Impact of liver diseases and pharmacological interactions on the transportome involved in hepatic drug disposition.

The liver plays a pivotal role in drug disposition owing to the expression of transporters accounting for the uptake at the sinusoidal membrane and the efflux across the basolateral and canalicular membranes of hepatocytes of many different compounds. Moreover, intracellular mechanisms of phases I and II biotransformation generate, in general, inactive compounds that are more polar and easier to eliminate into bile or refluxed back toward the blood for their elimination by the kidneys, which becomes crucial when the biliary route is hampered. The set of transporters expressed at a given time, i.e., the so-called transportome, is encoded by genes belonging to two gene superfamilies named Solute Carriers (SLC) and ATP-Binding Cassette (ABC), which account mainly, but not exclusively, for the uptake and efflux of endogenous substances and xenobiotics, which include many different drugs. Besides the existence of genetic variants, which determines a marked interindividual heterogeneity regarding liver drug disposition among patients, prevalent diseases, such as cirrhosis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and several cholestatic liver diseases, can alter the transportome and hence affect the pharmacokinetics of drugs used to treat these patients. Moreover, hepatic drug transporters are involved in many drug-drug interactions (DDI) that challenge the safety of using a combination of agents handled by these proteins. Updated information on these questions has been organized in this article by superfamilies and families of members of the transportome involved in hepatic drug disposition.

Cost-effectiveness study of prophylaxis with emicizumab versus bypassing agents in patients with severe hemophilia A in Peru. / Estudio de costo-efectividad de profilaxis con emicizumab versus agentes hemostáticos alternativos en pacientes con hemofilia A grave en Perú.

Settings: Hemophilia is a coagulation disorder that occurs in one in 5000 male births. Patients with untreated severe hemophilia A have hemorrhagic complications, including joint bleeds and decreased survival. Emicizumab is a monoclonal antibody approved by the United States for routine prophylaxis of pediatric and adult patients with severe hemophilia A with factor VIII inhibitors. Objectives: To perform a cost-effectiveness study of emicizumab prophylaxis for children and adults with severe hemophilia A compared with the current disease management in the Peruvian Ministry of Health and Social Security Health Insurance. Methods: The patient transition between medical states was modeled with Markov methodology, and the lifetime costs and incremental effects of emicizumab compared to current management were estimated. The budgetary impact of emicizumab was estimated by projecting annual net costs and its five-year present value. Results: In the Ministry of Health, emicizumab would generate savings between 14.6 and 16.0 per child and 11.8 per adult, in current US$ million. Social Security Health Insurance savings would be 12.8 to 14.9 per child and 40.1 per adult. In addition, this strategy would generate effectiveness gains, measured in quality-adjusted life-years, of 0.36 per child and 0.56 per adult and 0.25 per child, and 0.36 per adult in those respective institutions. The budgetary impact would be a net annual saving of 12.8 and 15.0 US$ million in those entities. Conclusions: The current management of hemophilia A is very costly and has health outcomes inferior to those possible with emicizumab. This drug would produce significant savings and better patient health. The Ministry of Health and Social Health Insurance should implement hemophilia prophylaxis and treatment protocols and finance this drug.

Contexto: La hemofilia es un trastorno hemorrágico de la coagulación que ocurre en uno de cada 5000 nacimientos masculinos. Los pacientes con hemofilia A grave no tratados tienen complicaciones hemorrágicas, incluyendo sangrados articulares y menor sobrevida. El emicizumab es un anticuerpo monoclonal aprobado por los Estados Unidos para la profilaxis rutinaria de pacientes pediátricos y adultos con hemofilia A grave con inhibidores del factor VIII de coagulación. Objetivos: Realizar un estudio de costo-efectividad de la profilaxis con emicizumab para niños y adultos con hemofilia A grave, en comparación con el actual manejo de esos pacientes en el Ministerio de Salud y el Seguro Social de Salud de Perú. Metodología: Se modeló la transición del paciente entre estados médicos con la metodología de Markov y se estimó a lo largo de su vida costos y efectos incrementales de emicizumab comparados con el actual manejo. Se estimó el impacto presupuestario de emicizumab proyectando costos netos anuales y su valor presente a cinco años. Resultados: Emicizumab generaría ahorros en el Ministerio de Salud entre 14,6 y 16,0 por niño y 11,8 por adulto, en US$ millones actuales, y en el Seguro Social de Salud de 12,8 a 14,9 por niño y 40,1 por adulto. Además, se generan ganancias en efectividad, medidas en años de vida ajustados por calidad, de 0,36 por niño y 0,56 por adulto y de 0,25 por niño y 0,36 por adulto en esas respectivas instituciones. El impacto presupuestario sería un ahorro anual neto, en US$ millones, de 12,8 y 15,0 en esas entidades. Conclusión: El actual manejo de la enfermedad es muy costoso y con resultados de salud inferiores a los posibles con emicizumab. Este fármaco produciría grandes ahorros y mejor salud. Ambas entidades debieran implementar protocolos para la profilaxis y tratamiento de la hemofilia y financiarla con presupuesto propio.

