Antonio Vallecillo Moreno

Effect of WEB 2086-BS, an antagonist of platelet-activating factor receptors, on retinal vascularity in diabetic rats

Specific antagonists of platelet-activating factor (PAF) receptors inhibit platelet aggregation and thromboxane synthesis. These two processes have been implicated in the course of diabetic retinopathy. We assessed the effect of a specific PAF receptor antagonist, WEB 2086-BS (3-(4-(2-chlorophenyl)-9-methyl-6H-thieno(3,2-f) (1,2,4 triazolo-(4,3-a(1,4)-diazepine-2-yl)-1-(4-morpholinyl)-1-propanone) on retinal vascularity in a model of experimental streptozocin-induced diabetes in rats. Rats were divided into five experimental groups (10 animals/group): group I, non-diabetic group II, untreated diabetic group III, diabetic given 1 mg/kg per day of WEB 2086-BS (p.o.) group IV, diabetic given 5 mg/kg per day (p.o.) and group V, diabetic given 10 mg/kg per day (p.o.). After 3-month treatment, platelet aggregometry, platelet synthesis of thromboxane B2, aortic production of 6-keto-prostaglandin F1alpha, platelet and vascular lipid peroxidation, and percentage of the retinal area occupied by horseradish peroxidase-labeled vessels were measured. Untreated diabetic rats showed an increase in platelet reactivity, reduced 6-keto-prostaglandin F1alpha production, increased thromboxane B2 and lipid peroxides, and a decrease in the percentage of retinal area occupied by horseradish peroxidase-labeled vessels. WEB 2086-BS produced a decrease in platelet aggregation induced by collagen in whole blood, in thromboxane B2 synthesis and lipid peroxide production, and an increase in the percentage of retinal area occupied by horseradish peroxidase-labeled vessels (13.9+/-1.1% in group II and 9.9+/-0.8% in group V). There was a statistically significant linear correlation (Y= -0.72 + 137X, r2 = 0.7247, P < 0.0007) between thromboxane B2 values and the percentages of retinal area occupied by horseradish peroxidase-labeled vessels in the groups of animals treated with WEB 2086-BS.

Effect of DT-TX 30, a combined thromboxane synthase inhibitor and thromboxane receptor antagonist, on retinal vascularity in experimental diabetes mellitus.

Combined thromboxane synthase inhibitors and thromboxane receptors antagonists have been shown to have a beneficial effect on different models of thrombosis in vivo. We studied the action of one of these compounds (DT-TX 30) compared with dazoxiben (a thromboxane synthase inhibitor) on retinal vascularity in streptozotocin-diabetic rats. Ten nondiabetic animals were treated with isotonic saline, 30 (10 animals per group) were given 0.4, 4, and 8 mg kg(-1) per day of DT-TX 30 (p.o.) and 30 (10 animals per group) were given 10, 50, and 100 mg kg(-1) per day of dazoxiben (p.o.) over a 90-day study period. DT-TX 30 caused a dose-dependent decrease of platelet aggregation and thromboxane B2 synthesis. There was an increase of 9, 65, and 166% in the synthesis of prostacyclin after treatment with 0.4, 4, and 8 mg kg(-1) per day, respectively. Retinal vascularity increased in 51, 72, and 182% of animals in response to the three doses used. Synthesis of prostacyclin and the degree of retinal vascularity showed a linear correlation (r2=0.6528,p<0.00001). Dazoxiben, at doses that inhibited thromboxane synthesis as much as DT-TX 30, increased prostacyclin production and retinal vascularity with less potency than DT-TX 30. In conclusion, the antagonism of thromboxane receptors may be an important additional effect to the inhibition of thromboxane synthase in the prevention of ischemic retinal lesions in experimental diabetes.

