BackgroundSchistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, th...
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BackgroundSchistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, the disease can cause life-threatening complications. The current treatment of schistosomiasis relies on a single drug, praziquantel (PZQ). However, there is increasing concern about emerging resistance to PZQ due to its frequent *** identify potential alternative drugs for repurposing, the Open Global Health Library (OGHL) was screened in vitro, using two different screening workflows at two institutions, against adult S. mansoni couples and newly transformed schistosomula. This was followed by confirmation of the effects of the lead structures against adult *** vitro screening at one of the institutions identified two fast-acting substances affecting worm physiology (OGHL00022, OGHL00121). The effects of the two lead structures were investigated in more detail by confocal laser scanning microscopy and 5-ethynyl 2-deoxyuridine (EdU) assays to assess morphological effects and stem cell effects. Both substances showed negative effects on stem cell proliferation in S. mansoni but no further morphological changes. The EC50values of both compounds were determined, with values for compound OGHL00022 of 5.955 mu M for pairing stability, 10.88 mu M for attachment, and 18.77 mu M for motility, while the values for compound OGHL00121 were 7.088 mu M for pairing stability, 8.065 mu M for attachment, and 6.297 mu M for motility 24 h after treatment. Furthermore, S. mansoni couples were treated in vitro with these two lead structures simultaneously to check for additive effects, which were found with respect to reduced motility. The second in vitro screening, primarily against newly transformed schistosomula and secondarily against adult worms, identified four lead structures in total (OGHL00006, OGHL00022, OGHL00169, OGHL00217). I
Detergent-mediated viral inactivation is an important process step for ensuring viral safety of parenteral biotherapeutics, including plasma proteins and monoclonal antibodies (mAb). The conventional Triton X-100 dete...
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Detergent-mediated viral inactivation is an important process step for ensuring viral safety of parenteral biotherapeutics, including plasma proteins and monoclonal antibodies (mAb). The conventional Triton X-100 detergent has ecological toxicity concerns and REACH classification that mandate replacement in the biopharmaceutical industry. Criteria for a replacement detergent include viral inactivation efficacy, acceptable safety and biodegradation profile, process removal, and quality suitable for parenteral drug product manufacturing. A non-ionic, C11-15 secondary alcohol ethoxylate, Deviron 13-S9 detergent, has been demonstrated to meet the necessary requirements for detergent performance. Benchmarking studies with Triton X-100 detergent demonstrate comparable performance with a panel of enveloped viruses in multiple matrices, including human IgG, clarified cell culture harvest, and fractionated plasma. Deviron 13-S9 detergent demonstrated viral inactivation efficiency comparable to or better than Triton X-100 detergent, achieving > 5 log reduction values. Critical micelle concentration was determined across different temperatures and media. Deviron 13-S9 detergent was demonstrated to be readily biodegradable according to OECD 301B guidelines. The absence of detergent binding to typical chromatography resins used in downstream purification was confirmed. The process removal of Deviron 13-S9 detergent from a protein-containing matrix was demonstrated using a protein A resin. These findings support Deviron 13-S9 detergent as a viable alternative to Triton X-100 detergent, ensuring robust viral inactivation, environmental compatibility, and alignment with regulatory requirements.
ObjectiveClinical trials have demonstrated the efficacy and safety of avelumab + axitinib in patients with advanced clear cell renal cell carcinoma (ccRCC). However, information is limited regarding the activity of av...
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ObjectiveClinical trials have demonstrated the efficacy and safety of avelumab + axitinib in patients with advanced clear cell renal cell carcinoma (ccRCC). However, information is limited regarding the activity of avelumab + axitinib in patients with non-clear cell RCC (nccRCC). In Japan, post-marketing surveillance (PMS) of patients with RCC receiving avelumab + axitinib treatment in general clinical practice was undertaken. We report ad hoc analyses of PMS data according to RCC pathological *** 328 patients with RCC who received >= 1 dose of avelumab and were enrolled between December 2019 and May 2021, 271 (82.6%) had ccRCC, 22 (6.7%) had nccRCC, and 35 (10.7%) had missing or unknown RCC pathology. Among patients with nccRCC, pathological subtypes were papillary in 12 (3.7%), translocation in 3 (0.9%), acquired cystic disease associated in 3 (0.9%), chromophobe in 2 (0.6%), mucinous tubular and spindle cell in 1 (0.3%), and Bellini duct in 1 (0.3%).ResultsAmong patients with ccRCC or nccRCC, any-grade adverse drug reactions of safety specifications occurred in 140 (51.7%) and 15 (68.2%), and of grade >= 3 in 48 (17.7%) and 6 (27.3%), respectively. The objective response rate in patients with ccRCC or nccRCC was 36.9% and 22.7%, respectively;in patients with papillary tumors, it was 33.3%. Median overall survival was not reached in patients with ccRCC or nccRCC, and 12-month overall survival rates were 86.8% and 76.7%, ***, subgroup analyses of PMS data suggest that avelumab + axitinib improved clinical outcomes in nccRCC in addition to ccRCC.
