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- protein binding (3)
- S-ADAPT (2)
- allometric scaling (2)
- body composition (2)
- body size (2)
- capillary electrophoresis (2)
- chemistry (2)
- cystic fibrosis patients (2)
- healthy volunteers (2)
- population pharmacokinetics (2)
- solubility (2)
- strategy (2)
- ultrafiltration (2)
- 2,5-diketopiperazines (1)
- 77-LH-28-1 (1)
- AChE inhibitor (1)
- AGP (1)
- Alzheimer’s disease (1)
- Analytical Quality by Design (1)
- Burkholderia pseudomallei Mip (1)
- CAD detection (1)
- Candida albicans (1)
- Candida auris (1)
- Cecropia telenitida (1)
- Charged aerosol detector (CAD) (1)
- Enterobacteriaceae (1)
- Escherichia coli (1)
- Fatty acids (1)
- GABA\(_{B}\) (1)
- Gradient boosted trees (GBT) (1)
- HNSCC (1)
- HPLC–MS (1)
- High-performance liquid chromatography (HPLC) (1)
- IR (1)
- Ibuprofen (1)
- Klebsiella pneumoniae (1)
- LC-MS/MS (1)
- Mip inhibitor (1)
- Osmunda regalis (1)
- PPIase (1)
- Paeonia (1)
- Quantitative structure-property relationship modeling (QSPR) (1)
- Red Sea (1)
- Schistosomiasis (1)
- T cell (1)
- Tanzania (1)
- V. wallichii (1)
- Valeriana wallichii (1)
- Xanomeline (1)
- \(^{1}\)HNMR (1)
- absolute bioavailability (1)
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- acid value (1)
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- albumin (1)
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- anti-schistosomal activity (1)
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- antileishmanial (1)
- antimicrobial resistance (1)
- autophagy (1)
- azobenzenes (1)
- baclofen (1)
- beta-lactam antibiotics (1)
- bioactivity (1)
- biodiversity (1)
- bitopic hybrid ligands (1)
- bitopic ligand (1)
- blood brain barrier (1)
- boat conformation (1)
- bone marrow (1)
- caffeic acid bornyl ester (1)
- cecropia telenitida (1)
- cefotiam (1)
- cerebEND cells (1)
- charged aerosol detector (1)
- chenopodium quinoa (1)
- chiral separation (1)
- cholinergic system (1)
- crystal structure (1)
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- design of experiments (1)
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- drugs (1)
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- enantiomers (1)
- enantioselectivity (1)
- ephedrine (1)
- epitope mapping (1)
- ester value (1)
- ethanol (1)
- eugenyl cinnamate (1)
- extraction (1)
- fatty acids (1)
- field testing (1)
- fluorescence polarization (1)
- fluorescence resonance energy transfer (1)
- fluoroquinolone (1)
- forms (1)
- gallotannins (1)
- gene expression (1)
- gentamicin sulfate (1)
- gradient HPLC–UV (1)
- head and neck carcinoma (1)
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- histamine (1)
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- hypoxia (1)
- impurity profiling (1)
- information technology (1)
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- invasion (1)
- iodine value (1)
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- isosteviol sodium (1)
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- ketamine (1)
- leaves (1)
- leishmaniasis (1)
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- liquid chromatography-mass spectrometry (1)
- maceration (1)
- macrophages (1)
- magnesium stearate (1)
- manufacturer (1)
- marine metagenomics (1)
- marine natural products (1)
- marine organisms (1)
- medicine authentication tools (1)
- metastasis (1)
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- muscarinic M1 receptor (1)
- muscarinic acetylcholine receptors (1)
- muscarinic receptors (1)
- natural product (1)
- neuroprotection (1)
- nicotinic receptors (1)
- nitric oxide (1)
- novel nepetolactone derivative (1)
- nuclear magnetic resonance spectroscopy (1)
- obtusifolia bertol (1)
- oleanane saponins (1)
- parasite (1)
- pefloxacin (1)
- pentacyclic triterpene (1)
- pharmaceutical analysis (1)
- phytochemicals (1)
- plant extract (1)
- plants (1)
- podophyllotoxin (1)
- polysorbate 80 (1)
- pressurized microwave‐assisted extraction (1)
- principal component analysis (1)
- proliferation (1)
- psidium guajava; (1)
- pyridobenzodiazepine (1)
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- quantitative 1H NMR (1)
- red fruit oil (1)
- required hydrophilic–lipophilic balance (1)
- sacha inchi oil (1)
- saponification Value (1)
- saturation transfer difference NMR (1)
- schistosoma (1)
