Nutritional Status of Breastfeeding Mothers and Impact of Diet and Dietary Supplementation: A Narrative Review.

Adequate nutrition during breastfeeding is crucial for ensuring the good health of mothers and babies. Despite the high energy and nutrient demands of breastfeeding, lactating women are often vulnerable from a nutritional perspective. The nutritional focus during breastfeeding tends to be on the newborn, often neglecting the mother's diet. Therefore, in the present narrative review, nutrient intakes were compared with the dietary reference values (DRVs) proposed by the European Food Safety Authority (EFSA) as well as by the World Health Organization/Food and Agriculture Organization (WHO/FAO). In the diets of lactating mothers, dietary inadequacies were observed in the intake of some vitamins, such as folic acid, vitamin B12, vitamin A, and vitamin D, and in the intake of certain minerals like calcium, iron, and iodine; polyunsaturated omega-3 fatty acid deficiencies, primarily in eicosapentaenoic acid and docosahexaenoic acid, were also observed. On the other hand, the debate on the necessity of supplementation during lactation continues; the need for nutritional supplementation during lactation depends on many factors, such us mothers' eating habits. There seems to be a positive association between nutritional supplementation of the lactating mother and the concentration of certain nutrients in human milk. The present narrative review provides an update on the nutritional status (fatty acids and micronutrients) of breastfeeding mothers and the impact of diet and dietary supplementation on human milk composition.

Novel transcriptomic signatures associated with premature kidney allograft failure.

BACKGROUND: The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. METHODS: In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. FINDINGS: Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. INTERPRETATION: Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3. FUNDING: Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.

Risk Factors for Perinatal Transmission of Hepatitis C Virus.

OBJECTIVE: To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for perinatal transmission. METHODS: This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody-positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2-6 months (HCV RNA testing) and at 18-24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point. RESULTS: A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0-8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2-11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio [aOR] 8.22, 95% CI 3.16-21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32-8.03). A viremic threshold for perinatal transmission could not be established. CONCLUSION: Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.

Morpho-Physiological Evaluation of Solanum betaceum Cav. In Vitro Cloned Plants: A Comparison of Different Micropropagation Methods.

Tamarillo (Solanum betaceum Cav.) is a subtropical solanaceous tree with increasing agronomic interest due to its nutritious edible fruits. Growing demand for tamarillo plants and fruits requires optimization of existing propagation methods and scaled-up systems for large-scale cloning of selected germplasm. Three in vitro protocols have been used to micropropagate tamarillo: (1) axillary shoot proliferation in a semisolid medium, (2) organogenesis, and (3) somatic embryogenesis procedures. Variables such as the age of the established shoot cultures and rooting treatments were also analyzed. The morphological and physiological quality of acclimatized plants derived from all the methodologies were compared, with seed-derived plants used as a control group. Overall, the results show that in vitro-derived plants have a similar development to seed-derived plants. Micropropagation by axillary shoot proliferation was highly efficient, with rooting rates above 80% in most treatments. Organogenesis induction was more effective from lamina explants using MS media with 2.0 mg·L-1 6-benzylaminopurine. Both organogenesis and somatic embryogenesis-derived plants were also morphologically and physiologically equivalent to seed and axillary shoot-derived plants. The specificities of each micropropagation method are discussed.

Omega-3 and Omega-6 Polyunsaturated Fatty Acid Intakes, Determinants and Dietary Sources in the Spanish Population: Findings from the ANIBES Study.

