Refine
Has Fulltext
- yes (213)
Is part of the Bibliography
- yes (213)
Year of publication
Document Type
- Journal article (107)
- Doctoral Thesis (104)
- Conference Proceeding (1)
- Review (1)
Language
- English (213) (remove)
Keywords
- HPLC (9)
- Bioverfügbarkeit (7)
- Instrumentelle Analytik (6)
- Löslichkeit (6)
- Muscarinrezeptor (6)
- NMR-Spektroskopie (6)
- Aminosäuren (5)
- Arzneimittel (5)
- Impurity Profiling (5)
- Ligand <Biochemie> (5)
- Targeted drug delivery (5)
- population pharmacokinetics (5)
- synthesis (5)
- Chemische Reinheit (4)
- Extrazelluläre Matrix (4)
- LC-MS/MS (4)
- Organische Synthese (4)
- Pharmakodynamik (4)
- Pharmakokinetik (4)
- Synthese (4)
- Synthesis (4)
- pharmacokinetics (4)
- therapeutic drug monitoring (4)
- Amino acids (3)
- Antibiotikum (3)
- Arzneimitteldesign (3)
- Arzneimittelüberwachung (3)
- Biomarker (3)
- Charged Aerosol Detection (3)
- Formulierungsentwicklung (3)
- Interleukin 4 (3)
- Ionic Liquids (3)
- Kontrollierte Wirkstofffreisetzung (3)
- LC-MS (3)
- Metabolismus (3)
- Naturstoff (3)
- Pharmaceutical Analysis (3)
- Solubilisation (3)
- Tuberkelbakterium (3)
- Verunreinigung (3)
- Wirkstofffreisetzung (3)
- antibiotics (3)
- capillary electrophoresis (3)
- charged aerosol detector (3)
- chemistry (3)
- click chemistry (3)
- drug delivery (3)
- drug design (3)
- human (3)
- medicine (3)
- metabolism (3)
- muscarinic receptors (3)
- natural products (3)
- nutrition (3)
- polyphenols (3)
- positron emission tomography (3)
- protein binding (3)
- solubility (3)
- ARONJ (2)
- Agonist (2)
- Alzheimerkrankheit (2)
- Alzheimer’s disease (2)
- Analoga (2)
- Antimikrobieller Wirkstoff (2)
- Arzneimittelforschung (2)
- Bitopische Liganden (2)
- Butyrylcholinesterase (2)
- Candida albicans (2)
- Chemie (2)
- Chemische Synthese (2)
- Cholinesterase (2)
- Chromatographie (2)
- Click-Chemie (2)
- Cytokine (2)
- Enterobacteriaceae (2)
- Ernährung (2)
- Fettsäurebiosynthese (2)
- Fibroblastenwachstumsfaktor (2)
- Flavonoids (2)
- Formulation development (2)
- Formulierung (2)
- GTP-bindende Proteine (2)
- Imatinib (2)
- Inhibitor (2)
- Insulin-like Growth Factor I (2)
- Kapillarelektrophorese (2)
- Kinaseinhibitor (2)
- Lebensmittelchemie (2)
- Lipide (2)
- Massenspektrometrie (2)
- Medizin (2)
- NMR spectroscopy (2)
- Permeabilität (2)
- Pharmacokinetic (2)
- Pharmazeutischer Hilfsstoff (2)
- Polyethylenglykole (2)
- Polymere (2)
- Poorly water soluble drugs (2)
- Populationskinetik (2)
- Populationspharmakokinetik (2)
- Positronen-Emissions-Tomografie (2)
- Protease-sensitive release (2)
- Pycnogenol (2)
- Qualitätskontrolle (2)
- Reinheitsanalytik (2)
- S-ADAPT (2)
- Stabilität (2)
- Staphylococcus aureus (2)
- Struktur-Aktivitäts-Beziehung (2)
- Supersaturation (2)
- TDM (2)
- Tandem-Massenspektrometrie (2)
- Therapeutisches Drug Monitoring (2)
- Tissue Engineering (2)
- Trypanosomiase (2)
- Tryptophan (2)
- Valeriana wallichii (2)
- Wirkstoff (2)
- allometric scaling (2)
- antileishmanial (2)
- azobenzenes (2)
- baclofen (2)
- biomarker (2)
- body composition (2)
- body size (2)
- butyrylcholinesterase (2)
- chiral separation (2)
- clinical study (2)
- crystal structure (2)
- cystic fibrosis patients (2)
- cytochrome P450 3A4 (CYP3A4) (2)
- dendritic cells (2)
- drugs (2)
- drug–drug interactions (DDIs) (2)
- dualsteric ligands (2)
- endothelium (2)
- estrogens (2)
- extracellular matrix (2)
- fatty acid biosynthesis (2)
- gene expression (2)
- graft versus host disease (2)
- healthy volunteers (2)
- human breast (2)
- impurity profiling (2)
- in vitro (2)
- kinetics (2)
- leishmaniasis (2)
- liquid chromatography (2)
- marine sponge (2)
- mass spectrometry (2)
- molecular modeling (2)
- multiple linear regression (2)
- neuroprotection (2)
- norepinephrine transporter (2)
- octopamine (2)
- oral bioavailability (2)
- osteoarthritis (2)
- osteonecrosis of the jaw (2)
- osteoradionecrosis (2)
- permeability (2)
- pharmaceutical analysis (2)
- pharmacodynamics (2)
- physiologically based pharmacokinetic (PBPK) modeling (2)
- screening (2)
- staphylococcus aureus (2)
- strategy (2)
- structure-activity relationship (2)
- structure-activity relationships (2)
- sympathetic nervous system (2)
- therapy (2)
- thermogenesis (2)
- ultrafiltration (2)
- 1 (1)
- 17beta-Estradiol (1)
- 17beta-estradiol (1)
- 2,5-diketopiperazines (1)
- 2-Thiazaphospholidines (1)
- 2-a:6 (1)
- 2-chloro (1)
- 2-halo (1)
- 2-imino- (1)
- 3 (1)
- 3 D bioprinting (1)
- 5-a']diindol (1)
- 5-a']diindole (1)
- 5-b']diindol (1)
- 5-b']diindole (1)
- 5]diazocino[1 (1)
- 77-LH-28-1 (1)
- AAA+ ATPase p97 (1)
- AChE inhibitor (1)
- AD mouse modele (1)
- ADAMTS (1)
- AGP (1)
- AOM/DSS (1)
- Acetaminophen (1)
- Acetylcysteinderivate (1)
- Achillea Fragrantissima (1)
- Acrylamid (1)
- Acrylamide (1)
- Actinomycetes (1)
- Active pharmaceutical ingredients (1)
- Adhäsion (1)
- Aescin (1)
- African Trypanosomiasis (1)
- Akt (1)
- Akt/PKB (1)
- Albendazol (1)
- Aldehyde (1)
- Alkamiden (1)
- Alkamides (1)
- Alkylpyrazine (1)
- Allosteric Modulator (1)
- Allosterisch Modurator (1)
- Allosterischer Effektor (1)
- Alzheimer (1)
- Alzheimer's diseas (1)
- Alzheimer's disease (1)
- Alzheimer′s disease (1)
- Amino Acids (1)
- Aminosäure (1)
- Anacardic acid derivatives (1)
- Anacardsäurederivate (1)
- Analyse (1)
- Analytical Quality by Design (1)
- Analytik (1)
- Anthocyane (1)
- Antibiotic (1)
- Antibiotika (1)
- Antiinfektiva (1)
- Antikörper (1)
- Antitrypanosomal (1)
- Antitrypanosomen (1)
- Antitumor (1)
- Arthrose (1)
- Arzneimittelwechselwirkung (1)
- Arzneistoffanalytik (1)
- Asymmetrie (1)
- Autoradiographie (1)
