RESUMO
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.
Assuntos
Comércio , Atenção à Saúde , Estados UnidosRESUMO
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 130â¯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.
Assuntos
Simulação por Computador , Desenho de Fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Relação Estrutura-Atividade , Receptor 4 Toll-Like/agonistas , Adjuvantes Imunológicos/metabolismo , Animais , Sítios de Ligação , Células CHO , Simulação por Computador , Cricetulus , Humanos , Concentração Inibidora 50 , Interleucina-6/sangue , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ressonância de Plasmônio de Superfície , Receptor 4 Toll-Like/metabolismo , Triptaminas/química , VacinasRESUMO
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.
Assuntos
Vacinas/química , Vacinas/imunologia , Adjuvantes Imunológicos , Antígenos/imunologia , Humanos , Sistema Imunitário/imunologia , Estrutura Molecular , VacinaçãoRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Simulação de Dinâmica Molecular , Piridinas/química , Piridinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Animais , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Fungos/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Piridinas/toxicidadeRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Isoquinolinas/síntese química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Isoquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Adjuvantes Imunológicos/farmacologia , Receptores Toll-Like/agonistas , Vacinas Sintéticas/farmacologia , Adjuvantes Imunológicos/química , Animais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Receptores Toll-Like/metabolismo , Vacinas Sintéticas/químicaRESUMO
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.
Assuntos
Substâncias para a Guerra Química/química , Inibidores da Colinesterase/química , Reativadores da Colinesterase/química , Compostos Organotiofosforados/química , Oximas/química , Compostos de Piridínio/química , Acetilcolinesterase/química , Animais , Ativação Enzimática , Proteínas Ligadas por GPI/agonistas , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Teoria Quântica , Ratos , TermodinâmicaRESUMO
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.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos de Quinolínio/química , Compostos de Quinolínio/síntese química , Animais , Anti-Infecciosos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , Testes de Sensibilidade Microbiana , Compostos de Amônio Quaternário/química , Compostos de Quinolínio/farmacologia , Compostos de Quinolínio/toxicidade , Sais/químicaRESUMO
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.
Assuntos
Eletroforese Capilar/métodos , Epilobium/química , Hidroxibenzoatos/análise , Isotacoforese/métodos , Onagraceae/química , Extratos Vegetais/análiseRESUMO
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.