Applicability of MDR1 Overexpressing Abcb1KO-MDCKII Cell Lines for Investigating In Vitro Species Differences and Brain Penetration Prediction.

Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico models. However, animal studies are still indispensable to obtaining brain concentration and determining the prediction performance of in vitro models. To reveal species differences and provide reliable data for IVIVE, in vitro models are required. Systems overexpressing MDR1 and BCRP are widely used to predict BBB penetration, highlighting the impact of the in vitro system on predictive performance. In this study, endogenous Abcb1 knock-out MDCKII cells overexpressing MDR1 of human, mouse, rat or cynomolgus monkey origin were used. Good correlations between ERs of 83 drugs determined in each cell line suggest limited species specificities. All cell lines differentiated CNS-penetrating compounds based on ERs with high efficiency and sensitivity. The correlation between in vivo and predicted Kp,uu,brain was the highest using total ER of human MDR1 and BCRP and optimized scaling factors. MDR1 interactors were tested on all MDR1 orthologs using digoxin and quinidine as substrates. We found several examples of inhibition dependent on either substrate or transporter abundance. In summary, this assay system has the potential for early-stage brain penetration screening. IC50 comparison between orthologs is complex; correlation with transporter abundance data is not necessarily proportional and requires the understanding of modes of transporter inhibition.

Improvement of drug processability in a connected continuous crystallizer system using formulation additive.

Continuous crystallization in the presence of polymer additives is a promising method to omit some drug formulation steps by improving the technological and also pharmacological properties of crystalline active ingredients. Accordingly, this study focuses on developing an additive-assisted continuous crystallization process using polyvinylpyrrolidone in a connected ultrasonicated plug flow crystallizer and an overflow mixed suspension mixed product removal (MSMPR) crystallizer system. We aimed to improve the flowability characteristics of small, columnar primary plug flow crystallizer-produced acetylsalicylic acid crystals as a model drug by promoting their agglomeration in MSMPR crystallizer with polyvinylpyrrolidone. The impact of the cooling antisolvent crystallization process parameters (temperature, polymer amount, total flow rate) on product quality and quantity was investigated. Finally, a spatially segmented antisolvent dosing method was also evaluated. The developed technology enabled the manufacture of purified, constant quality products in a short startup period, even with an 85% yield. We found that a higher polymer amount (7.5-14%) could facilitate agglomeration resulting in "good" flowability without altering the favorable dissolution characteristics of the primary particles.

Treatment of patients with malignant pleural effusion in a tertiary oncology center during the COVID-19 pandemic / Malignus pleuralis effusiókkal küzdo betegek ellátása egy regionális onkológiai központban a COVID-19-pandémia idoszakában

Introduction: Malignant pleural effusion is a complication of tumors heralding poor outcome. It may be life-threat- ening, so advanced cases should be treated as an oncological emergency. Objective: We aimed to provide complex care to patients with malignant pleural effusion during the COVID-19 pandemic at the University of Pecs Medical School, in the Department of Oncotherapy. During the pandemic, we introduced the thoracocentesis as a routine method in our department without previous experiences. Method: Results of diagnosing and treating pleural effusion of patients between March 18th of 2020 and May 31st of 2021 were summarized. Results: We have analyzed data of 45 patients, two-thirds (66.7%) of them were women, the median age was 67 years. 57.8% of patients received systemic anticancer therapy during the study. The total number of thoracocentesis was over 120, one-third of the patients required more than five interventions. Only three iatrogenic pneumothorax cases were detected, no other serious complications were experienced. The procedures - that were aimed to mitigate symptoms in most cases (80%) - were considered successful. However, 48.9% of the patients were no longer alive at the end of the study period indicating very poor prognosis of pleural carcinosis. Discussion and conclusion: Clinical care of oncological patients was continuous during the pandemic; patients treated as part of emergency care were often seen in advanced disease state. Treatment of malignant pleural effusion requires oncological foresight as well as implementing an invasive approach. Our study has shown that discussion of the topic is relevant, may reveal difficulties and need for improvement. Our results are consistent with literature data, we have experienced less complications than reported in the literature.

Long-term effects of grain husk and paper fibre sludge biochar on acidic and calcareous sandy soils - A scale-up field experiment applying a complex monitoring toolkit.

Biochar is produced from a wide range of organic materials by pyrolysis, specifically for improvement of poor quality soils. One of the main issues nowadays in studying biochar as soil amendment is to upscale experiments and move from short-term, laboratory conditions to long-term field trials. This paper presents a long-term field study, being the final step of a scale-up technology development, on grain husk and paper fibre sludge biochar application for soil improvement with focus on two degraded soil types of a temperate region. The effects of biochar on an acidic and a calcareous sandy agricultural soil were studied applying a complex approach including physico-chemical, biological and ecotoxicological methods. Our study demonstrated that the applied biochar had positive direct and indirect influences on the acidic sandy soil, but these effects were different in terms of extent and time. 30 t/ha biochar addition improved the pH of the acidic sandy soil by 24% and also increased significantly the nutrient concentrations (P2O5 by 68%, K2O by 11% and organic matter by 33%), and the water-holding capacity after 30 months. Furthermore, biochar addition improved also the microbiological activity and diversity in the acidic sandy soil. Biochar application did not induce any negative effects. Biochar had no toxic effect on the plants and the biochar-treated soil provided a more liveable habitat for soil living animals than the untreated acidic sandy soil. The favourable biochar-mediated influences on soil properties were manifested mainly in the acidic sandy soil, proving that the biochar-related advantages have to be verified for different soil types. The benefits of grain husk and paper fibre sludge biochar application in an acidic sandy soil were confirmed on the long term by the applied tiered approach.