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Bulk or supported tungstophosphates? Antioxidant and antimicrobial activities following pesticide removal
No full textThe study evaluates caesium, potassium, silver, and zinc tungstophosphates synthesized in bulk and Y zeolite-supported forms through a two-step process. Spectral investigation reveals the impact of cation size on tungstophosphates formation. The large cations form ion-ion interaction with the Keggin ion, while smaller cations form hydrogen bonds between the cation hydration sphere and terminal oxygens in the Keggin ion. Supported salts formation proceeds without Keggin ion distortion. Zeta potential showed the absence of particle aggregation for caesium and potassium tungstophosphate. Nicosulfuron removal by the supported salt exhibits enhanced retention, with the exception observed for zinc tungstophosphate suggesting a decomposition mechanism. Antimicrobial evaluations reveal silver salt's potency, especially in zeolite-supported form, emphasizing the role of zeolite support. In the presence of pesticide molecules, the antimicrobial activity of salts lowers, with the exception seen for fungus strain. The antioxidant assessments demonstrate superior inhibition for insoluble bulk salts, with caesium tungstophosphate exhibiting the highest inhibition, while supported silver salt enhances bulk salt performance. The presence of pesticides affects both antimicrobial and antioxidant activities, while a complex relationship with radical scavenging ability in bulk and supported salts is independent of their pesticide adsorption capacities. The study broadens the range of the versatile applications of tungstophosphates, highlighting their specific interactions with pesticides and their impact on bioactivity and environmental remediation
Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis
Get PDFImportance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization. Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions. Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis. Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant. Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers. Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs. © This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine 1of1 Top of page Cited by 0 documents Inform me when this document is cited in Scopus: Related documents Find more related documents in Scopus based on: Authors Keyword
Facile and Low-Cost Electrochemical Synthesis of Zinc Alginate Hydrogel Films for Biomedical Applications
No full textElectrochemical synthesis and characterization of Zn-alginate hydrogel films and their antioxidant and antimicrobial activity are evaluated. Swelling properties, zinc concentration and spectroscopic and morphological features were characterized and related to their antimicrobial and antioxidant activity. These results indicate a dependence of swelling on the degree of cross-linking, which, in turn, can be adjusted by manipulating the synthesis time, initial alginate concentration and/or zinc leaching. Hydrogel films with zinc showed remarkable antibacterial properties, especially against gram-positive bacteria. The absence of Zn resulted in less inhibition of gram-positive strains, although it had a positive effect on the inhibition of gram-negative strains, which was attributed to the degradation of alginate chains, affecting cell metabolism. Nitrogen-doped samples synthesized in rivanol-containing solution exhibited globular morphology and higher antioxidant activity. The electrochemical synthesis enables the facile preparation of highly active alginate hydrogels for biomedical applications
Linamarin Binding to Human Serum Albumin. A Spectroscopic and Molecular Docking Approach
No full textThe interaction between linamarin (LIN), a cyanogenic glycoside, and human serum albumin (HSA) was studied by multiple spectroscopic techniques and molecular docking simulation. All measurements were performed under physiological conditions. The obtained results (including the binding constants, effective quenching constant and a number of binding sites) showed that the complex of HSA-LIN is formed. The values of Stern-Volmer constants (6.70×103, 5.53×103 and 1.95×103) indicate that fluorescence quenching of HSA was static. Results of site marker experiments showed that the binding site of LIN is mainly located in site I (subdomain IIA) of HSA. The thermodynamic parameters showed that binding process occurs spontaneously through hydrophobic interactions. Molecular docking results are in good agreement with experimental data. Furthermore, computational results revealed LIN binds in the cavity of TRP 214, that is, subdomain IIA (site I) of HSA. This comprehensive study provides a deeper insight into ligand binding in HSA which may be useful in drug design and pharmacology
Involvement of different K+ channel subtypes in hydrogen sulfide-induced vasorelaxation of human internal mammary artery
No full textBackground: Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)-mediated vasorelaxation is still unclear, and data about human vessels are limited. Objective: To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA). Results: NaHS (1 × 10−6–3 × 10−3 mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01). Conclusion: Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx.Peer-reviewed manuscript: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/5790
Planar chromatography (TLC/HPTLC) in the development and control of active pharmaceutical ingredients (APIs) and drug products (DPs)
No full textThin-Layer Chromatography (TLC) and its improved type High-Performance Thin-Layer
Chromatography (HPTLC), known as fundamental chemical methods for separation of non
volatile compounds in the complex mixture, are still very important tools in the pharmaceutical
chemistry for APIs and DPs research. Several adventages, such as simple instrumentation
and sample preparation, low cost and short time analyses give to those techniques signifcant
role in the very early reasearch and development of drugs, also in the control strategy of
the whole lifecycle of drug after marketing authorisation. TLC is still an ofcial method for
related substances in European Pharmacopoeia APIs monographs, and very often it is mandatory
test for second identifcation of API in APIs or DPs monographs. TLC is used in the
investigation of lipophilicity of newly synthesized drugs which determines its bioavailability.