Effect of camonagrel, a selective thromboxane synthase inhibitor, on retinal vascularization in experimental diabetes

Platelet hyperactivity accompanied by an increased synthesis of thromboxane and/or a decreased prostacyclin production are important factors in ischemic diabetic retinopathy. We studied the effect of camonagrel and dazoxiben, two thromboxane synthase inhibitors, on retinal vascularization in a model of streptozotocin-induced diabetes in rats. Ten nondiabetic rats, 10 diabetic animals treated with saline (i.e., not treated), and 60 diabetic animals treated with dazoxiben or camonagrel (10, 50 or 100 mg kg(-1) day(-1) p.o.) were studied. All treatments lasted for 90 days. Dazoxiben and camonagrel produced a dose-dependent reduction in platelet aggregation and thromboxane synthesis. Dazoxiben increased prostacylin synthesis by 78% at 100 mg kg(-1) day(-1), and camonagrel by 154%. Dazoxiben increased retinal vascularity by 74%, and by 183% after camonagrel treatment. Prostacyclin synthesis showed a direct linear correlation with the degree of retinal vascularization (r2=0.6733, P < 0.00001). We conclude that an increased prostacyclin synthesis may have a greater influence than the inhibition of thromboxane synthesis in preventing ischemic diabetic retinopathy in experimental diabetes. Camonagrel may be an alternative treatment in the prevention of these lesions.

EFFECT OF ERYTHROCYTES AND PROSTACYCLIN PRODUCTION IN THE EFFECT OF FRUCTOSE AND SORBITOL ON PLATELET ACTIVATION IN HUMAN WHOLE BLOOD IN VITRO

We analyzed the in vitro effects of sorbitol and fructose on platelet function. Sorbitol and fructose increased platelet aggregation induced with adenosine diphosphate (ADP) or collagen in whole blood, but had no effect in platelet-rich plasma. The concentration that increased basal aggregation by 50% with ADP as the inducer was 12.89 +/- 1.55 mmol/L for fructose, and 18.99 +/- 2.01 mmol/L for sorbitol. When collagen was the inducer, these concentrations were 15.02 +/- 0.98 mmol/L for fructose, and 12.94 +/- 1.57 mmol/L for sorbitol. Both sugars increased, in a concentration-dependent way, the proaggregatory effect of erythrocytes, and erythrocyte uptake of adenosine. Time to uptake of 50% adenosine was 2.1 +/- 0.3 min in control samples, 0.14 +/- 0.01 min in the presence of fructose, and 0.23 +/- 0.03 min with sorbitol. Both sugars reduced vascular prostacyclin synthesis, with 50% inhibitory concentrations of 26.48 +/- 1.97 mmol/L for fructose, and 39.53 +/- 2.81 mmol/L for sorbitol. Both sugars also increased arterial lipid peroxidation by 30% (sorbitol) and 23% (fructose). We conclude that these two sugars enhance platelet function and disrupt the thromboxane/prostacyclin ratio.

Model-driven component adaptation in the context of Web Engineering

Currently, Web-based applications are no longer monolithic and isolated systems but, rather, distributed applications that need to interoperate with third-party systems, such as external Web services, LDAP repositories or legacy applications. When one component provides a service that the Web application requires, it is often not possible to bind the two systems together if they were not programmed to have compatible collaboration specifications. Modeling the adaptation between a Web application and external assets becomes therefore an essential issue in any realistic model-driven development scenario. However, most of the existing Web Engineering proposals do not take this issue into account, or they simply address it at the implementation level (in a platform-specific way). In this work, we discuss the problems involved in dealing with component adaptation within the context of Model-Driven Web Engineering and show how design patterns can help addressing it. We first identify the major interoperability problems that can happen when integrating third-party application or legacy systems into our Web systems, and then propose the mechanisms that need to be put in place at the design level to generate the appropriate specification of adapters that compensate for the possible mismatches and differences. We base our proposal on well-known design patterns as they are established solutions to recurring problems, and the generation of code from them is normally straightforward.

Dynamic Validation of Maude Prototypes of UML Models

We propose an approach for the validation of UML models annotated with OCL constraints. Specifically, we provide support for dynamically validating class invariants and operation pre/post conditions during the execution of prototypes automatically obtained from UML diagrams. The supported UML models specify both static and dynamic aspects, specifically, we focus on class and sequence diagrams. The proposal is based on Maude: UML models and OCL expressions are represented as Maude specifications, which allows us to evaluate OCL expressions on UML models by term rewriting. A model transformation allows us to accomplish this transformation automatically, and represents a first step towards the integration of the proposed facilities into development environments. The Maude specifications thus obtained can be seen as high-level executable prototypes of the annotated UML models.