Undesirable Interactions Research Articles

Potential Drug-Drug Interactions in Outpatient Lung Cancer Patients in a University Hospital

Introduction: Concomitant use of drugs in the same or different indications can sometimes lead to undesirable interactions. The prevalence of drug interactions is high in cancer patients. In this study, we aimed to determine the frequency and clinical severity of drug interactions in outpatient lung cancer patients. Methods: The drugs used, kidney and liver blood analysis results of 160 outpatient lung cancer patients over the age of 18 years who received chemotherapy between October 2020 and July 2021 were evaluated. The Lexi-Interact online database was used to identify the types of clinically significant drug interactions, frequently interacting drugs, and clinical outcomes predicted by the databases. Results: The average number of drugs per patient was 4.2 ± 2.3. It was determined that there was a relationship between multidrug use and comorbidity, and the number of drugs used increased as the number of diagnoses increased. A relationship was also found between potential drug-drug interactions (pDDIs), which we observed in 52.5% of the patients, and the number of drugs used and age. The most common clinically significant C- (36.9%), D- (16.9%), and X- (10.6%) type pDDIs were detected between conventional paclitaxel-hydrochlorothiazide, conventional paclitaxel-carboplatin, and ipratropium-tiotropium, respectively. Conclusions: The use of frequently interacting drugs in outpatient lung cancer patients can lead to pDDIs. In these patients, the application of therapy by observing the drug-drug interaction may improve the quality of life.

Evaluation of machine learning models for cytochrome P450 3A4, 2D6, and 2C9 inhibition.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC) of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition.

Precise Structural and Dynamical Details in Zeolites Revealed by Coupling-Edited 1H-17O Double Resonance NMR Spectroscopy.

Despite the extensive industrial and research interests in zeolites, their intrinsic catalytic nature is not fully understood due to the complexity of the hydroxyl-aluminum moieties. 17O NMR would provide irreplaceable opportunities for much-needed fine structural determination given the ubiquitous presence of oxygen atoms in nearly all species; however, the low sensitivity and quadrupolar nature of oxygen-17 make its NMR spectroscopic elucidation challenging. Here, we show that state-of-the-art double resonance solid-state NMR techniques have been combined with spectral editing methods based on scalar (through-bond) and dipolar (through-space) couplings, which allowed us to address the subtle protonic structures in zeolites. Notably, the often-neglected and undesired second-order quadrupolar-dipolar cross-term interaction ("2nd-QD interaction") can actually be exploited and can help gain invaluable information. Eventually, a comprehensive set of 1H-17O/1H-27Al double resonance NMR with J-/D-coupling spectral editing techniques have been designed in this work and enabled us to reveal atomic-scale precise structural and dynamical details in zeolites including: 1) The jump rate of the bridging acid site (BAS) proton is relatively low, i.e., far less than 100 s-1 at room temperature. 2) The Al-OH groups with 1H chemical shift at 2.6-2.8 ppm, at least for nonseverely dealuminated H-ZSM-5 catalysts, exhibit a rigid bridging environment similar to that of BAS. 3) The Si-OH groups at 2.0 ppm are not hydrogen bonded and undergo fast cone-rotational motion. The results in this study predict the 2nd-QD interaction to be universal for any rigid -17O-H environment, such as those in metal oxide surfaces or biomaterials.

Refinement of the Manufacturing Route and Evaluation of the Reinforcement Effect of MAX Phases in Al Alloy Matrix Composite Materials

Microwave Assisted Self-propagating High-temperature Synthesis (MASHS) was used to prepare open-porous MAX phase preforms in Ti-Al-C and Ti-Si-C systems, which were further used as reinforcements for Al-Si matrix composite materials. The pretreatment of substrates was investigated to obtain open-porous cellular structures. Squeeze casting infiltration was chosen to be implemented as a method of composites manufacturing. Process parameters were adjusted in order to avoid oxidation during infiltration and to ensure the proper filling. Obtained materials were reproducible, well saturated and dense, without significant residual porosity or undesired interactions between the constituents. Based on this and the previous work of the authors, the reinforcement effect was characterized and compared for both systems. For the Al-Si+Ti-Al-C composite, an approx. 4-fold increase in hardness and instrumental Young's modulus was observed in relation to the matrix material. Compared to the matrix, Al-Si+Ti-Si-C composite improved more than 5-fold in hardness and almost 6-fold in Young's modulus. Wear resistance (established for different loads: 0.1, 0.2 and 0.5 MPa) for Al-Si+Ti-Al-C was two times higher than for the sole matrix, while for Al-Si+Ti-Si-C the improvement was up to 32%. Both composite materials exhibited approximately two times lower thermal expansion coefficients than the matrix, resulting in enhanced dimensional stability.