The multiple roles of polyunsaturated fatty acids (PUFA) in growth and general health are well documented. However, available intake data for the Spanish population are limited and lack gender and age considerations. Therefore, our goal was to assess dietary intake adequacy of omega-3 and omega-6 PUFA, their determinants and their major food sources among the Spanish population. Due to their influence on various beneficial functions attributed to omega-3 PUFA, combined intake adequacy with folic acid (FA), vitamin B12 and choline was also assessed. Intake data were obtained from the ANIBES cross-sectional study on a representative sample of the Spanish population (9-75 years; n = 2009), where dietary intake was analysed with a three-day dietary record. Median intake of total omega-3 PUFA stood at 0.81 g/day (0.56-1.19 g/day), with α-linolenic acid (ALA) at 0.61 g/day (0.45-0.85 g/day), eicosapentaenoic acid (EPA) at 0.03 g/day (0.01-0.12 g/day) and docosahexaenoic acid (DHA) at 0.06 g/day (0.0-0.20 g/day). Accordingly, 65% of the Spanish population showed insufficient intakes for total omega-3 PUFA; 87% for ALA, and 83% for combined EPA and DHA. Inadequate intakes were significantly higher in children, adolescents, and younger women of childbearing age (18-30 years). In contrast, inadequacy due to excessive intakes was almost negligible. Regarding omega-6 PUFA, total intake was 10.1 g/day (7.0-14.0 g/day), 10.0 g/day (6.9-13.9 g/day) for linoleic acid (LA) and 0.08 g/day (0.05-0.13 g/day) for arachidonic acid (AA). Non-compliance due to either insufficient or excessive intakes of LA stood at around 5% of the sample, with the elderly showing significantly higher degrees of inadequacy due to insufficient intakes (10%; p ≤ 0.05). Median omega-6 to omega-3 ratio was 12:1, and significantly higher in men compared to women (p ≤ 0.05); in children, adolescents and adults compared to the elderly (p ≤ 0.05); and in younger women of childbearing age compared to the older group (31-45 years) (p ≤ 0.001). Oils and fats and meat and meat products were the main dietary sources for the essential fatty acids LA and ALA, respectively. Meat and meat products were as well the main providers of AA, while fish and shellfish were almost exclusively the only sources of EPA and DHA. However, main food sources identified showed important differences across age groups. Finally, the total combined degree of inadequacy observed for omega-3 PUFA, FA, vitamin B12 and choline reached 21.3% of the ANIBES population. The observed degree of inadequacy of omega-3 PUFA intakes among the Spanish population makes it urgent to increase its consumption and to consider the need for supplementation. This should also be the main strategy for the optimization of the omega-6/omega-3 ratio, as the adequacy observed for omega-6 intakes is relatively acceptable. Additional improvement of the dietary intake of FA, vitamin B12 and choline could contribute to the beneficial effects of omega-3 PUFA.

Perception and knowledge of low- and no-calorie sweeteners in multidisciplinary stakeholders from Spain.

Low- and no-calorie sweeteners (LNCS) as a category are one of the most thoroughly evaluated additives, and thus their safety has been largely recognised. However, their potential risks and benefits generate great controversy and discussion within countries' food policies and public debate. The goal of this study was to evaluate the degree of knowledge and the perception of key Spanish stakeholders about the role of LNCS in diet, their safety, regulatory issues and their impact on health and wellness, as well as to complete a SWOT analysis of the Strengths, Weaknesses, Opportunities and Threats regarding this topic from their perspective. Participants (n = 45 stakeholders) completed an anonymous survey about their knowledge and perception of LNCS, their role in the diet, safety and legislation, as well as health issues and completed a SWOT analysis. Most of them agreed with aspects related to safety guarantees and authorisation procedure of LNCS; however, certain disparity in their opinion in relation to several of the topics was observed, especially regarding the possible role of LNCS in diet quality and health. Effective communication strategies to inform professionals and the general population, as well as new research that deepens our knowledge of the role of LNCS in weight management and other health outcomes seem to be urgently needed.

Fermentation Extract of Naringenin Increases the Expression of Estrogenic Receptor ß and Modulates Genes Related to the p53 Signalling Pathway, miR-200c and miR-141 in Human Colon Cancer Cells Exposed to BPA.