- Aziridines (1)
- BRAF mutation (1)
- Baclofen (1)
- Bakterien (1)
- Benzimidazole (1)
- Beta-2-Rezeptor (1)
- Bile (1)
- Bioaccessibility (1)
- Bioanalytik (1)
- Bioavailability (1)
- Bioconjugate (1)
- Biodistribution (1)
- Bioengineering (1)
- Bioinks (1)
- Biologische Aktivität (1)
- Biologischer Abbau (1)
- Bioreactor System (1)
- Biosensor (1)
- Biotransformation (1)
- Bisoprolol (1)
- Bitopic Ligands (1)
- Blockcopolymere (1)
- Blut-Hirn-Schranke (1)
- Blutspiegel (1)
- Brustdrüse (1)
- Burkholderia pseudomallei Mip (1)
- C-3-substituiert (1)
- C-3-substituted (1)
- CAD detection (1)
- CAR T cells (1)
- CAR T-Zellen (1)
- CFC replacements (1)
- CO‐releasing molecules (CORMs) (1)
- CYP2C9 (1)
- CYP3A4 (1)
- Cabozantinib (1)
- Candida auris (1)
- Cannabinoid Receptor (1)
- Cannabinoide (1)
- Cannabinoids (1)
- Capillary Electrophoresis (1)
- Carbamate (1)
- Carbocistein (1)
- Carboxylates (1)
- Cecropia telenitida (1)
- Cerulenin (1)
- Characterization (1)
- Charged Aerosol Detektion (1)
- Charged aerosol detection (1)
- Charged aerosol detector (CAD) (1)
- Chemical stability (1)
- Chemometric (1)
- Chemometrie (1)
- Chewing Gum (1)
- Chinolon <2-> (1)
- Chinolonamide (1)
- Chinolonderivate (1)
- Chiralität (1)
- Chlorfluorkohlenstoffe (1)
- Cholinesteraseinhibitor (1)
- Chondrogenesis (1)
- Chromatographischer Detektor (1)
- Chromone (1)
- Citrus (1)
- Codon (1)
- Commercial preparations (1)
- Computational chemistry (1)
- Computational drug-design (1)
- Contaminants (1)
- Controlled release (1)
- Corona charged aerosol detector (1)
- Counterfeit Medicines (1)
- CuAAC (1)
- Cutaneous leishmaniasis (1)
- Cyclo-AMP (1)
- Cyclo-GMP (1)
- Cytochrom P-450 (1)
- Cytotoxicity (1)
- Cytotoxizität (1)
- DNA-encoded library synthesis (1)
- DNA-tagged amines (1)
- DPP IV (1)
- Deep Eutectics (1)
- Derivsatisierung (1)
- Detektor (1)
- Diabetes mellitus (1)
- Diagnostik (1)
- Dickdarmkrebs (1)
- Dimere (1)
- Dimerisierung (1)
- Dosis (1)
- Dosislinearität (1)
- Drug Delivery (1)
- Drug delivery platform (1)
- Drug delivery platforms (1)
- Drug design (1)
- Drug form selection (1)
- EDC-NHS chemistry (1)
- EDTA (1)
- East Africa (1)
- Effluxpumpen (1)
- Electrospinning (1)
- Elektronensprayionisations-Massenspektrometrie (1)
- Enantiomere (1)
- Enantiomerentrennung (1)
- Enantiomerüberschuss (1)
- Enantioselektivität (1)
- Encapsulation (1)
- Endothel (1)
- Enoyl-Reduktase (1)
- Enoyl-acyl-carrier-protein-Reductase (1)
- Enoyl-acyl-carrier-protein-Reductase <Enoyl-[acyl-carrier-protein]-Reductase> (1)
- Enzym (1)
- Enzyme inhibitor (1)
- Enzyminhibitor (1)
- Ephedrin (1)
- Eriodictyon californicum (1)
- Ersatzstoff (1)
- Escherichia coli (1)
- Estradiol (1)
- Estrogens (1)
- Europäsches Arzneibuch (1)
- Excipient selection (1)
- Expiry date (1)
- Extrakt (1)
- FCKW-Ersatzstoffe (1)
- FGF (1)
- FGF-2 (1)
- FRET (1)
- FV45 (1)
- FabI (1)
- Fatty acids (1)
- Fertigarzneimittel (1)
- Fett (1)
- Fettgewebe (1)
- Fettkennzahlen (1)
- Fettsäurestoffwechsel (1)
- Fibrinogen (1)
- Flavoniden (1)
- Flavonoide (1)
- Flavonoinds (1)
- Fluoreszenz (1)
- Fluoreszenz-Resonanz-Energie-Transfer (1)
- Fluoreszenzliganden (1)
- Fluoreszenzmikroskopie (1)
- Fluoreszenzpolarisation (1)
- Fluorine (1)
- Fluorverbindungen (1)
- Flux (1)
- Flüssigkeitschromatographie (1)
- Formulation (1)
- Functional properties (1)
- Funktionalisierung <Chemie> (1)
- Funktionalisierung von elektrogesponnenen Fasern (1)
- Fälschung (1)
- G-Protein gekoppelte Rezeptor (1)
- G-protein coupled receptor (1)
- GABA (1)
- GABA-Rezeptor-Agonist (1)
- GABAB (1)
- GABAB receptor agonists (1)
- GABA\(_{A}\) receptor (1)
- GABA\(_{B}\) (1)
- GPCR (1)
- Galle (1)
- Galle <Sekret> (1)
- Gallensalze (1)
- Gas chromatography (1)
- Gaschromatographie (1)
- Gentamicin (1)
- Geschichte (1)
- Glutamate (1)
- Glycinrezeptor (1)
- Glycoengineering (1)
- Glykosylierung (1)
- Gradient boosted trees (GBT) (1)
- Gyrasehemmer (1)
- HIV (1)
- HNSCC (1)
- HPLC-MS (1)
- HPLC–MS (1)
- Hepatotoxizität (1)
- High-performance liquid chromatography (1)
- High-performance liquid chromatography (HPLC) (1)
- Humane Afrikanische Trypanosomiasis (1)
- Hybrid (1)
- Hybrid GPCR Ligands (1)
- Hybrid-Molecules (1)
- Hybridliganden (1)
- Hydrogel (1)
- Hydrogels (1)
- Hydrogen-deuterium (1)
- Hydroperoxide (1)
- Hypoxia (1)
- Hypoxie (1)
- Hülsenfrüchte (1)
- IGF-I (1)
- IR (1)
- ISPMF (1)
- Ibuprofen (1)
- Imidates (1)
- Imidoyl halides (1)
- Impact-Faktor (1)
- In vitro (1)
- In vivo (1)
- In vivo studies (1)
- InhA (1)
- Inhalation (1)
- Inhibition (1)
- Insulin-like Growth Factor (1)
- Insulin-like growth factor-I (1)
- Integrasen (1)
- Interferon <alpha-2a-> (1)
- Ion Pairs (1)
- Ionic Liquid (1)
- Ionische Flüssigkeit (1)
- Isocyanate (1)
- Isolation and Characterization (1)
- Isotopenverhältnis-Massenspektrometrie (1)
- JAK inhibitor (1)
- Karibisches Meer (1)
- KasA (1)
- Kaugummi (1)
- Ketamin (1)
- Ketoacyl-ACP-Synthase <beta-> (1)
- Ketoacyl-ACP-synthase (1)
- Kiefernrindenextrakt (1)
- Klebsiella pneumoniae (1)
- Klinische Pharmazie (1)
- Klinische Studie (1)
- Knochenpenetration (1)
- Knorpelbildung (1)
- Kohlenhydrate (1)
- Kohlenmonoxid (1)
- Kokristallisation (1)
- Konjugation (1)
- Kristall (1)
- Kristallstruktur (1)
- LC-ESI/MS/MS (1)
- LMICS (1)
- Lactamantibiotikum <beta-> (1)
- Lebensmittelprodukte (1)
- Leber (1)
- Lebertoxizität (1)
- Legionella pneumophila (1)
- Legionnaires' Disease (1)
- Legionärskrankheit (1)
- Leishmania (1)
- Leishmaniose (1)
- Library of Phytochemicals (1)
- Library of plant species (1)
- Lipid-Peroxide (1)
- Liposomen (1)
- Low-income Countries (1)
- LpxC inhibitors (1)
