The pharmaceutical and biotechnology industries are experiencing rapid and multidimensional evolution, driven by advances in chemistry, biologics, data analytics, formulation, as well as regulatory and ethical frameworks [...]
The objective of this study was to explore the protective effect of astragaloside IV on a model of isoproterenol-induced (ISO) hyper-trophic injury in rat cardiomyocytes H9c2 (cell line derived from embryonic BD1X rat heart tissue). A cell hypertrophy injury model was established (H9c2 cells treated with 100 μmol L–1 ISO). The cells were divided into normal control, a model group, and an astragalo-side IV group at several concentrations. Astragaloside IV was pre-administered for 2 hours, followed by ISO treatment for 24 hours. Cell viability, cell surface area, apoptosis rate, lactate dehydrogenase (LDH) activity, reactive oxygen species (ROS), superoxide dismutase (SOD), the mRNA levels of Bcl-2, Bax, p62, and LC3, the protein expressions of Sirt1, p62, caspase-3, beclin, and p53 and the LC3II/LC3I ratio were detected. Astragaloside IV significantly alleviated ISO-induced hypertrophy injury in H9c2 cells, reduced cell surface area and LDH release, decreased apoptosis rate and intracellular ROS levels, increased SOD levels, upregulated the expressions of autophagy-related mRNA and proteins, and downregulated the expressions of apoptosis-related mRNA and proteins. Astragaloside IV can effectively inhibit ISO-induced hypertrophy and apoptosis in H9c2 cells, and its mechanism may be related to promoting auto-phagy and reducing oxidative stress.
Al-Shadidi JRMH, Al-Shammari S, Al-Mutairi D
et al.
Jafar RMH Al-Shadidi,1 Shahad Al-Shammari,1 Danah Al-Mutairi,1 Dalal Alkhudhair,1 Hnin Ei Thu,2 Zahid Hussain1,3 1Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; 2Department of Pharmacology, Faculty of Dentistry, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor Branch, Selangor, Malaysia; 3Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab EmiratesCorrespondence: Zahid Hussain, Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates, Email zhussain@sharjah.ac.aeAbstract: Despite all major advancements in drug discovery and development in the pharmaceutical industry, cancer is still one of the most arduous challenges for the scientific community. The implications of nanotechnology have certainly resolved major issues related to conventional anticancer modalities; however, the undesired recognition of nanoparticles (NPs) by the mononuclear phagocyte system (MPS), their poor stability in biological fluids, premature release of payload, and low biocompatibility have restricted their clinical translation. In recent decades, chitosan (CS)-based nanodelivery systems (eg, polymeric NPs, micelles, liposomes, dendrimers, conjugates, solid lipid nanoparticles, etc.) have attained promising recognition from researchers for improving the pharmacokinetics and pharmacodynamics of chemotherapeutics. However, the specialty of this review is to mainly focus on and critically discuss the targeting potential of various CS-based NPs for treatment of different types of cancer. Based on their delivery mechanisms, we classified CS-based NPs into stimuli-responsive, passive, or active targeting nanosystems. Moreover, various functionalization strategies (eg, grafting with polyethylene glycol (PEG), hydrophobic substitution, tethering of stimuli-responsive linkers, and conjugation of targeting ligands) adapted to the architecture of CS-NPs for target-specific delivery of chemotherapeutics have also been considered. Nevertheless, CS-NPs based therapeutics hold great promise for improving therapeutic outcomes while mitigating the off-target effects of chemotherapeutics, a long-term safety profile and clinical testing in humans are warranted for their successful clinical translation.Keywords: chitosan nanoparticles, targeted cancer therapy, tumor microenvironment, stimuli-responsive targeting, passive targeting, active targeting
AGBOKPONTO Engelbert, DAOUDA Mohamed M. Arêmou, POKOU Aurelle
et al.
