroprotectors are a new class of drugs, which target fundamental mechanisms of ageing and show promise in delaying the onset of or boosting resilience in frail older people. However, there are challenges to their clinical translation. Here we review the literature for evidence that frailty can be delayed or reversed and geroprotectors can improve frailty in murine models and in patients. We will then discuss the challenges, which make their clinical testing complex and propose potential options for moving forward
A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production
No full textA hallmark of chronic hepatitis B (CHB) virus infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A small molecule, RG7834, has been previously reported to inhibit HBsAg expression by targeting terminal nucleotidyltransferase proteins 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPR screen to identify other potential host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAg and identify additional factors involved in RG7834 activity, including a zinc finger CCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.
Hyrina et al. employ a non-biased functional CRISPR screening approach to identify host factors regulating HBsAg expression as well as those targeted by RG7834, a HBsAg inhibitor. The screen highlighted over 60 genes and identified a mechanism by which ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing