Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V., Weteringbrug​, The Netherlands) is a dynamic in vitro model with close simulation of the successive physiological conditions of the human stomach and small intestine. Tiny-TIM runs with pralsetinib were performed at doses of 200 mg and 400 mg under fasting conditions. Mechanistic modeling of absorption was performed in Simcyp V21 (Certara, Manchester, UK). Pralsetinib fasted bioaccessibility in the Tiny-TIM system was 63% at 200 mg and 53% at 400 mg; a 16% reduction at 400 mg was observed under elevated gastric pH. Maximum pralsetinib solubility from the small intestinal compartment in Tiny-TIM directly informed the supersaturation/precipitation model parameters. The PBPK model predicted a similar fraction absorbed at 200 mg and 400 mg, consistent with the dose proportional increases in observed pralsetinib exposure. Integrating dynamic in vitro systems with mechanistic absorption modeling provides a promising approach for understanding and predicting human absorption with challenging low solubility compounds.

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (Cmax) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for Cmax ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.

BACKGROUND: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced.
METHODS: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients (\"case series\"), who experienced TIC, were compared to 37 \"control group\" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity.
RESULTS: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC.
CONCLUSIONS: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren\'t available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Recently, anthelmintics have showcased versatile therapeutic potential in addressing various diseases, positioning them as promising candidates for drug repurposing. However, challenges such as low bioavailability and a lack of a solid pharmacokinetic basis impede successful repurposing. To overcome these flaws, we aimed to investigate the key pharmacokinetic factors of anthelmintics mainly focusing on the absorption, distribution, and metabolism profiles by employing niclosamide (NIC) as a model drug. The intestinal permeability of NIC is significantly influenced by solubility and doesn\'t function as a substrate for efflux transporters. It showed high plasma protein binding. Also, the metabolism study indicated that NIC would have low metabolic stability by extensively undergoing the intestinal glucuronidation. Additionally, we investigated the CYP-mediated drug-drug interaction potential of NIC in both direct and time-dependent ways. NIC showed strong inhibitory effects on CYP1A2 and CYP2C8 and is not likely to become a time-dependent inhibitor. Our findings could contribute to the identification of essential factors in the pharmacokinetics of anthelmintics, potentially facilitating their repositioning.

Hysteroscopy is an exploratory endoscopic technique that studies the interior of the uterine cavity and the endocervical canal. Various fluids, such as physiological saline, are used to optimise visualisation of the internal structures during this procedure. A rare complication of hysteroscopy is fluid overload, which can be associated with intravascular absorption syndrome, usually after lengthy procedures or tissue dissection. There are no data on the incidence and prevalence of this syndrome, and few cases involving physiological saline solution have been reported. We present a case of hysteroscopic myomectomy complicated by vascular absorption syndrome, which gave rise to acute pulmonary oedema that required admission to the intensive care unit.

UNASSIGNED: Replacement of conventional hydrometallurgical and pyrometallurgical process used in E-waste recycling to recover metals can be possible. The metallurgical industry has been considered biohydrometallurgical-based technologies for E-waste recycling. Biorecovery of critical metals from phosphor powder from spent lamps is an example of transition to a bio-based circular economy. E-waste contains economically significant levels of precious, critical metals and rare-earth elements (REE), apart from base metals and other toxic compounds. Recycling and recovery of critical elements from E-waste using a cost-effective technology are now among the top priorities in metallurgy due to the rapid depletion of their natural resources. This paper focuses on the perceptions of recovery of REE from phosphor powder from spent fluorescent lamps regarding a possible transition toward a bio-based economy. An overview of the worldwide E-waste and REE is also demonstrated to reinforce the arguments for the importance of E-waste as a secondary source of some critical metals. Based on the use of bioprocesses, we argue that the replacement of conventional steps used in E-waste recycling by bio-based technological processes can be possible. The bio-recycling of E-waste follows a typical sequence of industrial processes intensely used in classic pyro- and hydrometallurgy with the addition of bio-hydrometallurgical processes such as bioleaching and biosorption. We use the case study of REE biosorption as a new technology based on biological principles to exemplify the potential of urban biomining. The perspective of transition between conventional processes for the recovery of valuable metals for biohydrometallurgy defines which issues related to urban mining can influence the mineral bioeconomy. This assessment is necessary to outline future directions for sustainable recycling development to achieve United Nations Sustainable Development Goals.
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The historical stone heritage that we inherit must be passed on to future generations, not only in the same conditions that we found it but, if possible, in better ones. Construction also demands better and more durable materials, often stone. The protection of these materials requires knowledge of the types of rocks and their physical properties. The characterization of these properties is often standardized to ensure the quality and reproducibility of the protocols. These must be approved by entities whose purpose is to improve the quality and competitiveness of companies and to protect the environment. Standardized water absorption tests could be envisaged to test the effectiveness of certain coatings in protecting natural stone against water penetration, but we found that some steps of these protocols neglect any surface modification of the stones, and hence may not be completely effective when a hydrophilic protective coating (i.e., graphene oxide) is present. In this work, we analyze the UNE 13755/2008 standard for water absorption and propose alternative steps to adapt the norm for use with coated stones. The properties of coated stones may invalidate the interpretation of the results if the standard protocol is applied as is, so here we pay special attention to the characteristics of the coating applied, the type of water used for the test, the materials used, and the intrinsic heterogeneity of the specimens.

Development of prodrugs is a useful strategy to overcome some disadvantages of candidate drugs. Recently, we established a systematic approach to selecting appropriate prodrugs, and validated the utility of this approach using oseltamivir analogues. In this study, the utility of the approach was further examined using candesartan cilexetil and 20 kinds of its analogues having various types of side chain as model compounds. Log D values of analogues (2.5 to 4.7) were higher than that of candesartan (1.0), their active metabolite, and the results were reasonable for the purpose of improving permeability of candesartan. The analogues tended to be more soluble in artificial intestinal fluids than in artificial gastric fluid, owing to their acidic physicochemical characteristics. Their membrane permeabilities were not correlated with log D values, which can be attributed to the metabolism in Caco-2 cells used in this system. In human hepatocytes and enterocytes, 11 out of the 20 analogues were immediately hydrolyzed to candesartan, and species differences were observed in the hydrolysis efficiency. This study confirmed the utility of the systematic approach for selection of appropriate prodrugs that could be proceeded to in vivo pharmacokinetics study, with selection of suitable experimental animals.

After lung transplantation, itraconazole (ITCZ) is used as a prophylaxis for aspergillosis. ITCZ is a weak base with high lipophilicity, and the dissolution and absorption of ITCZ tablets and capsules are pH dependent. Therefore, ITCZ may not achieve sufficient serum concentrations in patients with higher gastric pH because of its poor bioavailability. We report a case of a woman in fifties with post-COVID-19 respiratory failure who successfully underwent lung transplantation, followed by improved bioavailability of ITCZ tablets when given with acidic lemon beverages. The patient was initially administered ITCZ oral solution; this was discontinued because of its unpleasant taste, nausea, and vomiting. The ITCZ oral solution was replaced with ITCZ tablets 78 days after transplantation; however, serum concentrations of ITCZ and hydroxy-ITCZ were below the detection limit (100 ng/mL). We co-administered ITCZ tablets with commercially available lemon beverages. Subsequently, serum concentrations of ITCZ and hydroxy-ITCZ increased to 341 and 673 ng/mL, respectively, on the 125th day after transplantation. Infection with fungi, including Aspergillus spp., was not observed in this case. The patient had no adverse events such as gastric ulcer or hyperglycemia. These results suggest that the co-administration of lemon beverages and ITCZ tablets may help achieve better absorption of ITCZ in patients taking acid suppressants.