L’eau est un produit vital pour l’Homme, mais également une source de nombreuses maladies hydriques. Au Bénin, avec les changements de mode de vie, le conditionnement de l'eau s'est rapidement répandu, avec de nombreuses unités de production qui échappent au contrôle sanitaire des autorités mettant en danger la santé des consommateurs. Au total 70 unités de production dont 64 d’ensachage d’eau et 6 de mise en bouteilles d’eau dans 4 départements du sud du Bénin ont été inspectées et des échantillons de lot issu de production récente ont été prélevés pour des tests physicochimiques et microbiologiques. De l’analyse des résultats, il ressort des risques de contamination notés à l'inspection sanitaire notamment : l’absence de filtres à charbon obligatoires (64,1%) et de lampe UV (42,2%), la présence de fuite d’eau (14,1%) sur le circuit de production d’eau en sachet ainsi que le manque d’hygiène (34,4%). Les analyses de laboratoire quant à elles ont rapporté que le pH des échantillons d’eau variait entre 3,94 et 7,74 avec 48,57% de non-conformité (norme pH : 6,5-8,5). Les tests microbiologiques ont mis en évidence une contamination des eaux conditionnées par des germes banals (64,1% ; n=47), des présumés coliformes (7,1% ; n=5) et Escherichia coli (1,4% ; n=1). Cette mauvaise qualité microbiologique concerne aussi bien les échantillons d’eau conditionnée en sachet (n=44 sur 64) que les échantillons d’eau en bouteille (n=3 sur 6). Ces résultats montrent la nécessité de renforcer le suivi des installations de conditionnement d'eau afin d'assurer la sécurité sanitaire des consommateurs.
El Hadi Erbiai, Abdelfettah Maouni, Luís Pinto da Silva
et al.
Mushrooms have been consumed for centuries and have recently gained more popularity as an important source of nutritional and pharmaceutical compounds. As part of the valorization of mushroom species in northern Morocco, the current study aimed to investigate the chemical compositions and antioxidant properties of two wild edible mushrooms, <i>Paralepista flaccida</i> and <i>Lepista nuda</i>. Herein, the bioactive compounds were determined using spectrophotometer methods, and results showed that the value of total phenolic content (TPC) was found to be higher in <i>P. flaccida</i> (32.86 ± 0.52 mg) than in <i>L. nuda</i> (25.52 ± 0.56 mg of gallic acid equivalents (GAEs)/mg of dry methanolic extract (dme)). On the other hand, the value of total flavonoid content (TFC) was greater in <i>L. nuda</i> than in <i>P. flaccida</i>, with values of 19.02 ± 0.80 and 10.34 ± 0.60 mg of (+)-catechin equivalents (CEs)/g dme, respectively. Moreover, the ascorbic acid, tannin, and carotenoids content was moderate, with a non-significant difference between the two samples. High-performance liquid chromatography–mass spectrometry (HPLC-MS) analysis allowed the identification and quantification of thirteen individual phenolic compounds in both <i>P. flaccida</i> and <i>L. nuda</i>, whereas <i>p</i>-Hydroxybenzoic acid was recognized as the major compound detected, with values of 138.50 ± 1.58 and 587.90 ± 4.89 µg/g of dry weight (dw), respectively. The gas chromatography–mass spectrometry (GC-MS) analysis of methanolic extracts of <i>P. flaccida</i> and <i>L. nuda</i> revealed the presence of sixty-one and sixty-six biomolecules, respectively. These biomolecules can mainly be divided into four main groups, namely sugars, amino acids, fatty acids, and organic acids. Moreover, glycerol (12.42%) and mannitol (10.39%) were observed to be the main chemical compositions of <i>P. flaccida</i>, while <i>L. nuda</i> was predominated by linolelaidic acid (21.13%) and leucine (9.05%). <i>L. nuda</i> showed a strong antioxidant property, evaluated by DPPH (half maximal effective concentration (EC<sub>50</sub>) 1.18–0.98 mg/mL); β-carotene bleaching (EC<sub>50</sub> 0.22–0.39 mg/mL); and reducing power methods (EC<sub>50</sub> 0.63–0.48 mg/mL), respectively. These findings suggested that both mushrooms are potential sources of various biomolecules, many of which possess important biological activities which are interesting for the foods and pharmaceuticals industry.
Dominika Gyuranová, Radka Štadániová, Zuzana Hegyi
et al.
Styrene monooxygenases are a group of highly selective enzymes able to catalyse the epoxidation of alkenes to corresponding chiral epoxides in excellent enantiopurity. Chiral compounds containing oxirane ring or products of their hydrolysis represent key building blocks and precursors in organic synthesis in the pharmaceutical industry, and many of them are produced on an industrial scale. Two-component recombinant styrene monooxygenase (SMO) from <i>Marinobacterium litorale</i> was expressed as a fused protein (StyAL2StyB) in <i>Escherichia coli</i> BL21(DE3). By high cell density fermentation, 35 g<sub>DCW</sub>/L of biomass with overexpressed SMO was produced. SMO exhibited excellent stability, broad substrate specificity, and enantioselectivity, as it remained active for months and converted a group of alkenes to corresponding chiral epoxides in high enantiomeric excess (˃95–99% ee). Optically pure (<i>S</i>)-4-chlorostyrene oxide, (<i>S</i>)-allylbenzene oxide, (2<i>R</i>,5<i>R</i>)-1,2:5,6-diepoxyhexane, 2-(3-bromopropyl)oxirane, and (<i>S</i>)-4-(oxiran-2-yl)butan-1-ol were prepared by whole-cell SMO.