- Lungenentzündung (1)
- Lungenkrebs (1)
- Lungenperfusionsmodell (1)
- M1 Muscarinic Receptor (1)
- M2 (1)
- M4 (1)
- MDR (1)
- MIR-Spektroskopie (1)
- MRONJ (1)
- MRSA (1)
- MYCNv (1)
- Makrophage (1)
- Malaria (1)
- Manganese Carbonyl ligands (1)
- Markierte Verbindungen (1)
- Masspectrometry (1)
- Matrix Effekte (1)
- Maus (1)
- Mebendazol (1)
- Melatonin (1)
- Merkaptursäuren (1)
- Metabolism (1)
- Method Validation (1)
- Microglia (1)
- Microwave Assisted Extraction (1)
- Mikrosphären (1)
- Milchdrüse (1)
- Mip (1)
- Mip Inhibitoren (1)
- Mip inhibitor (1)
- Mitsunobu (1)
- Modellierung (1)
- Modification (1)
- Modifikation von Biokeramiken (1)
- Molecular modelling (1)
- Molekular Modeling (1)
- Molekulardesign (1)
- Molekulardynamik (1)
- Monoklonaler Antikörper (1)
- Monomere (1)
- Monte Carlo Simulation (1)
- Monte Carlo simulation (1)
- Mucus (1)
- Mukovisdizose (1)
- Mukoviszidose (1)
- Multidrugresistant (1)
- Muscarinic receptor (1)
- Muskarinrezeptor (1)
- Muskelatrophie (1)
- Myositis (1)
- NIR-Spektroskopie (1)
- NMR Spektroskopie (1)
- NOX-Inhibitoren (1)
- Nanodraht (1)
- Naproxen (1)
- Natural product hybrids (1)
- Nature-Insipired Synthesis (1)
- Neuroprotection (1)
- Neuroprotektion (1)
- ONJ (1)
- Oberflächenfunktionalisierung (1)
- Opiatrezeptor (1)
- Osmunda regalis (1)
- Osteoarthritis (1)
- PDGF (1)
- PDGFR (1)
- PET (1)
- PI3K/Akt/mTor pathway (1)
- PPIase (1)
- Paeonia (1)
- Paracetamol (1)
- Paraffin (1)
- Parameter Quality Oil (1)
- Parenteral (1)
- Peptidsynthese (1)
- Peroxidzahl (1)
- Pflanzen (1)
- Pharmacokinetics (1)
- Pharmakologie (1)
- Pharmakometrie (1)
- Pharmakotherapie (1)
- Pharmazie (1)
- Phase separation (1)
- Phenolic acids (1)
- Photoswitchable (1)
- Pilocarpin (1)
- Pilokarpin (1)
- Plant extracts (1)
- Plants (1)
- Platelet-derived Growth Factor (1)
- Point-of-Care-testing (1)
- Polyglycerol (1)
- Polymilchsäure (1)
- Polyphenole (1)
- Poorly water-soluble drug (1)
- Praziquantel (1)
- Precision medicine (1)
- Probenaufarbeitung (1)
- Proliferation (1)
- Propenderivate (1)
- Proteasen (1)
- Protein Expression (1)
- Protein crystal (1)
- Protein-Protein-Wechselwirkung (1)
- Proteinbindung (1)
- Proteine (1)
- Proteinglutamin-Glutamyltransferase <Proteinglutamin-gamma-glutamyltransferase> (1)
- Protic Ionic Liquids (1)
- Protonen-NMR-Spektroskopie (1)
- Präamplifizierung (1)
- Pulmonale Applikation (1)
- Pulmonary delivery (1)
- Purity control (1)
- Pyridin (1)
- Pyrimidinone (1)
- Pyroglutaminsäure (1)
- Quality ccontrol (1)
- Quantitative 1H NMR (1)
- Quantitative structure-property relationship modeling (QSPR) (1)
- Quinolone Amides (1)
- Quinolone amides (1)
- RESP model (1)
- Radioindikator (1)
- Radiopharmaka (1)
- Reaktive Zwischenstufe (1)
- Receptor Dynamics (1)
- Red Fruit Oil (1)
- Red Sea (1)
- Rekombinantes Protein (1)
- Release system (1)
- Reproducibility challenges (1)
- Rhizom (1)
- Rifampicin (1)
- Risikobewertung (1)
- Risk Assessment (1)
- Robuvit\(^®\) (1)
- Ruxolitinib (1)
- Röstkaffee (1)
- SPECT (1)
- Salz (1)
- Schafgarbe <Gattung> (1)
- Schistosomiasis (1)
- Schleim (1)
- Schnelltest (1)
- Schwämme (1)
- Seide (1)
- Seiden-Fibroin (1)
- Sekundärmetabolit (1)
- Sensor (1)
- Sensoren (1)
- Sensors (1)
- Sesquiterpene lactones (1)
- Sesquiterpenlactonen (1)
- Shelf-life (1)
- Signaltransduktion (1)
- Silibinin (1)
- Silibinin ester (1)
- Silk Fibroin (1)
- Silk-Fibroin (1)
- Site-specific modification (1)
- Site-specific protein conjugation (1)
- Solubility (1)
- Sorafenib (1)
- Species Differences (1)
- Spectrofluorimetry (1)
- Speziesunterschiede (1)
- Spray drying (1)
- Springs and Parachutes (1)
- Sprühtrocknung (1)
- Stability (1)
- Stabilitätsstudien (1)
- Staphylococci (1)
- Statine (1)
- Stereoselektive Synthese (1)
- Sternpolymere (1)
- Stoffwechsel (1)
- Streptomyces (1)
- Streptomyces axinellae (1)
- Streptomycin (1)
- Strychnin (1)
- Strychnosalkaloide (1)
- Surface modification (1)
- Synthetische Biologie (1)
- Sythese (1)
- T cell (1)
- T-shaped π-π stacking (1)
- T-shaped π–π stacking (1)
- TDDFT (1)
- TGF-β3 (1)
- Tandem Mass Spectrometry (1)
- Tanzania (1)
- Tetrahydro-15aH-azocino[1 (1)
- Tetrahydro[1 (1)
- Tetrahydrochinazoline (1)
- Tierversuche (1)
- Tongue (1)
- Toxicokinetics (1)
- Toxikokinetik (1)
- Transgene Tiere (1)
- Trennung (1)
- Trypanosomen (1)
- Tuberculosis (1)
- Tuberkulose (1)
- Ugi-azide reaction (1)
- Universität Würzburg. Lehrstuhl für Pharmazeutische Technologie und Biopharmazie (1)
- Unterernährung (1)
- V. wallichii (1)
- VAMS (1)
- Validierung (1)
- Vascularisation (1)
- Verderb (1)
- Verkapselung (1)
- Volumetric absorptive microsampling (1)
- Weakly chromophore impurities (1)
- West Africa (1)
- Wissenschaftliches Arbeiten (1)
- Wurmmittel (1)
- Xanomeline (1)
- Zelloberfläche (1)
- Zellwand (1)
- Zunge (1)
- Zytotoxizität (1)
- \(^{1}\)HNMR (1)
- absolute bioavailability (1)
- absorption (1)
- acebutolol (1)
- acetic acid (1)
- acetones (1)
- acetonitrile (1)
- acetylcholinesterase (1)
- acid value (1)
- acids (1)
- activation (1)
- additive manufacturing (1)
- adipose tissue (1)
- adipose tissue engineering (1)
- advanced drug delivery system (1)
- afatinib (1)
- affinity (1)
- agar diffusion test (1)
- albumin (1)
- aldehydes (1)
- alignment (1)
- alkylpyrazines (1)
- allergic rhinitis (1)
- allosteric modulation (1)
- amber codon suppression (1)
- amber light (1)
- amino acid (1)
- amorphous solid dispersion (1)
- ampicillin (1)
- amyloid beta (1)
- amyloid-β (Aβ) (1)
- angiotensin II type 1 receptor (1)
- animal studies (1)
- anisotropy (1)
- anti-infectives (1)
- anti-inflammatory activity (1)
