Exploring the relationship between emotion regulation, inhibitory control, and eating psychopathology in a non-clinical sample.

OBJECTIVE: The present study aimed to explore the relationship between difficulties in emotion regulation and deficits in inhibitory control, and the role of these processes in eating psychopathology in a non-clinical sample. We also explored the specificity in which deficits in inhibitory control may underlie eating psychopathology, namely whether they can be conceptualised as context specific or more extensive in nature. METHOD: Participants were 107 healthy individuals recruited at a major Portuguese university, aged between 18 and 43 years-old (M = 21.23, SD = 4.79). Two computerised neuropsychological tasks (i.e., emotional go/no-go and food go/no-go tasks) were used to assess response inhibition in the presence of general versus context-specific stimuli. A set of self-report measures was used to assess variables of interest such as emotion regulation and eating psychopathology. RESULTS: Results indicated higher response inhibition deficits among participants with higher difficulties in emotion regulation comparing to those with lower difficulties in emotion regulation, particularly in the context of food-related stimuli. In addition, the relationship between difficulties in emotion regulation and eating psychopathology was moderated by inhibitory control deficits in both the context of food and pleasant stimuli. CONCLUSIONS: The present findings highlight inhibitory control as an important process underlying the relationship between difficulties in emotion regulation and eating psychopathology in non-clinical samples. Findings have important implications for clinical practice and the prevention of eating psychopathology in healthy individuals and individuals with eating disorders.

Temperature and microclimate refugia use influence migratory timings of a threatened grassland bird.

BACKGROUND: Seasonal changes in resource availability are known to influence the migratory behaviour of animals, including both timing and distance. While the influence of environmental cues on migratory behaviour has been widely studied at the population level, it has rarely been examined at the spatial scale at which individuals experience their environment. Here, we test the hypothesis that individuals exposed to similar large-scale environmental cues may vary in migratory behaviour in response to the different microclimate conditions they experience at fine scales. METHODS: We combine high-spatial and temporal resolution microclimate and habitat information with GPS tracking data for a partially migratory threatened grassland bird. Data from 47 little bustards (Tetrax tetrax; 67 breeding events) tracked between 2009 and 2019 was used to (i) evaluate individual consistency in migratory behaviour (timing and distance) and (ii) assess whether the local environmental characteristics experienced by individuals - and in particular their use of microclimate refugia - influence distance and timing of migration, from and to the breeding sites. RESULTS: Migratory distance was consistent for birds tracked over multiple years, while the timing of migration showed high variability among individuals. Departures from breeding areas spanned from May to August, with a few birds remaining in their breeding areas. Vegetation greenness (a proxy for food availability) was positively associated with the time birds spent in the breeding area. The best model also included a positive effect of microclimate refugia availability on breeding season length, although an interaction with temperature suggested that this effect did not occur at the highest relative temperatures. The return date to breeding grounds, although spanning from September to April, was not influenced by the environmental conditions or food availability. CONCLUSIONS: Food availability, measured by a vegetation greenness proxy, was associated with later migration at the end of the breeding season. Availability of cooler microclimate refugia may also allow for later departures from the breeding sites in all but the hottest conditions. Management measures that increase microclimate refugia availability and provide foraging resources can thus potentially increase the length of the breeding season for this species.

Corrigendum: Severe and enduring' stage in anorexia nervosa: comparing eating attitudes, impairment and associated psychopathology.

[This corrects the article DOI: 10.3389/fnut.2022.867401.].

Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

Eating disorders during lockdown: the transcultural influence on eating and mood disturbances in Ibero-Brazilian population.

