-
Oncology Letters Jan 2019Diprophylline (DPL) is identified as a methylxanthine (MX) derivative. A number of MX derivatives are reported to have anti-tumor effects. However, it is not clear...
Diprophylline (DPL) is identified as a methylxanthine (MX) derivative. A number of MX derivatives are reported to have anti-tumor effects. However, it is not clear whether DPL has a therapeutic effect on non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the effects of DPL on NSCLC and to elucidate the potential underlying mechanism. A Cell Counting Kit-8 assay was used to evaluate the potential effect of DPL on A549 cell proliferation. Transwell invasion and migration assays were performed to assess the effect of DPL on A549 cell migration and invasion. Furthermore, the percentage of apoptotic cells was detected by flow cytometric analysis, and proteins associated with apoptosis, including apoptosis regulator Bcl-2, apoptosis regulator BAX and active caspase-3, were examined by western blotting. Finally, the expression levels of molecules relevant to phosphoinositide 3-kinase (PI3K) signaling were detected by western blot analysis. The present study demonstrated that DPL may significantly inhibit A549 cell proliferation, migration and invasion. Furthermore, treatment with DPL may significantly induce A549 cell apoptosis. Finally, the protein expression levels associated with the PI3K signaling pathway were significantly inhibited in A549 cells following treatment with DPL. In conclusion, DPL may inhibit the proliferation and migration of NSCLC by inactivating the PI3K signaling pathway, and DPL is a promising novel therapeutic drug for NSCLC.
PubMed: 30655839
DOI: 10.3892/ol.2018.9678 -
The Journal of Physical Chemistry. B Aug 2017A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both...
A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (-140 °C), progressive heating below and above the glass transition (T ≈ 37 °C) induces two secondary relaxations (γ- and δ-) and primary relaxations (α-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no γ-process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi-identical. This study demonstrates that the relative stability and the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity.
Topics: Crystallization; Dielectric Spectroscopy; Pharmaceutical Preparations; Phase Transition; Stereoisomerism; Temperature; Theophylline
PubMed: 28726403
DOI: 10.1021/acs.jpcb.7b05667 -
International Journal of Pharmaceutics Jun 2017The aim of this study was to elucidate the importance of potential limited solubility effects for the control of drug release from hydrophilic matrix tablets loaded with...
The aim of this study was to elucidate the importance of potential limited solubility effects for the control of drug release from hydrophilic matrix tablets loaded with a freely water-soluble drug. It is often assumed that the considerable amounts of water penetrating into this type of advanced drug delivery systems are sufficient to rapidly dissolve the entire drug loading, and that limited drug solubility is not playing a role for the control of drug release. Here, we show that this assumption can be erroneous. HPMC/lactose matrix tablets were loaded with 5 to 60% diprophylline (e.g. solubility in 0.1M HCl at 37°C: 235mg/mL), and drug release was measured at low and neutral pH, respectively. A mechanistically realistic mathematical theory was applied, considering drug diffusion in axial and radial direction in the cylindrical matrices and the potential co-existence of dissolved and non-dissolved drug. Importantly, only dissolved drug is available for diffusion. It is demonstrated that during major parts of the release periods, non-dissolved drug excess exists within tablets containing 30% or more diprophylline, despite of the substantial water contents of the systems. This leads to partially almost linear drug concentration distance profiles within the tablets, and reveals a major contribution of limited drug solubility effects to the control of drug release, even in the case of freely water-soluble diprophylline. It can be expected that also in other types of drug delivery systems, e.g. microparticles and implants (containing much less water), limited drug solubility effects play a much more important role than currently recognized.
Topics: Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Liberation; Dyphylline; Excipients; Methylcellulose; Solubility; Tablets
PubMed: 28487190
DOI: 10.1016/j.ijpharm.2017.05.001 -
Faraday Discussions 2015A large variation is observed in induction times measured under equal conditions in 1 ml solutions. Ruling out experimental errors, this variation originates from the...
A large variation is observed in induction times measured under equal conditions in 1 ml solutions. Ruling out experimental errors, this variation originates from the nucleation process. The induction time distribution is explained by the stochastic nature of nucleation if the number of nuclei formed is approaching 1 per vial. Accurate heterogeneous crystal nucleation rates were determined from the induction time distributions on a 1 ml scale for racemic diprophylline in two solvents. The difference in nucleation behaviour in the two solvents originates from the energy barrier for nucleation, which is much higher in the solvent in which induction times are much longer. In addition the pre-exponential factor for the crystal nucleation rate in both solvents is rather low compared to predictions using Classical Nucleation Theory. Unfortunately, concentration and surface characteristics of the effective heterogeneous particles are not known which clouds a further molecular interpretation.
PubMed: 25865429
DOI: 10.1039/c4fd00230j -
International Journal of Pharmaceutics Jun 2016Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt... (Comparative Study)
Comparative Study
Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. (1)H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility.
Topics: Acetaminophen; Administration, Oral; Chemistry, Pharmaceutical; Crystallization; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Dyphylline; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Polyurethanes; Solubility; Tablets; Technology, Pharmaceutical; Theophylline
PubMed: 27113866
DOI: 10.1016/j.ijpharm.2016.04.057 -
Journal of Molecular Graphics &... Nov 2020Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective...
Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
Topics: Amino Acid Motifs; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Antiviral Agents; Betacoronavirus; COVID-19; Carbazoles; Catalytic Domain; Coronavirus Infections; Drug Repositioning; Dyphylline; Host-Pathogen Interactions; Humans; Hydroxamic Acids; Ligands; Molecular Docking Simulation; Pandemics; Paromomycin; Pemetrexed; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; SARS-CoV-2; Small Molecule Libraries; Structure-Activity Relationship; Thermodynamics
PubMed: 32739642
DOI: 10.1016/j.jmgm.2020.107697 -
Journal of Colloid and Interface Science May 2017In this work, solid-core@porous-shell alloyed PtAg nanocrystals (PtAg NCs) were fabricated via a simple one-pot co-reduction wet-chemical method on a large scale....
In this work, solid-core@porous-shell alloyed PtAg nanocrystals (PtAg NCs) were fabricated via a simple one-pot co-reduction wet-chemical method on a large scale. Diprophylline (DPP) was employed as the stabilizing agent and shape-directing agent, without any surfactant, polymer, seed or template. The products were mainly analyzed by a series of characterization technique. The hierarchical architectures had enhanced stability and improved electrocatalytic activity for hydrogen evolution reaction (HER) and glycerol oxidation reaction (GOR) in contrast with commercial available Pt/C and Pt black catalysts. For the prepared PtAg NCs catalyst, the Tafel slope is 40mVdec toward HER in 0.5M HSO, coupled with the specific activity and mass activity of 77.91mAcm and 1303mAmg toward GOR, respectively.
PubMed: 28131029
DOI: 10.1016/j.jcis.2017.01.030 -
Chemistry (Weinheim An Der Bergstrasse,... Nov 2016The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation,...
The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.
PubMed: 27667660
DOI: 10.1002/chem.201602707 -
European Journal of Pharmaceutics and... Feb 2015This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination...
This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM.
Topics: Administration, Oral; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dosage Forms; Drug Carriers; Drug Compounding; Dyphylline; Excipients; Hot Temperature; Humans; Metoprolol; Polyethylene Glycols; Polyurethanes; Porosity; Tablets
PubMed: 25448075
DOI: 10.1016/j.ejpb.2014.11.003