- anti-inflammatory cytokines (1)
- anti-proliferative effects (1)
- anti-protease (1)
- anti-schistosomal activity (1)
- anti-trypanosomal (1)
- antibacterial activity (1)
- antibacterials (1)
- antibiotic (1)
- antibiotic bone concentration (1)
- antifungal drug (1)
- antimicrobial resistance (1)
- antimicrobial stewardship (1)
- antiresorptive drug-related osteonecrosis of the jaw (1)
- antiviral agents (1)
- at-home sampling (1)
- autoinjector (1)
- autophagy (1)
- baclofen homologues (1)
- beta-lactam (1)
- beta-lactam antibiotics (1)
- bile (1)
- bile salt (1)
- binding analysis (1)
- bio-orthogonal chemistry (1)
- bioactivity (1)
- bioassay-guided fractionation (1)
- bioavailability (1)
- bioceramics (1)
- biochemical simulations (1)
- biocide polyhexamethylene biguanide (1)
- bioconjugation (1)
- biodegradable polymer (1)
- biodiversity (1)
- bioisosterism (1)
- biologics (1)
- biologische Körperflüssigkeiten (1)
- biomaterials (1)
- biophysics (1)
- bioresponsive (1)
- biosensor (1)
- biosynthesis (1)
- bitopic hybrid ligands (1)
- bitopic ligand (1)
- bitopic ligands (1)
- blood brain barrier (1)
- blood plasma (1)
- boat conformation (1)
- bone marrow (1)
- bone penetration (1)
- bronchial tissue (1)
- brucei (1)
- cAMP (1)
- cGMP (1)
- caffeic acid bornyl ester (1)
- carbamate (1)
- cardiac innervation imaging (1)
- cardiac neurohormonal system (1)
- cartilage (1)
- cartilage tissue engineering (1)
- cecropia telenitida (1)
- cefotiam (1)
- cell metabolism (1)
- cells (1)
- cerebEND cells (1)
- cerulenin (1)
- chemical crosslinking (1)
- chemically programmable (1)
- chemisch programmierbar (1)
- chemotherapy (1)
- chenopodium quinoa (1)
- chiral (1)
- chiral resolution (1)
- chirale Trennung (1)
- cholesterol and oxy-cholesterol (1)
- cholinergic system (1)
- cholinesterase (1)
- cholinesterase inhibitors (1)
- cholinesterases inhibitors (1)
- chronic IBD model (1)
- circular dichroism (1)
- citrus (1)
- clinical pharmacy (1)
- co-delivery (1)
- cocrystal (1)
- cofactors (biochemistry) (1)
- cold stress (1)
- colloid (1)
- commercial preparations (1)
- complementary medicine (1)
- computational chemistry (1)
- contaminants (1)
- coupled (1)
- crithidia fasciulata (1)
- cyclodextrins (1)
- cysteine protease (1)
- cystic fibrosis (1)
- cytokine modulation (1)
- cytokine production (1)
- cytotoxicity (1)
- dabrafenib (1)
- decafluoroazobezene (1)
- dehydration (1)
- derivates (1)
- design of experiments (1)
- detector (1)
- device-related infections (1)
- diabetes (1)
- diketopiperazines (1)
- dimeric strychnine ligands (1)
- discovery (1)
- dissolution (1)
- dissolution rates (1)
- dose individualization (1)
- dose linearity (1)
- drug formulation (1)
- drug impurities (1)
- drug metabolism (1)
- drug monitoring (1)
- drug-delivery systems (1)
- dualsteric (1)
- dualsteric ligand (1)
- effector Treg (eTreg) (1)
- efflux pumps (1)
- electroactive (1)
- electrohydrodynamic (1)
- electrophoresis (1)
- electrospun fibers (1)
- emulsions oil-in-water (1)
- enantiomerenrein (1)
- enantiomers (1)
- enantiopure (1)
- enantioselectivity (1)
- enoyl reductase (1)
- enoyl-ACP reductase inhibitors (1)
- enterohepatic recirculation (1)
- enzyme kinetics (1)
- enzymes (1)
- ephedrine (1)
- epitope mapping (1)
- ester value (1)
- ethanol (1)
- ethers (1)
- eugenyl cinnamate (1)
- evaporation based detectors (1)
- evaporationsbasierte Detektoren (1)
- ex vivo Modell (1)
- exchange reaction (1)
- excipient (1)
- experimental visceral leishmaniasis (1)
- extra cellular matrix (1)
- extraction (1)
- fatty acids (1)
- fenoterol (1)
- field testing (1)
- flavonoid (1)
- flavonoids (1)
- fluorescence (1)
- fluorescence polarization (1)
- fluorescence resonance energy transfer (1)
- fluorescent ligands (1)
- fluorescent probes (1)
- fluorine-18 (1)
- fluoroquinolone (1)
- fluticasone propionate (1)
- flux (1)
- food (1)
- forms (1)
- formulation development (1)
- fragment screening (1)
- fragment-based design (1)
- free fatty acids (1)
- funktionale Präpolymere (1)
- gallotannins (1)
- gastrointestinal (1)
- genetic codon expansion (1)
- genetics (1)
- gentamicin sulfate (1)
- glucos metabolism (1)
- glucose (1)
- glutamates (1)
- glutathione (1)
- glycocalyx (1)
- glycolytic flux control (1)
- gprotein (1)
- gradient HPLC–UV (1)
- gut microbiota; bioactivation; polyphenols; complex carbohydrates; tryptophan (1)
- hMSC-TERT (1)
- halo olefines (1)
- head and neck carcinoma (1)
- heart failure (1)
- hepatotoxicity (1)
- high performance liquid chromatography (1)
- high throughput screening (1)
- high-resolution tandem mass spectrometry (1)
- high-throughput screening (1)
- histamine (1)
- history (1)
- homodimerization (1)
- homology modeling (1)
- honeybee (1)
- honeybees (1)
- human African trypanosomiasis (1)
- human nutrition (1)
- human plasma (1)
- human receptor kinetics (1)
- hybrid ligands (1)
- hybrid molecules (1)
- hydnocarpin (1)
- hydrogels (1)
- hydrogen bonding (1)
- hydrogen bonding mycobacterium tuberculosis (1)
- hydrolysis (1)
- hydroperoxides (1)
- hydroxy-dabrafenib (1)
- hypoxia (1)
- hysterectomy (1)
- imaging (1)
- immunomodulatory (1)
- impurities (1)
- in vitro dissolution methods (1)
- in vitro dissolution testing (1)
- in vitro-in vivo correlation (1)
- in vitro/in vivo Korrelation (1)
- in vitro/in vivo correlation (1)
- in vivo dissolution (1)
- information technology (1)
- inhibitors (1)
- injectable protein formulation (1)
- interleukin-4 (1)
- internal transcribed spacer 2 (1)
- intestinal mucus (1)
- intestinal permeability (1)
- intramolecular Michael addition (1)
- intranasal corticosteroids (1)
