Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review.

Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.

Multimodal perioperative care plus immunonutrition versus traditional care in total hip arthroplasty: a randomized pilot study.

BACKGROUND: Multimodal protocols of perioperative care may enhance postoperative recovery. However, limited information is available on preoperative immune and carbohydrate (CHO)-enriched drinks in patients undergoing hip arthroplasty. We aimed to investigate the effect of a multimodal protocol (ACERTO protocol) plus preoperative immune nutrition on the length of stay (LOS) and the postoperative acute phase response of patients undergoing total hip arthroplasty. METHODS: Thirty-two patients (mean age, 58 years; range, 26-85 years; 16 males) were randomized to receive either the ACERTO protocol (n = 15, ACERTO Group), which consisted of 6 h preoperative fasting for solids, an oral drink (200 mL of 12.5 % maltodextrin) up to 2 h before induction of anesthesia, restricted intravenous fluids (only 1000 mL of crystalloid fluid after surgery) and preoperative immune nutrition (600 mL/day of Impact - Nestlé, Brazil) for five days prior to surgery, or traditional care (n = 17; control group), which consisted of 6-8 h preoperative fasting, intravenous hydration until the 1(st) postoperative day and no preoperative immune supplementation. The main endpoint was LOS. C-reactive protein (CRP) was the secondary endpoint and was assessed during induction of anesthesia and on postoperative day 2. RESULTS: Neither deaths nor postoperative complications occurred. The median LOS was 3 (2-5) days in the ACERTO group and 6 (3-8) days in controls (P <0.01). Postoperative CRP was higher in the control group (P <0.01). CONCLUSION: The ACERTO multimodal protocol of perioperative care plus preoperative immune nutrition may decrease LOS and postoperative CRP levels in total hip arthroplasty. CLINICAL TRIALS: NCT02580214.

Alternatives to antibiotic growth promoters for weanling pigs / Alternativas aos antibióticos melhoradores de desempenho para leitões desmamados

An experiment was conducted to evaluate the addition of sodium butyrate, plant extracts and nucleotides on weanling pig performance, digestive content pH, organ morphometry, and intestinal epithelial histology. A total of 90 piglets at 21 days of age and an average initial weight of 6.35±0.34kg were used. The piglets were distributed in a randomized complete block design with five treatments, six replicates, and three animals per experimental unit. The treatments consisted of the following: Control: basal diet without antibiotic; Antibiotic: basal diet with 40mg kg-1 colistin sulfate and Additive: 1000, 1500 and 2000mg kg-1 of a combination of sodium butyrate + plant extracts + nucleotides. The experiment lasted 35 days, at which time one animal was slaughtered to assess pH of the digestive contents, morphometry of the organs and histology of the intestinal epithelium. No differences were found (P>0.05) in the performance, pH of the digestive contents, morphometry of the organs or histology of the intestinal epithelium by the analysis of orthogonal polynomials or contrasts. The combination of sodium butyrate, plant extracts and nucleotides not improved the productive characteristics of weanling pigs.(AU)

Foi conduzido um experimento para avaliar a adição de butirato de sódio, extratos vegetais e nucleotídeos sobre desempenho, pH do conteúdo digestório, morfometria dos órgãos e histologia do epitélio intestinal de leitões desmamados. Foram utilizados 90 leitões, com idade média de 21 dias e peso médio inicial de 6,35±0,34kg. Os leitões foram distribuídos em um delineamento em blocos casualizados completos, com cinco tratamentos, seis repetições por tratamento e três animais por unidade experimental. As dietas experimentais consistiam de: Controle - dieta basal sem antibiótico; Antibiótico - dieta basal com 40mg kg-1 de sulfato de colistina; Aditivo: 1000, 1500 e 2000mg kg-1 de uma combinação de butirato de sódio + extrato vegetal + nucleotídeos. No 35o dia de experimentação, foi eutanasiado um animal por gaiola (unidade experimental) para avaliar o pH do conteúdo digestório, morfometria de órgãos e histologia do epitélio intestinal. Não foram observadas diferenças (P>0,05) para desempenho, pH do conteúdo digestório, morfometria de órgãos e histologia do epitélio intestinal por meio das análises de polinômios ortogonais ou mesmo pelos contrastes. A combinação de butirato de sódio, extratos vegetais e nucleotídeos não melhorou as características produtivas de leitões desmamados.(AU)

Desempenho e morfologia intestinal de frangos de corte na fase de crescimento, com e sem adição de nucleotídeos na dieta, em diferentes níveis proteicos / Performance and morphology of the intestinal mucosa of broilers during growth, with or without nucleotides, at different protein levels