Abstract Motivation Ether-a-go-go-related gene (hERG) channel blockade by small molecules is a big concern during drug development in the pharmaceutical industry. Blockade of hERG channels may cause prolonged QT intervals that potentially could lead to cardiotoxicity. Various in-silico techniques including deep learning models are widely used to screen out small molecules with potential hERG related toxicity. Most of the published deep learning methods utilize a single type of features which might restrict their performance. Methods based on more than one type of features such as DeepHIT struggle with the aggregation of extracted information. DeepHIT shows better performance when evaluated against one or two accuracy metrics such as negative predictive value (NPV) and sensitivity (SEN) but struggle when evaluated against others such as Matthew correlation coefficient (MCC), accuracy (ACC), positive predictive value (PPV) and specificity (SPE). Therefore, there is a need for a method that can efficiently aggregate information gathered from models based on different chemical representations and boost hERG toxicity prediction over a range of performance metrics. Results In this paper, we propose a deep learning framework based on step-wise training to predict hERG channel blocking activity of small molecules. Our approach utilizes five individual deep learning base models with their respective base features and a separate neural network to combine the outputs of the five base models. By using three external independent test sets with potency activity of IC50 at a threshold of 10 $$\upmu$$ μ m, our method achieves better performance for a combination of classification metrics. We also investigate the effective aggregation of chemical information extracted for robust hERG activity prediction. In summary, CardioTox net can serve as a robust tool for screening small molecules for hERG channel blockade in drug discovery pipelines and performs better than previously reported methods on a range of classification metrics.
Pseudomonas aeruginosa is a common opportunistic pathogen that causes acute nosocomial necrotizing pneumonia and is the predominant source of chronic lung infections in patients with the genetic disorder cystic fibrosis. Early diagnosis in infected patients and monitoring P. aeruginosa contamination is therefore of great importance in controlling disease spread and development with timely drugs intervention treatment and cut off infection source. Traditional culture-biochemical methods are time consuming and highly dependent on technicians and expensive instruments. To address these challenges, the present study aimed to develop a rapid, sensitive, and specific, on-site detection method for P. aeruginosa based on recombinase polymerase amplification (RPA) combined with lateral flow strip (LFS) technology. The experimental process included screening and modification of primer and probe sets targeting the unique virulence gene elastase B (lasB); specificity detection in 29 strains of P. aeruginosa and 23 closely-related pathogenic bacteria; sensitivity measurements with gradient-diluted P. aeruginosa genomic DNA and probit regression analysis; and clinical application evaluation using 574 patients samples and calculating coincidence rate and kappa index value in comparison with the culture-biochemical method. The P. aeruginosa RPA-LFS assay could complete the amplification process at 37°C constant temperature within 30 min and results could be visualized by the naked eye within 10 min on LFS. The assay displayed high sensitivity with a limit of detection of 3.05 CFU/reaction. It also demonstrated high specificity by showing no cross reaction with other pathogenic bacteria, and rapidness by being completed in less than an hour. Furthermore, when used with clinical samples, the assay had a coincidence rate of 98.26% with the culture-biochemical method and a kappa index value of 0.9433. These data indicate that the RPA-LFS assay represents a major improvement for P. aeruginosa detection, especially in resource-limited areas.
The objective of this article is to characterize and analyze the risk-sharing agreements proposed by the pharmaceutical industry to achieve coverage under the Financial Protection System for High Cost Diagnostics and Treatments in Chile (Ricarte Soto Law). Through a review of the literature on the subject, a taxonomy of risk-sharing agreements was elaborated, identifying the advantages and disadvantages of each type from the perspective of public health policies. Findings show that most of the offers received considered financial agreements, mainly price discounts. To a lesser extent, bonification and portfolio discount also stand out for their frequency. It is important to note that the case analyzed is one of the first formal experiences of requesting risk-sharing agreements in the Chilean public health sector. However, the design and implementation of these contracts require a more proactive role of the public buyer. This demands the development of skills and infrastructure in the public health sector that allow the measurement of the performance of health technologies in practice.
