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Docking studies of some pyrazole containing compounds in the cyclooxygenase-2 active site 含吡唑类化合物在环氧合酶-2活性位点的对接研究
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-44720
J. Savić, Marija Antonijević, Milkica Crevar, J. Brborić
Whereas nonselective nonsteroidal anti-inflammatory drugs, such as aspirin, ibuprofen and diclofenac, inhibit both cyclooxygenase-1 and cyclooxigenase-2 enzymes, selective inhibitors target cyclooxygenase-2, which is overexpressed in inflammation, but also in cancer, atherosclerosis, Alzheimer's disease, and Parkinson's disease. Potential cardiovascular and hepatic side effects of cyclooxygenase-2 inhibitors have limited their use. The development of selective and safe cyclooxygenase-2 inhibitors remains a high priority in drug discovery. Based on the structure of previously investigated newly synthesized b-hydroxy-b-arylpropanoic acids, two groups of compounds were designed: analogs in which one of the benzene rings was replaced by a pyrazole, while the carboxyl group was retained, and amides of b-hydroxy-b-arylpropanoic acids with pyrazole. The compounds were docked into the 3D structure of the catalytic site of the enzyme cyclooxygenase-2 using AutoDock Vina 1.2.0. and the obtained interactions were compared with the interactions of celecoxib, a selective inhibitor. The amides had lower binding energies than the designed acids, which makes them attractive target compounds for synthesis and further examination.
非选择性非甾体类抗炎药,如阿司匹林、布洛芬和双氯芬酸,抑制环氧化酶-1和环氧化酶-2酶,选择性抑制剂靶向环氧化酶-2,它在炎症中过度表达,但也在癌症、动脉粥样硬化、阿尔茨海默病和帕金森病中表达。环氧化酶-2抑制剂潜在的心血管和肝脏副作用限制了它们的使用。选择性和安全的环氧化酶-2抑制剂的开发仍然是药物发现的重中之重。根据已有研究的新合成的b-羟基-b-芳基丙烷酸的结构,设计了两组化合物:苯环被吡唑取代而羧基保留的类似物和吡唑酰胺。使用AutoDock Vina 1.2.0将化合物对接到酶环氧化酶-2的催化位点的3D结构中。并将得到的相互作用与选择性抑制剂塞来昔布的相互作用进行比较。酰胺的结合能比所设计的酸低,这使它们成为有吸引力的合成和进一步研究的目标化合物。
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引用次数: 0
Dietary interventions through supplementation with antioxidant compounds 通过补充抗氧化化合物的饮食干预
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-45141
V. Todorović, B. Đorđević
Dietary supplements (DS) are manufactured products consisting of one or more dietary ingredients; they are intended to supplement the diet and provide additional nutrients or other beneficial compounds that are lacking or insufficient in a regular diet. Dietary supplements containing antioxidant compounds have been shown to have positive effects in various (pato)physiological processes, i.e., any condition that is fundamentally redox imbalanced (cardiovascular diseases, cancer, aging, intense exercise). The most common antioxidants in dietary supplements are clearly antioxidant micronutrients such as vitamin C, vitamin E, zinc, and selenium, but also various secondary plant compounds, including polyphenols and carotenoids. The dosage of antioxidants administered through dietary supplements may not always be optimal, so some dietary interventions through supplementation with antioxidant compounds have been shown to have an effect that it is limited, or completely absent. Therefore, any dietary supplementation should be done only under appropriate guidance from health care professionals to ensure that it is safe, effective, and appropriate for the individual's condition and needs.
