Pharmacokinetics, efficacy, and safety of pravastatin in children : Studies in children with heterozygous familial hypercholesterolemia and in pediatric cardiac transplant recipients

Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD.

Identification of Early Biomarkers during Acetaminophen-Induced Hepatotoxicity by Fourier Transform Infrared Microspectroscopy

Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/ mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnf alpha and Ifn gamma in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.

A ingestão precoce de dieta enriquecida com óleo de peixe reverte alterações bioquímicas, hepáticas e do tecido adiposo na prole de camundongos submetidos à restrição proteica

Ingestão precoce de dieta enriquecida com óleo de peixe reverte alterações bioquímicas, hepáticas e do tecido adiposo na prole de camundongos submetidos à restrição protéica. 2010. 61 f. Dissertação (Mestrado em Biologia Humana e Experimental) Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2010. Estudos relacionam obesidade na vida adulta com baixo peso ao nascer (programação metabólica). O fígado é um dos órgãos mais afetados pela programação. O óleo de peixe é rico em ácidos graxos poli-insaturados (AGP) da família n-3: ácido eicosapentaenóico (EPA) e docosahexaenóico (DHA). O EPA e DHA são relacionados com redução da pressão arterial sistólica e ação anti-inflamatória. Testar a hipótese que a ingestão precoce de óleo de peixe (FO) pode reverter os efeitos deletérios da programação na prole adulta de camundongos. Fêmeas grávidas foram alimentadas com ração padrão (SC) ou dieta restrita em proteínas (LP) durante a gestação e lactação. Ao desmame, os seguintes grupos foram formados (de acordo com a suplementação com FO): SC-SC e SC-FO, LP-SC e LP-FO. Foram aferidas massa corporal, ingestão e eficiência alimentar, pressão arterial sistólica (PAS), insulina plasmática, glicose, fator de necrose tumoral (TNF)-alfa, colesterol total (CT), triglicerídeos (TG) e alanina aminotransferase (ALT), morfometria dos adipócitos, estereologia do fígado e expressão proteínas SREBP-1c e PPAR-alfa. A prole LP apresentou maior massa corporal, hipercolesterolemia e hiperglicemia Na idade adulta, os animais restritos tornaram-se hipertensos, com esteatose hepática e elevado nível da SREBP-1c. Entretanto, a prole LP com dieta suplementada com FO ocasionou menor ganho e menor massa corporal final. A dieta FO melhorou o metabolismo lipídico, diminuiu a concentração plasmática de CT e TG, reduziu a massa adiposa e o tamanho dos adipócitos. Além disso, LP-FO mostrou níveis reduzidos da ALT, redução da esteatose hepática, baixa expressão da SREBP-1c e aumento da expressão do PPAR-alfa, além de redução da PAS e dos níveis de TNF-alfa. A dieta com FO teve efeitos benéficos revertendo as respostas da programação sobre o metabolismo da glicose e lipídios, estrutura hepática e tecido adiposo na prole adulta programada.

Leptina e grelina na regulação do comportamento alimentar da tartaruga Eretmochelys imbricata (Linnaeus 1766)