BACKGROUND: COVID-19 pandemic has implied exceptional restrictive measures to contain its widespread, with adverse consequences on mental health, especially for those people with a background of mental illness, such as eating disorders (EDs). In this population, the influence of socio-cultural aspects on mental health has been still underexplored. Then, the main aim of this study was to assess changes in eating and general psychopathology in people with EDs during lockdown regarding the ED subtype, age, and provenance, and considering socio-cultural aspects (e.g., socioeconomical factors such as work and financial losses, social support, restrictive measures, or health accessibility, among others). METHODS: The clinical sample was composed of 264 female participants with EDs (74 anorexia nervosa (AN), 44 bulimia nervosa (BN), 81 binge eating disorder (BED), and 65 other specified feeding and eating disorder (OSFED)), with a mean age of 33.49 years old (SD = 12.54), from specialized ED units in Brazil, Portugal, and Spain. The participants were evaluated using the COVID-19 Isolation Eating Scale (CIES). RESULTS: A global impairment in mood symptoms and emotion regulation was reported in all the ED subtypes, groups of age, and countries. Spanish and Portuguese individuals seemed more resilient than Brazilian ones (p < .05), who reported a more adverse socio-cultural context (i.e., physical health, socio-familial, occupational, and economic status) (p < .001). A global trend to eating symptoms worsening during lockdown was observed, regardless of the ED subtype, group of age, and country, but without reaching statistical significance. However, the AN and BED groups described the highest worsening of the eating habits during lockdown. Moreover, individuals with BED significantly increased their weight and body mass index, similarly to BN, and in contrast to the AN and OSFED groups. Finally, we failed to find significant differences between groups of age although the younger group described a significant worsening of the eating symptoms during lockdown. CONCLUSIONS: This study reports a psychopathological impairment in patients with EDs during lockdown, being socio-cultural aspects potential modulatory factors. Individualized approaches to detect special vulnerable groups and long-term follow-ups are still needed.

Combining bird tracking data with high-resolution thermal mapping to identify microclimate refugia.

Elevated temperatures can have a range of fitness impacts, including high metabolic cost of thermoregulation, hence access to microclimate refugia may buffer individuals against exposure to high temperatures. However, studies examining the use of microclimate refugia, remain scarce. We combined high resolution microclimate modelling with GPS tracking data as a novel approach to identify the use and availability of cooler microclimate refugia (sites > 0.5 °C cooler than the surrounding landscape) at the scales experienced by individual animals. 77 little bustards (Tetrax tetrax) were tracked between 2009 and 2019. The 92,685 GPS locations obtained and their surrounding 500 m areas were characterised with hourly temperature and habitat information at 30 m × 30 m and used to determine microclimate refugia availability and use. We found that the semi-natural grassland landscapes used by little bustards have limited availability of cooler microclimate areas-fewer than 30% of the locations. The use of cooler microclimate sites by little bustards increased at higher ambient temperatures, suggesting that individuals actively utilise microclimate refugia in extreme heat conditions. Microclimate refugia availability and use were greater in areas with heterogeneous vegetation cover, and in coastal areas. This study identified the landscape characteristics that provide microclimate opportunities and shelter from extreme heat conditions. Little bustards made greater use of microclimate refugia with increasing temperatures, particularly during the breeding season, when individuals are highly site faithful. This information can help identify areas where populations might be particularly exposed to climate extremes due to a lack of microclimate refugia, and which habitat management measures may buffer populations from expected increased exposure to temperature extremes.

Bile acids profile and redox status in healthy infants.