- intrinsic metabolism (1)
- invasion (1)
- iodine value (1)
- ion-pair chromatography (1)
- ionic liquids (1)
- ipratropium bromide (1)
- isocyanide multicomponent reactions (1)
- isolation (1)
- isomerization (1)
- isosteviol sodium (1)
- isotope ratio mass spectrometry (1)
- isotopically labelled peptides (1)
- jaw bone (1)
- kappa-B activation (1)
- kasA (1)
- ketamine (1)
- kinase inhibitor (1)
- kinase inhibitors (1)
- lactams (1)
- lattice forces (1)
- leaves (1)
- linear discriminant analysis (1)
- lipid deterioration (1)
- lipid deterioration markers (1)
- liposomes (1)
- liquid chromatography electrospray ionization tandem mass spectrometry (1)
- liquid chromatography tandem mass spectrometry (LC-MS/MS (1)
- liquid chromatography-mass spectrometry (1)
- liver (1)
- liver impairment (1)
- lowering lattice forces (1)
- lung perfusion model (1)
- mRNA level (1)
- mRNA-Spiegel (1)
- maceration (1)
- macrophages (1)
- magnesium stearate (1)
- mammary gland (1)
- manufacturer (1)
- marine metagenomics (1)
- marine natural products (1)
- marine organisms (1)
- marine sponges (1)
- maritime pine bark extract (1)
- matrix metalloproteinase (1)
- matrix metalloproteinases (1)
- mechanistic drug-drug interactions (1)
- mechanistische Arzneistoffinteraktionen (1)
- mechanochemical degradation (1)
- medicine authentication tools (1)
- melanoma (1)
- melatonin (1)
- mercapturic acids (1)
- metabolic glycoengineering (1)
- metabolic network (1)
- metabolic network model (1)
- metabolisches Netzwerk (1)
- metastasis (1)
- micelles (1)
- microscopy (1)
- microspheres (1)
- mixed-mode chromatography (1)
- mobile apps (1)
- modelling (1)
- modified monosaccharides (1)
- molecular biopharmaceutics (1)
- molecular dynamics (1)
- molecular mechanics (1)
- molecular systematics (1)
- molekulares Modellieren (1)
- monoclonal antibodies (1)
- monoklonale Antikörper (1)
- mucin (1)
- multicomponent Ugi-type reaction (1)
- muscarinic (1)
- muscarinic M1 receptor (1)
- muscarinic acetylcholine receptor (1)
- muscarinic acetylcholine receptors (1)
- mycobacterium tuberculosis (1)
- natural product (1)
- natural product hybrids (1)
- nerve agent (1)
- neuroblastoma cell (1)
- neuroprotective (1)
- neuroprotectivity (1)
- nicotinic receptors (1)
- nitric oxide (1)
- non-chromophore analytes (1)
- non-racemic (1)
- nonhuman primates (1)
- novel nepetolactone derivative (1)
- nuclear cardiology (1)
- nuclear magnetic resonance spectroscopy (1)
- oak wood (1)
- oak wood extract (1)
- obtusifolia bertol (1)
- octopamine receptors (1)
- oleanane saponins (1)
- online monitoring system (1)
- opioid ligands (1)
- opioid receptors (1)
- oral anticancer drugs (1)
- oral drug absorption (1)
- oral microbiome (1)
- osimertinib (1)
- osteochondral implant (1)
- oxidative stress (1)
- oxime (1)
- oxygen (1)
- oxytosis/ferroptosis (1)
- paraffins (1)
- parasite (1)
- paromomycin (1)
- patch clamp recording (1)
- pefloxacin (1)
- pentacyclic triterpene (1)
- peptide sensors (1)
- peptide stapling (1)
- perfluoroarylation (1)
- peri-implant disease (1)
- personalized antimicrobial therapy (1)
- pharmacodynamic (1)
- pharmacokinetic (1)
- pharmacological evaluation (1)
- pharmacology (1)
- pharmacometrics (1)
- phosphoglycolate phosphatase (1)
- photocontrol (1)
- photopharmacology (1)
- phylogenetic analysis (1)
- phylogenetic tree (1)
- phylogeny (1)
- phytochemicals (1)
- phytochemistry (1)
- phytomedicine (1)
- phytoneering (1)
- pig (1)
- pine bark extract (1)
- piperacillin/tazobactam (1)
- plant extract (1)
- plants (1)
- plasma proteins (1)
- podophyllotoxin (1)
- poly(2-ethyl-2-oxazoline) (1)
- polyethylenglykole (1)
- polylactid (1)
- polymer drug interaction (1)
- polymer processing (1)
- polymers (1)
- polysorbate 80 (1)
- poor water-soluble drugs (1)
- poorly water soluble drugs (1)
- posaconazole (1)
- post-operative recovery (1)
- post-surgery recovery (1)
- postsurgical adhesion (1)
- pressurized microwave‐assisted extraction (1)
- principal component analysis (1)
- pro-inflammatory cytokines (1)
- profiles (1)
- proliferation (1)
- propionate (1)
- protease inhibition (1)
- protease inhibitors (1)
- protease-sensitive release (1)
- proteasome system (1)
- protein engineering (1)
- protein modification (1)
- protein nebulization (1)
- protein therapeutics (1)
- psidium guajava; (1)
- pulmonary absorption (1)
- purification (1)
- pyridine (1)
- pyridobenzodiazepine (1)
- pyroglutamic acid (1)
- qNMR (1)
- qPCR (1)
- quality evaluation (1)
- quantitative 1H NMR (1)
- quantum mechanics (1)
- radiotracer (1)
- radiotracer kinetics (1)
- radiotracers (1)
- randomized controlled study (1)
- rat study (1)
- reactive metabolites (1)
- reaktive Metabolite (1)
- receptors (1)
- red blood cells (1)
- red fruit oil (1)
- renal cell carcinoma (1)
- renin-angiotensin system (1)
- replica-exchange molecular dynamics (1)
- required hydrophilic–lipophilic balance (1)
- residence time (1)
- resistance (1)
- response surface (1)
- ribosomal RNA (1)
- roast coffee (1)
- ruxolitinib (1)
- sacha inchi oil (1)
- saponification Value (1)
- saturation transfer difference NMR (1)
- scar revision surgery (1)
- schistosmiasis (1)
- schistosoma (1)
- schistosomula (1)
- secondary structure (1)
- secretion (1)
- sensor (1)
- sensory chewing gums (1)
- serjanic acid (1)
- serum (1)
- short-range order (1)
- silk fibroin (1)
- silybin (1)
- simple (1)
- simulated intestinal fluid (1)
- single-molecule microscopy (1)
- sisomicin (1)
- site-specific protein modification (1)
- soil-transmitted helminthiases (1)
- solid dispersion (1)
- solid-state NMR spectroscopy (1)
- spectrofluorimetry (1)
