Effects of drugs on nutrition

Drugs can increase nutrient requirements through various mechanisms and if these requirements are not met by dietary modification or provision of nutrient supplements, deficiency disease will result. Commoner nutritional effects of drugs consist in the insidious development of hypovitaminoses; other serious nutritional consequences of drug intake include growth impairment and, in the case of vitamin antagonists, poisoning through interference with metabolic processes dependent on the activity of vitamins or coenzymes. Interactions may exist between pharmacologic agents and nutrients with respect to their absorption, transport, metabolism and excretion. Single drugs can cause nutrient depletion by more than one mechanism and multiple drug regimens can deplete nutrient stores by a synergistic effect. Risks of drug-induced malnutrition with drugs increase with dose and duration of intake, marginal diets and co-existence of disease which increases requirements for the same nutrients that are affected by the drug.     

Environmental factors in drug metabolism.

Although various kinds of environmental factors may alter the activity of cytochrome P-450 enzymes in liver micromes, their effects on the pharmacokinetics of drugs and other foreign compounds in living animals may not be as great as might be predicted from assays of these enzymes in vitro. Indeed, the effects will depend on the relative importance of excretory and metabolic mechanisms in the elimination of the drug, the relative importance of various metabolic reactions in different tissues, the extraction ratio of the drug by the liver, and in some instances on the route of administration of the drug. Moreover, the effect of the various environmental factors on the pharmacologic and the toxicologic actions of the drug will depend on whether these actions are caused by the parent foreign compounds or by one or more of their metabolites. It may also be important that the environmental factors may alter not only relative activiteis of the cytochrome P-450 in liver microsomes but also the activities of other drug-metabolizing enzymes and that the relative effects of the environmental factors of these enzymes may differ depending on the animal species or the animal strain. Indeed, a given factor may increase the pharmacologic effects of a drug metabolite in one animal species but decrease it in another. For these reasons, it frequently is not possible to predict the effects of environmental factors on drug action in living animals solely from in vitro rates of metabolism of model substrates.     

肝硬化疾病与支链氨基酸应用研究进展

蛋白质-营养不良是肝硬化病人最常见的并发症之一。肝脏作为蛋白质、脂类和糖代谢的主要器官,病变后的代谢紊乱随之而来。不适宜的蛋白质-能量摄入只会加重病情最后发生肝性脑病等危及生命的严重后果。因此,肝硬化病人的营养管理显得尤为重要,氨基酸的适宜供给无疑是营养治疗的重中之重。已知支链氨基酸能通过刺激肝细胞合成、减少肝损伤后的分解代谢等诸多方式改善营养状况,但是各种试验结果仍存在争议。最佳适宜量究竟多大,安全性范围的设定以及确切的保护机理等问题仍待进一步深入研究。     

Perinatal Protein Malnutrition Affects Mitochondrial Function in Adult and Results in a Resistance to High Fat Diet-Induced Obesity

Epidemiological findings indicate that transient environmental influences during perinatal life, especially nutrition, may have deleterious heritable health effects lasting for the entire life. Indeed, the fetal organism develops specific adaptations that permanently change its physiology/metabolism and that persist even in the absence of the stimulus that initiated them. This process is termed “nutritional programming”. We previously demonstrated that mothers fed a Low-Protein-Diet (LPD) during gestation and lactation give birth to F1-LPD animals presenting metabolic consequences that are different from those observed when the nutritional stress is applied during gestation only. Compared to control mice, adult F1-LPD animals have a lower body weight and exhibit a higher food intake suggesting that maternal protein under-nutrition during gestation and lactation affects the energy metabolism of F1-LPD offspring. In this study, we investigated the origin of this apparent energy wasting process in F1-LPD and demonstrated that minimal energy expenditure is increased, due to both an increased mitochondrial function in skeletal muscle and an increased mitochondrial density in White Adipose Tissue. Importantly, F1-LPD mice are protected against high-fat-diet-induced obesity. Clearly, different paradigms of exposure to malnutrition may be associated with differences in energy expenditure, food intake, weight and different susceptibilities to various symptoms associated with metabolic syndrome. Taken together these results demonstrate that intra-uterine environment is a major contributor to the future of individuals and disturbance at a critical period of development may compromise their health. Consequently, understanding the molecular mechanisms may give access to useful knowledge regarding the onset of metabolic diseases.     

