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BMB Reports Nov 2008Human microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane associated protein that catalyzes the conversion of prostaglandin H(2) (PGH(2)) into prostaglandin...
Human microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane associated protein that catalyzes the conversion of prostaglandin H(2) (PGH(2)) into prostaglandin E(2) (PGE(2)). In this study, the expression of human mPGES-1 in E. coli was significantly enhanced by modifying the utility of specific codons and the recombinant mPGES-1 was efficiently purified to homogeneity. The K(m) and V(max) of the purified enzyme were determined and the trimeric state characterized by chemical cross-linking with glutaraldehyde. The purified mPGES-1 was used for the screening of a chemical library of bioactive or drug compounds to identify novel inhibitors, and oxacillin and dyphylline were identified as moderately inhibiting mPGES-1 with IC(50) values of 100 and 200 microM, respectively. As these compounds competitively inhibited the catalysis of PGH(2), their binding sites appeared to be located near the PGH2 binding pocket.
Topics: Binding, Competitive; Drug Evaluation, Preclinical; Dyphylline; Enzyme Activation; Enzyme Inhibitors; Escherichia coli; Humans; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Oxacillin; Prostaglandin-E Synthases; Small Molecule Libraries; Transformation, Bacterial
PubMed: 19017494
DOI: 10.5483/bmbrep.2008.41.11.808 -
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 -
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 -
British Journal of Pharmacology Jun 19931. The effects of caffeine and related compounds on responses mediated by inhibitory amino acids were investigated in freshly dissociated rat hippocampal pyramidal...
1. The effects of caffeine and related compounds on responses mediated by inhibitory amino acids were investigated in freshly dissociated rat hippocampal pyramidal neurones by conventional and nystatin perforated patch-clamp techniques. 2. Glycine and gamma-aminobutyric acid (GABA) evoked Cl- currents in hippocampal neurones. The half-maximum effective concentrations (EC50) of glycine and GABA were 8.5 x 10(-5) and 5 x 10(-6) M, respectively. 3. Caffeine reversibly inhibited both 10(-4) M glycine- and 10(-5) M GABA-induced Cl-currents in a concentration-dependent manner. The half-maximum inhibitory concentrations (IC50) of caffeine were 4.5 x 10(-4) M for the glycine response and 3.6 x 10(-3) M for the GABA response. 4. Caffeine shifted the concentration-response curve of IGly to the right without affecting the maximum response. 5. The inhibitory action of caffeine did not show voltage-dependency. 6. The blocking action of caffeine was not affected by intracellular perfusion with 5 mM BAPTA or by pretreatment with the protein kinase A inhibitor, H-8. This excludes the participation of Ca2+ or cyclic AMP in the inhibitory action of caffeine. 7. Caffeine failed to inhibit the augmentations of aspartate- and N-methyl-D-aspartate (NMDA) -gated current by glycine, suggesting that caffeine has no effect on the allosteric glycine binding site on the NMDA receptor. 8. The inhibitory effects of some xanthine derivatives on IGly were compared. The inhibitory potency of those compounds on IGly was in the order of pentoxifylline > theophylline > or = caffeine > paraxanthine > IBMX > or = theobromine > dyphylline. Xanthine had no effect. 9. The results indicate that methylxanthines including caffeine may act directly on the glycine receptor Cl- channel complex in rat hippocampal pyramidal neurones. The blockade of the inhibitory amino acid response by methylxanthines may be involved in the excitatory side effects of methylxanthines in the mammalian central nervous system.
Topics: Amino Acids; Animals; Caffeine; Chloride Channels; Egtazic Acid; GABA Antagonists; Glycine; Hippocampus; In Vitro Techniques; Ion Channel Gating; Ion Channels; Membrane Proteins; N-Methylaspartate; Neurons; Rats; Rats, Wistar; Xanthines; gamma-Aminobutyric Acid
PubMed: 7689394
DOI: 10.1111/j.1476-5381.1993.tb13591.x -
AAPS PharmSci 2003In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of...
In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of various formulation and process variables, such as FPEC content, hardness of the tablet, and solubility of the drug, on the release of drug from these tablets was examined. Tablets were prepared by wet granulation of drug and FPEC in an appropriate mass ratio. Theophylline, caffeine, and dyphylline were selected as nonionizable model drugs with solubilities from 8.3 to 330 mg/mL at 25 degrees C. Ibuprofen, phenylpropanolamine hydrochloride, and pseudoephedrine hydrochloride were selected as ionizable drugs with solubilities from 0.1 to 2000 mg/mL at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection. As the FPEC content and the hardness of the tablets increased, the release rate of the drug decreased. The drug release rate increased with an increase in the solubility of the drug. Model equations, intended to elucidate the drug release mechanism, were fitted to the release data. Parameters were generated and data presented by SAS software. The Akaike Information Criterion was also considered to ascertain the best-fit equation. Fickian diffusion and polymer relaxation were the release mechanisms for nonionizable and ionizable drugs.
