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Drug Metabolism and Disposition: the... Nov 2015Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of... (Review)
Review
Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms "PBPK" and "physiologically based pharmacokinetic model" to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.
Topics: Animals; Computer Simulation; Drug Interactions; Humans; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 26296709
DOI: 10.1124/dmd.115.065920 -
Obesity Reviews : An Official Journal... Aug 2017Interval training (including high-intensity interval training [HIIT] and sprint interval training [SIT]) is promoted in both scientific and lay media as being a superior... (Meta-Analysis)
Meta-Analysis Review
Interval training (including high-intensity interval training [HIIT] and sprint interval training [SIT]) is promoted in both scientific and lay media as being a superior and time-efficient method for fat loss compared with traditional moderate-intensity continuous training (MICT). We evaluated the efficacy of HIIT/SIT when directly compared with MICT for the modulation of body adiposity. Databases were searched to 31 August 2016 for studies with exercise training interventions with minimum 4-week duration. Meta-analyses were conducted for within-group and between-group comparisons for total body fat percentage (%) and fat mass (kg). To investigate heterogeneity, we conducted sensitivity and meta-regression analyses. Of the 6,074 studies netted, 31 were included. Within-group analyses demonstrated reductions in total body fat (%) (HIIT/SIT: -1.26 [95% CI: -1.80; -0.72] and MICT: -1.48 [95% CI: -1.89; -1.06]) and fat mass (kg) (HIIT/SIT: -1.38 [95% CI: -1.99; -0.77] and MICT: -0.91 [95% CI: -1.45; -0.37]). There were no differences between HIIT/SIT and MICT for any body fat outcome. Analyses comparing MICT with HIIT/SIT protocols of lower time commitment and/or energy expenditure tended to favour MICT for total body fat reduction (p = 0.09). HIIT/SIT appears to provide similar benefits to MICT for body fat reduction, although not necessarily in a more time-efficient manner. However, neither short-term HIIT/SIT nor MICT produced clinically meaningful reductions in body fat.
Topics: Adiposity; Body Mass Index; Energy Metabolism; Exercise Therapy; High-Intensity Interval Training; Humans; Obesity; Overweight; Oxygen Consumption; Treatment Outcome; Weight Loss
PubMed: 28513103
DOI: 10.1111/obr.12536 -
British Journal of Sports Medicine Aug 2014Cardiorespiratory fitness (CRF) is a strong determinant of morbidity and mortality. In athletes and the general population, it is established that high-intensity... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND/AIM
Cardiorespiratory fitness (CRF) is a strong determinant of morbidity and mortality. In athletes and the general population, it is established that high-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICT) in improving CRF. This is a systematic review and meta-analysis to quantify the efficacy and safety of HIIT compared to MICT in individuals with chronic cardiometabolic lifestyle diseases.
METHODS
The included studies were required to have a population sample of chronic disease, where poor lifestyle is considered as a main contributor to the disease. The procedural quality of the studies was assessed by use of a modified Physiotherapy Evidence Base Database (PEDro) scale. A meta-analysis compared the mean difference (MD) of preintervention versus postintervention CRF (VO2peak) between HIIT and MICT.
RESULTS
10 studies with 273 patients were included in the meta-analysis. Participants had coronary artery disease, heart failure, hypertension, metabolic syndrome and obesity. There was a significantly higher increase in the VO2peak after HIIT compared to MICT (MD 3.03 mL/kg/min, 95% CI 2.00 to 4.07), equivalent to 9.1%.
CONCLUSIONS
HIIT significantly increases CRF by almost double that of MICT in patients with lifestyle-induced chronic diseases.