Risk of mortality in patients with end-stage renal disease: the role of malnutrition and possible therapeutic implications

The mortality rate of dialysis patients is still considerably high. Beside the traditional risk factors, specific uremia-related risk factors are identified. Among them, hypoalbuminemia and malnutrition have a strong association to mortality in chronic dialysis patients. Various studies document a strong relation between reduced calorie and protein uptake and mortality in uremic patients. Several factors responsible for malnutrition in dialysis patients have been identified. These factors may be dialysis-associated, due to intercurrent illnesses or are associated with uremic complications (e.g. hyperparathyroidism, anemia, acidosis, etc.). Malnutrition is treatable and can be avoided by several means. Beside the increase in the dose of dialysis and adequate protein and calorie intake, intradialytic nutrition is an additional choice. The combination with specific drugs (e.g. growth hormone) may potentiate the success of the modified treatment modalities, particularly in patients who need nutritional support during an intercurrent illness. Further studies are required to measure the impact of for example growth hormone supplementation on mortality rate and quality of life in malnourished patients on chronic dialysis.     

老年心力衰竭患者营养不良的影响因素分析及早期肠内营养对营养不良患者心功能、营养状况和肠道黏膜屏障功能的影响

摘要 目的：探讨老年心力衰竭（HF）患者营养不良的影响因素及早期肠内营养对营养不良患者心功能、营养状况和肠道黏膜屏障功能的影响。方法：选取2021年2月~2022年4月期间在我院接受治疗的180例老年HF患者作为研究对象。入院后采用微型营养评价简表（MNA-SF）评估患者的营养状况。根据MNA-SF评分结果分为营养不良组（n=83）和营养正常组（n=97）。应用单因素及多因素Logistic回归分析老年HF患者营养不良的危险因素。对老年HF营养不良患者给予早期肠内营养干预,观察其治疗前、治疗一周后心功能、营养状况和肠道黏膜屏障功能的变化情况。结果：老年HF患者营养不良与性别、居住地、饮酒史、病因、职业类别、谷丙转氨酶、血肌酐、收缩压（SBP）、舒张压（DBP）无关（P>0.05）,而与年龄、医保类型、病程、婚姻状况、美国纽约心脏病学会（NYHA）分级、文化程度、C反应蛋白（CRP）、家庭人均月收入、B型脑钠肽（BNP）、吸烟史、左心室射血分数（LVEF）有关（P<0.05）。Logistic回归分析结果显示：病程偏长、CRP偏高、BNP偏高、NYHA分级为IV级、年龄偏大、吸烟史是老年HF患者发生营养不良的危险因素（P<0.05）。治疗1周后,营养不良组老年HF患者的LVEF升高,BNP下降（P<0.05）。治疗1周后,营养不良组老年HF患者的前白蛋白（PA）、转铁蛋白（TRF）升高（P<0.05）。治疗1周后,营养不良组老年HF患者的D-乳酸（D-Lac）、二胺氧化酶（DAO）、肠脂肪酸结合蛋白（IFABP）下降（P<0.05）。结论：老年HF患者营养不良受到病程、CRP、BNP、NYHA分级、年龄、吸烟史等多种因素的影响,针对老年HF患者营养不良给予早期肠内营养,有助于改善患者心功能、营养状况和肠道黏膜屏障功能。     

Increased susceptibility to metabolic alterations in young adult females exposed to early malnutrition

Early malnutrition during gestation and lactation modifies growth and metabolism permanently. Follow up studies using a nutritional rehabilitation protocol have reported that early malnourished rats exhibit hyperglycemia and/or hyperinsulinemia, suggesting that the effects of early malnutrition are permanent and produce a "programming" effect on metabolism. Deleterious effects have mainly been observed when early-malnutrition is followed by a high-carbohydrate or a high-fat diet.The aim of this study was to evaluate whether following a balanced diet subsequent to malnutrition can deter the expression of metabolic disease and lead rats to exhibit metabolic responses, similar to those of well-nourished controls.Young rats, born from dams malnourished during gestation and lactation with a low protein diet, were provided with a regular balanced chow diet upon weaning. At 90 days of age, the effects of rehabilitation were determined under three different feeding conditions: ad libitum, fasting or fasting-reefed satiated.Early-malnourished rats showed an increased rate of body weight gain. Males under ad libitum conditions showed an elevated concentration of hepatic glycogen and low values of insulin. In the fasting-reefed satiated condition, only early-malnourished females showed an alteration in glucose response and glucagon level, compared with their well-nourished controls.Data indicate that a balanced diet along life after early malnutrition can mask the expression of metabolic disorders and that a metabolic challenges due to a prolonged fasting and reefed state unmask metabolic deficiencies in early-malnourished females.     