The estrogenic receptor beta (ERß) protects against carcinogenesis by stimulating apoptosis. Bisphenol A (BPA) is related to promoting cancer, and naringenin has chemoprotective activities both can bind to ERß. Naringenin in the colon is metabolized by the microbiota. Cancer involves genetic and epigenetic mechanisms, including miRNAs. The objective of the present study was to evaluate the co-exposure effect of colonic in vitro fermented extract of naringenin (FEN) and BPA, to elucidate molecular effects in HT-29 colon cancer cell line. For this, we quantified genes related to the p53 signaling pathway as well as ERß, miR-200c, and miR-141. As an important result, naringenin (IC50 250 µM) and FEN (IC50 37%) promoted intrinsic pathways of apoptosis through phosphatase and tensin homolog (PTEN) (+2.70, +1.72-fold, respectively) and CASP9 (+3.99, +2.03-fold, respectively) expression. BPA decreased the expression of PTEN (-3.46-fold) gene regulated by miR-200. We suggest that once co-exposed, cells undergo a greater stress forcing them to mediate other extrinsic apoptosis mechanisms associated with death domain FASL. In turn, these findings are related to the increase of ERß (5.3-fold with naringenin and 13.67-fold with FEN) gene expression, important in the inhibition of carcinogenic development.

Hearing Function and Nutritional Status in Aviation Pilots from Spain Exposed to High Acoustic Damage.

Noise-induced hearing loss is the most frequent and preventable occupational disease. Aviation pilots are a vulnerable population, as they spend many hours exposed to noise pollution in their working environment. Different studies suggest that certain dietary compounds may play a key role in the etiology and prevention of this pathology. We aimed to study the relationship linking auditory function, dietary intake, and some serum biomarkers in pilots, exposed to noise in the work environment. A total of 235 pilots, who undergo a periodic medical examination at the Centro de Instrucción de Medicina Aeroespacial (Madrid, SPAIN), were evaluated. Auditory function was assessed by tonal audiometry. Energy and nutrient intakes were estimated by 24 h recall (DIALTM program). Serum homocysteine (Hcy) was determined in a Cobas 6000TM multi-analyzer while folate, vitamin B12, and D were analyzed in a Cobas e411TM. The prevalence of hearing loss (HL) was 64.3%. HL was significantly related to age (r = 0.588, p ≤ 0.001) and flight hours (r = 0.283, p ≤ 0.001). A multiple linear regression model was used to assess the relationship among HL, flight hours, serum folate, and Hcy serum levels. HL was significantly (p < 0.050) associated with flight hours (ß = 0.246), serum folate (ß = −0.143), and serum Hcy (ß = 0.227). Nutritional interventions would be of great interest to monitor and slow down the HL progression in populations exposed to noise pollution in their workplace.

A Descriptive Analysis of Macronutrient, Fatty Acid Profile, and Some Immunomodulatory Nutrients in Standard and Disease-Specific Enteral Formulae in Europe.

Foods for special medical purposes (FSMPs) are commercially available formulations used as a source of nutrition when administered orally or by tube feeding. This study examines, for the first time, the nutritional composition of enteral formulae (EFs) according to European nutritional guidelines. We developed a descriptive study on 118 EFs from 2020 to 2021. Formulae were classified as standard (SFs) and disease-specific (DSF). According to the protein-energy content, SFs were classified into G1, normoprotein-normocaloric; G2, normoprotein-hypercaloric; G3, hyperproteic-normocaloric; and G4, hyperproteic-hypercaloric. Disease-related formulae for metabolic stress, renal, cancer, pulmonary, diabetes, malabsorption, and surgery were studied. Macronutrient distribution, fatty acid profile (monounsaturated [MUFA], polyunsaturated [PUFA], saturated [SFA]), derived fat quality indexes, and immuno-modulatory nutrients (omega-3, eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], arginine and nucleotides) per 1,500 kcal infused were calculated. In total, 53% were SFs, mainly normoproteic (G1, G2) with higher carbohydrate contents in normocaloric vs. hypercaloric SFs. The most balanced fatty acid profiles (MUFA: 17.7%; PUFA: 6.8%; SFA: 9.5%) belonged to G1. The PUFA/MUFA ratio: ≥0.5 was in 85.7% with a higher proportion of EPA+DHA (46%) vs. omega-3 (15.8%) in SFs. In DSFs (46.9%), higher carbohydrate content (>50%) was in malabsorption and surgery, whereas high-fat content (>50%) was in pulmonary and renal formulae. DSFs had higher SFA vs. MUFA content, except for diabetes. EPA and DHA were added in 45.5% (cancer, malabsorption, and surgery). Only 12.7% of DSFs had arginine and nucleotides. A higher proportion of SFs was found, in line with current European guidelines. Results highlighted a wide intra-group variability of nutrients among the formula selected. These findings are useful to evaluate the nutritional composition of EFs from a preventive and/or therapeutic perspective in clinical settings.