Topics: Antioxidants; Cardiac Rehabilitation; Chronic Disease; Exercise Therapy; Humans; Life Style; Metabolic Diseases; Oxygen Consumption; Patient Compliance; Quality of Life; Risk Factors; Treatment Outcome
PubMed: 24144531
DOI: 10.1136/bjsports-2013-092576 -
Nutrients May 2020Nitric oxide related ergogenic aids such as arginine (Arg) have shown to impact positively on sport performance through several physiological and metabolic mechanisms.... (Meta-Analysis)
Meta-Analysis
Nitric oxide related ergogenic aids such as arginine (Arg) have shown to impact positively on sport performance through several physiological and metabolic mechanisms. However, research results have shown to be controversial. The great differences regarding required metabolic pathways and physiological demands between aerobic and anaerobic sport disciplines could be the reasons. The aim of this systematic review and meta-analysis was to evaluate the effects of Arg supplementation on aerobic (≤VOmax) and anaerobic (>VOmax) performance. Likewise, to show the effective dose and timing of this supplementation. A structured search was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and PICOS guidelines in PubMed/MEDLINE, Web of Science (WOS), and Scopus databases from inception to January 2020. Eighteen studies were included which compare Arg supplementation with placebo in an identical situation and testing its effects on aerobic and anaerobic performance tests. Trials analyzing supplementation with other supplements were removed and there was not athlete's level, gender, ethnicity, or age filters. The performed meta-analysis included 15 studies and random effects model and pooled standardized mean differences (SMD) were used according to Hedges' g. Results revealed that Arg supplementation could improve aerobic (SMD, 0.84; 95% CI, 0.12 to 1.56; magnitude of SMD (MSMD), large; I2, 89%; = 0.02) and anaerobic (SMD, 0.24; 95% CI, 0.05 to 0.43; MSMD, small; I2, 0%; = 0.01) performance tests. In conclusion, acute Arg supplementation protocols to improve aerobic and anaerobic performance should be adjusted to 0.15 g/kg of body weight ingested between 60-90 min before. Moreover, chronic Arg supplementation should include 1.5-2 g/day for 4-7 weeks in order to improve aerobic performance, and 10-12 g/day for 8 weeks to enhance anaerobic performance.
Topics: Aerobiosis; Anaerobiosis; Arginine; Athletic Performance; Body Weight; Dietary Supplements; Energy Metabolism; Female; Humans; Male; Nitric Oxide; Performance-Enhancing Substances
PubMed: 32370176
DOI: 10.3390/nu12051300 -
American Journal of Physiology. Renal... Dec 2016Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the... (Review)
Review
Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.
Topics: Disease Progression; Glucose Clamp Technique; Humans; Inflammation; Insulin Resistance; Oxidative Stress; Renal Insufficiency, Chronic; Vitamin D Deficiency
PubMed: 27707707
DOI: 10.1152/ajprenal.00340.2016 -
Nutrients Oct 2020The Mediterranean diet (MD) may provide metabolic benefits but no systematic review to date has examined its effect on a multitude of outcomes related to metabolic... (Meta-Analysis)
Meta-Analysis
The Mediterranean diet (MD) may provide metabolic benefits but no systematic review to date has examined its effect on a multitude of outcomes related to metabolic health. This systematic review with meta-analysis (International Prospective Register of Systematic Reviews, PROSPERO; number CRD42019141459) aimed to examine the MD's effect on metabolic syndrome (MetSyn) incidence, components and risk factors (primary outcomes), and incidence and/or mortality from MetSyn-related comorbidities and receipt of pharmacologic treatment for MetSyn components and comorbidities (secondary outcomes). We searched Pubmed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science for controlled trials published until June 2019, comparing the MD with no treatment, usual care, or different diets in adults. Studies not published in English and not promoting the whole MD were excluded. Two authors independently extracted data and assessed risk of bias using the Cochrane Collaboration's and Risk of Bias in non-randomised studies (ROBINS-I) tools. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses, subgroup analyses and meta-regressions were performed, and heterogeneity was quantified using the I statistic. We identified 2654 reports and included 84 articles reporting 57 trials ( = 36,983). In random effects meta-analyses, the MD resulted in greater beneficial changes in 18 of 28 MetSyn components and risk factors (body weight, body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, total-, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, triglycerides, alanine transaminase, hepatic fat mass, C-reactive protein, interleukin-6, tumour necrosis factor-a, and flow-mediated dilatation) and lower risk of cardiovascular disease incidence (risk ratio (RR) = 0.61, 95% confidence intervals (CI) 0.42-0.80; I = 0%), and stroke (RR = 0.67, 95% CI 0.35-0.98; I = 0%). Only six studies reported effects on pharmacotherapy use, and pooled analysis indicated no differences between diet groups. Lack of consistency in comparator groups and other study characteristics across studies resulted in high heterogeneity for some outcomes, which could not be considerably explained by meta-regressions. However, a consistent direction of beneficial effect of the MD was observed for the vast majority of outcomes examined. Findings support MD's beneficial effect on all components and most risk factors of the MetSyn, in addition to cardiovascular disease and stroke incidence. More studies are needed to establish effects on other clinical outcomes and use of pharmacotherapy for MetSyn components and comorbidities. Despite the high levels of heterogeneity for some outcomes, this meta-analysis enabled the comparison of findings across studies and the examination of consistency of effects. The consistent direction of effect, suggesting the MD's benefits on metabolic health, supports the need to promote this dietary pattern to adult populations.
