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1.
Front Public Health ; 8: 308, 2020.
Article in English | MEDLINE | ID: mdl-32903646

ABSTRACT

Objective: Medical device development, from the product's conception to release to market, is very complex and relies significantly on the application of exact processes. This paper aims to provide an analysis and summary of current research in the field of medical device development methodologies, discuss its phases, and evaluate the associated legislative and risk aspects. Methods: The literature search was conducted to detect peer-reviewed studies in Scopus, Web of Science, and Science Direct, on content published between 2007 and November 2019. Based on exclusion and inclusion criteria, 13 papers were included in the first session and 11 were included in the second session. Thus, a total of 24 papers were analyzed. Most of the publications originated in the United States (7 out of 24). Results: The medical device development process comprises one to seven stages. Six studies also contain a model of the medical device development process for all stages or for just some of the stages. These studies specifically describe the concept stage during which all uncertainties, such as the clinical need definition, customer requirements/needs, finances, reimbursement strategy, team selection, and legal aspects, must be considered. Conclusion: The crucial factor in healthcare safety is the stability of factors over a long production time. Good manufacturing practices cannot be tested on individual batches of products; they must be inherently built into the manufacturing process. The key issues that must be addressed in the future are the consistency in the classification of devices throughout the EU and globally, and the transparency of approval processes.


Subject(s)
Commerce , Delivery of Health Care , United States
2.
Eur J Med Chem ; 146: 38-46, 2018 Feb 25.
Article in English | MEDLINE | ID: mdl-29407964

ABSTRACT

The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.


Subject(s)
Computer Simulation , Drug Design , Small Molecule Libraries/pharmacology , Toll-Like Receptor 4/antagonists & inhibitors , Cell Line , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
3.
Molecules ; 23(1)2018 Jan 04.
Article in English | MEDLINE | ID: mdl-29300367

ABSTRACT

In order to identify novel lead structures for human toll-like receptor 4 (hTLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the hTLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate hTLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.


Subject(s)
Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , High-Throughput Screening Assays/methods , Structure-Activity Relationship , Toll-Like Receptor 4/agonists , Adjuvants, Immunologic/metabolism , Animals , Binding Sites , CHO Cells , Computer Simulation , Cricetulus , Humans , Inhibitory Concentration 50 , Interleukin-6/blood , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Surface Plasmon Resonance , Toll-Like Receptor 4/metabolism , Tryptamines/chemistry , Vaccines
4.
Mini Rev Med Chem ; 17(5): 451-466, 2017.
Article in English | MEDLINE | ID: mdl-27488583

ABSTRACT

Vaccination is defined as the administration of an antigenic material in order to stimulate the immune system, leading to the development of adaptive immunity to a pathogen. Vaccines can prevent or reduce morbidity from a vast number of infections. This manuscript presents an analysis of vaccine types and vaccine substances, concentrating on individual components including the active ingredient, adjuvants, preservatives, stabilizers, inactivators, antibiotics, diluents and other substances. While many papers have been published on individual vaccine components, this review provides detail on a wide range of the most commonly-used vaccine ingredients and components that have been tested in clinical trials.


Subject(s)
Vaccines/chemistry , Vaccines/immunology , Adjuvants, Immunologic , Antigens/immunology , Humans , Immune System/immunology , Molecular Structure , Vaccination
5.
Eur J Med Chem ; 121: 699-711, 2016 Oct 04.
Article in English | MEDLINE | ID: mdl-27341309

ABSTRACT

In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Molecular Dynamics Simulation , Pyridines/chemistry , Pyridines/pharmacology , Quantitative Structure-Activity Relationship , Animals , Anti-Bacterial Agents/toxicity , Bacteria/drug effects , CHO Cells , Cell Survival/drug effects , Cricetinae , Cricetulus , Fungi/drug effects , Hydrophobic and Hydrophilic Interactions , Molecular Conformation , Pyridines/toxicity
6.
Bioorg Med Chem ; 24(4): 841-8, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26774252

ABSTRACT

In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Isoquinolines/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Fungi/drug effects , Fungi/growth & development , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Isoquinolines/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Quantum Theory , Structure-Activity Relationship
7.
Curr Med Chem ; 22(29): 3306-25, 2015.
Article in English | MEDLINE | ID: mdl-26295466

ABSTRACT

Toll like receptors (TLRs) are a family of transmembrane proteins which play a key role in innate immunity. When TLRs come into contact with a potential threat, they initiate a signaling cascade leading to release of cytokines and chemokines, maturation of antigen presenting cells and immune activation. Molecules which can activate TLRs may be utilized for vaccine development and act as vaccine adjuvants. Adjuvants can facilitate production of more effective vaccines based on antigens produced by recombinant techniques or by DNA vaccines, which are often poorly immunogenic since they lack the endogenous innate immunostimulatory components of the pathogen. In this paper the structural properties of such prospective compounds are thoroughly discussed.