O experimento foi conduzido com o objetivo de avaliar o desempenho e a morfologia intestinal de frangos de corte na fase de crescimento, com e sem adição de nucleotídeos na dieta, em diferentes níveis proteicos. Foram utilizados 868 pintos de cortes machos de 21 dias de idade, da linhagem Cobb, submetidos a um delineamento inteiramente casualizado. As dietas foram compostas por dois controles, de alta e baixa proteína bruta, com 18,86% e 16,80% respectivamente, com a exigência de 1,062% de lisina digestível. Tendo como base a dieta controle de baixa proteína foram traçados mais cinco tratamentos com adição de 0,5 kg de nucleotídeos/ton de ração, e diferentes níveis de lisina digestível: 1,262%, 1,162%, 1,062%, 0962% e 0,862%, com quatro repetições cada. O consumo alimentar (g) diminuiu linearmente (P≤0,05) no período de 20 a 27, de 20 a 35 e de 20 a 42 dias de idade, em que aumentando os níveis de lisina digestível na dieta, observou-se diminuição no consumo de ração. A conversão alimentar teve efeito quadrático (P≤0,05) para as aves do período de 20 a 27, de 20 a 35 e de 20 a 42 dias de idade, diminuindo à medida que os níveis de lisina digestível aumentaram, atingindo o mínimo com 1,119, 1,187 e 1,132% de lisina digestível, respectivamente. A dieta com 1,062% de lisina digestível não diferiu (P>0.05) da dieta controle com alta proteína, para altura das vilosidades e profundidade de cripta, no duodeno, ilustrando então efeito benéfico do uso de nucleotídeos em dietas com baixa proteína bruta.

The experiment was conducted to evaluate the performance and intestinal morphology of growing broilers, with and without addition of nucleotides in the diet at different protein levels. A total of 868 21-day-old male Cobb broiler chicks were used in a completely randomized design. The diets were: control with high crude protein (18.86%) and low crude protein (16.80%), both without nucleotides, meeting the requirement of 1.062% digestible lysine; and five treatments with the addition of 0.5 kg of nucleotides/ton of feed, with different levels of digestible lysine (1.262%, 1.162%, 1.062%, 0962% and 0.862%), all formulated based on the low-protein diet (16.80%), with four replications each. Feed intake (g) decreased linearly (P≤0.05) in the period from 20 to 27, 20 to 35, and 20 to 42 days of age; feed intake decreased by increasing levels of lysine in the diet. Feed-to-gain ratio showed a quadratic effect (P≤0.05) for birds of the period from 20 to 27, 20 to 35 and 20 to 42 days of age, decreasing as levels of digestible lysine increased, with minimum levels reaching 1.119%, 1.187% and 1.132% digestible lysine, respectively. The diet with 1.062% of lysine did not differ (P>0.05) from the negative control for villus height and crypt depth in the duodenum.

Desempenho e morfologia intestinal de frangos de corte na fase de crescimento, com e sem adição de nucleotídeos na dieta, em diferentes níveis proteicos / Performance and morphology of the intestinal mucosa of broilers during growth, with or without nucleotides, at different protein levels

O experimento foi conduzido com o objetivo de avaliar o desempenho e a morfologia intestinal de frangos de corte na fase de crescimento, com e sem adição de nucleotídeos na dieta, em diferentes níveis proteicos. Foram utilizados 868 pintos de cortes machos de 21 dias de idade, da linhagem Cobb, submetidos a um delineamento inteiramente casualizado. As dietas foram compostas por dois controles, de alta e baixa proteína bruta, com 18,86% e 16,80% respectivamente, com a exigência de 1,062% de lisina digestível. Tendo como base a dieta controle de baixa proteína foram traçados mais cinco tratamentos com adição de 0,5 kg de nucleotídeos/ton de ração, e diferentes níveis de lisina digestível: 1,262%, 1,162%, 1,062%, 0962% e 0,862%, com quatro repetições cada. O consumo alimentar (g) diminuiu linearmente (P≤0,05) no período de 20 a 27, de 20 a 35 e de 20 a 42 dias de idade, em que aumentando os níveis de lisina digestível na dieta, observou-se diminuição no consumo de ração. A conversão alimentar teve efeito quadrático (P≤0,05) para as aves do período de 20 a 27, de 20 a 35 e de 20 a 42 dias de idade, diminuindo à medida que os níveis de lisina digestível aumentaram, atingindo o mínimo com 1,119, 1,187 e 1,132% de lisina digestível, respectivamente. A dieta com 1,062% de lisina digestível não diferiu (P>0.05) da dieta controle com alta proteína, para altura das vilosidades e profundidade de cripta, no duodeno, ilustrando então efeito benéfico do uso de nucleotídeos em dietas com baixa proteína bruta.(AU)