BACKGROUND: At birth, human neonates are more likely to develop cholestasis and oxidative stress due to immaturity or other causes. We aimed to search for a potential association between bile acids profile, redox status, and type of diet in healthy infants. METHODS: A cross-sectional, exploratory study enrolled 2-month-old full-term infants (n = 32). We measured plasma bile acids (total and conjugated), and red blood cell (RBC) oxidative stress biomarkers. The type of diet (breastfeeding, mixed, formula) was used as an independent variable. RESULTS: Plasma total bile acids medium value was 14.80 µmol/L (IQR: 9.25-18.00). The plasma-conjugated chenodeoxycholic acid percentage (CDCA%) correlated significantly and negatively with RBCs membrane-bound hemoglobin percentage (MBH%) (r = -0.635, p < 0.01) and with RBC-oxidized glutathione (r = -0.403, p < 0.05) levels. RBC oxidative stress biomarkers (especially MBH%) were predictors of conjugated CDCA%, and this predictive ability was enhanced when adjusted for the type of diet (MBH, r = 0.452, p < 0.001). CONCLUSIONS: Our data suggest that the bile acid profile might play a role in the regulation of redox status (or vice versa) in early postnatal life. Eventually, the type of diet may have some impact on this process. IMPACT: The conjugated CDCA% in plasma is negatively correlated with biomarkers of RBC oxidative stress in healthy infants. Specific biomarkers of RBC oxidative stress (e.g. MBH, GSH, GSSG) may be promising predictors of conjugated CDCA% in plasma. The type of diet may influence the predictive ability of hit RBC oxidative stress biomarkers (e.g. MBH, GSH, GSSG). Our findings suggest a link between plasma bile acids profile and the RBC redox status in healthy infants, eventually modulated by the type of diet. The recognition of this link may contribute to the development of preventive and therapeutic strategies for neonatal cholestasis.

The mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and difficulties in emotion regulation.

OBJECTIVE: Difficulties in emotion regulation are thought to play a transdiagnostic role across eating disorders (ED). In the current study, we explored with a path analysis the mediating role of self-criticism, experiential avoidance and negative urgency on the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation. METHOD: Participants were 103 female outpatients recruited at a Portuguese ED hospital unit, diagnosed with an ED, aged 14-60 years old (M = 28.0, SD = 10.5), body mass index (BMI) ranging from 11.72 to 39.44 (M = 20.1, SD = 5.4). RESULTS: The path analysis resulted in a model with an adequate fit to the data (SRMR = 0.05; RMSEA = 0.07 [0.00, 0.12], PCLOSE = 0.269; TLI = 0.97; IFI = 0.99; GFI = 0.95). A final model in which the relationship between ED-related symptoms and dimensions of difficulties in emotion regulation was mediated by self-criticism, experiential avoidance and negative urgency, accounted for a variance of 71% for strategies, 57% for non-acceptance, 62% for impulses, 56% for goals and 20% for clarity. CONCLUSION: Results suggest that self-criticism, experiential avoidance and negative urgency, combined, are relevant in the relationship between ED-related symptoms and difficulties in emotion regulation. ED treatment and emotion regulation skills may be enhanced through the inclusion of specific components that target self-criticism, experiential avoidance and negative urgency, as they become prominent during the therapeutic process.

Severe and Enduring' Stage in Anorexia Nervosa: Comparing Eating Attitudes, Impairment and Associated Psychopathology.

This study aimed to assess differences in eating attitudes, impairment, and related psychopathology at treatment presentation for patients with "Non-severe and enduring Anorexia Nervosa" (illness duration of <7 years) and patients with "severe and enduring Anorexia Nervosa" (illness duration of 7 years or more). One hundred and thirty-nine patients diagnosed with Anorexia Nervosa participated in this study. Participants were interviewed with the Eating Disorder Examination (EDE) and asked to complete several questionnaires at the end of the first treatment appointment. We also explored differences at treatment presentation by considering alternative criteria to define groups, namely a composite of illness duration and clinical impairment (≥16 CIA total score). No differences were found when comparing participants based on illness duration. However, when participants were classified into a different classification scheme: "Non-severe and enduring Anorexia Nervosa" (illness duration <7 years and a CIA total score <16) vs. "severe and enduring Anorexia Nervosa" (illness duration ≥7 years and CIA total score ≥16), significant differences were found in terms of eating pathology, depressive symptomatology, psychological distress, and emotion dysregulation. Further research is needed to better understand the role of illness duration and clinical impairment in informing the course of AN.

Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.

Cortical auditory evoked potentials in 1-month-old infants predict language outcomes at 12 months.