Carbocationoids, a concept for controlling highly reactive cationic species

Carbocations, which are positively charged highly electrophilic intermediates, are efficacious for the direct alkylation of low-reactive nucleophiles. The utilization of carbocations in SN1 reactions relies on the activation of their precursors in the presence of a nucleophile. However, undesirable interactions between the nucleophile and the leaving group activator limit the scope of acceptable nucleophiles. Here we report a strategy to conduct SN1 reactions involving unstable carbocations in an alternative stepwise procedure, which was demonstrated by the benzylation of various neutral nucleophiles. In the first step, carbocations were accumulated in a nucleophile-free solution in the form of carbocationoids utilizing the coordinative stabilization of triazinediones. Subsequently, the addition of these solutions in the second step enabled room-temperature alkylation without the need for acidic additives. This methodology overcomes the inherent challenges of carbocations in SN1 reactions.

Potential-Resolved Ratiometric Aptasensor for Sensitive Acetamiprid Analysis Based on Coreactant-free Electrochemiluminescence Luminophores of Gd-MOF and "Light Switch" Molecule of [Ru(bpy)2dppz]2.

For conventional potential-resolved ratiometric electrochemiluminescence (ECL) systems, the introduction of multiplex coreactants is imperative. However, the undesirable interactions between different coreactants inevitably affect analytical accuracy and sensitivity. Herein, through the coordination of aggregation-induced emission ligands with gadolinium cations, the self-luminescent metal-organic framework (Gd-MOF) is prepared and serves as a novel coreactant-free anodic ECL emitter. By the intercalation of [Ru(bpy)2dppz]2+ with light switch effect into DNA duplex, one high-efficiency cathodic ECL probe is obtained using K2S2O8 as a coreactant. In the presence of acetamiprid, the strong affinity between the target and its aptamer induces the release of [Ru(bpy)2dppz]2+, resulting in a decreasing cathode signal and an increasing anode signal owing to the ECL resonance energy transfer from Gd-MOF to [Ru(bpy)2dppz]2+. In this way, an efficient dual-signal ECL aptasensor is constructed for the ratiometric analysis of acetamiprid, exhibiting a remarkably low detection limit of 0.033 pM. Strikingly, by using only one exogenous coreactant, the cross interference from multiple coreactants can be eliminated, thus improving the detection accuracy. The developed high-performance ECL sensing platform is successfully applied to monitor the residual level of acetamiprid in real samples, demonstrating its potential application in the field of food security.

Modification of Layered Cathodes of Sodium-Ion Batteries with Conducting Polymers

Layered oxides exhibit interesting performance as positive electrodes for commercial sodium-ion batteries. Nevertheless, the replacement of low-sustainable nickel with more abundant iron would be desirable. Although it can be achieved in P2-Na2/3Ni2/9Fe2/9Mn5/9O2, its performance still requires further improvement. Many imaginative strategies such as surface modification have been proposed to minimize undesirable interactions at the cathode–electrolyte interface while facilitating sodium insertion in different materials. Here, we examine four different approaches based on the use of the electron-conductive polymer poly(3,4-ethylene dioxythiophene) (PEDOT) as an additive: (i) electrochemical in situ polymerization of the monomer, (ii) manual mixing with the active material, (iii) coating the current collector, and (iv) a combination of the latter two methods. As compared with pristine layered oxide, the electrochemical performance shows a particularly effective way of increasing cycling stability by using electropolymerization. Contrarily, the mixtures show less improvement, probably due to the heterogeneous distribution of oxide and polymer in the samples. In contrast with less conductive polyanionic cathode materials such as phosphates, the beneficial effects of PEDOT on oxide cathodes are not as much in rate performance as in inhibiting cycling degradation, due to the compactness of the electrodes without loss of electrical contact between active particles.

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

Pasien Infark Miokard Akut pada Studi Penggunaan Obat Anti Platelet di RSUD Gambiran Kota Kediri

The purpose of this study was to determine the pattern of drug use, potential interactions, and side effects of antiplatelet drugs in acute myocardial infarction patients in inpatient installations to reduce morbidity and mortality rates at Gambiran Hospital, Kediri City. This study is a non-experimental study with descriptive research design and retrospective data collection, data collection using purposive sampling method. Retrospective data collection based on medical record data of patients with acute myocardial infarction, this research was conducted from January to December 2020, so that the pattern of use of anti-platelet drugs in patients with acute myocardial infarction was a combination of aspirin 80 mg 1x1 with clopidogrel 75mg 1x1 (93%), with the route of drug administration orally. Analysis of potential drug interactions was carried out using the Drugs Interaction Checker and obtained 4 occurrences of major potential interactions and 10 occurrences of moderate potential interactions. The desired potential drug interaction was to prevent platelet aggregation. There was an undesirable potential drug interaction related to decreased antihypertensive effect of the drug, while potential drug interactions in the form of gastrointestinal bleeding and decreased renal function could not be determined.