- sphingomonads (1)
- spray (1)
- steered molecular dynamics (1)
- sterubin (1)
- streptomyces (1)
- structural elucidation (1)
- structure–activity relationships (1)
- strychnine (1)
- subcutaneous fat layer (1)
- substandard and falsified medicines (1)
- surface functionalization (1)
- synovial fluid (1)
- system (1)
- tacrine (1)
- tandem mass spectrometry (1)
- tetromycin (1)
- therapeutic gases (1)
- thermodynamics (1)
- thin-layer chromatography (1)
- thymyl cinnamate (1)
- tofacitinib (1)
- tongue (1)
- topical treatment (1)
- toxicity (1)
- track and trace (1)
- trametinib (1)
- transcriptome (1)
- transglutaminase (1)
- transport (1)
- treatment regimens (1)
- triacylglycerides (1)
- trypanosoma cruzi (1)
- tuberculosis (1)
- type 2 diabetes (1)
- underutilized legumes (1)
- unnatural amino acid (1)
- unsaturated fatty acids (1)
- urolithins (1)
- ursolic acid (1)
- vacuoles (1)
- validation (1)
- valsartan (1)
- valtrates (1)
- vascularized fat construct (1)
- veterinarians (1)
- veterinary medicine (1)
- volumetric absorptive micro-sampling (VAMS) (1)
- volumetric absorptive microsampling (1)
- Öl (1)
- β2 - Agonisten (1)
- β2 - agonist (1)
Institute
- Institut für Pharmazie und Lebensmittelchemie (213) (remove)
Sonstige beteiligte Institutionen
- Universität Belgrad, Serbien (2)
- ACC GmbH Analytical Clinical Concepts (1)
- Apotheke, Universitätsklinikum Würzburg (1)
- Bundesinstitut für Arzneimittel und Medizinprodukte (1)
- Friedrich-Schiller-Universität Jena (1)
- Helmholtz Institute for RNA-based Infection Biology (HIRI), Josef-Schneider-Straße 2/D15, DE-9708 Wuerzburg, Germany (1)
- Helmholtz Institute for RNA-based Infection Biology (HIRI), Josef-Schneider-Straße 2/D15, DE-97080 Wuerzburg, Germany (1)
- IBMP - Institut für Biomedizinische und Pharmazeutische Forschung in Nürnberg-Heroldsberg (1)
- Johns Hopkins School of Medicine (1)
- Krankenhaushygiene und Antimicrobial Stewardship, Universitätsklinikum Würzburg (1)
EU-Project number / Contract (GA) number
- 26230120009 (1)
- 296679 (1)
- 311932 (1)
- 314911 (1)
- 701983 (1)
The high failure rate of new drug candidates in preclinical or clinical studies due to hepatotoxicity represents a considerable problem in the drug development. Hence, there is an urgent need to develop new approaches for early and reliable prediction of drug-induced hepatotoxicity that enables a better identification of drug candidates with high potential for toxicity at early stages of drug development. Therefore, the aim of this work was to improve the prediction of drug-induced liver injury in preclinical studies through evaluation of more reliable and sensitive biomarkers of hepatotoxicity and a better understanding of the underlying mechanistic basis for drug-induced toxicity. First, the ability of a set of potential markers (NGAL, thiostatin, clusterin, PON1) to detect early signs of liver injury was assessed in rats treated with drug candidates that were dropped from further development, in part due to toxic adverse effects in the liver. In summary, PON1 and clusterin were not consistently altered in response to liver injury and thus provide no additive information to the traditional liver enzymes in detecting drug-induced hepatotoxicity. In contrast, thiostatin and NGAL were increased in serum and urine of treated animals in a time- and dose-dependent manner. These changes correlated well with mRNA expression in the target organ and generally reflected the onset and degree of drug-induced liver injury. Receiver-operating characteristics analyses supported serum thiostatin, but not NGAL, as a better indicator of drug-induced hepatobiliary injury than conventional clinical chemistry parameters, such as ALP, ALT and AST. Although thiostatin, an acute phase protein expressed in a range of tissues, may not be specific for liver injury, our results indicate that thiostatin may serve as a sensitive, minimally-invasive diagnostic marker of inflammation and tissue damage in preclinical safety assessment. In the second part of this work, combined application of genomics profiling technology and RNAi to inhibit the pharmacological target of a drug candidate BAY16, a glucagon receptor (GCGR) antagonist, was used to determine if interference with the pharmacological target plays a role in the toxic response to BAY16, and to narrow down those molecular changes that are associated with toxicity, and not the pharmacological action of BAY16. In contrast to Bay 16, which was found to be cytotoxic at concentrations of 75 µM, silencing of the glucagon receptor did not affect cell viability in primary rat hepatocytes. Thus, it can be concluded that hepatotoxicity of Bay 16 was not related to the drugs inhibitory effect on the glucagon receptor in vitro and in vivo. These findings were supported by the fact that most of BAY16-induced changes in gene expression occurred independently of the pharmacological modulation of GCGR. These off-target effects include altered xenobiotic metabolism, oxidative stress, increased fatty acid synthesis, and alterations in cholesterol and bile acid metabolic processes. Although it was not possible to draw a final conclusion about the mechanism of BAY16 hepatotoxicity, changes in these molecular mechanisms appear contribute to progression of hepatic injury. With regard to drug safety assessment in preclinical studies, the utilization of siRNA technology in vitro represents a new approach to improve mechanistic understanding of the nature of drug’s toxicity, being either chemically mediated or due to primary or secondary pharmacological mode of action.