The neurophysiological assessment of infants in their first developmental year can provide important information about the functional changes of the brain and supports the study of behavioral and developmental characteristics. Infants' cortical auditory evoked potentials (CAEPs) reflect cortical maturation and appear to predict subsequent language abilities. This study aimed to identify CAEP components to two auditory stimulus intensities in 1-month-old infants and to understand how these are associated with social interactive and self-regulatory behaviors. In addition, it examined whether CAEPs predicted developmental outcomes when infants were assessed at 12 months of age. At 1 month, P2 and N2 components were present for both auditory stimulus intensities, with an increased P2 amplitude being observed for the higher-intensity stimuli. We also observed that an increased P2 amplitude in the lower intensity predicted receptive and expressive language competencies at 12 months. These results are consistent with previous findings indicating an association between auditory processing and developmental outcomes in infants. This study suggests that specific auditory neurophysiological markers are associated with developmental outcomes in the first developmental year.

Small Molecule Fisetin Modulates Alpha-Synuclein Aggregation.

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson's Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.

Impacts of sheep versus cattle livestock systems on birds of Mediterranean grasslands.

Mediterranean pastures are experiencing strong changes in management, involving shifts from sheep to cattle-based livestock systems. The impacts of such shifts on biodiversity are still poorly understood. Here, we sought to contrast the grazing regime, vegetation structure, bird species richness and abundance, between sheep and cattle grazed parcels, to understand the mechanisms through which management decisions impact farmland birds. During spring 2019, we characterized livestock management, bird populations and sward structure in 23 cattle and 27 sheep grazed parcels. We used a Structural Equation Model to infer the direct and indirect effects of sheep and cattle grazing on birds. Although no effects were found on overall species richness, there were species-specific responses to sheep and cattle grazed systems. Grazing pressure (variable integrating stocking rate and the number of days in the parcel) had negative impacts on the prevalence/abundance of Zitting Cisticola, Corn Bunting and Little Bustard, either directly or indirectly, through the effects of grazing pressure on vegetation height. Animal density and vegetation cover had direct positive effects in Galerida spp. and Common Quail, respectively. Zitting Cisticola and Little Bustard also showed a direct response to livestock type. Our study emphasizes the importance of grazing pressure as a driver of negative impacts for bird populations in Mediterranean grasslands. Since the ongoing transition from sheep to cattle-based systems involves increases in stocking rate, and therefore potentially higher grazing pressure, we propose a policy change to cap the maximum allowed grazing pressure. At the landscape scale, a mix of sheep and cattle grazed fields would be beneficial for maintaining bird diversity.

Impact of COVID-19 lockdown measures on a cohort of eating disorders patients.

BACKGROUND: Lockdown implemented to prevent the COVID-19 spread resulted in marked changes in the lifestyle. The objective of the current study was to assess the impact of lockdown measures on a cohort of eating disorder (ED) patients being followed as part of an ongoing naturalistic treatment study. METHODS: Ninety-nine patients aged 18 or older, currently or previously, in treatment at a Portuguese specialized hospital unit were contacted by phone and invited to participate in the current survey. Fifty-nine agreed to be interviewed by phone, and 43 agreed to respond to a set of self-report measures of ED symptoms, emotion regulation difficulties, clinical impairment, negative urgency, and COVID-19 impact, during the week after the end of the lockdown period. RESULTS: Data showed that of the 26 patients currently in treatment: 8 remained unchanged (31%), 7 deteriorated (27%), and 11 reliably improved (42%). Of the 17 participants not currently in treatment: 3 deteriorated (18%), 9 remained unchanged (53%), and 5 (29%) improved after the lockdown period. The Coronavirus Impact Scale showed that most patients considered their routines moderately or extremely impacted, experienced stress related to coronavirus, and showed difficulty in maintaining physical exercise and feeding routines. Results suggest that higher impact of COVID-19 lockdown was significantly correlated with eating disorder symptoms and associated psychopathology, impulsivity, difficulties in emotion regulation and clinical impairment measured at post-lockdown. In addition, the impact of COVID-19 and lockdown measures on clinical impairment was mediated by difficulties in emotion regulation. CONCLUSIONS: Findings suggest that some ED patients may experience worsening of their condition, especially if associated with difficulties in emotion regulation, and these difficulties might be exacerbated in the context of a stressful crisis and lockdown measures, highlighting the need for intervention strategies to mitigate its negative impact.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

AIM: This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. METHODS: This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. RESULTS: Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. CONCLUSION: Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Autoimmune Pancreatitis in an Adolescent: A Diagnostic Challenge.

