AN INTELLIGENT POWER MOSFET DRIVER ASIC CIRCUIT WITH ADDITIONAL INTEGRATED SAFETY OPERATION FUNCITIONALITY

This paper presents an extension to the previously presented conference paper [1] a power MOSFET driver ASIC with intelligent driving algorithm approach of the power modern MOSFET devices. The intelligent driving algorithm concept proposes a realization of power MOSFET gate driving with controlled source/sink current of the power MOSFET driver circuit. Such approach enables higher control of the power MOSFET operation behavior, especially during switching events.  Additionally to the previously published work this paper presents implementation of the intelligent driving algorithm and driver safety operation functions on a single integrated ASIC circuit. The paper concludes with presentation of some functions of the manufactured ASIC circuit in CMOS technology

Biopharmaceutical classification of desloratadine – not all drugs are classified the easy way

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers – a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated desloratadine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper

Koncentracije zdravilnih učinkovin v slovenskih komunalnih in bolnišničnih odpadnih vodah: preliminarna raziskava

Pharmaceuticals in wastewater have clearly raised concern and a broad range of analytical methods has been used to assess the risk as accurately as possible. The aim of our study was to measure and compare the concentrations of atorvastatin, bisoprolol, carbamazepine, ciprofloxacin, clofibric acid, diclofenac, fluoxetine, metoprolol, and sertraline in wastewater samples taken from one municipal and one hospital wastewater treatment plant in Slovenia and to predict the potential environmental burden using the risk quotient. In both effluents only clofibric acid and fluoxetine were not detected. The measured concentrations of the remaining seven pharmaceuticals varied between the ng L-1 and the μg L-1 range. Hospital effluent showed higher concentrations, except for diclofenac and carbamazepine. However, high risk quotient was found only for ciprofloxacin and diclofenac in both municipal and hospital effluent. In conclusion, our method can provide a useful tool for systematic monitoring of pharmaceuticals commonly found in wastewater, which will enable a reliable assessment of the risks for the aquatic biota and humans. Knowing the risks will help to plan wastewater treatment and preserve our environment.Koncentracije zdravilnih učinkovin v slovenskih komunalnih in bolnišničnih odpadnih vodah: preliminarna raziskava. Pojavljanje ostankov zdravilnih učinkovin v odpadnih vodah postaja vedno bolj aktualna tematika in posledično se širi nabor analiznih metod, ki omogočajo natančno ugotavljanje njihove prisotnosti in služijo kot orodje za napovedovanje tveganja teh onesnažil v vodnem okolju. Namen naše raziskave je bil kvantitativno ovrednotiti prisotnost izbranih zdravilnih učinkovin (atorvastatin, bisoprolol, ciprofloksacin, diklofenak, fluoksetin karbamazepin, klofibrinska kislina, metoprolol in sertralin) na iztoku ene komunalne in ene bolnišnične čistilne naprave. Na osnovi meritev koncentracij smo z uporabo količnika tveganja ocenili okoljsko breme vključenih spojin. Ugotovili smo prisotnost sedmih zdravilnih učinkovin, medtem ko klofibrinske kisline in fluoksetina nismo zaznali v nobenem vzorcu. Izmerjene koncentracije so bile v širokem koncentracijskem območju (od ng L-1 do μg L-1), praviloma višje v bolnišnični odpadni vodi, z izjemo diklofenaka in karbamazepina. Izračunan količnik tveganja nakazuje na visoko tveganje za ciprofloksacin in diklofenak v vseh analiziranih vzorcih odpadnih voda. Raziskava je pokazala, da je razvita metoda primerno orodje za nadaljnje študije, ki bodo na podlagi sistematičnega spremljanja teh novodobnih onesnažil v odpadnih vodah omogočile zanesljivejšo oceno tveganja za izpostavljene vodne organizme in tudi za zdravje ljudi. Poznavanje teh tveganj bo prispevalo k načrtovanju ustrezne tehnologije čiščenja odpadnih voda in posledično k ohranjanju čistega in zdravega okolja

Data on biosynthesis of BPAF glucuronide, enzyme kinetics of BPAF glucuronidation, and molecular modeling

Bisphenol AF (BPAF) is in the body mainly metabolized to the corresponding bisphenol AF glucuronide (BPAF-G). While BPAF-G is not commercially available, enzyme-assisted synthesis of BPAF-G using the human recombinant enzyme UGT2A1, purification of BPAF-G by solid phase extraction and semi-preparative HPLC and chemical characterization of BPAF-G by NMR and LC-MS/MS were performed and are described here. Furthermore, BPAF glucuronidation kinetics with the UGT enzymes that showed the highest glucuronidation activity in previous studies (i.e hepatic UGTs 1A3, 2B7, and 2B17, intestinal UGT 1A10 and UGT 2A1 that is present in airways) was performed and data is presented. Hepatic enzymes exhibited high affinities toward BPAF, while extrahepatic UGTs 2A1 and 1A10 showed the high v(max), values (3.3 and 3.0 nmol/min/mg, respectively). To understand molecular interactions of BPA, BPAF and BPAF-G with ligand biding sites of several nuclear receptors, molecular modeling was performed and data on the binding modes of BPAF, BPA, and BPAF-G in the ligand-binding sites of nuclear receptors are presented. This article is related to "Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite" (Skledar et al., 2019). (C) 2018 The Authors. Published by Elsevier Inc.Peer reviewe

Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite

Bisphenol AF (BPAF) is a fluorinated analog of bisphenol A (BPA), and it is a more potent estrogen receptor (ER) agonist. BPAF is mainly metabolized to BPAF-glucuronide (BPAF-G), which has been reported to lack ER agonist activity and is believed to be biologically inactive. The main goal of the current study was to examine the influence of the metabolism of BPAF via glucuronidation on its ER activity and adipogenesis. Also, as metabolites can have different biological activities, the effects of BPAF-G on other nuclear receptors were evaluated. First, in-vitro BPAF glucuronidation was investigated using recombinant human enzymes. Specific reporter-gene assays were used to determine BPAF and BPAF-G effects on estrogen, androgen, glucocorticoid, and thyroid receptor pathways, and on PXR, FXR, and PPAR gamma pathways. Their effects on lipid accumulation and differentiation were determined in murine 3T3L1 preadipocytes using Nile Red, with mRNA expression analysis of the adipogenic markers adiponectin, Fabp4, Cebp alpha, and PPAR gamma. BPAF showed strong agonistic activity for hER alpha and moderate antagonistic activities for androgen and thyroid receptors, and for PXR. BPAF-G was antagonistic for PXR and PPAR gamma. BPAF (0.1 mu M) and BPAF-G (1.0 mu M) induced lipid accumulation and increased expression of key adipogenic markers in murine preadipocytes. BPAF-G is therefore not an inactive metabolite of BPAF. Further toxicological and epidemiological investigations of BPAF effects on human health are warranted, to provide better understanding of the metabolic end-elimination of BPAF. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens

The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase. offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078-0.0625 mg/mL) and Gram-negative pathogens (MICs: range, 1-2 mg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance. (C) 2021 Elsevier Masson SAS. All rights reserved.Peer reviewe