Durante a temporada de nidação, fêmeas de tartarugas marinhas costumam reduzir ou cessar por completo a ingestão de alimentos. Este fato sugere que o armazenamento de energia e nutrientes para a reprodução ocorra durante o período que antecede a migração para os sítios reprodutivos, enquanto estes animais ainda se encontram nas áreas de alimentação. Do ponto de vista fisiológico, tartarugas em atividade reprodutiva são capazes de permanecer longos períodos em jejum. Fatores neuroendócrinos vêm sendo recentemente apontados como os mais relevantes para a manutenção da homeostase energética de todos os vertebrados; entre eles, a leptina (hormônio anorexígeno) e a grelina (peptídeo orexígeno). Com o objetivo de compreender o mecanismo de fome e saciedade nas tartarugas marinhas, investigamos os níveis séricos destes hormônios e de outros indicadores nutricionais em fêmeas de Eretmochelys imbricata desovando no litoral do Rio Grande do Norte, Brasil. Foram coletadas amostras de sangue de 41 tartarugas durante as temporadas reprodutivas de 2010/2011 e 2011/2012. Os níveis séricos de leptina diminuíram significativamente ao longo do período de nidação, de modo a explicar a busca por alimentos ao término da temporada. Ao mesmo tempo, registramos uma tendência crescente nos níveis séricos de grelina, fator este que também justifica a remigração para as áreas de alimentação no fim do período. Não foram observadas tendências lineares para alguns dos parâmetros avaliados, entre eles: hematócrito, alanina aminotransferase (ALT), aspartato aminotransferase (AST), fosfatase alcalina (FA), gama glutamil transferase (GGT), lipoproteínas de baixa densidade (LDL) e lipoproteínas de alta densidade (HDL). É possível que a maior parte dos indicadores nutricionais tenha apresentado redução gradativa devido ao estresse fisiológico decorrente da vitelogênese e de repetidas oviposições. No entanto, é valido ressaltar que o quadro de restrição calórica por tempo prolongado é o principal responsável pelas alterações em índice de massa corpórea e padrões bioquímicos nestes animais.

Prevalência da doença hepática gordurosa não alcoólica definida pela biópsia hepática: o verdadeiro espectro em diabéticos tipo II

A doença hepática gordurosa não alcoólica (DHGNA) tornou-se a hepatopatia crônica mais comum no mundo, afetando principalmente alguns grupos de pacientes, como os diabéticos tipo II. A biópsia hepática permanece como método padrão ouro para o seu diagnóstico. A prevalência da DHGNA e seus subtipos, em especial a esteatohepatite (EH), pode estar subestimada por métodos não invasivos de diagnóstico ou superestimada pela realização da biópsia em pacientes selecionados por alterações na ultrassonografia (US) ou nas aminotransferases. Os objetivos deste estudo foram: determinar a prevalência da DHGNA (esteatose, EH e cirrose) em uma amostra de pacientes diabéticos tipo II, com base na biópsia hepática; quantificar a esteatose, inflamação e fibrose quando presentes; identificar fatores preditivos de DHGNA, EH e fibrose significativa (≥ estágio 2) e avaliar o valor das aminotransferases e da US de abdome para o diagnóstico de EH e fibrose significativa. Todos os diabéticos tipo II, entre 18 e 70 anos, consecutivamente atendidos no ambulatório de Diabetes do Hospital Universitário Pedro Ernesto, eram candidatos a participar do estudo. Foram excluídos pacientes com sorologias positivas para hepatite B ou C, outras doenças hepáticas crônicas, uso de drogas hepatotóxicas ou esteatogênicas, etilismo (≥20g/dia), obesidade grau III, comorbidades graves, gravidez ou por recusa em participar do estudo. Dos 396 pacientes triados com critérios de inclusão, 85 foram incluídos. Todos os pacientes foram submetidos à avaliação clínica, exames laboratoriais, US de abdome e biópsia hepática. As lâminas foram analisadas por dois patologistas independentes e a DHGNA foi graduada pelo NASH Clinical Research Network Scoring System. A concordância entre os patologistas foi medida pelo coeficiente Kappa (k) e foi realizada análise multivariada por regressão logística para avaliação dos fatores associados de forma independente à DHGNA, EH e fibrose significativa. A prevalência de DHGNA na amostra foi de 92%, sendo 50% esteatose simples, 40% EH e 2% cirrose. A concordância (k) entre os patologistas foi 0,78. A esteatose foi leve na maior parte dos pacientes com esteatose simples e predominantemente acentuada nos pacientes com EH (p<0,001). A fibrose foi verificada em 76% dos pacientes com EH, sendo significativa em 41% deles. A presença de síndrome metabólica foi associada de forma independente à DHGNA, o índice de massa corporal e a circunferência abdominal aumentada à EH e a dosagem de alanina aminotransferase (ALT) à EH e à fibrose significativa. Apenas um de 21 pacientes (5%) com US e ALT normais apresentou EH. A prevalência da EH aumentou progressivamente com o aumento do grau de esteatose na US e com o aumento da ALT. Conclusão: A prevalência da DHGNA estimada pela biópsia hepática sem vieses de seleção foi muito elevada. Apesar de alto, o percentual de EH e fibrose significativa foi inferior ao dos estudos com biópsias em diabéticos selecionados por alterações na US e aminotransferases. EH foi associada a esteatose acentuada na histologia. A obesidade foi um cofator importante no diagnóstico de EH. O melhor desempenho da ALT e da US foi o de excluir as formas graves de DHGNA quando normais.