Political institutions and public administration (General)
Çevik Ulviye Acar, Osmaniye Derya, Levent Serkan
et al.
The synthesis of new N-(5-substituted-1,3,4-thiadiazol-2-yl)-2-[(5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives and investigation of their anticancer activities were the aims of this work. All the new compounds’ structures were elucidated by elemental analyses, IR, 1H NMR, 13C NMR and MS spectral data. Anticancer activity studies of the compounds were evaluated against MCF-7 and A549 tumor cell lines. In addition, with the purpose of determining the selectivity of cytotoxic activities, the most active compound was screened against a noncancer NIH3T3 cell line (mouse embryonic fibroblast cells). Among the tested compounds, compound 4y (N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide), showed promising cytotoxic activity against MCF7 cancer cell with an IC50value of 0.084 ± 0.020 mmol L−1 and against A549 cancer cell with IC50 value of 0.034 ± 0.008 mmol L−1, compared with cisplatin. The aromatase inhibitory activity was evaluated for compound 4y on MCF-7 cell line showing promising activity with IC50 of 0.062 ± 0.004 mmol L−1.
The article provides an overview of the current state of the use of TRIZ in the pharmaceutical industry and our R&D efforts in that area, based on TRIZ and computer mathematical modeling. Drug development is one of the most important research areas, which affects almost every family, and each one of us. However, nobody in the world has used TRIZ as a philosophy of solving problems in such important area as pharmaceutical research and development to develop new efficient medical drugs. The application of the principles of TRIZ in this arena opens up broad prospects in the creation of new classes of drugs that can independently adapt to the patient's body. The combination of contradictions, laws of development systems, algorithms, Su-field analysis, TRIZ principles, deep fundamentals of pharmaceutical industry and pharmacology, modern computer mathematical modeling, in the solution of each of the tasks at once, allows us to achieve extraordinary results and obtain significantly more effective novel drugs. For the first time in the World we have developed dynamic self-organizing, quasi live drugs, based on the principles of TRIZ and computerized mathematical modeling. These are drugs capable of adapting independently both to the human body and to molecular targets, including viruses, cancer cells and microorganisms. We have created 17 new projects, however, in this article we illustrate just 6 examples from our research and developments: 1. Novel directions to fight multidrug resistant microorganisms. 2. Polymyxin with reduced nephrotoxicity. 3. Dynamic drugs: Dynamic insulin. 4. Dynamic drugs: The dynamic anticancer drug Target-R to treat different cancers. 5. Dynamic drugs: Dynamic antiviral drug Albuvir. 6. Dynamic drugs: Hemostatic Gemma. Applying TRIZ and mathematical modeling in pharmaceutical industry, produces novel and future R&D trends. The proposed new paradigm of combating infectious diseases using TRIZ led to the creation of a unique pharmaceutical composition. The molecular modeling approach led to the intensification of research and for synthesis of drugs based on simulated inhibitor profiles. This increased the yield of novel dynamic drugs. The dynamic drugs can overcome many problems from resistance to the slippage effect, to eliminate the side effects of drugs. This will save millions of lives. We deeply integrated TRIZ and computer mathematical modeling in our R&D. In addition, our approach includes the application of the laws of quantum physics and quantum chemistry; additionally, knowledge of the behavior of molecules in different solutions and their interaction with each other at different temperatures, in the presence of salts and other compounds. Really effective drugs can be developed only on the basis of a systematic approach and in-depth knowledge in the fields of medical, pharmaceutical physical chemistry, analytical chemistry and pharmacognosy, chemistry of natural compounds, plant medicine technology, biochemistry and molecular biology, pharmacology and many other disciplines. Modeling these processes requires a large amount of not only computer time, but also knowledge in a number of broad areas: from quantum physics and chemistry to synthetic organic chemistry, in order to synthesize engineered substances. Despite changes in the concept of drug development: from banal screening (out of thousands of synthesized compounds, only one showed biological activity) to those obtained as a result of molecular modeling (another name is drug-design). (named as drug-design). The approach with the use of molecular modeling led to the intensification of research - to the synthesis of drugs based on simulated inhibitor profiles. This increased the yield of drugs - out of every hundreds of the synthesized substances, one showed the expected activity. The cost of pharmaceutical development software is currently quite high and can even reach tens of millions of dollars. But this is a reasonable amount, which makes it possible to obtain the required pharmaceutical preparations, at least for known target proteins. However, for the design of drugs of new generations at all stages of development - from building a model of a target protein to creating a drug profile and its synthesis, TRIZ has not been used systematically. Pharmaceutical industry is a huge area to be explored by TRIZ.
