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Journal of Translational Medicine Aug 2018Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences...
BACKGROUND
Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences in health and disease represents a crucial step towards precision medicine. Considering the significant differences between men and women in the response to pharmacotherapies, our aim was to develop an in silico model able to predict sex-specific drug responses in a large-scale.
METHODS
For this purpose, we focused on cardiovascular effects because of their high morbidity and mortality. Our model predicted several drugs (including acebutolol and tacrine) with significant differences in the heart between men and women. To validate the sex-specific drug responses identified by our model, acebutolol was selected to lower blood pressure in spontaneous hypertensive rats (SHR), tacrine was used to assess cardiac injury in mice and metformin as control for a non-sex-specific response.
RESULTS
As our model predicted, acebutolol exhibited a stronger decrease in heart rate and blood pressure in female than male SHRs. Tacrine lowered heart rate in male but not in female mice, induced higher plasma cTNI level and increased cardiac superoxide (DHE staining) generation in female than male mice, indicating stronger cardiac toxicity in female than male mice. To validate our model in humans, we employed two Chinese cohorts, which showed that among patients taking a beta-receptor blocker (metoprolol), women reached significantly lower diastolic blood pressure than men.
CONCLUSIONS
We conclude that our in silico model could be translated into clinical practice to predict sex-specific drug responses, thereby contributing towards a more appropriate medical care for both men and women.
Topics: Acebutolol; Animals; Blood Pressure; China; Computer Simulation; Drug Therapy; Female; Heart; Heart Injuries; Heart Rate; Humans; Hypertension; Male; Metformin; Mice; Mice, Inbred C57BL; Middle Aged; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sex Factors; Tacrine
PubMed: 30157868
DOI: 10.1186/s12967-018-1612-6 -
ACS Chemical Neuroscience Aug 2018Single-cell mass spectrometry has become an established technique to study specific molecular properties such as the neuropeptide complement of identified neurons. Here,...
Single-cell mass spectrometry has become an established technique to study specific molecular properties such as the neuropeptide complement of identified neurons. Here, we describe a strategy to characterize, by MALDI-TOF mass spectrometry, neurochemical composition of neurons that were identified by their electrophysiological and neuroanatomical characteristics. The workflow for the first time combined perforated patch clamp recordings with dye loading by electroporation for electrophysiological and neuroanatomical characterization as well as chemical profiling of somata by MALDI-TOF mass spectrometry with subsequent immunohistochemistry. To develop our protocol, we used identified central olfactory neurons from the American cockroach Periplaneta americana. First, the combined approach was optimized using a relative homogeneous, well-characterized neuron population of uniglomerular projection neurons, which show acetylcholine esterase immunoreactivity. The general applicability of this approach was verified on local interneurons, which are a diverse neuron population expressing highly differentiated neuropeptidomes. Thus, this study shows that the newly established protocol is suitable to comprehensively analyze electrophysiological, neuroanatomical, and molecular properties of single neurons. We consider this approach an important step to foster single-cell analysis in a wide variety of neuron types.
Topics: Acebutolol; Animals; Brain; Coloring Agents; Electroporation; Image Processing, Computer-Assisted; Immunohistochemistry; Lysine; Membrane Potentials; Neurons; Patch-Clamp Techniques; Periplaneta; Single-Cell Analysis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 29906100
DOI: 10.1021/acschemneuro.8b00163 -
Journal of Chromatography. A Jun 2018An environmentally friendly micro-solid phase extraction (μ-SPE) method utilizing a plant based nanocomposite as a sorbent for determination of trace level beta...
An environmentally friendly micro-solid phase extraction (μ-SPE) method utilizing a plant based nanocomposite as a sorbent for determination of trace level beta blockers (ß-blockers) in hospital wastewater prior to Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. μ-SPE extraction conditions were evaluated using a multivariate chemometric approach. Rice husk silica-carbon nanocomposite (5-20Wt.% Fe) in glycerol were synthesized via hydrolytic sol-gel method. The nanosorbent were fully characterized and then evaluated for μ-SPE of trace level ß-blockers in hospital wastewater. To establish the best extraction conditions at minimal experimental cost, multivariate techniques based on fractional factorial (FFD) and central composite designs (CCD) with desirability function (DF) were used to optimize the extraction conditions. Experimental results showed good agreement with predicted values and logical DF was realized at relatively low extraction time. Under optimized conditions, good linearity ranges (0.02-5.0μgL) with correlation of determinations higher than 0.9954 were obtained. The limits of detection and quantitation for the five ß-blockers (atenolol, alprenolol, pindolol, acebutolol and propranolol) ranged from 4.0-6.4 and 13.0-19.0ngL, respectively. Inter-day and intra-day precision (percent relative standard deviations, n=5) were lower than 8.3% while relative recoveries for hospital wastewater samples (80.6-105.1%) were in satisfactory ranges. This experimental approach therefore, demonstrated simplicity, reduction in the experimental runs, effectively increased sensitivity of LC-MS/MS and was hence suitable for complex matrix sample analysis.