National nutrition surveillance

National Nutrition Surveillance includes nutritional assessment surveys to ascertain the extent of malnutrition in populations, to identify possible causes, to establish baseline data for monitoring nutrition, and to select mechanisms for nutrition surveillance (in a restricted sense). An example of the results from a recent nutritional assessment survey in the United States is the negative association of obesity with energy intake, exercise and socioeconomic status, which has implications for public nutritional policy. Nutritional monitoring measures changes in population nutrition over time. An example of the results from nutritional monitoring is the unexpected and presently unexplained decrease in serum cholesterol levels of middle-aged women in the United States over the past decade. Nutritional surveillance in the restricted sense not only identifies malnutrition but is administratively organized to intervene rapidly. National Nutrition Surveillance depends on metabolic and clinical research to decide on its priorities. This research indicates that malnutrition involves more than under-nutrition, and greater emphasis should be given in National Nutrition Surveillance to this wider context of malnutrition. These results will in turn help set priorities for basic and applied research in nutrition. It is important that the research community participate in the review presently under way of the role of the National Center for Health Statistics in National Nutrition Surveillance.     

Relationships between undernutrition,infection, and growth and development

Interactions between undernutrition, infection, and growth and development are complex, and are reviewed in this article. Anthropometry is a common means of nutritional assessment, but the relationship between food availability and anthropometric status is at best very loose, at least at the national level. This suggests that anthropometric assessment is less a measure of nutritional status than of the totality of environmental factors that influence growth, including infectious disease. The effects of diet, nutrition and infection on the nutritional status of a child can vary according to the disease ecology, the age of the child, patterns of feeding and types of food consumed. There are two possible ways in which this relationship can begin; one in which poor nutritional status leads to impaired immunocompetence and reduced resistance to infection, and the other in which exposure to infectious disease can lead to appetite loss and anorexia, malabsorption, and elevated metabolism of energy and other nutrients. Once started, the interactions between these two major environmental stressors becomes increasingly complex, with the nature of the disease ecology influencing the balance of immunoparesis and adaptive immunity its effect on subsequent disease experience, and the extent, if any, of anorexia, fever, and malabsorption during infectious episodes which has an impact on nutritional status. Specific nutritional deficiencies can subsequently influence immune status and responsiveness, and adaptive immunity. In addition, cultural factors can influence patterns of disease management and sickness behaviour, which can in turn affect the incidence, severity and duration of infection, and their effects on nutritional status, while deficiencies of vitamins and trace elements can have major effects on immune responsiveness.     

Effect of nutrition on reproduction in llamas and alpacas

The role of nutrition, especially the role of energy and protein status, on reproductive performance of production animals has been well documented. Comparatively, there is a true paucity of literature regarding nutritional mediation of reproductive performance in llamas and alpacas. Following seasonal patterns of feed availability in South America, adverse effects of nutritional deprivation on reproductive performance are well recognized, suggesting similar nutrition-reproduction interrelationships. Camelids, with their unique metabolism, may have some peculiar interrelationships between reproduction and protein and phosphorus nutrition. This presentation will review basic issues of energy and protein nutrition relative to reproductive performance in llamas and alpacas, based primarily on hypotheses and extrapolation from other species. Opportunities for research on this topic will be discussed, including preliminary data from current research.     