Salt content in bread in Spain, 2014.

INTRODUCTION: excess salt intake is associated to the risk of cardiovascular diseases. Bread is one of the foods that contributes the most salt to the diet in Spain. It is important to monitor the salt content of bread. OBJECTIVE: to quantify the amount of salt in bread in Spain in 2014, and to compare it to the amount of salt in 2008. METHODS: this cross-sectional study was conducted in Spain in 2014, and 1,137 loaves of bread (three types: barra, a Spanish style, similar in shape to a baguette; baguettes and wholemeal) were purchased at bakeries with and without on-site workrooms and at supermarkets in all of Spain's autonomous communities. Salt content (g/100 g bread) was estimated by determining total sodium. In one subsample, mean salt content was estimated by determining chlorides; it was compared to previous data of 2008 salt content (chloride determination). RESULTS: the mean salt content was 2.08 g/100 g (SD: 0.32) with a minimum value of 0.30 and a maximum of 3.33. The mean salt content was similar in barraand baguette-type breads (2.09 g/100 g) and somewhat lower in wholemeal. The mean salt was 2.07 g/100 g in breads made with fresh dough and 2.12 g/100 g in breads made with frozen dough. The mean salt content (chlorides) was 1.64 g/100 g (SD: 0.42) in 2014 and 1.63 g/100 g (SD: 0.37) in 2008. This was not a significant difference (p = 0.428). CONCLUSIONS: the amount of salt in common bread in Spain remains stable from 2008.

Estudio de costo-efectividad de profilaxis con emicizumab versus agentes hemostáticos alternativos en pacientes con hemofilia A grave en Perú / Cost-effectiveness study of prophylaxis with emicizumab versus bypassing agents in patients with severe hemophilia A in Peru

Contexto La hemofilia es un trastorno hemorrágico de la coagulación que ocurre en uno de cada 5000 nacimientos masculinos. Los pacientes con hemofilia A grave no tratados tienen complicaciones hemorrágicas, incluyendo sangrados articulares y menor sobrevida. El emicizumab es un anticuerpo monoclonal aprobado por los Estados Unidos para la profilaxis rutinaria de pacientes pediátricos y adultos con hemofilia A grave con inhibidores del factor VIII de coagulación. Objetivos Realizar un estudio de costo-efectividad de la profilaxis con emicizumab para niños y adultos con hemofilia A grave, en comparación con el actual manejo de esos pacientes en el Ministerio de Salud y el Seguro Social de Salud de Perú. Metodología Se modeló la transición del paciente entre estados médicos con la metodología de Markov y se estimó a lo largo de su vida costos y efectos incrementales de emicizumab comparados con el actual manejo. Se estimó el impacto presupuestario de emicizumab proyectando costos netos anuales y su valor presente a cinco años. Resultados Emicizumab generaría ahorros en el Ministerio de Salud entre 14,6 y 16,0 por niño y 11,8 por adulto, en US$ millones actuales, y en el Seguro Social de Salud de 12,8 a 14,9 por niño y 40,1 por adulto. Además, se generan ganancias en efectividad, medidas en años de vida ajustados por calidad, de 0,36 por niño y 0,56 por adulto y de 0,25 por niño y 0,36 por adulto en esas respectivas instituciones. El impacto presupuestario sería un ahorro anual neto, en US$ millones, de 12,8 y 15,0 en esas entidades. Conclusión El actual manejo de la enfermedad es muy costoso y con resultados de salud inferiores a los posibles con emicizumab. Este fármaco produciría grandes ahorros y mejor salud. Ambas entidades debieran implementar protocolos para la profilaxis y tratamiento de la hemofilia y financiarla con presupuesto propio.