Topics: Adrenergic beta-Antagonists; Chromatography, High Pressure Liquid; Gels; Glycerol; Hydrogen-Ion Concentration; Limit of Detection; Nanocomposites; Osmolar Concentration; Silicon Dioxide; Solid Phase Microextraction; Tandem Mass Spectrometry; Wastewater
PubMed: 29705646
DOI: 10.1016/j.chroma.2018.04.044 -
Biomolecules & Therapeutics Sep 2018The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation,...
The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.
PubMed: 29129046
DOI: 10.4062/biomolther.2017.123 -
Applied Biochemistry and Biotechnology Apr 2018Neuraminidase (NA), a surface protein, facilitates the release of nascent virus and thus spreads infection. It has been renowned as a potential drug target for influenza...
Neuraminidase (NA), a surface protein, facilitates the release of nascent virus and thus spreads infection. It has been renowned as a potential drug target for influenza A virus infection. The drugs such as oseltamivir, zanamivir, peramivir, and laninamivir are approved for the treatment of influenza infection. Additionally, investigational drugs namely MK2206, tamiphosphor, crenatoside, and dehydroepiandrosterone (DHEA) are also available for the treatment. However, recent outbreaks of highly pathogenic and drug-resistant influenza A strains highlighted the need to discover novel NA inhibitor. Keeping this in mind, in the current investigation, an effort was made to ascertain potent inhibitors using pharmacophore-based virtual screening and docking approach. A 3D pharmacophore model was generated based on the chemical features of approved and investigational NA inhibitors using PHASE module of Schrödinger suite. The model consists of two hydrogen bond acceptors (A), one hydrogen bond donor (D), and one positively charged group (P), AADP. Subsequently, molecules with same pharmacophoric features were screened from among the two million compounds available in the ZINC database using the generated pharmacophore hypothesis. Ligand filtration was also done to obtain an efficient collection of hit molecules by employing Lipinski "rule of five" using Qikprop module. Finally, the screened molecule was subjected to docking and molecular dynamic simulations to examine the inhibiting activity of the compounds. The results of our analysis suggest that "acebutolol hydrochloride" (156792) could be the promising candidates for the treatment of influenza A virus infection.
Topics: Antiviral Agents; Enzyme Inhibitors; Influenza A virus; Molecular Docking Simulation; Molecular Dynamics Simulation; Neuraminidase; Viral Proteins
PubMed: 29063410
DOI: 10.1007/s12010-017-2625-y -
British Journal of Pharmacology Jan 2018Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in...
BACKGROUND AND PURPOSE
Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible.
EXPERIMENTAL APPROACH
Previous PBPK model development of enantiomers of a series of seven racemic β-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design.
KEY RESULTS
Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments.
CONCLUSIONS AND IMPLICATIONS
PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.
Topics: Adrenergic beta-Antagonists; Animals; Injections, Intravenous; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 29053169
DOI: 10.1111/bph.14071 -
Talanta Jan 2018In the last few years, a number of studies were conducted which aimed at understanding the mechanisms of cardiovascular drug, metabolism, and there is still the need to...
Structural characterization of electrochemically and in vivo generated potential metabolites of selected cardiovascular drugs by EC-UHPLC/ESI-MS using an experimental design approach.