It can be used in force degradation studies of API and DP for fast prediction of degradation
potential of API/DP and their stability. HPTLC hyphenated with some hybrid techniques
for detection (e.g. tandem mass spectrometry (MS/MS), Fourier Transform Infrared spectroscopy
(FTIR) etc.) is very useful for the very early identifcation of potential genotixic
impurities with structural alerts, which could be of toxicological concern. TLC can be used
in order to confrm some therapeutic efect (antioxidative, antifungal, аntibacterial charscteristics)
and to investigate drug metabolites in early pharmacokinetic studies. In the routine
analysis, planar chromatography could be used in enantioseparation of hiral compounds, assay
of API in APIs and DPs, determination of impurities in starting materials, intermediates
, reagents of the synthesis of API, also to determine purity of API and DP. TLC is used as in
process control in the synthesis of APIs in order to follow kinetic of reaction. Finally, after
all, TLC, specially HPTLC, has high green chemistry potential as considerably less quantity
of solvents are used compared to HPLC
In Vitro Evaluation of Pharmacokinetic Properties of Selected Dual COX-2 and 5-LOX Inhibitors
No full textEvaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds 1, 2, 3, 11, and 12, respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC k values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA –logPe values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC logk values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds 1, 2, 3, 11, and 12 will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07–58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%)
Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design
No full textBackground/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics—ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies
Cytotoxic and genotoxic potential of Achillea millefolium herb methanol and dichloromethane extracts
No full textCancer stands as the leading cause of mortality worldwide, and multidrug resistance represents a significant obstacle in treating
the disease, complicating effective treatment strategies. Today, research is shifting towards identifying new natural agents and
strategies due to the decreasing effectiveness of available drugs. Plants are promising sources of such agents because of their
broad biological activities and minimal side effects. Achillea millefolium L. (yarrow) is commonly used in both folk medicine and
modern phytotherapy. The aim of this study was to chemically characterise dried methanol and dichloromethane extracts of
yarrow flowering tops (herb) and provide information about their cytotoxicity and genotoxicity. Wild-growing yarrow herb was
collected in Serbia; the presence of sesquiterpene lactones in prazulenes was proved by an appropriate colour reaction according
to European Pharmacopeia. LC-MS analysis of the methanol extract revealed 28 caffeoylquinic acids and flavonoids. GC-FID and
GC-MS analysis showed that among phytosterols and triterpenes of dichloromethane extract, β-sitosterol and α-amyrin were the
most abundant. The cytotoxic effect of tested extracts on lung adenocarcinoma (A549), colorectal adenocarcinoma (HCT116),
and normal foetal fibroblast (MRC-5) cell lines was evaluated using the MTT test. The results highlight the dichloromethane
extract as the most potent against all tested cell lines, with the highest cell viability reduction seen on A549 cells (up to 94%). Both
tested extracts of yarrow demonstrated selective toxicity towards cancer cells compared to normal cells. Dichloromethane extract
exhibited the highest selectivity index value towards A549 cells (SI>3). Additionally, the genotoxicity was investigated through the
alkaline comet assay on all cell lines. These results revealed that both extracts induced damage to DNA at all tested concentrations
in a dose-dependent manner, with 23.9% as the highest observed tail intensity. Based on the obtained results, A. millefolium extracts
surface as potential candidates for novel anticancer therapeutics, although additional research into their underlying mechanisms is
required.
Supported by the Ministry of Science, Technological Development and Innovation of Republic of Serbia (Contracts No. 451-03-66/2024-03/200178,
451-03-65/2024-03/200178, 451-03-65/2024-03/200161 and 451-03-66/2024-03/200161).52nd European Environmental Mutagenesis and Genomics Society (EEMGS) & 15th International Comet Assay Workshops (ICAW) meeting, Rovinj, Croatia, 23rd – 27th September 2024, Abstract
Erectile Dysfunction Therapy of Bariatric Patients: Tadalafil Biopharmaceutics and Pharmacokinetics Before vs. After Gastric Sleeve/Bypass
No full textBariatric surgery introduces significant changes in the gastrointestinal tract, which may affect oral drug absorption/bioavailability. Here we investigate the phosphodiesterase-5 inhibitor (PDE5i) tadalafil for potentially impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in vitro in different pHs, and ex vivo in gastric content aspirated from patients pre/post-surgery. Dissolution was studied in conditions mimicking pre/post-surgery stomach. Finally, the experimental data were used in physiologically-based pharmacokinetic (PBPK) model (GastroPlus®) to simulate pre- vs. post-surgery tadalafil PK. Tadalafil demonstrated low and pH-independent solubility, both in vitro and ex vivo. Tadalafil release from all drug products and under all gastric conditions was incomplete, with particularly poor dissolution (2%) of the highest dose under post-bariatric conditions. PBPK simulations revealed altered tadalafil PK after gastric bypass—but not after sleeve gastrectomy—compared to unoperated individuals, with 44–48% decreased Cmax, 35–56% decreased AUC and 44% shorter Tmax. This mechanistic analysis suggests that tadalafil may be as effective after sleeve gastrectomy as before the procedure; meanwhile, results after gastric bypass raise concerns regarding the bioperformance of the drug. In addition, the drug's duration of action may be much shorter after gastric bypass. Thus, the effectiveness of tadalafil, widely regarded as the ‘weekend pill’, may be shorter than expected among gastric bypass patients. Graphical Abstract: (Figure presented.