An investigation of the drug release kinetics of 3D-Printed two compartment Theophylline and Prednisolone tablets.

Pharmaceutical 3D printing (3DP) not only offers the possibility of dose personalization but also the co-administration of multiple active pharmaceutical ingredients (APIs) in one combination tablet. In this study, Theophylline (TPH) and Prednisolone (PSL) were printed as bi-tablets, which are single tablets with two distinct separate compartments. New findings show that the combination therapy of TPH with systemic corticosteroids shows a highly synergistic effect in the treatment of pulmonary diseases.

Targeted and untargeted urinary metabolomics of alkaptonuria patients using ultra high-performance liquid chromatography-tandem mass spectrometry.

Alkaptonuria (AKU) is a rare autosomal-recessive disease which is characterized through black urine and ochronosis. It is caused by deficiency of the enzyme Homogentisate 1,2-dioxygenase in the Phenylalanine/Tyrosine degradation pathway which leads to the accumulation of Homogentisic acid (HGA). Urine was provided by AKU patients and healthy controls.

Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.

Investigation of the suitability of confocal Raman spectroscopy for the demonstration of bioequivalence of topical products.

Bioequivalence studies of topical formulations have attracted increased interest as the European Medicines Agencies "Guideline on quality and equivalence on locally applied, locally acting cutaneous products" describes them in the context of the approval of generics. Since the guideline only proposes tape stripping as a destructive method for bioequivalence testing in in vitro skin penetration, the aim of this study was to investigate the suitability of confocal Raman spectroscopy (CRS) as a non-destructive alternative. To validate the CRS results, tape stripping and CRS experiments using ketoprofen as a model API were performed consecutively on the same samples of ex vivo porcine skin after frozen storage and compared.

Metabolic Biomarkers of Liver Failure in Cell Models and Patient Sera: Toward Liver Damage Evaluation In Vitro.

Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry.

Probing the Protein Kinases' Cysteinome by Covalent Fragments.

Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines.

A Defined Diet Combined with Sonicated Inoculum Provides a High Incidence, Moderate Severity Form of Experimental Autoimmune Encephalomyelitis (EAE).

Background: Myelin oligodendrocyte glycoprotein 35-55 (MOG)-peptide induced experimental autoimmune encephalomyelitis (EAE) is a model for inflammation of the brain and spinal cord. However, its severity and incidence vary within and between laboratories. Severe scores can lead to premature termination and are both unnecessary for readouts and detrimental to animal welfare.

Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example.

The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of cancer.

Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors.

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored.

Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship and Efficacy.

The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screened, the causative agent of human and animal African trypanosomiasis, with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit the20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells.

Ribosomal peptides with polycyclic isoprenoid moieties.

Isoprenoid modifications of proteins and peptides serve fundamental biological functions and are of therapeutic interest. While C (farnesyl) and C (geranylgeranyl) moieties are prevalent among proteins, known ribosomal peptide prenylations involve shorter-chain units not exceeding farnesyl in size. To our knowledge, cyclized terpene moieties have not been reported from either biomolecule class.

Comprehensive Coverage of Glycolysis and Pentose Phosphate Metabolic Pathways by Isomer-Selective Accurate Targeted Hydrophilic Interaction Liquid Chromatography-Tandem Mass Spectrometry Assay.

The accurate liquid chromatography-tandem mass spectrometry analysis of phosphorylated isomers from glycolysis and pentose phosphate pathways is a challenging analytical problem in metabolomics due to extraction problems from the biological matrix, adherence to stainless steel surfaces leading to tailing in LC, and incomplete separation of hexose and pentose phosphate isomers. In this study, we present a targeted HILIC-ESI-MS/MS method based on a BEH amide fully porous 1.7 μm particle column with an inert surface coating of column hardware and multiple reaction monitoring (MRM) acquisition fully covering the glycolysis and pentose phosphate pathway metabolites.

CE-MS and CE-MS/MS for the multiattribute analysis of monoclonal antibody variants at the subunit level.

The analysis of product-related substances and impurities is a critical step in the biopharmaceutical quality control of multiattribute monoclonal antibodies (mAbs), as posttranslational modifications or other variants can influence the product's biological activity. Many approaches are available for variant analysis; however, they are either variant-specific, mAb-specific, time-consuming, or require expensive equipment. Here, we present a generic capillary electrophoretic method based on a neutral-coated capillary which was coupled to mass spectrometry (MS) via the nanoCEasy interface for mAb variant analysis at the subunit level (enzymatically digested and reduced mAb).

