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Summary: Background & aims: Administration of glutamine in patients with renal dysfunction is considered to be potentially adverse. In a rat model of moderate kidney dysfunction dose-dependent effects of intravenous alanyl-glutamine infusion on possible biochemical and histological signs of toxicity were investigated. Methods: Rats with renal dysfunction resulting from 5/6 nephrectomy received a 9 days continuous intravenous infusion of either saline or 0.5 g/kg/day or 3.0 g/kg/day alanyl-glutamine (Dipeptiven®) or 3.0 g/kg/day alanine. Dose-dependent effects on kidney and other organs were assessed by analyzing blood levels of creatinine, ammonia, urea, ALT, AST, ALP, pH, pO2, pCO2, glutamine, and histopathology. Results: Continuous intravenous infusion of 3.0 g/kg/day alanyl-glutamine increased plasma glutamine concentrations up to 60% without aggravating the underlying kidney injury. In contrast, the morphology of the kidneys was improved due to reduced glomerulosclerosis and tubular proteinaceous casts. An increase in plasma urea concentrations observed in the 3.0 g/kg/day alanyl-glutamine group only was not associated with worsening of the phenotype. Conclusions: Continuous intravenous infusion of alanyl-glutamine at 0.5 and 3.0 g/kg/day up to 9 consecutive days is safe in a rat model of chronic moderate kidney dysfunction and improved the renal morphology by reducing glomerulosclerosis and tubular proteinaceous casts. In these animals a decreased incidence and severity of chronic progressive nephropathy was observed compared to the saline and alanine treated animals. Keywords: Renal dysfunction, Glomerulosclerosis, Proteinaceous casts, Glutamine, Urea

Summary: Background & aims: Administration of glutamine in patients with liver failure is thought to possibly increase blood ammonia levels, thereby contributing to hepatic encephalopathy. In a rat model of moderate liver dysfunction with elevated plasma glutamine concentrations dose-dependent effects of intravenous alanyl-glutamine infusion on possible biochemical and histological signs of toxicity were investigated. Methods: Rats with moderate liver dysfunction resulting from alpha-naphthylisothiocyanate (ANIT) induced cholestasis received a 9 days continuous intravenous infusion of 0.5 g/kg/day or 3.0 g/kg/day alanyl-glutamine (Dipeptiven®). Dose-dependent effects on liver injury were assessed by analyzing blood levels of ammonia, urea, ALT, AST, and ALP, glutamine, and histopathology. Results: Continuous intravenous infusion of 3.0 g/kg/day alanyl-glutamine increased plasma glutamine concentrations up to 30% without increasing blood ammonia levels or inducing astrocyte swelling. Alanyl-glutamine did not aggravate underlying liver injury shown by absent increase in plasma levels of ALT, AST, ALP and no signs of histopathologic alterations. Conclusions: Continuous intravenous infusion of alanyl-glutamine at 0.5 and 3.0 g/kg/day up to 9 consecutive days is safe in a rat model of moderate liver dysfunction based on ANIT-induced cholestasis. Keywords: Ammonia, Astrocyte swelling, Brain edema, Cholestasis, Glutamine, Liver injury

Background: The compliance of lipid admixtures to physical emulsion stability parameters is extremely important to ensure the safety of patients. For example, admixtures containing a percentage of fat globules larger than 5 μm in diameter (concept known as PFAT5) of more than 0.05% might produce toxic effects in lung and liver. This concern is mainly based on a limited number of animal studies investigating admixtures with high PFAT5 levels resulting from 48 h of admixture storage. However, all effects observed in these studies might as well be attributed to chemical instability like lipid oxidation, which was not analysed and therefore could not be excluded. Aims: This study aims at investigating the correlation of high levels of PFAT5 in lipid emulsion admixtures with lipid oxidation parameters under different storage conditions. Methods: We studied the physical (PFAT5 value) as well as the chemical (pH, primary and secondary oxidation parameters) stability of an admixture of a lipid emulsion and an amino acid solution after up to 48 h following different storage conditions (exposure to oxygen, exposure to artificial light). Results: High levels of PFAT5 were only observed after exposure of the admixture to oxygen. Additional exposure to artificial light led to a parallel increase in the primary and secondary oxidation parameters, while the pH was unchanged. Conclusions: The admixtures investigated in the former animal studies were obviously both physically and chemically unstable and all effects observed in the studies could just as well be caused by chemical instability, namely the administration of lipid peroxides with the admixture.

Background: Ticagrelor is an orally available, direct acting and reversible P2Y12 receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance. Methods: The following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) in vitro and in vivo genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) in vitro pharmacological profiling for more than 300 assays, and (5) in vivo ovariectomized rat assay. Results: The carcinogenicity study indicated Ticagrelor increased uterine tumor incidence while decreasing mammary and pituitary tumors/hyperplasia incidences in only high dose female rats. However, this altered tumor incidences were not P2Y12 target related since marketed non-reversible P2Y12 receptor antagonists were not associated with alter tumor incidences. MOA studies determined Ticagrelor exposure in the anterior pituitary and Ticagrelor was (1) non-genotoxic, (2) peripherally-restricted, (3) a dopamine transport (DAT) inhibitor with an IC50 lower than systemic free exposure in the rat carcinogenic study and more than a log higher than the free systemic exposure seen in clinical trials and (4) an inhibitor of estradiol-induced prolactin secretion. Discussion: Similar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor) will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.