Autoimmune pancreatitis (AIP) is a distinct subtype of pancreatitis, rare in the pediatric population. Its pathophysiology is poorly understood. A pancreatic focal mass is frequently the clinical presentation, which imposes the differential diagnosis with a pancreatic tumor. This distinction is essential because the treatment of pancreatic tumors is surgical in contrast to the treatment of AIP, which is pharmacological. We describe a case of a 16-year-old girl with AIP who presented with obstructive jaundice, weight loss, fatigue, and a pancreatic mass. This case emphasizes the importance of considering this diagnosis to correctly treat and prevent an abusive pancreatic resection.

A pancreatite autoimmune (PAI) é um subtipo distinto de pancreatite, raro na população pediátrica, e com fisiopatologia ainda pouco conhecida. A apresentação clínica com massa pancreática é frequente, o que impõe o diagnóstico diferencial com neoplasia pancreática. A distinção entre estas duas entidades é fundamental uma vez que o tratamento dos tumores pancreáticos é cirúrgico, ao contrário da terapêutica farmacológica da PAI. Descrevemos o caso de uma adolescente de 16 anos diagnosticada com PAI, cujas manifestações clínicas foram icterícia obstrutiva, perda de peso, fadiga e massa pancreática. Realçamos a importância da suspeição e reconhecimento deste diagnóstico, para uma adequada intervenção terapêutica, que pode obstar a uma abusiva resseção pancreática.

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases.

Plants are a reservoir of high-value molecules with underexplored biomedical applications. With the aim of identifying novel health-promoting attributes in underexplored natural sources, we scrutinized the diversity of (poly)phenols present within the berries of selected germplasm from cultivated, wild, and underutilized Rubus species. Our strategy combined the application of metabolomics, statistical analysis, and evaluation of (poly)phenols' bioactivity using a yeast-based discovery platform. We identified species as sources of (poly)phenols interfering with pathological processes associated with redox-related diseases, particularly, amyotrophic lateral sclerosis, cancer, and inflammation. In silico prediction of putative bioactives suggested cyanidin-hexoside as an anti-inflammatory molecule which was validated in yeast and mammalian cells. Moreover, cellular assays revealed that the cyanidin moiety was responsible for the anti-inflammatory properties of cyanidin-hexoside. Our findings unveiled novel (poly)phenolic bioactivities and illustrated the power of our integrative approach for the identification of dietary (poly)phenols with potential biomedical applications.

Perceived Well-Being, Social Support, and Self-Management Behavior among Women Experiencing Chemotherapy-Related Nausea and Vomiting in A Tertiary Hospital in Lahore, Pakistan.

OBJECTIVE: The basic objective is to determine the level of the self-management behaviors (SMB), perceived well-being, and social support of patients in the outpatient settings at tertiary care hospital at Lahore Pakistan. It also explores if there is any significant relationship among all three variables. METHODS: A descriptive-correlational study design has been used. The data have been collected at single setting of 32-bedded chemotherapy unit of a tertiary care hospital of Pakistan. The purposive sampling method has been employed. The IBM SPSS version 20 (IBM Corp., Armonk, NY, USA) has been utilized for statistical analyses. RESULTS: A total of 317 patients' data were analyzed. The average age of patients was 42 years, and they received chemotherapy for different cancers. It was revealed that the SMB, for example, taking anti-emetics on time, and applying physical and cognitive distractions, have strong association with psychological, social, physical, and emotional dimensions of the perceived well-being. Similar self-managing strategies have associations with the provision of social support from the health-care team, personal, and family side. CONCLUSIONS: To conclude, the most common self-care methods of women receiving chemo are pharmacological management, applying physical and cognitive distraction, executing relaxation measures to control chemo-induced nausea.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.