Determination of double bond positions in unsaturated fatty acids by pre-column derivatization with dimethyl and dipyridyl disulfide followed by LC-SWATH-MS analysis.

Comprehensive in-depth structural characterization of free mono-unsaturated and polyunsaturated fatty acids often requires the determination of carbon-carbon double bond positions due to their impact on physiological properties and relevance in biological samples or during impurity profiling of pharmaceuticals. In this research, we report on the evaluation of disulfides as suitable derivatization reagents for the determination of carbon-carbon double bond positions of unsaturated free fatty acids by UHPLC-ESI-QTOF-MS/MS analysis and SWATH (sequential windowed acquisition of all theoretical mass spectra) acquisition. Iodine-catalyzed derivatization of C = C double bonds with dimethyl disulfide (DMDS) enabled detection of characteristic carboxy-terminal MS2 fragments for various fatty acids in ESI negative mode.

We are MedChem: The Frontiers in Medicinal Chemistry 2024.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17 to 20 2024 in Munich. Co-organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs-Maximilians-University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four-day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators.

Elongation of Very Long-Chain Fatty Acids (ELOVL) in Atopic Dermatitis and the Cutaneous Adverse Effect AGEP of Drugs.

Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin's stratum corneum. Palmitic acid and stearic acid, along with C-ceramide and 2-hydroxy C-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier.

It Is Not All about Alkaloids-Overlooked Secondary Constituents in Roots and Rhizomes of (L.) J.St.-Hil.

(L.) J.St.

Novel Small-Molecule Atypical Chemokine Receptor 3 Agonists: Design, Synthesis, and Pharmacological Evaluation for Antiplatelet Therapy.

ACKR3, an atypical chemokine receptor, has been associated with prothrombotic events and the development of cardiovascular events. We designed, synthesized, and evaluated a series of novel small molecule ACKR3 agonists. Extensive structure-activity relationship studies resulted in several promising agonists with potencies ranging from the low micromolar to nanomolar range, for example, (EC = 111 nM, = 95%) and (EC = 69 nM, = 82%) in the β-arrestin-recruitment assay.

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry.

This review article aims to highlight the role of methyltransferases within the context of ribosomally synthesised and post-translationally modified peptide (RiPP) natural products. Methyltransferases play a pivotal role in the biosynthesis of diverse natural products with unique chemical structures and bioactivities. They are highly chemo-, regio-, and stereoselective allowing methylation at various positions.

Non-enantioselective, enantioselective, and two-dimensional liquid chromatography coupled with tandem mass spectrometry for the study of stereochemical disposition of oxylipins in cGMP-regulated hemin-treated platelets.

Oxylipins are important low abundant signaling molecules in living organisms. In platelets they play a primary role in platelet activation and aggregation in the course of thrombotic events. In vivo, they are enzymatically synthesized by cyclooxygenases, lipoxygenases, or cytochrome P450 isoenzmes, resulting in diverse polyunsaturated fatty acid (FA) metabolites including hydroxy-, epoxy-, oxo-FAs, and endoperoxides with pro-thrombotic or anti-thrombotic effects.

From Stem to Spectrum: Phytochemical Characterization of Five Species and Evaluation of Their Antioxidant Potential.

The Equisetaceae family, commonly known as horsetails, has been of scientific interest for decades due to its status as one of the most ancient extant vascular plant families. Notably, the corresponding species have found their place in traditional medicine, offering a wide array of applications. This study presents a comprehensive phytochemical analysis of polar secondary metabolites within the sterile stems of five distinct species using HPLC-DAD-ESI-MS.

Two-dimensional sequential selective comprehensive chiral×reversed-phase liquid chromatography of synthetic phosphorothioate oligonucleotide diastereomers.

In recent years, many nucleic acid-based pharmaceuticals have been approved and entered the market, and even a larger number are in late stage clinical trials. Conventional oligonucleotides are facing issues in vivo like fast renal clearance and nuclease degradation. Therefore, to increase their stability, phosphorothioation is a frequent modification of therapeutic oligonucleotides (ONs) which also leads to improved binding affinity facilitating cell internalization and intracellular distribution.

Probing intracellular potassium dynamics in neurons with the genetically encoded sensor lc-LysM GEPII 1.0 in vitro and in vivo.

Neuronal activity is accompanied by a net outflow of potassium ions (K) from the intra- to the extracellular space. While extracellular [K] changes during neuronal activity are well characterized, intracellular dynamics have been less well investigated due to lack of respective probes. In the current study we characterized the FRET-based K biosensor lc-LysM GEPII 1.