Topics: Adult; Biomarkers; Blood Pressure; Comorbidity; Controlled Clinical Trials as Topic; Diet, Mediterranean; Health; Humans; Incidence; Insulin Resistance; Metabolic Syndrome; Metabolism; Oxidative Stress; Risk Factors
PubMed: 33143083
DOI: 10.3390/nu12113342 -
The British Journal of Nutrition Dec 2020This systematic review and meta-analysis compared the effects of different rates of weight loss (WL), but equivalent total WL, on body composition and RMR. Studies... (Meta-Analysis)
Meta-Analysis
This systematic review and meta-analysis compared the effects of different rates of weight loss (WL), but equivalent total WL, on body composition and RMR. Studies examining gradual v. rapid WL on body composition and RMR in participants with overweight/obesity published up to October 2019 were identified through PubMed, the Cochrane Library, Web of Science, Embase, Scopus and Ovid databases. Meta-analysis was carried out using a fixed or random effects model as appropriate. Although the magnitude of WL was similar (mean difference 0·03 kg, 95 % CI –0·65, 0·71), gradual WL promoted greater reductions in fat mass (FM) (–1 kg, 95 % CI –1·70, –0·29) and body fat percentage (BFP) (–0·83 %, 95 % CI –1·49, –0·17). Gradual WL significantly preserved RMR compared with rapid WL (407·48 kJ, 95 % CI 76·76, 118·01). However, there was no significant difference in waist and hip circumferences, waist:hip ratio and fat-free mass (FFM) between gradual and rapid WL. The present systematic review and meta-analysis indicates beneficial effects of gradual WL, as compared with rapid WL, on FM, BFP and RMR in individuals with overweight/obesity. However, FFM changes and anthropometric indices did not significantly differ following different rates of WL.
Topics: Adolescent; Adult; Aged; Anthropometry; Basal Metabolism; Body Composition; Body Mass Index; Female; Humans; Male; Middle Aged; Obesity; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Weight Loss; Young Adult
PubMed: 32576318
DOI: 10.1017/S000711452000224X -
Nutrients Aug 2020Beta-alanine supplementation (BA) has a positive impact on physical performance. However, evidence showing a benefit of this amino acid in aerobic-anaerobic transition... (Meta-Analysis)
Meta-Analysis
Beta-alanine supplementation (BA) has a positive impact on physical performance. However, evidence showing a benefit of this amino acid in aerobic-anaerobic transition zones is scarce and the results controversial. The aim of this systematic review and meta-analysis is to analyze the effects of BA supplementation on physical performance in aerobic-anaerobic transition zones. At the same time, the effect of different dosages and durations of BA supplementation were identified. The search was designed in accordance with the PRISMA guidelines for systematic reviews and meta-analyses and performed in Web of Science (WOS), Scopus, SPORTDiscus, PubMed, and MEDLINE between 2010 and 2020. The methodological quality and risk of bias were evaluated with the Cochrane Collaboration tool. The main variables were the Time Trial Test (TTT) and Time to Exhaustion (TTE) tests, the latter separated into the Limited Time Test (LTT) and Limited Distance Test (LDT). The analysis was carried out with a pooled standardized mean difference (SMD) through Hedges' g test (95% CI). Nineteen studies were included in the systematic review and meta-analysis, revealing a small effect for time in the TTT (SMD, -0.36; 95% CI, -0.87-0.16; I = 59%; = 0.010), a small effect for LTT (SMD, 0.25; 95% CI, -0.01-0.51; I = 0%; = 0.53), and a large effect for LDT (SMD, 4.27; 95% CI, -0.25-8.79; I = 94%; = 0.00001). BA supplementation showed small effects on physical performance in aerobic-anaerobic transition zones. Evidence on acute supplementation is scarce (one study); therefore, exploration of acute supplementation with different dosages and formats on physical performance in aerobic-anaerobic transition zones is needed.