膳食补充剂是由一种或多种膳食成分组成的制成品;它们的目的是补充饮食,并提供常规饮食中缺乏或不足的额外营养素或其他有益化合物。含有抗氧化化合物的膳食补充剂已被证明在各种(pato)生理过程中具有积极作用,即在任何根本上氧化还原不平衡的情况下(心血管疾病、癌症、衰老、剧烈运动)。膳食补充剂中最常见的抗氧化剂显然是抗氧化剂微量营养素,如维生素C、维生素E、锌和硒,还有各种次生植物化合物,包括多酚类和类胡萝卜素。通过膳食补充剂给予的抗氧化剂剂量可能并不总是最佳的,因此一些通过补充抗氧化剂化合物的饮食干预已被证明具有有限的效果,或完全没有效果。因此,任何膳食补充剂都应该在卫生保健专业人员的适当指导下进行,以确保它是安全、有效的,并且适合个人的状况和需求。
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引用次数: 0
Methods for the determination of antioxidant activity of plant extracts in vitro 植物提取物体外抗氧化活性的测定方法
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-38573
J. Kukić-Marković
Plants are rich sources of secondary metabolites that exhibit diverse biological and pharmacological effects. Some plant ingredients, primarily phenolics, have significant in vitro antioxidant activity, which implies their contribution to the maintenance of redox balance in the body. These potential antioxidant agents are structurally very diverse, having different mechanisms of antioxidant activity. Since there is a growing necessity to detect, develop and understand effective antioxidant compounds, interest in the identification and the measurement of antioxidants in various plant isolates is persistently growing and many methods are being established. Most of the available in vitro tests are affordable and easy to perform, but due to the complex composition of plant extracts, different kinetics, mechanisms and specificity of the chemical reactions underlying these tests, there is no universal parameter for the assessment of antioxidant activity. In this paper, some of the currently most used in vitro methods for investigating and evaluating antioxidant activity of plant extracts are presented, emphasizing their advantages and weaknesses.
植物是次生代谢物的丰富来源,具有多种生物学和药理作用。一些植物成分,主要是酚类物质,具有显著的体外抗氧化活性,这意味着它们有助于维持体内氧化还原平衡。这些潜在的抗氧化剂结构多样,具有不同的抗氧化活性机制。由于检测、开发和了解有效抗氧化化合物的必要性日益增加,对各种植物分离物中抗氧化剂的鉴定和测量的兴趣不断增长,许多方法正在建立。大多数可用的体外测试都是负担得起且易于执行的,但由于植物提取物的复杂组成,这些测试背后的化学反应的不同动力学,机制和特异性,没有一个通用的参数来评估抗氧化活性。本文介绍了目前常用的几种体外研究和评价植物提取物抗氧化活性的方法,并着重介绍了它们的优缺点。
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引用次数: 0
Comparative risk assessment study of elemental impurities in Montelukast chewable tablets and film-coated tablets 孟鲁司特咀嚼片与膜包衣片中元素杂质的比较风险评价研究
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-41263
Stefan Angelevski, Irena Slaveska-Spirevska, Elena Lazarevska-Todevska, Tanja Bakovska-Stoimenova, M. Glavaš-Dodov, Maja Simonoska-Crcarevska, R. Slaveska-Raički
It is well documented that elemental impurities (EIs) are critical in the field of pharmaceutical development since they could affect the quality, efficacy and safety of the finished dosage form (FDF). The responsibility of pharmaceutical manufacturers is to demonstrate via assessment approach, risk-based control strategy and/or required data analysis that the FDFs are compliant with ICH Q3D (R2). The aim of this research is to conduct a comprehensive comparative EIs risk assessment study of three different Montelukast dosage forms produced as chewable tablets (4 mg and 5 mg) and film-coated tablets 10 mg. The inductively coupled plasma-mass spectrometry (ICP-MS) system was used for the determination of EIs in samples of Montelukast sodium as the active pharmaceutical ingredient (API), placebos for all FDFs, and FDFs. Moreover, the analyses were also conducted on three batches from all three studied FDFs. Based on ICH Q3D (R2) guidelines, the tested products for EIs Class 1 and Class 2A showed that EIs levels in the API and placebos are well below the ICH Option 1 oral and parenteral limits. For the examined batches of each FDF strength (total of 9), none of the EI exceeds their concentration limits.