The experiment was conducted to evaluate the performance and intestinal morphology of growing broilers, with and without addition of nucleotides in the diet at different protein levels. A total of 868 21-day-old male Cobb broiler chicks were used in a completely randomized design. The diets were: control with high crude protein (18.86%) and low crude protein (16.80%), both without nucleotides, meeting the requirement of 1.062% digestible lysine; and five treatments with the addition of 0.5 kg of nucleotides/ton of feed, with different levels of digestible lysine (1.262%, 1.162%, 1.062%, 0962% and 0.862%), all formulated based on the low-protein diet (16.80%), with four replications each. Feed intake (g) decreased linearly (P≤0.05) in the period from 20 to 27, 20 to 35, and 20 to 42 days of age; feed intake decreased by increasing levels of lysine in the diet. Feed-to-gain ratio showed a quadratic effect (P≤0.05) for birds of the period from 20 to 27, 20 to 35 and 20 to 42 days of age, decreasing as levels of digestible lysine increased, with minimum levels reaching 1.119%, 1.187% and 1.132% digestible lysine, respectively. The diet with 1.062% of lysine did not differ (P>0.05) from the negative control for villus height and crypt depth in the duodenum.(AU)

Comparative efficacy of oral nucleoside or nucleotide analog monotherapy used in chronic hepatitis B: a mixed-treatment comparison meta-analysis.

STUDY OBJECTIVE: To compare the efficacy of nucleoside or nucleotide analog monotherapy for the treatment of chronic hepatitis virus B (HBV) with adefovir dipivoxil, entecavir, lamivudine, telbivudine, and tenofovir disoproxil fumarate. DESIGN: Mixed-treatment comparison meta-analysis of nine randomized controlled clinical trials. PATIENTS: A total of 3972 adults with a diagnosis of chronic hepatitis B. MEASUREMENTS AND MAIN RESULTS: A systematic review was conducted to search for randomized clinical trials that evaluated the efficacy of nucleoside or nucleotide analogs used as monotherapy. The evaluated outcomes were reduction of HBV DNA levels, normalization of alanine aminotransferase levels, and seroconversion of hepatitis B e antigen (HBeAg). A mixed-treatment comparison was conducted to compare the odds ratios among the treatments and to rank the therapies to determine the optimal treatment option. Tenofovir had the best results among the nucleoside or nucleotide analogs for the three evaluated efficacy outcomes in both HBeAg-positive and -negative patients. CONCLUSION: Tenofovir has the highest probability of reducing HBV DNA, normalizing alanine aminotransferase levels and inducing HBeAg seroconversion after 1 year of treatment. An efficacy comparison of therapies is an important tool to guide clinicians in selecting the optimal treatment option.

Does pre-liver transplant HBV DNA level affect HBV recurrence or survival in liver transplant recipients receiving HBIg and nucleos(t)ide analogues?

BACKGROUND AND AIMS: The risk of recurrent hepatitis B virus (HBV) infection and prognosis of liver transplantation in patients with HBV has dramatically changed with the use of prophylaxis including hepatitis B immune globulin (HBIg) and antiviral agents. METHODS: This study analyzes the prognostic value of HBV DNA level before orthotopic liver transplantation (OLT) and the effect of HBV prophylaxis on rates of HBV recurrence and survival. Between 1988 and 2008, 859 patients underwent OLT in our center; 60 patients had HBV-related liver disease and in 49, HBV DNA was determined by real time-PCR before OLT. Survival and HBV recurrence were analyzed according to preoperative viral load (HBV DNA <10(3) IU/mL vs. HBV DNA ≥10(3)) and prophylaxis regimens (HBIg vs HBIg and antivirals). RESULTS: On multivariate analysis, prophylaxis with HBIg alone, but not HBV-DNA levels was independently associated with poor survival, with a relative risk (RR) of death of 6.5 (95% CI 2.1-19.8, P = 0.001). The risk of HBV recurrence, in this small series, was also associated with monoprophylaxis with HBIg (RR 27, 95% CI 5.2-147.2, P < 0.0001), but not with HBV-DNA levels. CONCLUSIONS: When prophylaxis with HBIg and antiviral agents was administered, survival and HBV recurrence were not influenced by HBV-DNA levels determined by real time-PCR prior to OLT.