Iron Supplementation at the Crossroads of Nutrition and Gut Microbiota: The State of the Art.

Gut microbiota has received significant attention owing to its decisive role in human health and disease. Diet exerts a significant influence on the variety and number of bacteria residing in the intestinal epithelium. On the other hand, as iron is a key micronutrient for blood formation and oxygen supply, its deficiency is highly prevalent worldwide. In fact, it is the most common cause of anemia and thus, iron supplementation is widespread. However, there is concern due to some potential risks linked to iron supplementation. Therefore, we have reviewed the available evidence of the effects that iron supplementation exerts on the gut microbiota as well as its potential benefits and risks. The compiled information suggests that iron supplementation is potentially harmful for gut microbiota. Therefore, it should be performed with caution, and by principle, recommended only to individuals with proven iron deficiency or iron-deficiency anemia to avoid potential adverse effects. In any case, large and long-term population studies are urgently needed to confirm or refute these results, mainly focused on vulnerable populations.

Low- and No-Calorie Sweetener (LNCS) Presence and Consumption among the Portuguese Adult Population.

The use of low and no-calorie sweeteners (LNCS) in food and beverages has become increasingly common in the development and reformulation of products to reduce energy derived from added sugars. Our aim was to identify the presence and consumption of LNCS through food and beverages according to consumption patterns in a representative sample (n = 256) of the Portuguese adult population. The study had a descriptive cross-sectional observational design and was based on the application of a Food Frequency Questionnaire. Overall, it was found that 4.1% of the foods and 16.7% of the beverages consumed by the Portuguese adult population contained LNCS. Food groups mostly contributing to LNCS consumption were non-alcoholic beverages such as soft drinks and juices (34.2%); milk and dairy products (16.5%); appetizers such as chips (8.6%); sugars and sweets such as chocolates, candies, or chewing gums (6.1%); meat and derivative products (2.2%); cereals and derivatives (1.2%) and canned fruits (1.2%). Main LNCS consumed were acesulfame-K, sucralose, and aspartame, single or combined, although their prevalence of use differs greatly among foods, beverages, or tabletop sweeteners. In conclusion, LNCS were found across a wide variety of products available in the Portuguese market and their prevalence of inclusion in the diet of the population evidences the need to develop more studies on the evolution of LNCS intake and its impact on the full dietary model and health. Consequently, these food additives should be included in food composition databases and, periodically, updated to reflect the recurrent reformulation strategies adopted by the food industry in its efforts to reduce the energy contribution of added sugars.

Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer's Disease: A Narrative Review.

Cognitive impairment and Alzheimer's Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer's Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer's Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings.

How a concentration-effect analysis of data from the eliglustat thorough electrocardiographic study was used to support dosing recommendations.

Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have cytochrome P450 (CYP) 2D6 extensive, intermediate, or poor metabolizer phenotypes. Per International Conference on Harmonisation (ICH) E14 guidance, a Phase 1 thorough electrocardiographic (ECG) study was done during drug development to assess eliglustat's effects on cardiac repolarization by measuring ECG intervals in healthy adult subjects. Using data from the thorough ECG study, we performed pharmacokinetic/pharmacodynamic-ECG modeling to establish the relationship between eliglustat concentrations and their effects on ECG intervals. We then used that concentration-response relationship to predict the effects of eliglustat on each ECG interval for each CYP2D6 metabolizer phenotype (the main determinant of eliglustat exposure) and in different drug-drug interaction scenarios. These predictions, together with other exposure-related factors, contributed to the CYP2D6 phenotype-based dosing recommendations for eliglustat, including dose adjustments and contraindications when co-administered with drugs metabolized by the CYP2D6 and CYP3A pathways.

STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1ß isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1α/α) or the STAT1ß (Stat1ß/ß ) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1ß/ß mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1ß/ß mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1ß/ß mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

Effectiveness of Community-Based Interventions Programs in Childhood Obesity Prevention in a Spanish Population According to Different Socioeconomic School Settings.

Overweight and obesity amongst childhood are currently global health issues. However, this is the best stage of life to prevent diseases and to promote healthy habits. In our study, we evaluate the effectiveness of the THAO Salud Infantil, a community-based intervention program, by means of a cross-sectional study carried out from 2009 to 2019 surveying children aged 3 to 12 years old (n = 27,686). During the study timeframe, overweight and obesity prevalence, according to both the International Obesity Task Force and Orbegozo Foundation criteria, showed a downward trend. Differences in the anthropometric variables were observed from the beginning to the end of the study, mainly in girls. Analysis of the influence of the socioeconomic status revealed that children from families with lower incomes are in greater risk of suffering from overweight and obesity and showed lower effectiveness of the actions proposed by the program. The overall results of the study confirmed the effectiveness of community-based interventions in terms of childhood overweight/obesity prevention.

Derivation and external validation of the SIMPLICITY score as a simple immune-based risk score to predict infection in kidney transplant recipients.

Existing approaches for infection risk stratification in kidney transplant recipients are suboptimal. Here, we aimed to develop and validate a weighted score integrating non-pathogen-specific immune parameters and clinical variables to predict the occurrence of post-transplant infectious complications. To this end, we retrospectively analyzed a single-center derivation cohort of 410 patients undergoing kidney transplantation in 2008-2013 in Madrid. Peripheral blood lymphocyte subpopulations, serum immunoglobulin and complement levels were measured at one-month post-transplant. The primary and secondary outcomes were overall and bacterial infection through month six. A point score was derived from a logistic regression model and prospectively applied on a validation cohort of 522 patients undergoing kidney transplantation at 16 centers throughout Spain in 2014-2015. The SIMPLICITY score consisted of the following variables measured at month one after transplantation: C3 level, CD4+ T-cell count, CD8+ T-cell count, IgG level, glomerular filtration rate, recipient age, and infection within the first month. The discrimination capacity in the derivation and validation cohorts was good for overall (areas under the receiver operating curve of 0.774 and 0.730) and bacterial infection (0.767 and 0.734, respectively). The cumulative incidence of overall infection significantly increased across risk categories in the derivation (low-risk 13.7%; intermediate-risk, 35.9%; high-risk 77.6%) and validation datasets (10.2%, 28.9% and 50.4%, respectively). Thus, the SIMPLICITY score, based on easily available immune parameters, allows for stratification of kidney transplant recipients at month one according to their expected risk of subsequent infection.

Effect of eliglustat on the pharmacokinetics of digoxin, metoprolol, and oral contraceptives and absorption of eliglustat when coadministered with acid-reducing agents.

Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess the potential for drug-drug interactions between eliglustat and digoxin (P-glycoprotein substrate), metoprolol (sensitive CYP2D6 substrate), a combined oral contraceptive (CYP3A substrate), and acid-reducing agents. Healthy subjects were enrolled in four Phase 1 clinical studies to evaluate the effect of eliglustat on the pharmacokinetics, safety, and tolerability of digoxin (N = 28), metoprolol (N = 14), and a combined oral contraceptive (N = 30) and the effect of acid-reducing agents on eliglustat pharmacokinetics, safety, and tolerability (N = 24). Coadministration resulted in increased exposure to digoxin (1.49-fold) and metoprolol (2-fold) with eliglustat, negligible effects on oral contraceptive pharmacokinetics with eliglustat, and a negligible effect of acid-reducing agents on eliglustat pharmacokinetics. Across all studies, eliglustat was well-tolerated. One serious adverse event (spontaneous abortion) and one discontinuation due to an adverse event (urinary tract infection) were reported, both during the acid-reducing agents study. When eliglustat is coadministered with medications that are P-glycoprotein or CYP2D6 substrates, lower doses of these concomitant medications may be required. Eliglustat may be coadministered with oral contraceptives and acid-reducing agents without dose modifications for either drug.