Topics: Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Hardness; Models, Theoretical; Particle Size; Solubility; Tablets; Technology, Pharmaceutical
PubMed: 12866940
DOI: 10.1208/ps050213 -
AAPS PharmSciTech 2008The stability of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and its potential incompatibility with active pharmaceutical ingredients (API) carrying...
The stability of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and its potential incompatibility with active pharmaceutical ingredients (API) carrying hydroxyl group(s) were investigated in this research. HPMC-AS may undergo hydrolysis under harsh processing conditions with the generation of succinic acid and acetic acid, which can form ester bond(s) with the hydroxyl group(s) in API. In this case, the hot-melt extrusion (HME) product prepared from HPMC-AS and our model compound (compound A) was tested after heating at 140 degrees C up to 5 h. The succinate esters of compound A and its epimer were found in the product, suggesting potential drug-excipient incompatibility during formulation development. In addition, dyphylline was also tested with HPMC-AS and the potential incompatibility was further confirmed.
Topics: Chemistry, Pharmaceutical; Chromatography, Liquid; Drug Incompatibility; Dyphylline; Esterification; Excipients; Hydrolysis; Methylcellulose; Tandem Mass Spectrometry
PubMed: 18758966
DOI: 10.1208/s12249-008-9138-5 -
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 -
Pharmaceutics Oct 2011Active coating is an important unit operation in the pharmaceutical industry. The quality, stability, safety and performance of the final product largely depend on the...
BACKGROUND
Active coating is an important unit operation in the pharmaceutical industry. The quality, stability, safety and performance of the final product largely depend on the amount and uniformity of coating applied. Active coating is challenging regarding the total amount of coating and its uniformity. Consequently, there is a strong demand for tools, which are able to monitor and determine the endpoint of a coating operation. In previous work, it was shown that Raman spectroscopy is an appropriate process analytical tool (PAT) to monitor an active spray coating process in a pan coater [1]. Using a multivariate model (Partial Least Squares-PLS) the Raman spectral data could be correlated with the coated amount of the API diprophylline. While the multivariate model was shown to be valid for the process in a mini scale pan coater (batch size: 3.5 kg cores), the aim of the present work was to prove the robustness of the model by transferring the results to tablets coated in a micro scale pan coater (0.5 kg).
METHOD
Coating experiments were performed in both, a mini scale and a micro scale pan coater. The model drug diprophylline was coated on placebo tablets. The multivariate model, established for the process in the mini scale pan coater, was applied to the Raman measurements of tablets coated in the micro scale coater for six different coating levels. Then, the amount of coating, which was predicted by the model, was compared with reference measurements using UV spectroscopy.
RESULTS
For all six coating levels the predicted coating amount was equal to the amounts obtained by UV spectroscopy within the statistical error. Thus, it was possible to predict the total coating amount with an error smaller than 3.6%. The root mean squares of errors for calibration and prediction (root mean square of errors for calibration and prediction-RMSEC and RMSEP) were 0.335 mg and 0.392 mg, respectively, which means that the predictive power of the model is not dependent on the scale or the equipment.
CONCLUSION
The scale-down experiment showed that it was possible to transfer the PLS model developed on a mini scale coater to a micro scale coater.
PubMed: 24309305
DOI: 10.3390/pharmaceutics3040723 -
Polskie Archiwum Medycyny Wewnetrznej 2007
Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Dyphylline; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Survival Analysis; Treatment Outcome
PubMed: 17642199
DOI: No ID Found -
Thorax Mar 1985The airway response to the inhalation of four alkyl xanthines was studied in 17 subjects with moderately severe asthma (mean FEV1 1.19 litres, 42% predicted).... (Clinical Trial)
Clinical Trial
The airway response to the inhalation of four alkyl xanthines was studied in 17 subjects with moderately severe asthma (mean FEV1 1.19 litres, 42% predicted). Theophylline (10 mg/ml), glycine theophyllinate (50 mg/ml), theophylline ethylenediamine (aminophylline 50 mg/ml), and diprophylline (125 mg/ml) were administered by nebulisation and the airway response was measured as percentage change from baseline of specific airway conductance (sGaw). All xanthine derivatives had an unpleasant taste and produced coughing at the onset of nebulisation. All four xanthines produced a significant increase in sGaw by comparison with saline placebo, with a maximum mean increase from baseline of 35% for theophylline, 40% for glycine theophyllinate, 60% for aminophylline, and 32% for diprophylline. Inhalation of 200 micrograms salbutamol from a metered dose inhaler produced an additional increase in sGaw of 149%. Thus alkyl substituted xanthines administered by inhalation to patients with asthma cause significant short lived bronchodilatation, but this effect is small compared with that of a conventional dose of an inhaled beta 2 adrenoceptor agonist.
Topics: Adult; Aerosols; Aged; Airway Resistance; Aminophylline; Asthma; Bronchi; Dyphylline; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Respiratory Therapy; Theophylline; Xanthines
PubMed: 3983884
DOI: 10.1136/thx.40.3.176