Subject(s)
Adjuvants, Immunologic/pharmacology , Toll-Like Receptors/agonists , Vaccines, Synthetic/pharmacology , Adjuvants, Immunologic/chemistry , Animals , Humans , Molecular Structure , Structure-Activity Relationship , Toll-Like Receptors/metabolism , Vaccines, Synthetic/chemistry
8.
J Mol Graph Model ; 56: 113-29, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25588616

ABSTRACT

To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds.


Subject(s)
Chemical Warfare Agents/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Reactivators/chemistry , Organothiophosphorus Compounds/chemistry , Oximes/chemistry , Pyridinium Compounds/chemistry , Acetylcholinesterase/chemistry , Animals , Enzyme Activation , GPI-Linked Proteins/agonists , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/chemistry , Kinetics , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Quantitative Structure-Activity Relationship , Quantum Theory , Rats , Thermodynamics
9.
Bioorg Med Chem Lett ; 24(22): 5238-41, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25442318

ABSTRACT

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C10 to C18) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.


Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Quinolinium Compounds/chemistry , Quinolinium Compounds/chemical synthesis , Animals , Anti-Infective Agents/chemistry , CHO Cells , Cell Survival/drug effects , Cricetinae , Cricetulus , Microbial Sensitivity Tests , Quaternary Ammonium Compounds/chemistry , Quinolinium Compounds/pharmacology , Quinolinium Compounds/toxicity , Salts/chemistry
10.
J Sep Sci ; 36(4): 729-35, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23401390

ABSTRACT

A novel transient ITP-CZE for preconcentration and determination of seven phenolic acids (caffeic acid, cinnamic acid, p-coumaric acid, ferulic acid, protocatechuic acid, syringic acid, and vanilic acid) was developed and validated. Effects of several factors such as control of EOF, pH and buffer concentration, addition of organic solvents and CDs, and conditions for sample injection were investigated. Sample self-stacking was applied by means of induction of transient ITP, which was realized by adding sodium chloride into the sample. The CZE was realized in 200 mM borate buffer ((w)(s)pH 9.2) containing 37.5% methanol, 0.001% hexadimethrine bromide, and 15 mM 2-hydroxypropyl-ß-CD. Under the optimal conditions for analysis, analytes were separated within 20 min. Linearity was tested for each compound in the concentration range of 0.1-10 µg/mL (R = 0.9906-0.9968) and the detection limits (S/N = 3) ranged from 11 ng/mL (protocatechuic acid) to 31 µg/mL (syringic acid). The validated method was applied to the ethanolic extract of Epilobium parviflorum, Onagraceae. The method of SPE was used for the precleaning of the sample.


Subject(s)
Electrophoresis, Capillary/methods , Epilobium/chemistry , Hydroxybenzoates/analysis , Isotachophoresis/methods , Onagraceae/chemistry , Plant Extracts/analysis
11.
J Chromatogr A ; 1171(1-2): 124-32, 2007 Nov 09.
Article in English | MEDLINE | ID: mdl-17920611

ABSTRACT

A method utilising isotachophoresis and capillary zone electrophoresis in the column coupling configuration with UV detection at 320 nm was developed for separation and determination of five phenolic acids (rosmarinic, p-coumaric, ferulic, caffeic and chlorogenic) and flavonoid quercitrin in a methanolic extract of Melissae herba. The proposed method has been validated with correlation coefficients from 0.9842 to 0.9988, RSD values between 0.39% and 0.83% for migration times and between 0.40% and 2.05% for peak areas.


Subject(s)
Antioxidants/analysis , Electrophoresis, Capillary/instrumentation , Electrophoresis/instrumentation , Melissa/chemistry , Plant Extracts/analysis , Specimen Handling/instrumentation , Antioxidants/chemistry , Electrophoresis/methods , Electrophoresis, Capillary/methods , Flavonoids/analysis , Hydrogen-Ion Concentration , Hydroxybenzoates/analysis , Methanol/chemistry , Reproducibility of Results , Sensitivity and Specificity , Specimen Handling/methods , Spectrophotometry, Ultraviolet
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