Diabetes mellitus patients with increased death rates and clinical complications in patients with CoV-19 pneumonia: A systematic review

Diabetes Mellitus (DM) is a chronic condition that has been associated with Corona virus (CV) sickness and has the potential to cause catastrophic multisystemic consequences. They used a complete meta-analysis and review to examine the connection among DM and a bad prognosis in COVID-19 pneumonia individuals. We searched many online databases for articles assessing the correlation between DM and outcome in COVID-19 pneumonia. This study's principal result was an undesirable interaction of three secondary results: the occurrence of severe cardiovascular disease (CVD), acute respiratory distress syndrome (ARDS), and death. All 17 studies had 6452 participants. After eliminating the duplicates, the number of records remained at 350. After first looking at the titles and abstracts, we discarded 310 articles. After reviewing 43 full-text publications, 13 were ruled ineligible owing to a lack of mortality, interest, or disease progression outcomes, including those for severe ARDS which is disease progression, ARDS, Mortality and COVID-19 severity, were increased in COVID-19 patients with DM.

Antibiotic Drug Interaction in Prescribing Asthma Patients in One of the Clinics in the Surabaya Area

Drug interactions are interactions that can occur if the effects of a drug are changed by other drugs, food or drinks. The aim of this research is to determine the potential for interactions between antibiotics and other drugs prescribed to asthma patients. Antibiotics are the drugs most widely used for infections caused by bacteria. Determining the mechanism of potential interactions between antibiotics and other drugs prescribed to asthma patients in this study using the Medscape application. The research results showed that there were 2044 prescriptions for the period Juli - December 2022, which provided the highest potential for drug interactions, namely interactions with pharmacokinetic mechanisms in the metabolic phase with 69 incidents (20.47%). Meanwhile, the highest level of severity was monitoring closely, 291 (86.35%) and those with the potential for serious interactions were 46 incidents (13.65%). In this research, the active role of Pharmacy Technicians and Pharmacists is needed to monitor the use of drugs that have the potential to cause drug interactions with prescribing doctors in the hope that undesirable drug interactions can be avoided.

Power Quality Survey in a State of the Art Microgrid

The power quality in a state of the art microgrid has been examined using power quality analysers from Elspec Ltd and A-Eberle GmbH. The microgrid employs PV, CHP and three battery banks with a total of 120 kW / 204 kWh dividing the microgrid into three subnetworks with different network topologies. Different power quality measurements during different stages of construction shows that there are some power quality issues in the microgrid. These issues relate to transitioning to island mode, increase of harmonic noise during island mode, and undesirable equipment interactions. These are increasingly important issues to address as microgrids are becoming more widely adopted and increasingly complex.

Steric protection of near-infrared fluorescent dyes for enhanced bioimaging.

Near-fluorescent (NIR) dyes that absorb and emit light in the wavelength range of 650-1700 nm are well-suited for bioimaging due to the improved image contrast and increased penetration of the long-wavelength light through biological tissue. However, the imaging performance of NIR fluorescent dyes is limited by several inherent photophysical and physicochemical properties including, low fluorescence quantum yield, high chemical and photochemical reactivity, propensity to self-aggregate in water, non-specific association with off-target biological sites, and non-optimal pharmacokinetic profiles in living subjects. In principle, all these drawbacks can be alleviated by steric protection which is a structural process that surrounds the fluorophore with bulky groups that block undesired intermolecular interactions. The literature methods to sterically protect a long-wavelength dye can be separated into two general strategies, non-covalent dye encapsulation and covalent steric appendage. Illustrative examples of each method show how steric protection improves bioimaging performance by providing: (a) increased fluorescence brightness, (b) higher fluorophore ground state stability, (c) decreased photobleaching, and (d) superior pharmacokinetic profile. Some sterically protected dyes are commercially available and further success with future systems will require experts in chemistry, microscopy, cell biology, medical imaging, and clinical medicine to work closely as interdisciplinary teams.

Interfacial rheology of lanthanide binding peptide surfactants at the air-water interface.