Purinergic receptor agonists modulate phagocytosis and clearance of apoptotic cells in macrophages.

Phagocytosis plays an important role in controlling inflammation and antigen cross-presentation through the uptake of apoptotic bodies from dying cells. As dying cells are known to release nucleotides and other "danger signals", we investigated whether extracellular nucleotides may affect phagocytosis through binding to P2 purinergic receptors on phagocytic cells. We here show that the purinergic receptor agonists, ATP, ADP, α,ß-methylene ATP (α,ß-meATP), 3'-O-(4-benzoyl)benzoyl ATP, UTP and UDP, increased phagocytosis of latex beads, and some of them increased endocytosis and/or macropinocytosis of dextran by macrophages. The enhanced phagocytosis could be inhibited by pre-treatment with the P2X and P2Y antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid and suramin, and the P2Y1-selective antagonist, MRS2179. The nucleotides induced upregulation in macrophages of the ß2 integrin CD11b/CD18 (Mac-1) and the vitronectin receptor (α(v)ß3, CD51/CD61), both of which are involved in recognition and internalization of apoptotic cells. In addition, ATP and α,ß-meATP increased adhesion of apoptotic cells to macrophages, both in vitro and in vivo, and α,ß-meATP had a small effect on adhesion of necrotic cells. The nucleotides had no effect on adhesion of viable cells. We propose that engagement of the P2 receptors (P2X1, or P2X3) by extracellular nucleotides released from dying cells increases the ability of macrophages to bind apoptotic bodies, thus enhancing their ability to internalize and present antigens from the dying cells.

Nucleótidos y carotenoides naturales / Nucleotides and carotenoids

El concepto de los nucleótidos no es nuevo; máxime que son elementos que hacen parte de los componentes naturales de la leche materna. Casi todos los estudios señalan que el consumo de carotenoides, previenen el desarrollo de enfermedades crónicas en la edad adulta, posiblemente por su efecto antioxidante que disminuye el estrés oxidativo, mejorando enfermedades degenerativas y malignas.

The concept of nucleotides is not new, especially since they are elements that are part of the natural components of human milk. Most studies indicate that the consumption of carotenoids, prevent the development of chronic diseases in adulthood, possibly by its antioxidant effect that reduces oxidative stress, improving degenerative diseases and malignancies.

Effect of nucleotide intake and nutritional recovery on insulin-like growth factor I and other hormonal biomarkers in severely malnourished children.

The objective of the present study is to demonstrate the effect of nucleotide intake and intensive nutritional support on the concentration of insulin-like growth factor I (IGF-I) and other hormonal biomarkers in severely malnourished children. Twenty-six severely malnourished children < 48 months of age received formula without lactose via enteral feeding for 2 weeks and ad libitum for an additional 2 weeks. Anthropometrical measurements were performed and serum concentrations of IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3), leptin, soluble leptin receptor (sOB-R), as well as the estimated molar excess of sOB-R over leptin were obtained. Two groups were formed. One group received formula with nucleotides (NT+; n 13) and the other without nucleotides (NT-; n 13). A control group was included (n 13). Parametric and non-parametric tests as well as ANOVA models were used. Nutritional recovery, nucleotides intake, type of malnutrition, age and the interaction between gender and malnutrition influenced the concentration of IGF-I (P < 0.001). Nutritional recovery, nucleotides intake, gender and type of malnutrition had an effect on IGFBP-3 (P < 0.001). Nutritional recovery had a significant effect on serum leptin (P = 0.001). Age and nutritional recovery had an effect on sOB-R (P < 0.001); all variables included affected the molar excess of sOB-R over leptin (P < 0.001). In conclusion, nucleotide intake and nutritional recovery had a notable effect on IGF-I, IGFBP-3 and other hormonal biomarkers. This outcome could stimulate the catch-up growth of severely malnourished infants and toddlers during the nutritional recovery period.

Nutritional support with nucleotide addition favors immune response in severely malnourished infants.