- schistosomula (1)
- serjanic acid (1)
- sisomicin (1)
- structural elucidation (1)
- structure-activity relationship (1)
- substandard and falsified medicines (1)
- synthesis (1)
- thin-layer chromatography (1)
- thymyl cinnamate (1)
- track and trace (1)
- transport (1)
- triacylglycerides (1)
- type 2 diabetes (1)
- unsaturated fatty acids (1)
- ursolic acid (1)
- vacuoles (1)
- validation (1)
- valtrates (1)
- veterinarians (1)
- veterinary medicine (1)
Institut
- Institut für Pharmazie und Lebensmittelchemie (34) (entfernen)
Plant extracts from Cecropia genus have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous reports have shown that roots of Cecropia telenitida that contains serjanic acid as one of the most prominent and representative pentacyclic triterpenes. The study aimed to isolate serjanic acid and evaluate its effect in a prediabetic murine model by oral administration. A semi-pilot scale extraction was established and serjanic acid purification was followed using direct MALDI-TOF analysis. A diet induced obesity mouse model was used to determine the impact of serjanic acid over selected immunometabolic markers. Mice treated with serjanic acid showed decreased levels of cholesterol and triacylglycerols, increased blood insulin levels, decreased fasting blood glucose and improved glucose tolerance, and insulin sensitivity. At transcriptional level, the reduction of inflammation markers related to adipocyte differentiation is reported.
Background
Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of Albendazole, Mebendazole and Praziquantel locally collected in Burkina Faso, Côte d’Ivoire, Ghana and Tanzania were analysed.
Methods
Samples of 88 different batches were obtained from randomly selected facilities. Sampling took place in Northwest Tanzania, Western Burkina Faso, Southeast Côte d’Ivoire and Southwest Ghana. Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC).
Findings
Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6% of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all. Evaluating TLC results, only 4 out of 83 batches narrowly missed specification limits, 18 batches slightly exceeded them. Not more than 46.3% (31 / 67) of the tablets assayed passed the respective pharmaceutical criteria for dissolution. HPLC findings confirmed TLC results despite shifted specification limits: 10 out of 83 tested batches contained less than 90%, none exceeded 110%.
Conclusion
In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or fall below specification limits. Galenic characteristics however, especially dissolution profiles, revealed great deficits.
The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.
Most drugs are no longer produced in their own countries by the pharmaceutical companies, but by contract manufacturers or at manufacturing sites in countries that can produce more cheaply. This not only makes it difficult to trace them back but also leaves room for criminal organizations to fake them unnoticed. For these reasons, it is becoming increasingly difficult to determine the exact origin of drugs. The goal of this work was to investigate how exactly this is possible by using different spectroscopic methods like nuclear magnetic resonance and near- and mid-infrared spectroscopy in combination with multivariate data analysis. As an example, 56 out of 64 different paracetamol preparations, collected from 19 countries around the world, were chosen to investigate whether it is possible to determine the pharmaceutical company, manufacturing site, or country of origin. By means of suitable pre-processing of the spectra and the different information contained in each method, principal component analysis was able to evaluate manufacturing relationships between individual companies and to differentiate between production sites or formulations. Linear discriminant analysis showed different results depending on the spectral method and purpose. For all spectroscopic methods, it was found that the classification of the preparations to their manufacturer achieves better results than the classification to their pharmaceutical company. The best results were obtained with nuclear magnetic resonance and near-infrared data, with 94.6%/99.6% and 98.7/100% of the spectra of the preparations correctly assigned to their pharmaceutical company or manufacturer.
