Meta-analysis of cardiovascular toxicity risks in cancer patients on selected targeted agents.

PURPOSE: The purpose was to estimate the risk and severity of cardiovascular toxicities associated with selected targeted agents. METHODS: We searched English-language literature for randomized clinical trials published between January 1, 2000 and November 30, 2013 of targeted cancer therapy drugs approved by the FDA by November 2010. One hundred ten studies were eligible. Using meta-analytic methods, we calculated the relative risks of several cardiovascular toxicities [congestive heart failure (CHF), decreased left ventricular ejection fraction (DLVEF), myocardial infarction (MI), arrhythmia, and hypertension (HTN)], adjusting for sample size using the inverse-variance technique. For each targeted agent and side effect, we calculated the number needed to harm. RESULTS: Regarding CHF, trastuzumab showed significantly greater risk of all-grade and high-grade CHF. There was significant increased risk of all-grade DLVEF with sorafenib, sunitinib, and trastuzumab and high-grade DLVEF with bevacizumab and trastuzumab. Sorafenib was associated with significant increased all-grade risk of MI based on one study. None was associated with high-grade risk of MI or increased risk of arrhythmia. Bevacizumab, sorafenib, and sunitinib had significant increased risk of all-grade and high-grade HTN. CONCLUSIONS: Several of the targeted agents were significantly associated with increased risk of specific cardiovascular toxicities, CHF, DLVEF, and HTN. Several had significant increased risk for high-grade cardiovascular toxicities (CHF, DLVEF, and HTN). Patients receiving such therapy should be closely monitored for these toxicities and early and aggressive treatment should occur. However, clinical experience has demonstrated that some of these toxicities may be reversible and due to secondary effects.

Oxygen and parenteral nutrition two main oxidants for extremely preterm infants: 'It all adds up'.

OBJECTIVES: To assess the effect of early exposure to O2 and parenteral nutrition (PN) on oxidative stress at 36 weeks post-menstrual age (PMA) and on bronchopulmonary dysplasia (BPD) in extremely preterm infants. STUDY DESIGN: A prospective observational study including 116 infants <29 weeks of gestation. Baseline clinical characteristics, FiO2 on day 7, duration of PN and clinical outcomes data were collected. In 39 infants, whole blood glutathione (GSH) and oxidized glutathione (GSSG) at 36 weeks PMA were measured and the redox potential was calculated using Nernst equation. Student's t-test, Chi-square, Spearman correlation, ANOVA, and logistic regression analyses were used as appropriate. P <  0.05 was considered significant. RESULTS: FiO2 ≥25% was associated with higher level of GSSG (0.29 ± 0.04 versus 0.18 ± 0.02 nmol/mg of protein), a more oxidized redox potential (-191 ± 2 versus -198 ± 2 mV) and more BPD (90% versus 45%). PN duration >14 days was also associated with higher level of GSSG (0.26 ± 0.03 versus 0.13 ± 0.02 nmol/mg of protein), a more oxidized redox potential (-193 ± 5 versus -203 ± 2 mV) and more BPD (89% versus 24%). In logistic regression model, each 1% increase in FiO2 and each day increase in PN duration resulted in an increase in the OR for BPD by 1.57 (1.09 -2.28) and 1.17 (1.03 -1.33) respectively. CONCLUSION: Early O2 supplement and PN have additive effects that were associated with prolonged oxidative stress and increased risk of BPD. Strategies targeting judicious use of O2 and decreasing the duration or developing a safer formulation of PN can be targeted to decrease BPD.

Peroxide-like oxidant response in lungs of newborn guinea pigs following the parenteral infusion of a multivitamin preparation.