Benefícios do treinamento intervalado de alta intensidade (natação) na obesidade (estudo experimental)

É um desafio na sociedade moderna controlar a obesidade e comorbidades associadas na população. O objetivo do estudo foi avaliar o impacto do treinamento intervalado de alta intensidade no contexto da obesidade induzida por dieta em modelo animal. Camundongos C57BL/6 foram alimentados com ração padrão (grupo magro - LE) ou dieta rica em gordura (grupo obeso - OB). Após 12 semanas, os animais foram divididos em grupos não treinados (LE-NT e OB-NT) e grupos treinados (LE-T e OB-T) e teve início um protocolo de exercício. Nos grupos treinados em comparação aos grupos não treinados observou-se que o treinamento intervalado de alta intensidade levou a reduções significativas na massa corporal, glicemia e tolerância oral à glicose, colesterol total, triglicérides, lipoproteína de baixa densidade-colesterol, aspartato transaminase e alanina aminotransferase no fígado. Além disso, nos grupos treinados, o protocolo de exercício melhorou a imunodensidade de insulina nas ilhotas, reduziu os níveis de citocinas inflamatórias, adiposidade e esteatose hepática. O treinamento de alta intensidade melhorou a beta-oxidação e os níveis de receptores ativados por proliferador de peroxissomo (PPAR)-alfa e reduziu os níveis de lipogênese e de PPAR-gama no fígado. No músculo esquelético, o treinamento de alta intensidade também melhorou o PPAR-alfa e transportador de glicose (GLUT) -4 e reduziu os níveis de PPAR-gama. Esses achados reforçam a noção de que o treinamento de alta intensidade é relevante como uma abordagem não farmacológica para controlar a resistência à insulina, glicemia, e esteatose hepática. Em conclusão, treinamento de alta intensidade leva à perda de massa corporal e pode atenuar os efeitos adversos causados pela ingestão crônica de uma dieta rica em gordura. Apesar de uma ingestão contínua dessa dieta, o treinamento de alta intensidade melhora as enzimas hepáticas e o perfil inflamatório.

Feeding stimulatory effects of Cyperus rotundus tuber on Cirrhinus mrigala

Traditionally tubers of cyperus (Cyperus rotundus) and its extracts have been used for alluring fish during harvesting in India. An experiment was conducted to evaluate its feeding stimulatory activity and effect on the growth of a commercially important freshwater fish, Cirrhinus mrigala. Three isonitrogenous and isocaloric formulated diets viz. plant ingredient based control and control supplemented with cyperus tuber (CS) at 1% and 5% levels were fed to the fingerlings of mrigal, C. mrigala (2.68+0.20 g) for a period of 45 days. The growth performance and the activity of metabolic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), in liver, gill and muscle tissues of mrigal were studied during every 15 days interval. Highest relative growth (72.28%) was obtained in the mrigal fed with the diet containing 5% cyperus (5% CS), while the relative growths were 66.18% and 43.40% for the fish fed with the 1% CS diet and control respectively. The activities of AST and ALT were significantly higher (p<0.01) in both 1% and 5% CS diets as compared to the control in all the tissues studied. Higher aminotransferase activities were observed in the tissues of 5% CS group than in those of 1% CS group throughout the experimental period. The observed higher enzymatic activity was concomitant with the higher growth rate in fish. The results suggested that cyperus tuber supplementation increased feed palatability and growth.