Maternal micronutrient disturbance as risks of offspring metabolic syndrome

Metabolic syndrome (MetS) is defined as a constellation of individual metabolic disturbances, including central obesity, hypertension, dyslipidemia, and insulin resistance. The established pathogenesis of MetS varies extensively with gender, age, ethnic background, and nutritional status. In terms of nutritional status, micronutrients are more likely to be discounted as essential components of required nutrition than macronutrients due to the small amount required. Numerous observational studies have shown that pregnant women frequently experience malnutrition, especially in developing and low-income countries, resulting in chronic MetS in the offspring due to the urgent and increasing demands for micronutrients during gestation and lactation. Over the past few decades, scientific developments have revolutionized our understanding of the association between balanced maternal micronutrients and MetS in the offspring. Examples of successful individual, dual, or multiple maternal micronutrient interventions on the offspring include iron for hypertension, selenium for type 2 diabetes, and a combination of folate and vitamin D for adiposity. In this review, we aim to elucidate the effects of maternal micronutrient intake on offspring metabolic homeostasis and discuss potential perspectives and challenges in the field of maternal micronutrient interventions.     

维持性腹膜透析患者认知功能障碍与营养状况的关系研究

摘要 目的：探究维持性腹膜透析患者认知功能障碍与营养状况的关系。方法：前瞻性纳入2019年1月至2020年6月在济宁医学院附属医院就诊的172例维持性腹膜透析患者，收集患者一般资料。采用蒙特利尔认知评估量表（MoCA）评估患者的认知功能，根据MoCA评分分为认知功能正常组及认知功能障碍组。采用微型营养评估量表（MNA）评估患者营养状态，以MNA评分分为营养正常组、潜在营养不良组、营养不良组，比较认知功能正常组及认知功能障碍组营养状况占比情况，分析维持性腹膜透析患者认知功能与营养状况的相关性及影响认知功能的相关因素。结果：与认知功能正常组比较，认知功能障碍组患者透析时间明显延长，MNA总分、MoCA总分明显降低（P<0.05）。与认知功能正常组比较，认知功能障碍组患者营养正常者比例明显降低，营养不良者比例明显升高（P<0.05），潜在营养不良者比例有所升高但差异无统计学意义（P>0.05）。经Pearson相关性检验分析显示，维持性腹膜透析患者MoCA总分与MNA总分呈明显正相关（P<0.05）。经Logistic回归分析显示，透析时间（延长）、营养不良均为维持性腹膜透析患者认知功能障碍的危险因素（P<0.05）。结论：维持性腹膜透析认知功能障碍患者营养不良发生率明显升高，且患者认知功能障碍与营养状况具有明显相关性，加强患者的营养状况有助于降低认知功能障碍的发生风险。     

A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the “effect space” comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.     

Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon

Preclinical drug safety evaluation studies, typically conducted in two or more animal species, reveal and define dose-dependent toxicities and undesirable effects related to pharmacological mechanism of action. Idiosyncratic toxic responses are often not detected during this phase in development due to their relative rarity in incidence and differences in species sensitivity. This paper reviews and discusses the metabolic idiosyncratic toxicity and species differences observed for the experimental non-benzodiazepine anxiolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or monkey preclinical studies. However, subsequent studies in Dutch-belted rabbits revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity using rabbits and cultured hepatocytes from several species, including human, provided a sketch of the complex pathway required to produce hepatic injury. This pathway includes drug metabolism to a carboxylic acid metabolite (cyclopropane carboxylic acid), inhibition of mitochondrial fatty acid beta-oxidation, and effects on intermediary metabolism including depletion of glycogen and disruption of glucose homeostasis. We also provide evidence suggesting that the carboxylic acid metabolite decreases the availability of liver CoA and carnitine secondary to the formation of unusual acyl derivatives. Hepatic toxicity could be ameliorated by administration of carnitine, and to a lesser extent by pantothenate. These hepatocellular pathway defects, though not directly resulting in cell death, rendered hepatocytes sensitive to secondary stress, which subsequently produced apoptosis and hepatocellular necrosis. Not all rabbits showed evidence of hepatic toxicity, suggesting that individual or species differences in any step along this pathway may account for idiosyncratic responses. These differences may be roughly applied to other metabolic idiosyncratic hepatotoxic responses and include variations in drug metabolism, effects on mitochondrial function, nutritional status, and health or underlying disease.     