BACKGROUND: Adequate nutritional support of severe primary protein energy malnutrition (PEM) is indispensable for achieving normal immune response. However, an ideal dietetic criterion has not yet been established or accepted by the majority of health professionals caring for malnourished infants. Our objective was to demonstrate improvement in immune response in infants with PEM who received starting infant formula with nucleotides. METHODS: Twelve malnourished infants 3-18 months of age were included in our study and were fed through a nasogastric tube with infant formula (3.35 kJ/mL) for 2 weeks and ad libitum for an additional 2 weeks. Anthropometric measurements and immunologic indicators such as phagocytosis, microbicidal activity, chemotaxis, and cell proliferation index were determined. The sample was divided into two groups; group 1 (n=6) was fed formula with nucleotides added, while group 2 (n=6) was fed a formula with no nucleotides. Paired t test was used to determine differences between initial and final results for each group for comparison between group 1 vs. group 2; a nonparametric Mann-Whitney U test was used for immunologic indicators. RESULTS: Comparison of immunologic indicators showed no significant difference between groups. Groups 1 and 2 showed improvement in phagocytosis and microbicidal activity (p <0.05) and group 2 additionally showed improvement in cell proliferation index. CONCLUSIONS: Infant formula with intake of 837 kJ/kg/d (200 kcal/kg/d) and proteins of 4 g/kg/d in infants with PEM had a favorable impact on immunologic indicators regardless of addition of nucleotides.

Suplementos nutricionales en pediatría / Dietary supplements in pediatric nutrition

Existe en el mercado una oferta creciente de suplementos nutricionales así como de información disponible, siendo pocos los estudios sometidos a una rigurosa metodología. Los suplementos nutricionales y específicamente las vitaminas son usados ampliamente en la población pediátrica, muchas veces sin justificación. Este artículo tiene por objeto entregar una visión general sobre las indicaciones del uso de suplementos nutricionales en pediatría en las dos edades más críticas del desarrollo: lactante y adolescente y en dos situaciones que se presentan cada vez con mayor frecuencia: el niño deportista y el niño vegetariano

The influence of dietary nucleotides and long-chain polyunsaturated fatty acids on the incorporation of [3H] arachidonic acid on experimental liver cirrhosis.

The purposes of this study were to determine: a) the incorporation of labeled [3H] arachidonic acid on the intestinal mucosa, the liver and plasma, after 1,3 and 5 hours of administration, b) preferential incorporation by different tissues, c) and the effects on experimental rats with thioacetamide-induced cirrhosis, after four weeks of a dietary supplementation with nucleotides and long-chain polyunsaturated fatty acids. 209 female Wistar rats were divided into two groups (control and TAA group). The TAA group was given 300 mg of thioacetamide/L, in their drinking water for four months. After this period, a sample of 6 rats were taken from each group and examined, to evaluate the biochemical and histological changes of the experimental model, and 36 rats were taken to determine the incorporation of radioactivity by the groups. The rest of the animals were divided into four subgroups. Each group, receiving a supplementary diet with only long-chain polyunsaturated fatty acids and/or nucleotides or neither, for 4 weeks. After four months of thioacetamide, the incorporation of the [3H] arachidonic acid showed: a) an increased within 3 h in the intestinal mucosa, b) a decreased in the liver after 3 to 5 h c) and a drastic decrease in the plasma after 3 to 5 h. With a dietary supplementation of long-chain polyunsaturated fatty acids and nucleotides combined, there was a decrease of accumulate [3H] arachidonic acid in the intestine and a increase in the liver and plasma. The simultaneous supply of dietary polyunsaturated fatty acids and nucleotides was beneficial in the reversal of abnormalities of the lipid metabolism, in this experimental model of liver cirrhosis.

Nucleótidos en Pediatría / Nuecleotides in Pediatrics

La leche humana contiene 13 nucleótidos. Varias investigaciones en relación a la alimentación de los lactantes han sido llevadas a cabo para demostrar las ventajas de la adición de nucleótidos a las fórmulas de iniciación. Los nucleótidos están involucrados en la mayoría de los procesos celulares y juegan un papel importante en la función estructural, metabólica, energética y reguladora celular. Estos pueden afectar la diferenciación del enterocito, son importantes en el mantenimiento óptimo de la inmunidad celular y humoral e influyen en la síntesis de lipoproteínas. El propósito de este artículo es revisar los estudios que soportan el efecto de los nucleótidos cuando son adicionados a las fórmulas de iniciación en la función inmunológica, metabolismo de los lípidos y sistema gastrointestinal

Nutrición enteral en pediatría / Enteral nutrition in pediatrics

Se hace una revisión de los Conceptos Actuales de la Nutrición Enteral en niños enfermos, estableciéndose la dieta como factor terapéutico. Remarcando que el tratamiento dietético se basa en el conocimiento de la historia de la enfermedad, haciendo especial énfasis en las condiciones prácticas, eficacia, posibles ventajas y desventajas, riesgo de complicaciones, así como los requerimiento metabólicos especiales en relación con diferentes entidades.