Proteolysis-targeting chimeras (PROTACs (c)) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. With this study...
Proteolysis-targeting chimeras (PROTACs (c)) have recently emerged as a promising new drug modality. Residing beyond the rule-of-five space, they pose challenges in terms of physicochemical properties. With this study, we contribute to enhancing the understanding of their early ADME characterization. For permeability assessment, transwell assays such as Caco-2 remain challenging. Although the addition of serum may reduce unspecific binding and improve recovery, the assay was not found predictive for absorption. As a surrogate, we propose to focus optimization on molecular descriptors and support a preferred space for oral PROTACs (c) with <= 3 H-bond donors (HBDs), molecular weight (MW) <= 950 Da and number of rotatable bonds <= 12. We have developed a predictive score serving as initial guidance for design and prioritization according to this property space. In addition, the reduction of exposed polar surface area, e.g. through shielding of HBDs, is a powerful approach to optimize permeability. Using standard small molecule-based methods for in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CLint) with experimentally determined hepatocyte CLint and fraction unbound in plasma, and predicted fraction unbound in the incubation (fu,inc), a systematic under-prediction from mouse hepatocytes was observed for PROTACs (c). In line with our observation that the Kilford equation was not suitable for PROTAC (c) fu,inc prediction, this bias could be overcome by using experimentally determined fu,inc. Taken together, this study suggests a tailored in vitro DMPK discovery assay cascade and frontloading in vivo studies. It also underlines the need for inclusion of surrogate permeability descriptors and experimentally determined values for IVIVE of CLint.
Real-World Evidence (RWE), as an important pillar of Integrated Evidence Plans (IEP), offers a promising tool to address numerous hurdles impeding patients to receive timely and adequate treatments.
Real-World Evidence (RWE), as an important pillar of Integrated Evidence Plans (IEP), offers a promising tool to address numerous hurdles impeding patients to receive timely and adequate treatments.
BackgroundPromising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those *** ...
BackgroundPromising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those *** semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination. Key features of the DNA damage response were incorporated into the model to allow the emergence of synthetic lethality, including redundant DNA repair pathways that may be impaired due to genetic mutations, and due to PARP and ATR inhibition. Model parameters were calibrated using preclinical in vivo data for PARP inhibitors rucaparib and talazoparib and the ATR inhibitor *** model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response *** enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations.
Hypothyroidism is a relatively common condition that may affect as many as 10% of the population worldwide when its overt and subclinical presentations are considered. Important clinical comorbidities are highly preva...
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Hypothyroidism is a relatively common condition that may affect as many as 10% of the population worldwide when its overt and subclinical presentations are considered. Important clinical comorbidities are highly prevalent in people with hypothyroidism and diminish quality of life and functional status in a manner that is proportional to the number of comorbidities present and their severity. This article reviews the common comorbidities of hypothyroidism, as reported in the literature. The comorbidities of hypothyroidism include clinical conditions commonly associated with hypothyroidism, such as dyslipidaemia, hypertension, fatigue or (possibly) cardiovascular disease, and can appear whether or not intervention with LT4 is applied appropriately to ensure biochemical euthyroidism. Other comorbidities may share some pathogenetic background with hypothyroidism, including depression or anxiety, or autoimmune conditions. Hypothyroidism may arise as a comorbidity of some other conditions, e.g. following the application of targeted cancer therapies or some disease-modfying treatments for multiple sclerosis. Other common treatments, including metformin, glucocorticoids or proton pump inhibitors, among others, may alter levels of thyrotropin, thus impacting on the monitoring of thyroid dysfunction and the diagnosis of thyroid dysfunction. Ensuring good control of hypothyroidism is a necessary first step in managing any patient with hypothyroidism. Then, physicians should be aware of the possibility of other comorbid conditions that must be addressed to achieve an optimal patient outcome.
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