The multivitamin solution is a major component responsible for the photo-induced generation of peroxides in parenteral nutrition. The lung is a target of oxidant injury; however, the specific role of infused peroxides is unknown. The aim of this study was to determine if parenteral multivitamins induce in the lung an oxidant challenge similar to that of peroxides. Newborn guinea pigs were infused with dextrose plus relevant concentrations of H(2)O(2) (0,250,500 microM) or multivitamins (0,1%), as well as parenteral nutrition supplemented with multivitamins (0,1%). After 4 days, total glutathione, glutathione-related enzymes, and oxidant-sensitive eicosanoids were measured in the lungs. Peroxides as well as multivitamins led to a significant decrease in glutathione and the activity of glutathione synthase, indicating that infused peroxides were not entirely transformed into free radicals, which would have stimulated glutathione synthesis. The multivitamin solution induced a response in oxidant-sensitive eicosanoids similar to the response to peroxides, suggesting an oxidant stress that was not alleviated by the antiradical properties of its components. The effects on prostaglandins occurred independently from the stimulation in glutathione levels induced by parenteral nutrition. The multivitamin solution carries an oxidant load and causes effects similar to those of peroxides in the lungs of newborn guinea pigs.

Photoprotection of solutions of parenteral nutrition decreases the infused load as well as the urinary excretion of peroxides in premature infants.

Light exposure and multivitamins are contributing factors to the generation of peroxides in solutions of parenteral nutrition. This article verifies if peroxides infused with parenteral nutrition are of biological significance in neonates. The mechanisms responsible for the generation of peroxides in total parenteral nutrition solutions are reviewed. The consequences of infused peroxides on an index of oxidant stress and on levels of a central antioxidant are evaluated in an animal model. The effect of photoprotection of parenteral nutrition on a biological marker of redox imbalance is evaluated in the urine of premature infants. Parenteral multivitamins produce a drop in glutathione and an oxidant stress similar to peroxides in the lungs of newborn guinea pigs. Infused peroxides elicited an increased urinary peroxide excretion in infants receiving parenteral nutrition exposed to light. Photoprotection reduced levels of infused and excreted peroxides. The results suggest that peroxides infused with total parenteral nutrition are not fully quenched by premature infants.

Significance of transported glycine in the conjugation of sodium benzoate in spf mutant mice with ornithine transcarbamylase deficiency.

3H-glycine and 14C-serine were injected intraperitoneally, during treatment of spf mutant mice with 2% sodium benzoate in drinking water. Urinary hippurate was separated by thin layer chromatography and counted for 3H and 14C labels representing transported and newly synthesized glycine, respectively. The specific activity of 3H-hippurate increased significantly in mutant and normal groups, while the increase of 14C was seen only in mutants. The ratio of specific activity 3H:14C showed significant increases in normal (0.99 to 1.93; p less than 0.01) and mutant (1.53 to 3.05; p less than 0.05) groups, which shows that glycine transported from body pools played a significantly greater role in the conjugation of benzoate, compared to glycine synthesized de novo from serine. In spf mice, benzoate treatment also resulted in a decrease in orotate excretion, indicating amelioration of the hyperammonemic state. It is postulated that the elimination of glycine transported from body pools may be the primary mechanism for the reduction of ammoniagenicity in benzoate therapy, and that the de novo synthesis of glycine may have a secondary effect.

Parenteral multivitamin supplementation induces both oxidant and antioxidant responses in the liver of newborn guinea pigs.

