RESUMEN
The fibrinolytic and anticoagulant activities of heparan sulphate (HS) and dermatan sulphate (DS) were compared with those of heparin using in vitro tests. Our results demonstrate that HS has higher profibrinolytic activity than heparin and DS. Although 50 times less potent than heparin in inhibiting factor IIa, HS is three times more active than DS. The action of HS resides in HCH-mediated factor IIa inhibition combined with an ATIII-mediated inhibition. DS has no action on ATIII-mediated inhibition of factor IIa. The comparison of the anticoagulant activities of the three compounds confirmed the very limited anticoagulant effect of both HS and DS in comparison with heparin.
Asunto(s)
Dermatán Sulfato/farmacología , Heparina/farmacología , Heparitina Sulfato/farmacología , Animales , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fibrinólisis/efectos de los fármacos , Técnicas In Vitro , Masculino , Peso Molecular , Conejos , Ratas , Ratas WistarRESUMEN
A fluoresceinated derivative of a new heparan sulfate fraction (HS) was administered by intravenous route to rats. The compound was similar to the unlabelled compound and biologically active. After i.v. injection, pharmacokinetic parameters were analyzed and discussed according to a two-compartment open model. In addition, experiments performed with the unlabelled compound indicate that the HS is absorbed through the intestinal mucosa, reaches the highest plasmatic concentration after 90 min and is partially recovered, unmodified, in urine. Other sets of experiments, in vitro, show that the compound is degraded in the presence of hepatic microsomal preparation while it is not metabolized by plasma, confirming that the liver plays an important role in the metabolism and consequently on the activity of the compound. The overall results are in accordance with the fibrinolytic and antithrombotic activity of HS administered orally to animals and man.
Asunto(s)
Fibrinolíticos/farmacocinética , Heparina/farmacocinética , Administración Oral , Animales , Cromatografía por Intercambio Iónico , Fibrinolíticos/sangre , Fibrinolíticos/orina , Fluoresceínas , Jugo Gástrico/química , Heparina/sangre , Heparina/orina , Técnicas In Vitro , Inyecciones Intravenosas , Absorción Intestinal , Masculino , Microsomas Hepáticos/metabolismo , Modelos Biológicos , Peso Molecular , Ratas , Ratas WistarRESUMEN
The effects of a new aldose reductase inhibitor, 7-fluoro-2-(N-methyl-N-carboxymethyl)sulfamoyl xanthone (BAL-ARI8, CAS 124066-40-6), on the diabetic complications of streptozotocin-induced diabetic rats were studied. The daily administration of BAL-ARI8 throughout the 8-week course of the experiment sharply decreased the sorbitol accumulation in the lens of the diabetic rats. The incidence of cataract formation was also reduced, being detected in only 45% of BAL-ARI8 treated animals, against the 100% of diabetic controls showing cataract after 8 weeks from diabetes onset. On the other hand, the serum glucose levels remained unchanged. In diabetic controls, there was about a 2.5-fold increase of the total protein urinary excretion during the 24 h. Treatment with BAL-ARI8 prevented up to 70% of this increase. Individual protein components were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins with molecular weight in the range 30,000-60,000 D, together with an increase of albumin (25% of the total excretion) and the presence of new higher molecular weight proteins (greater than 66,000 D). BAL-ARI8 administration resulted in a shift of the protein profile back toward normality i.e. 73% of proteins with molecular weight below 30,000 D, 7.5% albumin and no proteins above 66,000 D. These results suggest that BAL-ARI8 may represent a therapeutic approach for the management of diabetic complications.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Experimental/complicaciones , Xantenos/farmacología , Xantonas , Animales , Glucemia/metabolismo , Catarata/etiología , Catarata/prevención & control , Electroforesis en Gel de Poliacrilamida , Cristalino/efectos de los fármacos , Cristalino/metabolismo , Masculino , Peso Molecular , Proteínas/metabolismo , Proteinuria/metabolismo , Ratas , Ratas Endogámicas , Sorbitol/sangre , Sorbitol/metabolismoRESUMEN
Kappa-carrageenan (kappa-carrageenin; kappa-carragheen) was found to be thrombogenic in rats. After i.p. injection of 3 mg/kg of kappa-carrageenan the thrombosis extended to a maximum 7.5 cm from the tip of the tail. Infarction frequency as well as the extent of infarction were inhibited by oral administration of a new heparan sulphate of low molecular weight (LMW-HS) (alpha-idosane). Mesoglycan and heparin were active when administered by parenteral route, and aspirin showed no effect; mesoglycan was inactive at 50 mg/kg per os. The present data confirm the validity of this experimental model for evaluating the protective effects of antithrombotic drugs and show the activity of oral administration of a new drug endowed with fibrinolytic activity.
Asunto(s)
Carragenina/antagonistas & inhibidores , Fibrinolíticos/farmacología , Heparina de Bajo-Peso-Molecular/farmacología , Trombosis/prevención & control , Animales , Aspirina/farmacología , Glicosaminoglicanos/farmacología , Infarto/prevención & control , Masculino , Ratas , Ratas Endogámicas , Flujo Sanguíneo Regional/efectos de los fármacos , Cola (estructura animal)/irrigación sanguínea , Trombosis/inducido químicamente , Trombosis/patologíaRESUMEN
A low molecular weight heparan sulfate derivative, alpha-idosane was separated from a mixture of glycosaminoglycans extracted from porcine mucosa. Its molecular weight, sulfur, uronic acid and hexosamine contents, C-NMR spectrum and electrophoretic properties are reported in this paper. The pharmacological effects of a-idosane were investigated "ex vivo" in dogs and rats. At doses of 10-50 mg/kg p.o., a-idosane shows fibrinolytic activity but it is devoid of anticoagulant action. At the dose of 100 mg/kg p.o. a-idosane exertes a significant anti-inflammatory effect but is unable to protect the rats against arachidonate-induced sudden death.
Asunto(s)
Heparina de Bajo-Peso-Molecular/química , Heparitina Sulfato/química , Animales , Antiinflamatorios no Esteroideos , Anticoagulantes , Ácido Araquidónico , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/toxicidad , Fenómenos Químicos , Química Física , Perros , Fibrinólisis/efectos de los fármacos , Heparina de Bajo-Peso-Molecular/farmacología , Heparitina Sulfato/farmacología , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Peso Molecular , Ratas , Ratas EndogámicasRESUMEN
A peptide fraction of low molecular weight prepared from bovine Factor VIII by enzymatic hydrolysis (Vueffe) reduces bleeding time in laboratory animals. In this study the haemostatic action in mice, rats and rabbits was investigated using different experimental conditions. This action was observed in animals with either normal or experimentally prolonged bleeding time, thus suggesting better efficacy in pathological situations. The evidence obtained following different routes of administration confirmed the activity of the compound. The efficacy was present at very low doses in all animal species without interfering either with platelets or with blood coagulation.