In the last few years, a number of studies were conducted which aimed at understanding the mechanisms of cardiovascular drug, metabolism, and there is still the need to determine the metabolites of cardiac drugs for the purpose of metabolism control. In this study, we employ a direct combination of electrochemical oxidation and mass spectrometric (EC-MS) identification for monitoring the oxidation pathway of ten cardiovascular drugs (metoprolol, propranolol, propafenone, mexiletine, oxprenolol, pirbuterol, pindolol, cicloprolol, acebutolol and atenolol). Oxidation was accomplished in an electrochemical thin-layer cell coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). For further characterization of electrochemical products, the approach involving liquid chromatography linked to tandem mass spectrometry was used. Appropriate conditions for oxidation and identification processes with such parameters as the potential value, mobile phase (type and pH) and working electrode were optimized. Optimization was performed with the use of central composite design (CCD). Besides electrochemical oxidation of analytes (phase I of metabolic transformation), addition of glutathione (GSH) for follow-up reactions (phase II conjunction) was also investigated. The electrochemical results were compared to in-vivo experiments by analyzing plasma and urine samples from patients who had been administered selected cardiovascular drugs. These results show that electrochemistry coupled to mass spectrometry turned out to be an analytical tool suitable to procure a feasible analytical base for the envisioned in vivo experiments.
Topics: Cardiovascular Agents; Chromatography, High Pressure Liquid; Electrochemical Techniques; Electrochemistry; Glutathione; Humans; Molecular Structure; Oxidation-Reduction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 28917751
DOI: 10.1016/j.talanta.2017.08.041 -
Scientific Reports Aug 2017In this paper the relaxation dynamics of ionic glass-former acebutolol hydrochloride (ACB-HCl) is studied as a function of temperature and pressure by using dynamic...
In this paper the relaxation dynamics of ionic glass-former acebutolol hydrochloride (ACB-HCl) is studied as a function of temperature and pressure by using dynamic light scattering and broadband dielectric spectroscopy. These unique experimental data provide the first direct evidence that the decoupling between the charge transport and structural relaxation exists in proton conductors over a wide T-P thermodynamic space, with the time scale of structural relaxation being constant at the liquid-glass transition (τ = 1000 s). We demonstrate that the enhanced proton transport, being a combination of intermolecular H hopping between cation and anion as well as tautomerization process within amide moiety of ACB molecule, results in a breakdown of the Stokes-Einstein relation at ambient and elevated pressure with the fractional exponent k being pressure dependent. The dT /dP coefficient, stretching exponent β and dynamic modulus E /ΔV were found to be the same regardless of the relaxation processes studied. This is in contrast to the apparent activation volume parameter that is different when charge transport and structural dynamics are considered. These experimental results together with theoretical considerations create new ideas to design efficient proton conductors for potential electrochemical applications.
PubMed: 28765639
DOI: 10.1038/s41598-017-07136-5 -
Journal of Chromatographic Science Sep 2017A highly sensitive method for the determinations of acebutolol, clenbuterol, nadolol, oxprenolol, propranolol, terbutaline and timolol β-blockers and β2-agonists in...
A highly sensitive method for the determinations of acebutolol, clenbuterol, nadolol, oxprenolol, propranolol, terbutaline and timolol β-blockers and β2-agonists in plasma and urine was developed. The method was optimized using electrospray ionization liquid chromatography-tandem mass spectrometry (LC-ESI-MS-MS) and clean screen solid phase extraction cartridges. Matrix effect was reduced by removing co-extractives from the SPE cartridges using methanol prior to drugs' elution. Using blood and serum matrices for calibration and applying the internal standard method has also contributed to the reduction of matrix effect. Method's validation yielded linear dynamic ranges of 5.0-50.0 and 50.0-1000.0 ng/ml for drugs spiked in plasma and urine respectively. It also gave correlation coefficients of 0.94-0.99, detection limits ranged in 0.06-5.04 pg/ml and quantification limits ranged in 0.14-22.88 pg/ml for the target drugs. Developed method was successfully applied to the analysis of β-blockers and β2-agonists in plasma and urine samples. Plasma samples fortified with drugs at 7.5, 40.0 and 75.0 ng/ml gave percentage recoveries ranged in 78.66-118.10, 67.02-83.97 and 74.77-93.80, respectively. Urine samples fortified with drugs at 80.0, 400.0 and 800.0 ng/ml gave percentage recoveries ranged in 104.68-130.18, 110.23-125.16 and 109.46-116.89, respectively. Variance coefficients ranged in 0.05-0.35 and 0.04-0.12 were, respectively, obtained for the analyses of drugs in plasma and urine samples. Results suggest that developed method is well suited for the analysis of investigated drugs in biological fluids.
Topics: Adrenergic beta-Antagonists; Chromatography, Liquid; Humans; Limit of Detection; Linear Models; Reproducibility of Results; Solid Phase Extraction; Tandem Mass Spectrometry
PubMed: 28633284
DOI: 10.1093/chromsci/bmx045