Peptide surfactants (PEPS) are studied to capture and retain rare earth elements (REEs) at air-water interfaces to enable REE separations. Peptide sequences, designed to selectively bind REEs, depend crucially on the position of ligands within their binding loop domain. These ligands form a coordination sphere that wraps and retains the cation. We study variants of lanthanide binding tags (LBTs) designed to complex strongly with Tb3+. The peptide LBT5- (with net charge -5) is known to bind Tb3+ and adsorb with more REE cations than peptide molecules, suggesting that undesired non-specific coulombic interactions occur. Rheological characterization of interfaces of LBT5- and Tb3+ solutions reveal the formation of an interfacial gel. To probe whether this gelation reflects chelation among intact adsorbed LBT5-:Tb3+ complexes or destruction of the binding loop, we study a variant, LBT3-, designed to form net neutral LBT3-:Tb3+ complexes. Solutions of LBT3- and Tb3+ form purely viscous layers in the presence of excess Tb3+, indicating that each peptide binds a single REE in an intact coordination sphere. We introduce the variant RR-LBT3- with net charge -3 and anionic ligands outside of the coordination sphere. We find that such exposed ligands promote interfacial gelation. Thus, a nuanced requirement for interfacial selectivity of PEPS is proposed: that anionic ligands outside of the coordination sphere must be avoided to prevent the non-selective recruitment of REE cations. This view is supported by simulation, including interfacial molecular dynamics simulations, and interfacial metadynamics simulations of the free energy landscape of the binding loop conformational space.

A multifunctional protein pre-coated metal-organic framework for targeted delivery with deep tissue penetration.

Targeted drug delivery using metal-organic frameworks (MOFs) has shown significant progress. However, the tumor microenvironment (TME) impedes efficient MOF particle transfer into tumor cells. To tackle this issue, we pre-coated nano-sized MOF-808 particles with multifunctional proteins: glutathione S-transferase (GST)-affibody (Afb) and collagenase, aiming to navigate the TME more effectively. The surface of MOF-808 particles is coated with GST-Afb-a fusion protein of GST and human epidermal growth factor receptor 2 (HER2) Afb or epidermal growth factor receptor (EGFR) Afb which has target affinity. We also added collagenase enzymes capable of breaking down collagen in the extracellular matrix (ECM) through supramolecular conjugation, all without chemical modification. By stabilizing these proteins on the surface, GST-Afb mitigate biomolecule absorption, facilitating specific tumor cell targeting. Simultaneously, collagenase degrades the ECM in the TME, enabling deep tissue penetration of MOF particles. Our resulting system, termed collagenase-GST-Afb-MOF-808 (Col-Afb-M808), minimizes undesired interactions between MOF particles and external biological proteins. It not only induces cell death through Afb-mediated cell-specific targeting, but also showcases advanced cellular internalization in 3D multicellular spheroid cancer models, with effective deep tissue penetration. The therapeutic efficacy of Col-Afb-M808 was further assessed via in vivo imaging and evaluation of tumor inhibition following injection of IR-780 loaded Col-Afb-M808 in 4T1tumor-bearing nude mice. This study offers key insights into the regulation of the multifunctional protein-adhesive surface of MOF particles, paving the way for the designing even more effective targeted drug delivery systems with nano-sized MOF particles.

Suppression of deep-level traps via semicarbazide hydrochloride additives for high-performance tin-based perovskite solar cells

Tin perovskites with exemplary optoelectronic properties offer potential application in lead-free perovskite solar cells. However, Sn vacancies and undercoordinated Sn ions on the tin perovskite surfaces can create deep-level traps, leading to non-radiative recombination and absorption of nucleophilic O2 molecules, impeding further device efficiency and stability. Here, in this study, a new additive of semicarbazide hydrochloride (SEM-HCl) with a N–C=O functional group was introduced into the perovskite precursor to fabricate high-quality films with a low concentration of deep-level trap densities. This, in turn, serves to prevent undesirable interaction between photogenerated carriers and adsorbed oxygen molecules in the device’s operational environment, ultimately reducing the proliferation of superoxide entities. As the result, the SEM-HCl-derived devices show a peak efficiency of 10.9% with improved device stability. These unencapsulated devices maintain almost 100% of their initial efficiencies after working for 100 h under continuous AM1.5 illumination conditions.Graphical