Topics: Aerobiosis; Anaerobiosis; Dietary Supplements; Humans; Physical Functional Performance; Sports Nutritional Physiological Phenomena; beta-Alanine
PubMed: 32824885
DOI: 10.3390/nu12092490 -
British Journal of Sports Medicine Mar 2017The current review clarifies the cardiometabolic health effects of high-intensity interval training (HIIT) in adults. A systematic search (PubMed) examining HIIT and... (Meta-Analysis)
Meta-Analysis Review
The current review clarifies the cardiometabolic health effects of high-intensity interval training (HIIT) in adults. A systematic search (PubMed) examining HIIT and cardiometabolic health markers was completed on 15 October 2015. Sixty-five intervention studies were included for review and the methodological quality of included studies was assessed using the Downs and Black score. Studies were classified by intervention duration and body mass index classification. Outcomes with at least 5 effect sizes were synthesised using a random-effects meta-analysis of the standardised mean difference (SMD) in cardiometabolic health markers (baseline to postintervention) using Review Manager 5.3. Short-term (ST) HIIT (<12 weeks) significantly improved maximal oxygen uptake (VO max; SMD 0.74, 95% CI 0.36 to 1.12; p<0.001), diastolic blood pressure (DBP; SMD -0.52, 95% CI -0.89 to -0.16; p<0.01) and fasting glucose (SMD -0.35, 95% CI -0.62 to -0.09; p<0.01) in overweight/obese populations. Long-term (LT) HIIT (≥12 weeks) significantly improved waist circumference (SMD -0.20, 95% CI -0.38 to -0.01; p<0.05), % body fat (SMD -0.40, 95% CI -0.74 to -0.06; p<0.05), VO max (SMD 1.20, 95% CI 0.57 to 1.83; p<0.001), resting heart rate (SMD -0.33, 95% CI -0.56 to -0.09; p<0.01), systolic blood pressure (SMD -0.35, 95% CI -0.60 to -0.09; p<0.01) and DBP (SMD -0.38, 95% CI -0.65 to -0.10; p<0.01) in overweight/obese populations. HIIT demonstrated no effect on insulin, lipid profile, C reactive protein or interleukin 6 in overweight/obese populations. In normal weight populations, ST-HIIT and LT-HIIT significantly improved VO max, but no other significant effects were observed. Current evidence suggests that ST-HIIT and LT-HIIT can increase VO max and improve some cardiometabolic risk factors in overweight/obese populations.
Topics: Adult; Aged; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Female; High-Intensity Interval Training; Humans; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Obesity; Overweight; Oxygen Consumption; Waist Circumference; Young Adult
PubMed: 27797726
DOI: 10.1136/bjsports-2015-095841 -
Lipids in Health and Disease Oct 2019Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions...
BACKGROUND
Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions involve interactions between environmental, genetic, and epigenetic factors. Recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. This systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations.
METHODS
A targeted search was conducted in the PubMed/Medline databases using the keywords "fatty acids and epigenetic". The data were analyzed according to the PRISMA-P guidelines.
RESULTS
Consumption fatty acids like n-3 PUFA: EPA and DHA, and MUFA: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. On the other hand, fatty acids that have been associated with the presence or development of obesity, T2D, pro-inflammatory profile, atherosclerosis and IR were n-6 PUFA, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes.
CONCLUSIONS
Fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.
Topics: Animals; Cardiovascular Diseases; Chronic Disease; DNA Methylation; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Epigenesis, Genetic; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Gene-Environment Interaction; Humans; Insulin Resistance; Lipid Metabolism; Obesity; Trans Fatty Acids
PubMed: 31615571
DOI: 10.1186/s12944-019-1120-6