Assessment of the environmental fate and effects of azilsartan, a selective antagonist of angiotensin II type 1.

In this paper the results of a thorough evaluation of the environmental fate and effects of azilsartan are presented. Azilsartan medoxomil is administered as a pro-drug for the treatment of patients with essential hypertension. The pro-drug is converted by hydrolysis to the active pharmaceutical ingredient azilsartan. Laboratory tests to evaluate the environmental fate and effects of azilsartan medoxomil were conducted with azilsartan and performed in accordance with OECD test guidelines. The predicted environmental concentration (PEC) in surface water was estimated at 0.32 µg L(-1) (above the action limit of 0.01 µg L(-1)), triggering a Phase II assessment. Azilsartan is not readily biodegradable. Results of the water sediment study demonstrated significant shifting of azilsartan metabolites to sediment. Based on the equilibrium partitioning method, metabolites are unlikely to pose a risk to sediment-dwelling organisms. Ratios of the predicted environmental concentrations (PECs) to the predicted-no-effect concentrations (PNECs) did not exceed the relevant triggers, and the risk to aquatic, sewage treatment plant (STP), groundwater and sediment compartments was concluded acceptable. A terrestrial assessment was not triggered. Azilsartan poses an acceptable risk to the environment.

Reactions of monosaccharides during heating of sugar-casein systems: building of a reaction network model.

The Maillard reaction is important during the heating and processing of foods for its contribution to food quality. To control a reaction as complex as the Maillard reaction, it is necessary to study the reactions of interest quantitatively. In this paper the main reaction products in monosaccharide-casein systems, which were heated at 120 degrees C and pH 6.7, were identified and quantified, and the reaction pathways were established. The main reaction routes were (i) sugar isomerization, (ii) degradation of the sugar into carboxylic acids, and (iii) the Maillard reaction itself, in which not only the sugar itself but also its reaction products react with the epsilon-amino group of lysine residues of the protein. Significant differences in reaction mechanism between aldose and ketose sugars were observed. Ketoses seemed to be more reactive in the sugar degradation reactions than their aldose isomers, and whereas the Amadori product was detected as a Maillard reaction intermediate in the aldose-casein system, no such intermediate could be found in the ketose-casein system. The reaction pathways found were put together into a model, which will be evaluated by kinetic modeling in a subsequent paper.

Mutagenicity of heated sugar-casein systems: effect of the Maillard reaction.

The formation of mutagens after the heating of sugar-casein model systems at 120 degrees C was examined by the Ames test, using Salmonella typhimurium strain TA100. Several sugars (glucose, fructose, galactose, tagatose, lactose, and lactulose) were compared in their mutagenicities. Mutagenicity could be fully ascribed to Maillard reaction products and strongly varied with the kind of sugar. The differences in mutagenicity among the sugar-casein systems were caused by a difference in reaction rate and a difference in reaction mechanism. Sugars with a comparable reaction mechanism (glucose and galactose) showed a higher mutagenic activity corresponding with a higher Maillard reactivity. Disaccharides showed no mutagenic activity (lactose) or a lower mutagenic activity (lactulose) than their corresponding monosaccharides. Ketose sugars (fructose and tagatose) showed a remarkably higher mutagenicity compared with their aldose isomers (glucose and galactose), which was due to a difference in reaction mechanism.

Inactivation of a subtilisin in colloidal systems.

The aim of the present study is to establish the relation between the inactivation of the proteolytic enzyme Savinase and its adsorption at different types of solid-liquid interfaces. The loss of activity has been determined both in solution and in the presence of colloidal particles, which provide a surface area for adsorption of 25% of the enzyme population. Analysis of the remaining solution at different periods of incubation of the various systems shows that the intact protein is converted into autolytic degradation products at the expense of biological activity. The different particles, however, deactivate the enzymes to a different extent. Under the experimental conditions the half-life of the enzymatic activity in solution is 3.5 hours. In the presence of particles that have hydrophobic surface properties (teflon- or polystyrene latex) the half-life is reduced to 0.7 hours. On the contrary, hydrophilic silica particles stabilize the enzyme against autolysis as compared to the inactivation in solution. Polystyrene latex particles which are chemically grafted with short poly(ethylene oxide) chains ([EO]8) are, for steric reasons, also mild with respect to the reduction of enzymatic stability. It is thus concluded that the type of surface determines the mode in which the enzyme is adsorbed on a particle which, in turn, affects the autocatalytic rate.