AMA0076, a Novel, Locally Acting Rho Kinase Inhibitor, Potently Lowers Intraocular Pressure in New Zealand White Rabbits with Minimal Hyperemia

PURPOSE. To determine whether ROCK inhibition for the treatment of glaucoma can be improved by using novel, locally acting Rho kinase (ROCK) inhibitors, such as AMA0076, that lower IOP without inducing hyperemia. METHODS. On-target potency of AMA0076 was compared with other ROCK inhibitors (Y-27632 and Y-39983) and conversion of AMA0076 into its functionally inactive metabolite was evaluated in rabbit eye tissues. Human trabecular meshwork (HTM) cell morphology, actin filaments, and focal adhesion were studied in vitro after exposure to AMA0076. The effect of AMA0076 on IOP was investigated in normotensive rabbits and a new, acute hypertensive rabbit model. Intraocular pressure lowering efficacy of AMA0076 was compared with pharmacologic treatments. Hyperemia after single topical dosing of AMA0076 and Y-39983 was scored. RESULTS. AMA0076 and Y-39983 showed similar on-target potency. AMA0076 was most stable in aqueous humor and converted into its metabolite in other eye tissues. Exposure of HTM cells to AMA0076 led to significant and reversible changes in cell shape and a decrease in actin stress fibers and focal adhesions. Both AMA0076 and Y-39983 provided an equivalent IOP control. Compared with latanoprost and bimatoprost, AMA0076 was more potent in preventing the IOP elevation in the acute hypertensive rabbit model. The degree of hyperemia was significantly lower in rabbits treated with AMA0076 then with Y-39983. CONCLUSIONS. AMA0076 is a locally acting ROCK inhibitor that is able to induce altered cellular behavior of HTM cells. Administration of AMA0076 effectively reduces IOP in ocular normotensive and acute hypertensive rabbits without causing distinct hyperemia

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11β-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1

De jaarrekening doorgelicht - Financiële analyse en interpretatie in de praktijk

Deze uitgave is een handleiding bij de analyse en interpretatie van de cijfers van de gepubliceerde jaarrekening. Door middel van een in detail uitgewerkte case geven de auteurs de lezer een fundamenteel inzicht in de financiële analyse van de externe rapportering van een onderneming. De manier waarop de accountant de gepubliceerde cijfers van een onderneming analyseert, wordt op een praktijkgerichte manier benaderd. De interpretatie van de analyse wordt uitvoerig belicht. Naast de traditionele technieken die gebruikt worden om de bekende ratio's te berekenen, geven de auteurs een duidelijk inzicht in de interpretatie van de cijfers. De cijfers van de bestudeerde onderneming worden voortdurend vergeleken met andere ondernemingen uit de sector. Het boek richt zich tot studenten accountancy. Doordat gekozen werd voor een praktijkgerichte benadering is het boek ook zeer toegankelijk voor niet-accountancy studenten. Bovendien kunnen professionele gebruikers hun parate kennis over deze materie bijschaven

Predicting Residual Adsorbable Organic Halides Concentrations in Industrial Wastewater Using Typical Wastewater Parameters

The aim of this study was to predict the residual adsorbable organic halides (AOX) concentration in an industrial wastewater using conventional, easy-to-measure wastewater parameters. In a pilot test unit, the wastewater was subjected to ozonation at various intensities, resulting in an AOX-removal and hence varying AOX concentrations. In first instance, the parameters used for modeling were selected using Pearson and Spearman correlations. Secondly, multiple linear regression (MLR) was used as a modeling tool to predict both the soluble and total AOX concentration in wastewater samples. To prevent overfitting, a 10-fold cross-validation was carried out. It was found that both the soluble and the total AOX concentration can be predicted using typical wastewater parameters. The measured parameters were pH, chloride concentration, Water-Soluble Organic Carbon concentration (WSOC), UV-VIS spectrum, turbidity, and Solids Removable by Filtration (SRF). Out of these parameters, the following parameters were found to be significant for prediction of the total AOX concentration: turbidity; SRF; UV-VIS absorbance at 200; 227, and 250 nm; and pH. UV-VIS absorbance at 200 and 227 nm and turbidity of the wastewater were found to contribute significantly to the final model. For the soluble AOX concentration, the significant parameters were turbidity; SRF; absorbance at 200, 227, and 250 nm; pH, and chloride concentration. Here, UV-VIS absorbance at 200 and 227 nm were found to contribute significantly to the final model. The obtained final models had an adjusted R2 of 0.921 and 0.916 for the total and soluble AOX, respectively. As a result of the obtained models, both AOX concentrations can be predicted using parameters that are easier to determine. This allows for a significant reduction in wastewater sampling and analysis time and offers the opportunity to optimize the ozone dosing in the wastewater treatment process in the future