Blacklight sintering of garnet-based composite cathodes

Garnet-structured Li7La3Zr2O12 (LLZO) is an attractive electrolyte for lithium solid-state batteries (SSBs), but its processing requires long sintering at temperatures above 1000 °C to achieve sufficient ionic conductivity. Such sintering is not only time and energy consuming, but also leads to undesirable material interactions. Therefore, a significant reduction of the sintering time is very important for the future development of garnet-based batteries. A promising method is the recently introduced photonic blacklight sintering with light sources in the UV spectrum, which enables energy-efficient sintering of ceramic layers within seconds. In this work, blacklight sintering of garnet-based SSBs is validated using a model cell consisting of LLZO and LiCoO2 (LCO) composite cathode layers printed on dense LLZO pellets. An optimized sintering program allowed the production of working cells in only 20 s. This study demonstrates the suitability of blacklight sintering for processing garnet-based SSBs and provides guidance for future process optimization.

Sustainable asymmetric synthesis of diltiazem precursor enabled by recombinant Escherichia coli whole cells co-expressing an engineered ketoreductase and glucose dehydrogenase.

As a key synthetic intermediate of the cardiovascular drug diltiazem, methyl (2R,3S)-3-(4-methoxyphenyl) glycidate ((2R,3S)-MPGM) (1) is accessible via the ring closure of chlorohydrin (3S)-methyl 2-chloro-3-hydroxy-3-(4-methoxyphenyl)propanoate ((3S)-2). We report the efficient reduction of methyl 2-chloro-3-(4-methoxyphenyl)-3-oxo-propanoate (3) to (3S)-2 using an engineered enzyme SSCRM2 possessing 4.5-fold improved specific activity, which was obtained through the structure-guided site-saturation mutagenesis of the ketoreductase SSCR by reliving steric hindrance and undesired interactions. With the combined use of the co-expression fine-tuning strategy, a recombinant E. coli (pET28a-RBS-SSCRM2 /pACYCDuet-GDH), co-expressing SSCRM2 and glucose dehydrogenase, was constructed and optimized for protein expression. After optimizing the reaction conditions, whole-cell-catalyzed complete reduction of industrially relevant 300gL-1 of 3 was realized, affording (3S)-2 with 99% ee and a space-time yield of 519.1g∙L-1 ∙d-1 , representing the highest record for the biocatalytic synthesis of (3S)-2 reported to date. The E-factor of this biocatalytic synthesis was 24.5 (including water). Chiral alcohol (3S)-2 generated in this atom-economic synthesis was transformed to (2R,3S)-MPGM in 95% yield with 99% ee.

A directional coupler for partial discharge measurements in gas-insulated substations

This paper introduces a directional coupler for partial discharge (PD) measurements in gas-insulated substations (GIS). The sensor comprises a combination of magnetic and electric couplers, effectively segregating forward and backward pulses to enhance PD charge estimation and defect location. The sensor's design was supported with finite element method simulations and measurements conducted in a transverse electromagnetic test bench. Comparative analyses were performed against independent magnetic and electric couplers. The charge estimation and the directional coupler's directivity were evaluated in both the test bench and a full-scale GIS with different PD defects. Initially, the combined magnetic and the electric couplers exhibited undesired interactions, prompting corrective measures. Subsequent adjustments included changes to the electric coupler material and modifications to the magnetic coupler construction. The resulting high-voltage directional coupler performed better than the separated couplers in a GIS with discontinuities. This partial discharge sensor emerges as a candidate for future SF6-free alternative GIS.

Experimental and numerical study on RBCC engines performance in simultaneous and combustion cycle

The simultaneous mixing and combustion (SMC) cycle is a simple yet effective approach to augment the specific impulse of rocket-based combined cycle (RBCC) engines in ejector mode. However, the thrust performance of RBCC engines in the SMC cycle has not been adequately explored. This study investigates the effects of the flight Mach number, mixer shapes, and mixture ratio (MR) on the thrust performance of an axisymmetric kerosene-fueled RBCC engine. Ground free-suction experiments were conducted, employing a supersonic air ejector to simulate varying flight backpressures. Wall pressure distributions and axial thrusts were obtained. To eliminate undesirable interactions between MRs and backpressures inherent in experiments, numerical simulations were performed. The experimental results show that as flight Mach number increases, specific impulse improves rapidly, and specific impulse augmentation is achieved in the transonic regime. Simulations conducted at H4.0km/Mach0.88 with the expansion mixer reveal that as MR decreases, both mixing efficiency and combustion intensity increase. The balance between specific impulse gain from the secondary stream and loss from the primary stream is achieved at MR = 2.2, with the highest specific impulse being achieved at MR = 2.0. These insights provide valuable guidance for advancing the development of more efficient RBCC engines using the SMC cycle.