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Tierarztliche Praxis. Ausgabe K,... Apr 2024In 2023, 2 novel pharmaceutical agents for small animals were released on the German market: the structural but non-functional analog of the inhibitory neurotransmitter...
In 2023, 2 novel pharmaceutical agents for small animals were released on the German market: the structural but non-functional analog of the inhibitory neurotransmitter gamma-aminobutyric acid pregabalin with an anxiolytic active component and the dopamine agonist ropinirole in form of eye drops to induce vomiting. Two established active veterinary pharmaceutical ingredients became available for additional species: The phosphorus compound butafosfan was additionally approved for horses, dogs and cats and the mineral sodium chloride as an isotonic sodium chloride solution was also approved for rabbits and guinea pigs. In addition, for small animals, there were new releases of an agent (dexamethasone) in a novel pharmaceutical formulation, one drug with a new route of administration (hydrocortisone aceponate), one drug with a new content of the active ingredient (firocoxib) as well as one veterinary drug with a new combination of active ingredients in a novel pharmaceutical formulation (gentamicin+mometasone+posaconazole). Furthermore, one combination of active ingredients (diprophylline+heptaminol) is available on the market for small animals again.
Topics: Animals; Veterinary Drugs; Dogs; Cats; Horses; Germany; Rabbits
PubMed: 38701806
DOI: 10.1055/a-2291-7019 -
Bioorganic Chemistry Jan 2021A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) - diprophylline and xanthinol nicotinate - is reported for the...
A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) - diprophylline and xanthinol nicotinate - is reported for the first time. The decisive step is an enantioselective lipase-mediated methanolysis of racemic chlorohydrin-synthon acetate, namely 1-chloro-3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propan-2-yl acetate, performed under kinetically-controlled conditions on a preparative 500 mg-scale. The best results in terms of reaction enantioselectivity (E = 14) were obtained for the enantiomers resolution performed with lipase type B from Candida antarctica immobilized on acrylic resin (CAL-B, Novozym 435) suspended in homophasic acetonitrile-methanol mixture. The elaborated biocatalytic system furnished the key chlorohydrin intermediate (in 71% ee and 38% yield), which was then smoothly converted into enantioenriched active agents: (R)-(-)-diprophylline (57% ee) and (S)-(+)-xanthinol nicotinate (65% ee). To support the assignment of absolute configurations of EKR-products as well as to confirm the stereochemical outcome of the remaining reaction steps, docking studies toward the prediction of enantiomers binding selectivity in CAL-B active site as well as the respective chemical correlations with enantiomerically enriched analytical standards obtained from commercially available (R)-(-)-epichlorohydrin, were applied. In addition, single-crystal X-ray diffraction (XRD) analyses were performed for the synthesized optically active APIs furnishing by this manner a first crystal structures of nicotinic acid salt of xanthinol.
Topics: Basidiomycota; Biocatalysis; Dyphylline; Enzymes, Immobilized; Esterification; Fungal Proteins; Hydrogen Bonding; Hydrolysis; Lipase; Molecular Docking Simulation; Protein Binding; Stereoisomerism; Xanthinol Niacinate
PubMed: 33229120
DOI: 10.1016/j.bioorg.2020.104448 -
Journal of Hepatology May 2022The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver...
BACKGROUND & AIMS
The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model.
METHODS
Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case.
RESULTS
Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients.
CONCLUSIONS
Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis.
LAY SUMMARY
The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.
Topics: Biopsy; Chemical and Drug Induced Liver Injury; Dyphylline; Humans; Risk Factors
PubMed: 35074471
DOI: 10.1016/j.jhep.2021.12.043 -
Chemical & Pharmaceutical Bulletin 2018A mixture of pharmaceuticals having a xanthine skeleton, theophylline, proxyphylline, diprophylline and (-)-epigallocatechin-3-O-gallate (EGCg) in water created a sticky...