元素杂质(ei)在药物开发领域至关重要,因为它们会影响成品剂型(FDF)的质量、疗效和安全性。药品制造商的责任是通过评估方法、基于风险的控制策略和/或所需的数据分析来证明fdf符合ICH Q3D (R2)。本研究的目的是对三种不同的孟鲁司特咀嚼片剂(4mg和5mg)和薄膜包膜片剂(10mg)进行全面的比较ei风险评估研究。采用电感耦合等离子体质谱法(ICP-MS)测定孟鲁司特钠作为活性药物成分(API)、所有fdf安慰剂和fdf样品中的ei。此外,还对所有三个研究的fdf中的三个批次进行了分析。根据ICH Q3D (R2)指南,1类和2A类ei的测试产品显示,原料药和安慰剂中的ei水平远低于ICH选项1口服和肠外限制。对于每个FDF强度的检查批次(共9个),EI均未超过其浓度限值。
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引用次数: 0
Design of Experiments (DoE)-based approach for improvement of dry mixing processes in the production of low-dose Alprazolam tablets using Raman spectroscopy for content uniformity monitoring 基于实验设计的改进低剂量阿普唑仑片生产中干混工艺的方法,利用拉曼光谱进行含量均匀性监测
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-41376
Liljana Makraduli, P. Makreski, Filip Makraduli, Irena Slaveska-Spirevska, Tanja Bakovska-Stoimenova, Elena Lazarevska-Todevska, M. Piponski, Maja Anevska, M. Glavaš-Dodov, Maja Simonoska-Crcarevska, K. Mladenovska, K. Goracinova, Nikola Geškovski
A low-dose tablet formulation, containing a potent Benzodiazepine derivative Alprazolam was developed, considering the achievement of appropriate content uniformity of the active substance in powder blends and tablets as a major challenge. Two different types of lactose monohydrate (Tablettose 80 and Granulac 200) and two different types of dry mixing processes (high-shear mixing and "in bulk" mixing) were employed. To evaluate the influence of the variables (mixing speed, mixing time, filling level of the high-shear and cube mixer, lactose monohydrate type) and their interactions upon the response (content uniformity of Alprazolam in the powder blends), a Factorial 2 4 design (with 4 factors at 2 levels in 1 block) was generated for each type of mixer. For high-shear dry mixing the Response Surface, D-optimal Factorial 2 4 design (with 2 replications and 31 experiments) was used, while for the "in bulk" dry mixing the Response Surface, Central Composite Factorial 2 4 design (with 34 experiments) was used. The process parameters for the high-shear mixer were varied within the following ranges: filling level of 70-100%, impeller mixing speed of 50-300 rpm and mixing time of 2-10 minutes. For the cube mixer the following process parameter ranges were employed: filling level of 30-60%, mixing speed of 20-390 rpm and mixing time of 2-10 minutes. Raman spectroscopy in conjunction with a validated Partial Least Square (PLS) regression model was used as a Process Analytical Technology (PAT) tool for Alprazolam content determination and content uniformity monitoring. The DoE model was further employed to optimize the powder blending process in regard to the achievement of appropriate Alprazolam content uniformity using high-shear mixing and Tabletosse 80 as filler. The desirability function revealed that the following process parameters: a mixing time of 2 minutes, a mixing speed of 300 rpm and a 70% filling level of the mixer would produce powder blends with the lowest variability in Alprazolam content. The three independent lab batches of low-dose Alprazolam tablets, produced with high-shear mixing using these process parameters, conformed to the requirements of the European Pharmacopoeia for content (assay) of Alprazolam and uniformity of the dosage units.