Settings Hemophilia is a coagulation disorder that occurs in one in 5000 male births. Patients with untreated severe hemophilia A have hemorrhagic complications, including joint bleeds and decreased survival. Emicizumab is a monoclonal antibody approved by the United States for routine prophylaxis of pediatric and adult patients with severe hemophilia A with factor VIII inhibitors. Objectives To perform a cost-effectiveness study of emicizumab prophylaxis for children and adults with severe hemophilia A compared with the current disease management in the Peruvian Ministry of Health and Social Security Health Insurance. Methods The patient transition between medical states was modeled with Markov methodology, and the lifetime costs and incremental effects of emicizumab compared to current management were estimated. The budgetary impact of emicizumab was estimated by projecting annual net costs and its five-year present value. Results In the Ministry of Health, emicizumab would generate savings between 14.6 and 16.0 per child and 11.8 per adult, in current US$ million. Social Security Health Insurance savings would be 12.8 to 14.9 per child and 40.1 per adult. In addition, this strategy would generate effectiveness gains, measured in quality-adjusted life-years, of 0.36 per child and 0.56 per adult and 0.25 per child, and 0.36 per adult in those respective institutions. The budgetary impact would be a net annual saving of 12.8 and 15.0 US$ million in those entities. Conclusions The current management of hemophilia A is very costly and has health outcomes inferior to those possible with emicizumab. This drug would produce significant savings and better patient health. The Ministry of Health and Social Health Insurance should implement hemophilia prophylaxis and treatment protocols and finance this drug.

Adequacy of Usual Vitamin and Mineral Intake in Spanish Children and Adolescents: ENALIA Study.

Background: The National Dietary Survey on the Child and Adolescent Population in Spain (ENALIA) provides data to assess the usual micronutrient intake among Spanish infants, children, and adolescents. Methods: Cross-sectional survey (November 2012-July 2014) of a representative sample of Spanish children and adolescents (six months-17 years) (n = 1862). Dietary information was collected using two non-consecutive one-day food diaries (six months-10 years old) or two 24 h dietary recalls (11 years and older) separated by at least 14 days. Estimates were calculated using the Iowa State University method and PC-SIDE software (version 1.0, department of statistics, center for agricultural and rural development, Ames, IA, USA) to account for within- and between-person variation. Results: Usual intake of vitamin D was insufficient in practically all individuals. Vitamin E, folate, and calcium were insufficient, especially from nine years of age, and magnesium and iodine from 14 years of age. The percentage of subjects with insufficient intakes was higher among females. Sodium intake was excessive in a considerable percentage of the population, especially in males, and it increased with age. Finally, over half of children under four years of age had zinc usual intakes that exceeded the Tolerable Upper Level. Conclusion: Vitamin and mineral intake in Spain should be improved, especially in late childhood and adolescence. Nutritional intervention and educational strategies are needed to promote healthy eating habits and correct micronutrient inadequacies in Spanish children and adolescents.

A Comprehensive Lifestyle Peer Group-Based Intervention on Cardiovascular Risk Factors: The Randomized Controlled Fifty-Fifty Program.