A mixture of pharmaceuticals having a xanthine skeleton, theophylline, proxyphylline, diprophylline and (-)-epigallocatechin-3-O-gallate (EGCg) in water created a sticky precipitates, which were thought to be 2 : 2 complexes of the pharmaceuticals and EGCg. The molecular capture ability of the pharmaceuticals having a xanthine skeleton by EGCg was estimated by the amount of the pharmaceuticals included in the precipitates of the complexes, and measured by the integrated value of proton signals in the quantitative H-NMR spectra. Based on changes in chemical shifts of proton signals of the pharmaceuticals with a xanthine skeleton in H-NMR spectra by adding standard amounts of EGCg, the xanthine skeleton of the pharmaceuticals was considered to exist in the hydrophobic space formed by the three aromatic A, B, B' rings of EGCg, and a part of the proxyphylline and diprophylline side chains existed out of the hydrophobic space. In the H-NMR spectra of the mixture of (R)- and (S)-proxyphylline, (R)- and (S)-diprophylline and an equimolecular amount of EGCg, the N-CH signal of (R)- and (S)-proxyphylline, and (R)- and (S)-diprophylline was clearly observed as two singlets. This suggested that EGCg recognized the chirality of proxyphylline and diprophylline in water.
Topics: Catechin; Molecular Structure; Pharmaceutical Preparations; Stereoisomerism; Water; Xanthine
PubMed: 29863063
DOI: 10.1248/cpb.c18-00027 -
Chemical Biology & Drug Design Oct 2021Natural diphyllin glycosides were identified as potent vacuolar H -ATPase (V-ATPase) inhibitors. A series of diphyllin β-hydroxyl amino derivatives were designed and...
Natural diphyllin glycosides were identified as potent vacuolar H -ATPase (V-ATPase) inhibitors. A series of diphyllin β-hydroxyl amino derivatives were designed and synthesized as novel diphyllin derivatives. Most of these derivatives displayed potent cytotoxicity against six cancer cell lines with IC values in the submicromolar to nanomolar concentration range. Compounds 2b, 2c, 2l, 2m, and 2n showed similar V-ATPase inhibitory potency to Bafilomycin A1. Compound 2l exhibited potent activity of modulation of lysosomal pH and cytoplasmic pH.
Topics: Adenosine Triphosphatases; Apoptosis; Biological Products; Cell Line, Tumor; Dyphylline; Enzyme Inhibitors; Glycosides; Humans; Hydrogen-Ion Concentration; Lysosomes; Macrolides
PubMed: 34233089
DOI: 10.1111/cbdd.13920 -
Open Access Macedonian Journal of... May 2018Blocking effect of leukotriene biosynthesis-zileuton and blocking the effect of phosphodiesterase enzyme-diprophylline in the treatment of patients with bronchial asthma...
AIM
Blocking effect of leukotriene biosynthesis-zileuton and blocking the effect of phosphodiesterase enzyme-diprophylline in the treatment of patients with bronchial asthma and bronchial increased reactivity, and tiotropium bromide as an antagonist of the muscarinic receptor studied in this work.
METHODS
Parameters of the lung function are determined with Body plethysmography. The resistance of the airways (Raw) was registered and measured was intrathoracic gas volume (ITGV), and specific resistance (SRaw) was also calculated. For the research, administered was zileuton (tabl. 600 mg) and diprophylline (tabl. 150 mg).
RESULTS
Two days after in-house administration of leukotriene biosynthesis blocker-zileuton (4 x 600 mg orally), on the day 3 initial values of patients measured and afterwards administered 1 tablet of zileuton, and again measured was Raw and ITGV, after 60, 90 and 120 min. and calculated was SRaw; (p < 0.01). Diprophylline administered 7 days at home in a dose of (2 x 150 mg orally), on the day 8 to same patients administered 1 tablet of diprophylline, and performed measurements of Raw, ITGV, after 60, 90 and 120 min, and calculated the SRaw (p < 0.05). Treatment of the control group with tiotropium bromide - antagonist of the muscarinic receptor (2 inh. x 0.18 mcg), is effective in removal of the increased bronchomotor tonus, by also causing the significant decrease of the resistance (Raw), respectively of the specific resistance (SRaw), (p < 0.05).
CONCLUSION
Effect of zileuton in blocking of leukotriene biosynthesis is not immediate after oral administration, but the effect seen on the third day of cys-LTs' inhibition, and leukotriene B4 (LTB4) and A4 (LTA4) in patients with bronchial reactivity and bronchial asthma, which is expressed with a high significance, (p < 0.01). Blockage of phosphodiesterase enzyme-diprophylline decreases the bronchial reactivity, which is expressed with a moderate significance, (p < 0.05).