First Identification of the Hepatotoxic Microcystins in the Serum of a Chronically Exposed Human Population Together with Indication of Hepatocellular Damage

Hepatotoxic microcystins (MCs) are the most commonly reported cyanotoxins in eutrophic freshwaters. In 1996, human intoxications by MCs caused deaths of 76 patients at Caruaru dialysis centers in Brazil. So far, there have been no direct evidences of MC occurrence in human tissue in consequence of exposure to MC. In this study, we improved cleanup procedures for detecting MCs in serum sample using liquid chromatographymass spectrometry, and confirmed for the first time the presence of MCs in serum samples (average 0.39 ng/ml, which amounts to ca. 1/87 of the concentrations found in tissue samples of the Caruaru victims) of fishermen at Lake Chaohu. Daily intake by the fishermen was estimated to be in the range of 2.2-3.9 mu g MC-LReq, whereas the provisional World Health Organization tolerable daily intake (TDI) for daily lifetime exposure is 0.04 mu g/kg or 2-3 mu g per person. Moreover, statistical analysis showed closer positive relationships between MC serum concentrations and concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase than between the MC concentrations and other biochemical indicators. Thus, the data raise the question whether extended exposure in the range of the TDI or up to a factor of 10 above it may already lead to indication of liver damage. The results also demonstrate a risk of health effects from chronic exposure to MCs at least for populations with high levels of exposure, like these fishermen.

Plasma biochemical responses of the omnivorous crucian carp (Carassius auratus) to crude cyanobacterial extracts

Healthy crucian carp (Carassius auratus) were treated by intraperitoneal (i.p.) injection of crude cyanobacterial extracts at two doses, 50 and 200 mu g MC-LR equiv kg(-1) BW. High mortality (100%) was observed within 60 h post injection in the high-dose group. In the treated fish, activities of four plasma enzymes, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), all showed substantial increases, with both dose and time-dependent effects. These increases of enzyme activity indicate severe impairment occurred in the liver of crucian carp over time. Plasma concentrations of energy-related biomolecules including glucose (GLU), cholesterol (CHO), triglyceride (TG), and total protein (TP) showed marked changes in the high-dose group, possibly a nutritional imbalance correlated with the liver injury caused by intraperitoneal exposure to crude cyanobacterial extracts.

Sequential ultrastructural and biochemical changes induced in vivo by the hepatotoxic microcystins in liver of the phytoplanktivorous silver carp Hypophthalmichthys molitrix

Up to now, in vivo studies on the toxic effects of microcystins (MCs) on the ultrastructures of fish liver have been very limited. The phytoplanktivorous silver carp was injected i.p. with extracted hepatotoxic microcystins (mainly MC-RR and -LR) at a dose of 1000 mu g MC-LReq. kg(-1) body weight, showing a time-dependent ultrastructural change in liver as well as significant increases in enzyme activity of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). We observed for the first time the occurrence of a large amount of activated secondary lysosomes, which might be an adaptive mechanism to eliminate or lessen cell damage caused by MCs through lysosome activation. Quantitative and qualitative determinations of MCs in the liver were conducted by HPLC and LC-MS2, respectively. MCs concentration in the liver reached the maximum (114.20 mu g g(-1) dry weight) after 3 h post-injection, and then rapidly dropped to 7.57 mu g g(-1) dry weight at 48 h, indicating a deputation of 99% accumulated MC-LReq. On the other hand, a decrease trend in glutathione (GSH) concentration was observed in the liver of silver carp while the activity of glutathione S-transferase (GST) increased significantly after injection. The high tolerance of silver carp to MCs might be due to the high basic GSH level in their liver, and/or an increased GSH synthesis. (C) 2007 Elsevier Inc. All rights reserved.

Meat and bone meal replacement in diets for juvenile gibel carp (Carassius auratus gibelio): effects on growth performance, phosphorus and nitrogen loading