BACKGROUND: Cardiovascular diseases stem from modifiable risk factors. Peer support is a proven strategy for many chronic illnesses. Randomized trials assessing the efficacy of this strategy for global cardiovascular risk factor modification are lacking. OBJECTIVES: This study assessed the hypothesis that a peer group strategy would help improve healthy behaviors in individuals with cardiovascular risk factors. METHODS: A total of 543 adults 25 to 50 years of age with at least 1 risk factor were recruited; risk factors included hypertension (20%), overweight (82%), smoking (31%), and physical inactivity (81%). Subjects were randomized 1:1 to a peer group-based intervention group (IG) or a self-management control group (CG) for 12 months. Peer-elected leaders moderated monthly meetings involving role-play, brainstorming, and activities to address emotions, diet, and exercise. The primary outcome was mean change in a composite score related to blood pressure, exercise, weight, alimentation, and tobacco (Fuster-BEWAT score, 0 to 15). Multilevel models with municipality as a cluster variable were applied to assess differences between groups. RESULTS: Participants' mean age was 42 ± 6 years, 71% were female, and they had a mean baseline Fuster-BEWAT score of 8.42 ± 2.35. After 1 year, the mean scores were significantly higher in the IG (n = 277) than in the CG (n = 266) (IG mean score: 8.84; 95% confidence interval (CI): 8.37 to 9.32; CG mean score: 8.17; 95% CI: 7.55 to 8.79; p = 0.02). The increase in the overall score was significantly larger in the IG compared with the CG (difference: 0.75; 95% CI: 0.32 to 1.18; p = 0.02). The mean improvement in the individual components was uniformly greater in the IG, with a significant difference for the tobacco component. CONCLUSIONS: The peer group intervention had beneficial effects on cardiovascular risk factors, with significant improvements in the overall score and specifically on tobacco cessation. A follow-up assessment will be performed 1 year after the final assessment reported here to determine long-term sustainability of the improvements associated with peer group intervention. (Peer-Group-Based Intervention Program [Fifty-Fifty]; NCT02367963).

The ALADINO study: a national study of prevalence of overweight and obesity in Spanish children in 2011.

The aim of the study was to determine the prevalence of overweight and obesity in children in Spain using different sets of cut-off criteria, through a community-based cross-sectional study. The study was conducted in a representative sample of Spanish children between 6 and 9 years, recruited in Spanish schools, between October 2010 and May 2011. 7,569 boys and girls were selected. All were weighed and measured, and their parents were asked about their socioeconomic background, food habits and physical activity. The BMI of each was calculated, and the prevalence of overweight and obesity was determined by age and sex using Spanish reference tables (SPART), IOTF reference values, and WHO growth standards. The prevalence of overweight in boys ranged from 14.1% to 26.7%, and in girls from 13.8% to 25.7%, depending on the cut-off criteria. The prevalence of obesity in boys ranged from 11.0% to 20.9%, and in girls from 11.2% to 15.5%. The prevalence of obesity was the highest among those same children when using the SPART or WHO criteria. Overweight and obesity remain widespreading among Spanish children; a consensus on the definition of overweight and obesity cut-off criteria is necessary.

Sex does not influence prognosis in diabetic patients. The Barbanza Diabetes study.

INTRODUCTION AND OBJECTIVES: To determine the influence of sex on cardiovascular complications in diabetic patients. METHODS: This multicenter prospective cohort study involved 1423 consecutive patients with diabetes mellitus who were recruited during consultations with 31 primary care physicians. The patients' characteristics were recorded and they were followed up for 45 + or - 10 months. RESULTS: The mean age of the patients (50% female) was 66 years, 64% had hypertension, 70% had dyslipidemia, and 26% had had a previous cardiovascular event. Cardiovascular disease, predominantly ischemic heart disease, was observed more frequently in men and a higher percentage had end-organ damage (57.7% of males versus 45.4% of females; P< .0001). Women had poorer glycemic control, higher total cholesterol levels and lower high-density lipoprotein cholesterol levels. By the end of follow-up, 81 patients had died (5.7% of males versus 6.7% of females; P=.513). There were no sex differences in cardiovascular complications during follow up (15.8% in males versus 13.7% in females; P=.368). Multivariate analysis identified the following factors as independent predictors of morbidity or mortality: age (hazard ratio [HR]=1.04; 95% confidence interval [CI], 1.02-1.06), existing cardiovascular disease (HR=1.96; 95% CI, 1.38-2.79), diuretic treatment (HR=1.62; 95% CI, 1.10-2.38), and albuminuria (HR=1.86; 95% CI, 1.33-2.61). CONCLUSIONS: No difference was observed in mediumterm prognosis, with regard to mortality and cardiovascular selecmorbidity, between male and female diabetics from the same geographical area, despite the presence of clinical differences between the sexes.