The aim of the present study was to design different dosage forms as carrier systems to deliver sorafenib to the lung of BXB-23 transgenic mice using different routes of administration. Three dosage forms were used one of them was an oil-in-water emulsion and the oral route was chosen for this experiment. The other delivery system was a liposome preparation for intratracheal instillation. In this case the oral route was considered as a control experiment. The last dosage form was PLGA microspheres. Before sorafenib administration it was important to develop a HPLC method to assess sorafenib absorption after its administration and to determine its concentrations in mouse serum. The HPLC method allowed sorafenib quantification in small volumes (30 µl) of mouse serum and tissues. The developed HPLC method was validated resulting in satisfactory selectivity, good linearity, good accuracy and precision over the concentration range examined. Sorafenib was successfully incorporated in a fat emulsion (o/w) using a traditional method resulting in a white homogenous emulsion and no particle aggregation was observed. Sorafenib exhibited antitumor activity on the lung adenoma in BXB-23 transgenic mice when administered orally (2 mg sorafenib per mouse) in the emulsion preparation. The determined effect was an approximately 29 % reduction in the tumor area of the adenoma foci and a proliferation reduction. In order to improve the pharmacological effects of sorafenib on the lung adenoma in BXB-23 mice, the targeting of sorafenib directly to the site of action (the lung) was an attractive concept. For this purpose the intratracheal route was used. Since sorafenib administration by instillation required incorporation of sorafenib in a dosage form suitable for its lipophilic nature, a liposome suspension was the second dosage form used. A lyophilization method was employed for sorafenib liposome preparation utilizing dilauroylphosphatidylcholine (DLPC) which is safe and tolerable for the lung. Incorporation of sorafenib in the liposomes did not influence the particle size and its distribution. The sorafenib liposomes showed high encapsulation efficiency, good stability at 4 °C for one month and satisfactory in vitro release properties and inhibited Raf-1 mediated activation of ERK in cell culture assay. In a pharmacokinetic experiment sorafenib loaded liposomes were instilled directly into the lung. The results revealed that a significant level of sorafenib was achieved in the lung tissues after 2 hours and then reduced after 48 h and remained nearly constant for one week. On the other hand, only traces of sorafenib were found in the mice serum up to 48 h. Subsequently, the pharmacological activity of sorafenib (1 mg per mouse) was studied when delivered in a liposomal suspension intratracheally to treat the lung adenoma of BXB-23 mice. The data of this experiment demonstrated that sorafenib intratracheal instillation resulted in a reduction of tumor area of adenoma foci (67 %) and an elevation of the percent of apoptotic cells. In contrast, prolongation of the treatment period did not further enhance sorafenib activity on the lung adenoma. This previous finding suggested a development of multidrug resistance (MDR) by the adenoma foci cells against sorafenib instillation, which was examined by immunohistochemistry staining. The percent of MDR positive cells was higher after two and three weeks sorafenib liposome instillation treatment than that after one week treatment. The last dosage form used for sorafenib was microspheres, which were prepared by emulsion-diffusion-evaporation method using biodegradable PLGA 50:50 resulting in a white lyophilized powder. The system was characterized physicochemically and revealed a good microspheres yield, high encapsulation efficiency, a homogenous particle size distribution and slow in vitro release of sorafenib. The other strategy studied in the present research project was gene delivery to target the lung bearing tumor of BXB-23 mice using a non-viral vector (polyethylenimine). Polyethylenimine (PEI) was used to investigate its efficiency in transfecting lung bearing tumor of BXB-23 mice model and its ability to transfect the adenoma foci cells. LacZ, which encodes Beta-galactosidase was used in the present study as a reporter gene and was complexed with PEI before delivered intravenously. A high LacZ expression in the alveolar region with some expression in the adenoma foci was observed. On contrary, a low LacZ expression in the alveoli and in the adenoma foci was achieved after instillation of the same polyplex intratracheally.
A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.
The work presented in this thesis was mainly targeted at exploring the capabilities of evaporation based LC detectors as well as further alternatives for the control of impurities in substances not exhibiting a suitable chromophore for UV-detection. In the course of the work carried out, several new methods for the identification, impurities control and composition testing of APIs were elaborated. An evaporation based detector that entered into the field of pharmaceutical analysis in the recent years was the Evaporative Light Scattering Detector (ELSD). However, non-reproducible spikes were reported when injecting concentrated test solutions as they are usually required for the control of impurities. The reasons, for the appearance of these spikes as well as possibilities for their avoidance were explored in a systematic study. Moreover, the dependence of the detector sensitivity on different eluent composition, eluent flow-rate and ELSD settings was investigated. In the course of the revision of the Ph.Eur. monographs for aspartic acid and alanine, a C18 reversed phase ion-pair LC method using 1 mmol/L of perfluoroheptanoic acid as an ion-pair reagent and a charged aerosol detector (CAD) was developed and fully validated for the purity control of Asp. The method was capable of separating the organic acids and major amino acids known to occur as process related impurities. With a slight modification, the method was also applicable for the purity control of Ala. Based on the developed LC-CAD method for the impurity control of alanine, a comparative study of the performance characteristics of different evaporation based LC detectors, i.e. ELSD, CAD and the recently developed Nano Quantity Analyte Detector (NQAD) was carried out. Additionally, an MS detector and qNMR were included in this study. It was found that the control of impurities in Alanine at an ICH conform level could be ensured using LC coupled to CAD, MSD and NQAD detection as well as by the use of qNMR. In terms of performance, prize and ease of use CAD and NQAD were found to be the most suitable alternatives. In terms of repeatability and sensitivity, the CAD appeared slightly superior to the NQAD. The quality of streptomycin sulfate is not sufficiently controlled by the current Ph.Eur. monograph in that an appropriate test for the control of the related substances is missing. A study was carried out to develop a C18 reversed phase ion-pair LC method using pentafluoropropionic acid as an ion-pair reagent and a CAD for the identification and control of the related substances. The developed method allowed the separation of 21 impurities from streptomycin. Moreover, coupling of the method to MS allowed the identification of the separated impurities. The method was shown to be sufficiently sensitive to control the related substances with a disregard limit of 0.1% as it is normally applied in the Ph.Eur. for products derived from fermentation. Currently, the aescin content of horse-chestnut standardized dry extract is determined using a complex and laborious photometric determination. A more selective LC-UV assay determination for beta-aescin has been proposed for the Ph.Eur. draft monograph of horse-chestnut standardized dry extract. Possibilities were explored to further improve the LC-method using detection by CAD. It was demonstrated that by the use of a modified LC-CAD method several problems related to the differences in the UV-response of the various components contained in the active aescin fraction could be eliminated. Moreover the proposed reference standard strategy was reviewed. Eventually, it was demonstrated on the example of two different clusters of pharmacologically active peptides how low energy collision induced dissociation mass spectrometry (low energy CID-MS) can successfully be used for identification testing in pharmacopoeial monographs. In this respect, the combination of a direct confirmation of the molecular mass via the m/z-ratio of the molecule ions with structural sequence information obtained by low energy CID-MS experiments was found to deliver a higher degree of certainty of the identity of a given substance than the set of tests currently described in the monographs. A significant gain in efficiency and throughput and important reduction of the amount of sample consumed during testing were identified as being additional advantages of this approach. Taken together, it could be demonstrated on various examples how recent technological advancements in the field of analytical chemistry can contribute to improve the quality control of APIs.
Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac\(_4\)ManNAz) and N-alkyneacetylmannosamine (Ac\(_4\)ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac\(_4\)ManNAz was detectable for up to six days while Ac\(_4\)ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.