The charged aerosol detector (CAD) is the latest representative of aerosol-based detectors that generate a response independent of the analytes' chemical structure. This study was aimed at accurately predicting the CAD response of homologous fatty acids under varying experimental conditions. Fatty acids from C12 to C18 were used as model substances due to semivolatile characterics that caused non-uniform CAD behaviour. Considering both experimental conditions and molecular descriptors, a mixed quantitative structure-property relationship (QSPR) modeling was performed using Gradient Boosted Trees (GBT). The ensemble of 10 decisions trees (learning rate set at 0.55, the maximal depth set at 5, and the sample rate set at 1.0) was able to explain approximately 99% (Q\(^2\): 0.987, RMSE: 0.051) of the observed variance in CAD responses. Validation using an external test compound confirmed the high predictive ability of the model established (R-2: 0.990, RMSEP: 0.050). With respect to the intrinsic attribute selection strategy, GBT used almost all independent variables during model building. Finally, it attributed the highest importance to the power function value, the flow rate of the mobile phase, evaporation temperature, the content of the organic solvent in the mobile phase and the molecular descriptors such as molecular weight (MW), Radial Distribution Function-080/weighted by mass (RDF080m) and average coefficient of the last eigenvector from distance/detour matrix (Ve2_D/Dt). The identification of the factors most relevant to the CAD responsiveness has contributed to a better understanding of the underlying mechanisms of signal generation. An increased CAD response that was obtained for acetone as organic modifier demonstrated its potential to replace the more expensive and environmentally harmful acetonitrile.
Background
Reproducibility of reported antibacterial activities of plant extracts has long remained questionable. Although plant-related factors should be well considered in serious pharmacognostic research, they are often not addressed in many research papers. Here we highlight the challenges in reproducing antibacterial activities of plant extracts.
Methods
Plants with reported antibacterial activities of interest were obtained from a literature review. Antibacterial activities against Escherichia coli and Klebsiella pneumoniae were tested using extracts’ solutions in 10% DMSO and acetone. Compositions of working solutions from both solvents were established using LC-MS analysis. Moreover, the availability of details likely to affect reproducibility was evaluated in articles which reported antibacterial activities of studied plants.
Results
Inhibition of bacterial growth at MIC of 256–1024 μg/mL was observed in only 15.4% of identical plant species. These values were 4–16-fold higher than those reported earlier. Further, 18.2% of related plant species had MICs of 128–256 μg/mL. Besides, 29.2% and 95.8% of the extracts were soluble to sparingly soluble in 10% DMSO and acetone, respectively. Extracts’ solutions in both solvents showed similar qualitative compositions, with differing quantities of corresponding phytochemicals. Details regarding seasons and growth state at collection were missing in 65% and 95% of evaluated articles, respectively. Likewise, solvents used to dissolve the extracts were lacking in 30% of the articles, whereas 40% of them used unidentified bacterial isolates.
Conclusion
Reproducibility of previously reported activities from plants’ extracts is a multi-factorial aspect. Thus, collective approaches are necessary in addressing the highlighted challenges.
In 1998, the aminoglycoside antibiotic gentamicin sulfate caused several cases of deaths in the United States, after the switch from twice- to once-daily application. Endotoxins were discussed as the cause for the adverse effects and sisomicin was identified as the lead impurity; batches containing sisomicin were contaminated with more impurities and were responsible for the fatalities. In 2016, anaphylactic reactions in horses, and later in humans with one fatality, were observed after application of gentamicin sulfate contaminated with histamine. To determine whether histamine was responsible for the 1990s death cases as well, histamine was quantified by means of liquid chromatography–tandem mass spectrometry (LC-MS/MS) in 30 samples of gentamicin sulfate analyzed in previous studies. Furthermore, a relative quantification of sisomicin was performed to check for a correlation between histamine and the lead impurity. A maximum amount of 11.52 ppm histamine was detected, which is below the limit for anaphylactic reactions of 16 ppm, and no correlation of the two impurities was observed. However, the European Medicines Agency recommends a stricter limit with regard to the maximum single dose of gentamicin sulfate to reach a greater gap between the maximum histamine exposition of 4.3 µg and the quantity known to cause hypotension of 7 µg. The low amounts of histamine and the fact that there is no connection with the contamination with sisomicin showed that histamine was not the cause for the death cases in the United States in 1998, and endotoxins remain the most probable explanation.