考虑到粉末混合物和片剂中活性物质的适当含量均匀性是一个主要挑战,开发了一种含有强效苯二氮卓衍生物阿普唑仑的低剂量片剂配方。采用两种不同类型的一水乳糖(Tablettose 80和Granulac 200)和两种不同类型的干混合工艺(高剪切混合和散装混合)。为了评价各变量(混合速度、混合时间、高剪切和立方体混合器的填充水平、一水乳糖类型)及其相互作用对响应(混合粉中阿普唑仑的含量均匀性)的影响,对每种混合器进行了析因24设计(1块中2个水平有4个因素)。对于高剪切干混合,响应面采用d -最优析因24设计(2个重复,31个试验),而对于“散装”干混合,响应面采用中心复合析因24设计(34个试验)。高剪切混合器的工艺参数为:填充量70 ~ 100%,叶轮搅拌转速50 ~ 300 rpm,搅拌时间2 ~ 10 min。对于立方体混合器,采用以下工艺参数范围:填充量30-60%,混合速度20-390 rpm,混合时间2-10分钟。拉曼光谱结合验证的偏最小二乘(PLS)回归模型作为过程分析技术(PAT)工具,用于阿普唑仑含量测定和含量均匀性监测。采用DoE模型对高剪切混合、Tabletosse 80为填料的阿普唑仑的掺混工艺进行优化,以达到合适的含量均匀性。期望函数表明,以下工艺参数:混合时间为2分钟,混合速度为300转/分,混合器填充量为70%,将产生阿普唑仑含量变化最小的粉末混合物。使用这些工艺参数进行高剪切混合生产的三个独立实验室批次的低剂量阿普唑仑片符合欧洲药典对阿普唑仑含量(测定)和剂量单位均匀性的要求。
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引用次数: 0
Biochemical and hematological parameters in the 1st trimester of pregnancy 妊娠前三个月的生化和血液学指标
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-41999
J. Ivanišević, D. Ardalić, A. Zeljković, J. Vekić, T. Gojković, S. Vladimirov, T. Antonić, Jelena Munjas, A. Stefanović
The 1st trimester of pregnancy is accompanied with changes in different biochemical and hematological parameters. Analyses scheduled to be performed in the 1st trimester are complete blood count, blood group, Rh factor and the double test. Many experts also suggest the determination of lipid status parameters as a routine analysis in the early pregnancy. Reliable data about maternal and fetal health can be obtained by the assessment of the above-mentioned parameters. They may be helpful in assessing the risk for pregnancy complication development and/or perinatal adverse outcomes.
妊娠早期伴有各种生化和血液学指标的变化。计划在妊娠早期进行的分析包括全血细胞计数、血型、Rh因子和双重检查。许多专家还建议将血脂状态参数的测定作为妊娠早期的常规分析。通过对上述参数的评估,可以获得有关孕产妇和胎儿健康的可靠数据。它们可能有助于评估妊娠并发症发展和/或围产期不良后果的风险。
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引用次数: 0
Redox homeostasis, oxidative stress and antioxidant system in health and disease: The possibility of modulation by antioxidants 健康和疾病中的氧化还原稳态、氧化应激和抗氧化系统:抗氧化剂调节的可能性
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-45369
J. Kotur-Stevuljević, J. Savić, Milena Simić, J. Ivanišević
Redox imbalance occurs when the factors of oxidative stress, known as prooxidants, outweigh the mechanisms of antioxidant protection. In a healthy state, homeostatic mechanisms ensure the balanced production of free radicals and a complete series of antioxidants responsible for their safe removal. The generation of free radicals is a part of physiological processes in a healthy organism, some of which act as specific signaling molecules, and their presence and activity are necessary in these processes. In various diseases such as cancer, cardiovascular disease, diabetes, autoimmune diseases, rheumatic diseases, systemic lupus, and skin diseases, the generation of free radicals overwhelms the protective mechanisms, leading to the development of "oxidative stress" that damages cells and tissues. To prevent the harmful effects of free radicals within cells, there exists a system of enzymatic antioxidant protection composed of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione reductase (GR), glutaredoxin, reduced/oxidized glutathione (GSH/GSSG), and thioredoxin (TRX). The examples of non-enzymatic antioxidants are: antioxidant vitamins such as A, C and E, dihydrolypoic acid, metallothioneins, ceruloplasmin, coenzyme Q 10, urea, creatinine, etc. Redox balance is influenced by the circadian rhythm and external factors that constitute the "exposome", including dietary habits and lifestyle. Antioxidant supplementation has become increasingly popular for maintaining optimal body function. However, it is important to note that some antioxidants can exhibit prooxidant activity, emphasizing the need for controlled use. The relationship between the redox status of the body and the action of antioxidants enables the development of multidisciplinary research that connects biochemistry, molecular biology, nutritional science, natural product chemistry, and clinical practice.