A 11-week growth trial was conducted in a flow-through system with juvenile gibel carp Carassius auratus gibelio to evaluate the effects of gradual replacement of fish meal (FM) by meat and bone meal (MBM) on growth performance, phosphorus (P) and nitrogen (N) loading. Six isonitrogenous (crude protein: 410 g kg(-1)) and isoenergetic (gross energy: 18 kJ g(-1)) diets were formulated. FM was used as the control protein. In the other five diets, 20, 40, 60, 80 and 100% FM protein was substituted with MBM20, MBM40, MBM60, MBM80, MBM100, respectively. Total P content in the diets ranged from 16.0 to 28.3 g kg(-1) and the available P was 5.0-6.6 g kg(-1). The results showed that the best growth was achieved with fish fed on the control diet and MBM20. Final body weight, weight gain, feed efficiency, protein retention efficiency and energy retention efficiency decreased with increased dietary MBM. No significant differences were found in the feeding rate and hepatosomatic index between the groups. Apparent digestibility coefficient (ADC) of dry matter, protein and P decreased with increase in dietary MBM, while there were no significant differences in the ADC of energy. P and N retention decreased linearly while P and N loading increased linearly with the increased dietary MBM levels. No significant differences were observed in the activity of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase, as well as pyruvate kinase in liver or in serum. Total superoxide dismutase activity in MBM20 was significantly higher than that of MBM100.

Effect of inclusion of blue-green algae meal on growth and accumulation of microcystins in gibel carp (Carassius auratus gibelio)

Six isonitrogenous (crude protein content: 38%) and isoenergetic (gross energy content: 17 kJ g(-1)) diets were formulated to investigate the effects of inclusion of blue-green algae meal on gibel carp (Carassius auratus gibelio). In each diet, 15% of the protein was supplied by fishmeal; the remainder was supplied by soybean meal and blue-green algae meal. Diet 1 was used as control with no blue-green algae meal whereas the content in diets 2-6 was 15.15, 29.79, 44.69, 59.58 and 74.48%, respectively. Each diet was fed to five groups of gibel carp for 12 weeks in a flow-through system. Final body weight and specific growth rate (SGR) of fish fed diet 5 were significantly lower than the control diet (P < 0.05). Mortality of gibel carp increased with increase in algae meal inclusion (P < 0.05), but there was no significant difference between fish fed diets 3-6 (P > 0.05). Feed conversion efficiency (FCE) decreased with the increase in algae meal inclusion (P < 0.05). Fish-fed diet 6 showed the highest feeding rate (P < 0.05), while there were no significant differences among the other groups (P > 0.05). Apparent digestibility coefficient of dry matter, protein, and energy decreased with increasing algae meal inclusion in the diets (P < 0.05). Aspartate aminotransferase (GOT) activity in the liver was not significantly different among groups (P > 0.05). Liver alanine aminotransferase (GPT) activity of fish-fed diets 4, 5 and 6 was significantly lower than the control diet (diet 1; P < 0.05). Microcystins in the muscle, liver, gallbladder, and spleen increased with increasing algae inclusion (P < 0.05).

Prevalence and incidence of liver enzyme elevations in a pooled oncology clinical trial cohort.

Few epidemiologic studies describe longitudinal liver chemistry (LC) elevations in cancer patients. A population-based retrospective cohort was identified from 31 Phase 2-3 oncology trials (excluding targeted therapies) conducted from 1985 to 2005 to evaluate background rates of LC elevations in patients (n = 3998) with or without liver metastases. Patients with baseline liver metastases (29% of patients) presented with a 3% prevalence of alanine transaminase (ALT) ≥ 3x upper limits normal (ULN) and 0.2% prevalence of bilirubin ≥ 3xULN. During follow-up, the incidence (per 1000 person-months) of new onset ALT elevations ≥3xULN was 6.1 (95% CI: 4.5, 8.0) and 2.2 (95% CI: 0.9, 4.5) in patients without and with liver metastases, respectively. No new incident cases of ALT and bilirubin elevations suggestive of severe liver injury occurred among those with liver metastases; a single case occurred among those without metastasis. Regardless of the presence of liver metastases, LC elevations were rare in cancer patients during oncology trials, which may be due to enrollment criteria. Our study validates uniform thresholds for detection of LC elevations in oncology studies and serves as an empirical referent point for comparing liver enzyme abnormalities in oncology trials of novel targeted therapies. These data support uniform LC stopping criteria in oncology trials.

Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration.

AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement. METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ(2) test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group. RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, ≤ 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up. CONCLUSION: While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes.

GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat

GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H2S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappa B;B activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Tune-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappa B and STAT-3). These results suggest ail anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H2S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study. (C) 2009 Elsevier Inc. All rights reserved.