Investigation of isomerization of dexibuprofen in a ball mill using chiral capillary electrophoresis
(2021)
Besides the racemate, the S‐enantiomer of ibuprofen (Ibu) is used for the treatment of inflammation and pain. Since the configurational stability of S‐Ibu in solid state is of interest, it was studied by means of ball milling experiments. For the evaluation of the enantiomeric composition, a chiral CE method was developed and validated according to the ICH guideline Q2(R1). The addition of Mg\(^{2+}\), Ca\(^{2+}\), or Zn\(^{2+}\) ions to the background electrolyte (BGE) was found to improve Ibu enantioresolution. Chiral separation of Ibu enantiomers was achieved on a 60.2 cm (50.0 cm effective length) x 75 μm fused‐silica capillary using a background electrolyte (BGE) composed of 50 mM sodium acetate, 10 mM magnesium acetate tetrahydrate, and 35 mM heptakis‐(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin (TM‐β‐CD) as chiral selector. The quantification of R‐Ibu in the mixture was performed using the normalization procedure. Linearity was evaluated in the range of 0.68–5.49% R‐Ibu (R\(^{2}\) = 0.999), recovery was found to range between 97 and 103%, the RSD of intra‐ and interday precision below 2.5%, and the limit of quantification for R‐ in S‐Ibu was calculated to be 0.21% (extrapolated) and 0.15% (dilution of racemic ibuprofen), respectively. Isomerization of S‐Ibu was observed under basic conditions by applying long milling times and high milling frequencies.
Extraction is a key step in studying compounds from plants and other natural sources. The common use of high temperatures in pressurized microwave‐assisted extraction (PMAE) makes it unsuitable for the extraction of compounds with low or unknown thermal stability. This study aimed at determining the suitability of low‐temperature, short‐time PMAE in attaining yields comparable to those of prolonged maceration at room temperature. Additionally, we explored the phytochemical differences of the extracts from both techniques. Maceration at room temperature for 24 hr and PMAE at 40–45°C and 10 bar for 30 min were carried out on 18 samples from 14 plant species at a solvent‐to‐feeds ratio of 10. The PMAE yields of 16 out of 18 samples were within the proportions of 91–139.2% as compared with the respective extracts from maceration. Varying numbers of nonmatching peaks were noted in MS chromatograms of five extract pairs, indicating selective extraction of some compounds. Low‐temperature PMAE can attain reasonable extraction efficiency with the added value of sparing compounds of low thermal stability. The method can also enable the recovery of compounds distinct from those obtained by maceration.
Microbial, mammalian, and plant cells produce and contain secondary metabolites, which typically are soluble in water to prevent cell damage by crystallization. The formation of ion pairs, for example, with carboxylic acids or mineral acids, is a natural blueprint to maintain basic metabolites in solution. Here, we aim at showing whether the mostly large carboxylates form soluble protic ionic liquids (PILs) with the basic natural product papaverine resulting in enhanced aqueous solubility. The obtained PILs were characterized by H-1-N-15 HMBC nuclear magnetic resonance (NMR) and in the solid state using X-ray powder diffraction, differential scanning calorimetry, and dissolution measurements. Furthermore, their supramolecular pattern in aqueous solution was studied by means of potentiometric and photometrical solubility, NMR aggregation assay, dynamic light scattering, zeta potential, and viscosity measurements. Thereby, we identified the naturally occurring carboxylic acids, citric acid, malic acid, and tartaric acid, as being appropriate counterions for papaverine and which will facilitate the formation of PILs with their beneficial characteristics, like the improved dissolution rate and enhanced apparent solubility.