BACKGROUND: The multivitamin solution is a major component of photo-induced generation of peroxides in parenteral nutrition. The aim of this study was to determine whether the parenteral multivitamin preparation induces in the liver a peroxide-induced oxidant challenge or an antioxidant protection associated with the antiradical components of the solution. METHODS: Newborn guinea pigs were infused with dextrose supplemented with peroxides (250 micromol/L H2O2 or 350 micromol/L tert-butylhydroperoxide) or with a multivitamin preparation (MVP, 1% vol/vol). After 4 days, total glutathione and a free radical-sensitive eicosanoid marker (prostaglandin I2 [PGI2]/total prostaglandins) were measured in livers. RESULTS: There was a significant decrease in the PGI2/total prostaglandin ratio (mean +/- SEM) [dextrose: 0.068 +/- 0.007 vs. (dextrose + H2O2: 0.048 +/- 0.001, dextrose + TBH: 0.043 +/- 0.001)] and glutathione concentrations decreased [dextrose: 55 +/- 7 vs. (dextrose + H2O2: 37 +/- 7, dextrose + TBH: 18 +/- 7 nmol/mg protein)] after infusion of peroxides. Despite the peroxide load in the multivitamin solution, it did not alter the measured variables as prostanoid ratio remained at control concentrations (dextrose: 0.066 +/- 0.008 vs. dextrose + MVP: 0.065 +/- 0.006), as did glutathione levels (dextrose: 52 +/- 6 vs. dextrose + MVP: 45 +/- 7 nmol/mg prot). CONCLUSION: In the liver of guinea pig pups, infused peroxides cause oxidation of membrane-derived prostanoids. The decrease in glutathione in response to administration of peroxides suggests consumption rather than a response to a free radical attack. Despite the oxidant load associated with peroxides generated in MVP, the multivitamin preparation protected membranes as the prostanoid ratio, and glutathione levels remained at control levels.

Impact of essential fatty acid deficiency on hepatic sterol metabolism in rats.

The major aim of the current investigation was to define whether essential fatty acid (EFA) deficiency modifies the intrahepatic metabolism and biliary output of sterols in rats. EFA-deficient diet caused an impoverishment in linoleic, arachidonic, and docosahexaenoic acids, and a marked enrichment in the eicosatrienoic acid of the plasma, liver, and hepatic microsomes. During a short term of biliary drainage, a significant decline of the pool size of biliary sterols was noted in EFA-deficient rats compared with control rats. To assess the biosynthesis of biliary components, the common bile duct was cannulated and the pool size depleted (24 hours). Subsequently, a 6-hour bile collection disclosed a significant decrease (nmoles/min/g liver) in bile acids (4.8 +/- 0.3 vs. 8.4 +/- 0.7, P < .005), cholesterol (0.26 +/- 0.01 vs. 0.34 +/- 0.02, P < .05), and phospholipids (1.49 +/- 0.11 vs. 2.82 +/- 0.32, P < .005) in EFA-deficient rats compared with controls (n = 6/group). When cholesterogenesis was measured by the incorporation of [14C]acetate and 3H20 into cholesterol, using liver slices, it was also found to be significantly (P < .001) reduced in EFA-deficient rats. The activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, was consistently lower (80 percent, P < .001) in EFA-deficient rats. In parallel experiments, the direct measurement of microsomal acyl-CoA:cholesterol acyl-transferase (ACAT) showed a decrease averaging 52 percent (P < .001). This is in striking contrast to the elevated activity (157 percent, P < .005) of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. Current experiments also suggest that the enzyme regulation involving phosphorylation and dephosphorylation is modified by EFA deficiency. Among the structural alterations observed in the morphology of hepatocytes in EFA-deficient rats, the lumen of bile canaliculi was reduced in size. These results underline the importance of EFA in the major mechanisms involved in the maintenance of hepatocyte sterol balance.

Modulation of apo A-IV transcript levels and synthesis by n-3, n-6, and n-9 fatty acids in CACO-2 cells.

It has been postulated that apolipoprotein (apo) A-IV plays various significant roles in lipid transport and lipoprotein metabolism. Although it is controlled by fat feeding, so far little else is known about its regulation by specific fatty acids. In this study, we focused on the modulation of apo A-IV mRNA levels, mass, and biogenesis by mono- and polyunsaturated fatty acids (FA) in the human intestinal Caco-2 cell line. In confluent cells incubated with 1 mM oleic (n-9), linoleic (n-6), alpha-linolenic (n-3), or docosahexaenoic (n-3) acids for a long-term period, both apo A-IV protein levels and de novo synthesis were increased. The induction resulted from the up-regulation of apo A-IV mRNA transcripts. In contrast, an inhibitory effect was evident with short-term incubation. FA chain length and degree of unsaturation had little effect altering apo A-IV transcript and biogenesis. These data offer evidence that isolated fatty acids regulate gene expression and the production of apo A-IV in the enterocyte.