Predicting Residual Adsorbable Organic Halides Concentrations in Industrial Wastewater Using Typical Wastewater Parameters

The aim of this study was to predict the residual adsorbable organic halides (AOX) concentration in an industrial wastewater using conventional, easy-to-measure wastewater parameters. In a pilot test unit, the wastewater was subjected to ozonation at various intensities, resulting in an AOX-removal and hence varying AOX concentrations. In first instance, the parameters used for modeling were selected using Pearson and Spearman correlations. Secondly, multiple linear regression (MLR) was used as a modeling tool to predict both the soluble and total AOX concentration in wastewater samples. To prevent overfitting, a 10-fold cross-validation was carried out. It was found that both the soluble and the total AOX concentration can be predicted using typical wastewater parameters. The measured parameters were pH, chloride concentration, Water-Soluble Organic Carbon concentration (WSOC), UV-VIS spectrum, turbidity, and Solids Removable by Filtration (SRF). Out of these parameters, the following parameters were found to be significant for prediction of the total AOX concentration: turbidity; SRF; UV-VIS absorbance at 200; 227, and 250 nm; and pH. UV-VIS absorbance at 200 and 227 nm and turbidity of the wastewater were found to contribute significantly to the final model. For the soluble AOX concentration, the significant parameters were turbidity; SRF; absorbance at 200, 227, and 250 nm; pH, and chloride concentration. Here, UV-VIS absorbance at 200 and 227 nm were found to contribute significantly to the final model. The obtained final models had an adjusted R2 of 0.921 and 0.916 for the total and soluble AOX, respectively. As a result of the obtained models, both AOX concentrations can be predicted using parameters that are easier to determine. This allows for a significant reduction in wastewater sampling and analysis time and offers the opportunity to optimize the ozone dosing in the wastewater treatment process in the future.status: publishe

The Effect of AMA0428, a Novel and Potent ROCK Inhibitor, in a Model of Neovascular Age-Related Macular Degeneration

Rho kinase (ROCK) is associated with VEGF-driven angiogenesis, as well as with inflammation and fibrosis. Therefore, the effect of AMA0428, a novel ROCK inhibitor, was studied in these processes, which highly contribute to the pathogenesis of neovascular AMD.status: publishe

AMA0076, a novel, locally acting rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia

PURPOSE: To determine whether ROCK inhibition for the treatment of glaucoma can be improved by using novel, locally acting Rho kinase (ROCK) inhibitors, such as AMA0076, that lower IOP without inducing hyperemia. METHODS: On-target potency of AMA0076 was compared with other ROCK inhibitors (Y-27632 and Y-39983) and conversion of AMA0076 into its functionally inactive metabolite was evaluated in rabbit eye tissues. Human trabecular meshwork (HTM) cell morphology, actin filaments, and focal adhesion were studied in vitro after exposure to AMA0076. The effect of AMA0076 on IOP was investigated in normotensive rabbits and a new, acute hypertensive rabbit model. Intraocular pressure lowering efficacy of AMA0076 was compared with pharmacologic treatments. Hyperemia after single topical dosing of AMA0076 and Y-39983 was scored. RESULTS: AMA0076 and Y-39983 showed similar on-target potency. AMA0076 was most stable in aqueous humor and converted into its metabolite in other eye tissues. Exposure of HTM cells to AMA0076 led to significant and reversible changes in cell shape and a decrease in actin stress fibers and focal adhesions. Both AMA0076 and Y-39983 provided an equivalent IOP control. Compared with latanoprost and bimatoprost, AMA0076 was more potent in preventing the IOP elevation in the acute hypertensive rabbit model. The degree of hyperemia was significantly lower in rabbits treated with AMA0076 then with Y-39983. CONCLUSIONS: AMA0076 is a locally acting ROCK inhibitor that is able to induce altered cellular behavior of HTM cells. Administration of AMA0076 effectively reduces IOP in ocular normotensive and acute hypertensive rabbits without causing distinct hyperemia.status: publishe