当氧化应激因子(称为促氧化剂)超过抗氧化保护机制时,氧化还原失衡就会发生。在健康状态下,体内平衡机制确保自由基的平衡产生和一系列完整的抗氧化剂,负责它们的安全清除。自由基的产生是健康生物体生理过程的一部分,其中一些自由基作为特定的信号分子,它们的存在和活动在这些过程中是必要的。在各种疾病中,如癌症、心血管疾病、糖尿病、自身免疫性疾病、风湿性疾病、系统性狼疮和皮肤病,自由基的产生压倒了保护机制,导致“氧化应激”的发展,损害细胞和组织。为了防止细胞内自由基的有害影响,存在由超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSHPx)、谷胱甘肽还原酶(GR)、谷胱甘肽、还原性/氧化性谷胱甘肽(GSH/GSSG)和硫氧还蛋白(TRX)组成的酶促抗氧化保护系统。非酶促抗氧化剂的例子有:抗氧化维生素如A、C和E、二氢磷酸、金属硫蛋白、铜蓝蛋白、辅酶q10、尿素、肌酐等。氧化还原平衡受昼夜节律和构成“暴露体”的外部因素的影响,包括饮食习惯和生活方式。为了维持最佳的身体机能,抗氧化剂补充剂越来越受欢迎。然而,重要的是要注意一些抗氧化剂可以表现出促氧化活性,强调需要控制使用。人体氧化还原状态与抗氧化剂作用之间的关系促进了多学科研究的发展,将生物化学、分子生物学、营养科学、天然产物化学和临床实践联系起来。
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引用次数: 0
Principles and applications of interfacial rheology in (pre)formulation development of pharmaceutical preparations 界面流变学原理及其在药物制剂(预)配方开发中的应用
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-46316
Veljko Krstonošić, Nebojša Pavlović, Dejan Ćirin
Rheology is a science that deals with the movement and deformation of materials, while interfacial rheology is a branch of rheology that focuses on the study of the mechanical properties of fluid interfaces, such as liquid-liquid and liquid-gas interfaces. The behavior of fluid interfaces differs significantly from that of bulk materials, and standard rheological measurements of bulk materials cannot adequately describe their properties. Interfacial rheology is a specialized approach to the study of viscoelasticity and interfacial tension at liquid interfaces and provides valuable insight into intermolecular interactions and surface forces. This knowledge is particularly important for the development of advanced formulations and systems with tailored properties and functionalities. Interfacial rheology is a rapidly growing research field with diverse applications in science and industry. It plays a pivotal role in the development and optimization of pharmaceutical formulations and design of innovative drug delivery carriers with improved stability, enhanced drug release profiles, and targeted delivery capabilities. This review article aims to provide a comprehensive overview of interfacial rheology, its principles, measurement techniques, and applications in various industries. By exploring recent advancements and emerging trends in the field, we aim to highlight the significance of interfacial rheology in optimizing formulations, enhancing product performance, and driving innovations, particularly in pharmaceutical science.