The clinical and nutritional implications of lipid-lowering drugs that act in the gastrointestinal tract

PURPOSE OF REVIEW: A new class of cholesterol-lowering therapy that reduces intestinal sterol absorption has recently been introduced. This increases the number of classes of lipid-lowering agents that directly affect gastrointestinal function and raises questions concerning the overall effect of these agents on absorption and nutritional status. RECENT FINDINGS: A recent assessment notes a paucity of information concerning the factors that affect the bioavailability and intestinal absorption of lipophilic nutrients. By contrast, the specificity of the mechanisms of action of new drugs acting on the gastrointestinal tract may circumvent some of the detrimental effects on nutrient and drug bioavailability that have been noted with older forms of treatment. SUMMARY: The clinical imperative for aggressive control of lipid and metabolic risk factors makes widespread use, alone or in combination, of lipid-lowering agents that affect the gastrointestinal tract seem increasingly likely. Whilst the opportunity for therapeutic synergy is attractive, care will be required to avoid interference with intestinal absorptive function.     

Diet and metabolic development

For many years, investigators have been concerned with mechanisms that control and alter genetically regulated development. An intriguing aspect of these mechanisms is the ability of environmental factors to induce certain metabolic processes. Animal studies have shown that dietary manipulation of cholesterol and fatty acid metabolism during development can have persistent and permanent effects. In addition, there appears to be a critical period when changes in the diet can have lasting consequences. The changes in the control exerted by nutritional factors on metabolic development coincide with three phases of development: prenatal, suckling, and weaning. The effects of diet on cholesterol and fatty acid metabolism throughout these three phases of development will be addressed in this review.     

Nutritional influences on lipids and future atherosclerosis beginning prenatally and during childhood.

Autopsy findings of pre-atherosclerotic changes in the coronaries and other arteries of young soldiers killed in action in the Korean war stimulated studies on the mechanisms that regulate the development of atherosclerosis. The data confirmed that vascular changes obviously begin developing much earlier than the manifestation of clinical symptoms, and numerous risk factors for atherosclerosis have been firmly identified. The mechanisms consist of the effects of numerous poorly characterized genes and a complex mixture of environmental factors, dominated by factors associated with nutrition. Observational and epidemiological studies also showed that the pathogenesis is not restricted to the postnatal period. The nutrition of the fetus during the 40 weeks of pregnancy may also play an important role both directly and by determining metabolism in the individual more widely than was previously believed. At the same time, several studies suggested that biochemical predictors of atherosclerosis, e.g. a high concentration of serum LDL cholesterol, a low concentration of serum HDL cholesterol and other lipid and lipoprotein abnormalities, may already in early infancy and childhood predict values later in life quite well. We now review recent studies that deal with the effects of fetal and childhood nutrition on serum lipid values, and discuss the likelihood that clinically meaningful changes of atherosclerosis may appear earlier than expected.     

Cytochromes P450 and drug resistance

Cytochromes P450 are the key enzymes for activating and inactivating many drugs, in particular anticancer drugs. Therefore, individual expression levels of cytochromes P450 may play a crucial role in drug safety and drug efficacy. Overexpression of cytochrome P450 may yield rapid turnover and elimination of drugs before the target site was reached and any pharmacological effect is observed. Therefore, it may be vital to know the individual cytochrome P450 status in order to select the appropriate drug before drug resistance occurs. Expression levels and activity of cytochromes P450 depend on many different factors. These factors include tissue and organ specific expression, sex- and age-dependent expression, genetic differences yielding polymorphic forms, competitive inhibition or induction of cytochromes P450 due to multiple drug interaction, nutrition and diet. Genetically engineered test cells defined for cytochromes P450 are available for studying drugs for metabolic activation and for identifying the metabolically competent cytochrome P450 isoform.     

胃癌术后早期经鼻空肠营养管肠内营养患者的强化护理的临床效应

目的:探讨强化护理措施对胃癌患者术后营养状态的改善作用,为减少术后营养相关并发症的发生提供可借鉴的方法。方法:选择2012年1月-2013年12月在我科实施胃癌手术患者的临床资料进行分析,根据术后营养支持方式的不同,将患者分为早期肠内营养支持组和常规肠内营养组。观察并比较两组患者的生命体征变化、术后肛门排气时间及并发症的发生情况等。结果:强化护理组23例胃癌患者给予术后早期肠内营养治疗后,恢复肛门排气时间为53±7.4 h,经过5±2.1 d的肠内营养后,术后体重增加1.2±0.4 kg,无肠内营养相关并发症发生,肠外营养支持时间明显缩短。结论:本研究显示强化早期肠内营养护理具有迅速改善胃癌病人营养不良状态,减少营养不良相关并发症发生,减轻病人经济负担等优点。