The development of new and improvement of existing methods for determining antioxidant activity is an urgent task of pharmacy, cosmetic and food industries. In the present work, the systematization and analysis of methods for determining antioxidant activity have been carried out, which have found the widest application and are described in the domestic literature. The most widely used electro-chemical and spectrophotometric methods of analysis. Today there is no method that would give complete information about the state and interactions of complex systems in which antioxidants are formed and enter into the reaction. There is also no single term that would determine the antioxidant properties of the compound. All existing methods for determining antioxidant activity suffer from one or other of the following drawbacks. It should be noted the objective impossibility of existence is not that of a single method, but even the possibility of comparing the results obtained by different methods. Therefore, each researcher, based on his goals and capabilities, chooses the ready, creates a new one, modifies an already known method, or often resorts to the study of the antioxidant activity of the studied object using a set of different methods.
Agustín Estrada-Peña, Matías Szabó, Marcelo Labruna
et al.
Ticks and transmitted pathogens constitute a major burden for cattle industry in the Neotropics. To address this limitation, the Spanish Ibero-American Program of Science and Technology in Development office (CYTED) supported from 2018 a network of scientists named “LaGar” (CYTED code 118RT0542) aimed at optimizing the control strategies of cattle ticks in the neotropical region. As part of network activities, a meeting and course were organized on 4−8 November 2019 in Querétaro, Mexico to address the objective of developing the infrastructure necessary for an effective, sustainable (i.e., combination of efficacious acaricides with anti-tick vaccines) and rational (i.e., considering tick ecology, seasonal dynamics and cattle-wildlife interactions) control of cattle tick infestations and transmitted pathogens. The course was focused on scientists, students, cattle holders and producers and pharmaceutical/industry representatives. In this way the course addressed the different views presented by participants with the conclusion of producing a research-driven combination of different interventions for the control of tick tick-borne diseases.
Sílvia Regina Pengo Machado, Raul Cesar Evangelista
Nanoparticles containing cefoxitin (CEF) made of D,L-PLA (PLA) were designed by a multiple emulsion/solvent evaporation method. The particles were extensively evaluated in relation to morphology, encapsulation efficiency, drug-polymer interactions as well as in vitro drug release kinetics. Nanoparticles were spherical in shape and isolated, with a mean diameter of about 600 nm. The thermal behaviour (DSC) of CEF-containing nanoparticles suggested that the drug was dispersed at a molecular level within the system. The drug encapsulation efficiency in the system for a CEF concentration of 30 mg/mL was 5.5%, as assessed after the drug extraction, by a validated HPLC method. This low encapsulation efficiency is understandable, since CEF is highly hydrophilic. The in vitro assays showed a strong sustained drug release profile from the nanoparticles with kinetics following pure Fickian diffusion. Keywords: Nanoparticles. Controlled release. D,L-PLA. Cefoxitin. In vitro release. RESUMO Desenvolvimento e Caracterização de Nanopartículas de D,L-PLA contendo Cefoxitina As nanopartículas de D, L-PLA (PLA) contendo cefoxitina (CEF) foram preparadas pelo método de emulsão múltipla / evaporação do solvente. As partículas foram avaliadas em relação à morfologia, à eficiência de encapsulação, às interações polímero-fármaco, bem como à cinética de liberação do fármaco in vitro . As nanopartículas são esféricas e isoladas, com um diâmetro médio de cerca de 600 nm. O comportamento térmico (DSC) das nanopartículas contendo CEF sugeriu que o fármaco está disperso em um nível molecular dentro do sistema. A eficiência de encapsulação do fármaco no sistema quando a concentração de CEF é 30 mg / mL foi de 5,5%, determinada após a extração de fármaco, através de um método de HPLC validado. Esta baixa eficiência de encapsulação é compreensível, uma vez que a CEF é altamente hidrofílica. Os ensaios in vitro mostraram um perfil de liberação do fármaco a partir das nanopartículas fortemente sustentado e com uma cinética de difusão Fickiana pura. Palavras-chave: Nanopartículas. Liberação controlada. D,L-PLA. Cefoxitina. Liberação In vitro.
Pharmaceutical industry, Pharmacy and materia medica