Synthesis of (RS)-5-amino-3-aryl (methyl)-pentanoic acid hydrochlorides, 3 aminomethyl-5-chloro-benzoic acid hydrochloride and (RS)-4-amino-3-(4`-ethynyl(iodo)-phenyl)-butanoic acid hydrochlorides have been accomplished. The aim of their synthesis was to evaluate their GABABR agonist activity and to derive a model which will correlate their structure with the observed pEC50. The GABABR agonist activity of the prepared compounds has been determined in functional assay based on calcium measurement in vitro using tsA cells transfected with GABAB1b/GABAB2/Gαq-z5. Reviews on the neurotransmitter receptors (ligand-gated ion channel receptors and G protein-coupled receptors), their agonists and antagonists have been given in the general part of this work. A detailed discussion on the strategy followed for the synthesis of the designed compounds as well as the starting materials and intermediates has been described and illustrated in Schemes 2-6. The synthesized compounds were evaluated for their GABABR agonist activity. Furthermore, these compounds were docked in the available 3D homology model of GABABR using the program FlexiDock implemented in SYBYL software. Subsequently, we derived a predictive model which correlates the experimentally determined pEC50 with the calculated binding energy of certain baclofen analogues and homologues. In addition, we used the program DISCO (DIStance COmparisons) implemented in SYBYL software to find the pharmacophore features of GABAB agonists.
Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABAB receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABAB receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a–h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABABR agonists. Compound 1a is an agonist to GABAB receptors with an EC50 value of 46 μM on tsA201 cells transfected with GABAB1b/GABAB2/Gqz5, being the most active congener among all the synthesized compounds.
Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with \(IC_{50}\) values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.
Staphylococcus epidermidis, the common inhabitant of human skin and mucosal surfaces has emerged as an important pathogen in patients carrying surgical implants and medical devices. Entering the body via surgical sites and colonizing the medical devices through formation of multi-layered biofilms leads to refractory and persistent device-related infections (DRIs). Staphylococci organized in biofilms are more tolerant to antibiotics and immune responses, and thus are difficult-to-treat. The consequent morbidity and mortality, and economic losses in health care systems has strongly necessitated the need for development of new anti-bacterial and anti-biofilm-based therapeutics. In this study, we describe the biological activity of a marine sponge-derived Streptomyces sp. SBT348 extract in restraining staphylococcal growth and biofilm formation on polystyrene, glass, medically relevant titan metal, and silicone surfaces. A bioassay-guided fractionation was performed to isolate the active compound (SKC3) from the crude SBT348 extract. Our results demonstrated that SKC3 effectively inhibits the growth (MIC: 31.25 \(\mu\)g/ml) and biofilm formation (sub-MIC range: 1.95-<31.25 \(\mu\)g/ml) of S. epidermidis RP62A in vitro. Chemical characterization of SKC3 by heat and enzyme treatments, and mass spectrometry (HRMS) revealed its heat-stable and non-proteinaceous nature, and high molecular weight (1258.3 Da). Cytotoxicity profiling of SKC3 in vitro on mouse fibroblast (NIH/3T3) and macrophage (J774.1) cell lines, and in vivo on the greater wax moth larvae Galleria mellonella revealed its non-toxic nature at the effective dose. Transcriptome analysis of SKC3 treated S. epidermidis RP62A has further unmasked its negative effect on central metabolism such as carbon flux as well as, amino acid, lipid, and energy metabolism. Taken together, these findings suggest a potential of SKC3 as a putative drug to prevent staphylococcal DRIs.
Starting in the late 1990s ionic liquids (ILs) gained momentum both in academia as well as industry. ILs are defined as organic salts with a melting point below 100 °C. Active pharmaceutical ingredients (APIs) may be transferred into ILs by creating salts with a bulky counterion with a soft electron density. ILs have demonstrated the potential to tune important pharmaceutical features such as the solubility and the dissolution rate, particularly addressing the challenge of poor water soluble drugs (PWSD). Due to the tunability of ILs, modification of physico-chemical properties of APIs may be envisioned without any modifications of the chemical structure.
In the first chapter the potential as well as the limitation of ILs are discussed. The chapter commences with an overview of preparation and characterization of API-ILs. Moreover, examples for pharmaceutical parameters are presented which may be affected by IL formation, including the dissolution rate, kinetic solubility or hygroscopicity as well as biopharmaceutical performance and toxicology. The impact of IL formation on those pharmaceutically relevant features is highlighted, resulting in a blueprint for a novel formulation concept to overcome PWSD challenges without the need for structural changes of the API.
Within the second chapter the IL concept is detailed for one specific API - counterion combination. A poorly water soluble acidic API against migraine attacks was transformed into an IL in an effort to minimize the time to maximum plasma concentration (tmax) and optimize the overall bioavailability. These studies were conducted in parallel to a prodrug of the API for comparison of the IL strategy versus a strategy involving modification of the API’s structure. A significantly longer duration of API supersaturation and a 700 fold faster dissolution rate of the IL in comparison to the free acid were obtained and the underlying mechanism was elucidated. The transepithelial absorption was determined using Caco-2 cell layers. For the IL about 3 times more substance was transported in comparison to the prodrug when substances were applied as suspensions, despite the higher permeability of the prodrug, as increased solubility of the IL exceeded this effect. Cytotoxicity of the counterion was assessed in hepatic, renal and macrophage cell lines, respectively, and IC50 values were in the upper µM / lower mM range. The outcome of the study suggested the IL approach instrumental for tuning biopharmaceutical properties, without structural changes of the API as required for preparation of prodrugs. Thus the toolbox for formulation strategies of poorly water soluble drugs could be extended by an efficient concept.
The third chapter focuses on the effect of different counterions on the physico-chemical properties of an API-IL, in particular to overcome the challenge of poor water solubility. Therefore, the same poorly water soluble acidic API against migraine attacks mentioned above was combined with 36 counterions resulting in ILs and low lattice enthalpy salts (LLES). Depending on the counterions, different dissolution rates, durations of supersaturation and hygroscopicities were obtained and release profiles could be tailored from immediate to sustained release. Besides, in vitro the cytotoxicity of the counterions was assessed in three cell lines. Using molecular descriptors such as the number of hydrophobic atoms, the graph theoretical diameter and the number of positive charges of the counterion, the dissolution rate, supersaturation and hygroscopicity as well as the cytotoxicity of counterions could be adequately modeled, rendering it possible to predict properties of new LLESs.
Within the forth chapter different poorly water soluble APIs were combined with the counterion tetrabutylphosphonium (TBP) studying the impact on the pharmaceutical and physical properties of the APIs. TBP-ILs and low lattice enthalpy salts were prepared of the acidic APIs Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole and Tolbutamide. NMR and IR spectroscopy, DSC, XRPD, DVS and dissolution rate measurements, release profiles and saturation concentration measurements were used to characterize the free acids and TBP salts as compared to the corresponding sodium salts. The TBP salts as compared to the free acids displayed lower melting points and glass transition temperatures and up to 1000 times higher dissolution rates. The increase in the dissolution rate directly correlated with the salts’ hygroscopicity, an aspect which is critically discussed in terms of pharmaceutical translation challenges. In summary TBP ILs of solid salts were proved instrumental to approach the challenge of poor water solubility. The outcome profiled tailor-made counterions as a powerful formulation strategy to address poor water solubility, hence bioavailability and ultimately therapeutic potential of challenging APIs.
In summary, a plethora of ILs and LLESs were prepared by combination of different acidic APIs and counterions. The IL and LLESs concept was compared to conventional salt and prodrug strategies. By choice of the counterion, biopharmaceutical relevant parameters were deliberately modified and release profiles were tuned ranging from immediate to prolonged release. The impact of distinct structural counterion features controlling the dissolution, supersaturation, hygroscopicity and counterion cytotoxicity were identified, correlations were presented and predictive models were built. ILs and LLESs could be proven to be a powerful concept for the formulation of poorly water soluble acidic APIs.