PubMed: 29875845
DOI: 10.3889/oamjms.2018.187 -
Tierarztliche Praxis. Ausgabe G,... Apr 2024In 2023, no new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. Two established veterinary active...
In 2023, no new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. Two established veterinary active pharmaceutical ingredients became available for additional species: The phosphorus compound butafosfan was also approved for horses, dogs, and cats and the mineral sodium chloride as an isotonic sodium chloride solution was also approved for rabbits and guinea pigs. In addition, for small animals, there were new releases of an agent (pergolidmesilate) in a novel pharmaceutical formulation and a lower content of the active ingredient, one drug (fluralaner) in a smaller package size as well as one drug (oxalic acid dehydrate) with a new route of administration. Furthermore, one combination of active ingredients (diprophylline+heptaminol) is available on the market for horses and food producing animals again.
Topics: Animals; Horses; Veterinary Drugs; Germany; Dogs; Cats; Guinea Pigs; Rabbits
PubMed: 38701800
DOI: 10.1055/a-2291-7062 -
Journal of Cellular Physiology Jun 2018Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. Identification of factors... (Comparative Study)
Comparative Study
Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. Identification of factors influencing osteoblast differentiation and bone formation is very important. Previously, we identified parbendazole to be a novel compound that stimulates osteogenic differentiation of human mesenchymal stromal cells (hMSCs), using gene expression profiling and bioinformatic analyzes, including the Connectivity Map (CMap), as an in-silico approach. The aim for this paper is to identify additional compounds affecting osteoblast differentiation using the CMap. Gene expression profiling was performed on hMSCs differentiated to osteoblasts using Illumina microarrays. Our osteoblast gene signature, the top regulated genes 6 hr after induction by dexamethasone, was uploaded into CMap (www.broadinstitute.org/cmap/). Through this approach we identified compounds with gene signatures positively correlating (withaferin-A, calcium folinate, amylocaine) or negatively correlating (salbutamol, metaraminol, diprophylline) to our osteoblast gene signature. All positively correlating compounds stimulated osteogenic differentiation, as indicated by increased mineralization compared to control treated cells. One of three negatively correlating compounds, salbutamol, inhibited dexamethasone-induced osteoblastic differentiation, while the other two had no effect. Based on gene expression data of withaferin-A and salbutamol, we identified HMOX1 and STC1 as being strongly differentially expressed . shRNA knockdown of HMOX1 or STC1 in hMSCs inhibited osteoblast differentiation. These results confirm that the CMap is a powerful approach to identify positively compounds that stimulate osteogenesis of hMSCs, and through this approach we can identify genes that play an important role in osteoblast differentiation and could be targets for novel bone anabolic therapies.
Topics: Bone Density; Bone Density Conservation Agents; Cell Differentiation; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Glycoproteins; Heme Oxygenase-1; Humans; Mesenchymal Stem Cells; Oligonucleotide Array Sequence Analysis; Osteoblasts; Osteogenesis; Protein Interaction Maps; Signal Transduction
PubMed: 29194609
DOI: 10.1002/jcp.26298 -
European Journal of Pharmaceutical... Oct 2017The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three...
The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t) from 8mm tablets ranged from 1.5h to 18h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50-100rpm) and ionic strength of the release media (100-600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity.
Topics: Administration, Oral; Caffeine; Chemistry, Pharmaceutical; Diffusion; Drug Delivery Systems; Drug Liberation; Excipients; Hydrophobic and Hydrophilic Interactions; Nanoparticles; Osmolar Concentration; Particle Size; Phosphatidylcholines; Porosity; Solubility; Tablets; Theophylline
PubMed: 28716757
DOI: 10.1016/j.ejps.2017.07.017 -
Molecular Pharmaceutics Nov 2019The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled...
The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.
Topics: Butanols; Crystallization; Crystallography, X-Ray; Dyphylline; Solubility; Solutions; Solvents; Stereoisomerism; Theophylline; X-Ray Diffraction
PubMed: 31545612
DOI: 10.1021/acs.molpharmaceut.9b00805