流变学是研究材料运动和变形的科学,而界面流变学是流变学的一个分支,主要研究流体界面的力学性质,如液-液和液-气界面。流体界面的行为与块状材料的行为有很大的不同,块状材料的标准流变测量不能充分描述其性质。界面流变学是研究液体界面粘弹性和界面张力的一种专门方法,为分子间相互作用和表面力提供了有价值的见解。这些知识对于开发具有定制属性和功能的高级配方和系统尤其重要。界面流变学是一个快速发展的研究领域,在科学和工业上有着广泛的应用。它在药物配方的开发和优化以及创新药物递送载体的设计中发挥着关键作用,具有更好的稳定性,增强的药物释放谱和靶向递送能力。本文综述了界面流变学的基本原理、测量技术及其在工业中的应用。通过探索该领域的最新进展和新兴趋势,我们的目标是强调界面流变学在优化配方,提高产品性能和推动创新方面的重要性,特别是在制药科学方面。
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引用次数: 0
Antioxidant activity of plant secondary metabolites 植物次生代谢产物的抗氧化活性
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-45560
M. Marčetić, Jelena Arsenijević
Oxidative stress can induce the development of many different disorders. Plant secondary metabolites may act as antioxidants by neutralisation of free radicals and by stimulation of endogenous antioxidant mechanisms. One of the important secondary plant metabolites with antioxidant activity are polyphenols. They can exert activity through different mechanisms depending on their structure. Polyphenols are widely present in herbal drugs, and some of the commonly used ones are aronia berry (Aroniae fructus) and bilberry fruit (Myrtilli fructus), both rich in anthocyanins and tannins and with high antioxidant activity. The main compounds in turmeric rhizome (Curcumae rhizome) are curcuminoides that manifest antioxidant and anti-inflammatory activity. Furthermore, tea leaf (Camelliae sinensis folium) and coffee bean (Coffeae semen), highly present in everyday life, significantly contribute to the daily intake of antioxidants and provide necessary protection of the organism from the consequences of oxidative stress.
氧化应激可诱发多种疾病的发生。植物次生代谢物可能通过中和自由基和刺激内源性抗氧化机制发挥抗氧化剂的作用。多酚是具有抗氧化活性的重要次生代谢产物之一。它们可以通过不同的机制发挥作用,这取决于它们的结构。多酚类物质广泛存在于中草药中,常用的有野越橘(Aroniae fructus)和越橘(Myrtilli fructus),均含有丰富的花青素和单宁,具有较高的抗氧化活性。姜黄根茎(Curcumae rhizome)中的主要化合物是姜黄素,具有抗氧化和抗炎活性。此外,茶叶(Camelliae sinensis folium)和咖啡豆(coffae semen)在日常生活中高度存在,它们显著地促进了每日抗氧化剂的摄入,并为机体免受氧化应激的影响提供了必要的保护。
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引用次数: 0
Agri-food by-products as a source of sustainable ingredients for the production of functional foods and nutraceuticals 农业食品副产品是生产功能性食品和营养保健品的可持续原料来源
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.5937/arhfarm73-44481
Nevena Ivanović, Tijana Ilić, Milica Zrnić-Ćirić, V. Todorović, I. Đuričić, Nevena Dabetić
The disposal of waste generated in the agri-food industry is one of the greatest challenges in achieving sustainable development. Although agri-food residues are a potential source of bioactive compounds with proven health benefits, they are largely unused and disposed of as organic waste. The recovery of bioactive compounds from agri-food waste to obtain products with high biological value, such as functional foods and nutraceuticals, is an idea that stems from the concept of bioeconomy and combines environmental issues with economically viable production. Some of the main agri-food wastes in Serbia that have the potential to be recycled into value-added products are apple, plum, grape, tomato, and beet pomace, and oilseed cakes. Bioactive compounds isolated from these wastes include polyphenols, fibers, essential fatty acids, minerals, various volatiles and pigments. This article focuses on the most common food wastes and the potential reuse of these undervalued material to produce value-added products such as functional foods, nutraceuticals or food additives.
处理农业食品工业产生的废物是实现可持续发展的最大挑战之一。虽然农业食品残留物是经证实有益健康的生物活性化合物的潜在来源,但它们大多未被使用,并作为有机废物处理。从农业食品垃圾中回收生物活性化合物,以获得具有高生物价值的产品,如功能食品和营养保健品,是一个源于生物经济概念的想法,将环境问题与经济上可行的生产相结合。在塞尔维亚,一些有潜力被回收利用的主要农业食品废弃物是苹果、李子、葡萄、番茄、甜菜渣和油籽饼。从这些废物中分离出的生物活性化合物包括多酚、纤维、必需脂肪酸、矿物质、各种挥发物和色素。这篇文章的重点是最常见的食物浪费和潜在的再利用这些被低估的材料,以生产增值产品,如功能性食品,保健品或食品添加剂。
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引用次数: 0
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Arhiv za Farmaciju
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