RESUMEN
Heparins are useful for the protection of residual renal function in several nephropathies, but the anticoagulant action and the need of parenteral administration are two main drawbacks limiting their use in chronic renal failure patients. Heparan sulphate (HS) is a heparin-like mucopolysaccharide devoid of anticoagulant action and active orally. In this study, the effects of HS oral administration have been evaluated in 18 subtotally nephrectomized rats;18 untreated remnant kidney rats served as control. No mortality was observed in the HS-treated rats, whereas in the control rats the survival rate was 72.2% at 18 weeks. At the end of the study, HS-treated rats showed lower urinary protein excretion (44 +/- 22 vs. 80 +/- 54 mg/24 h, p < 0.01), lower urea plasma levels (75 +/- 34 vs. 134 +/- 105 mg/dl, p < 0.01) and higher creatinine clearance (66 +/- 15 vs. 47 +/- 21 ml/min. 10(2), p < 0.05) than control rats. Remnant kidney weight (2.3 +/- 1.1 vs. 1.3 +/- 0.2 g, p < 0.01) and heart weight (1.3 +/- 0.2 vs. 1.1 +/- 0.1 g, p < 0.05) were greater in the control than in the HS-treated rats, as well as the systemic blood pressure values (167 +/- 19 vs. 115 +/- 32 mm Hg, respectively, p < 0.001). The remnant kidney histological examination in the HS-treated rats showed a lower prevalence of glomerular sclerosis, mesangial proliferation, and a much less evident tubulointerstitial damage than in controls. The antiproliferative and anti-inflammatory actions of HS together with its protective action on the endothelium are the putative mechanisms that could account for our findings. In conclusion, the present study supports evidence of an antiproteinuric and a renoprotective effect of orally administered HS in subtotally nephrectomized rats. This is in keeping with the well-known effects exerted also by other heparins, but the effectiveness of an orally available heparin-like product in this animal model could suggest the possibility of a clinical use also in progressing chronic renal failure patients.
Asunto(s)
Heparitina Sulfato/administración & dosificación , Fallo Renal Crónico/prevención & control , Administración Oral , Animales , Modelos Animales de Enfermedad , Riñón/patología , Riñón/fisiopatología , Fallo Renal Crónico/patología , Fallo Renal Crónico/fisiopatología , Masculino , Nefrectomía , Proteinuria/prevención & control , Ratas , Ratas WistarRESUMEN
In order to reduce the extrahepatic side-effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara-AMP), conjugated with lactosaminated human serum albumin (L-HSA) and administered to hepatitis B virus (HBV)-infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side-effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine (Lac-poly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac-poly(Lys) conjugates, one with ara-AMP and one with ribavirin, are reported in this review.
Asunto(s)
Antivirales/administración & dosificación , Hígado/metabolismo , Nucleósidos/administración & dosificación , Receptores de Superficie Celular/metabolismo , Fosfato de Vidarabina/administración & dosificación , Animales , Antivirales/metabolismo , Antivirales/farmacología , Receptor de Asialoglicoproteína , Asialoglicoproteínas/metabolismo , Asialoglicoproteínas/farmacología , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacología , Fetuínas , Galactanos/metabolismo , Galactanos/farmacología , Humanos , Lactosa/metabolismo , Lactosa/farmacología , Lipoproteínas/metabolismo , Lipoproteínas/farmacología , Nucleósidos/metabolismo , Nucleósidos/farmacología , Polilisina/metabolismo , Polilisina/farmacología , Albúmina Sérica/metabolismo , Albúmina Sérica/farmacología , Fosfato de Vidarabina/metabolismo , Fosfato de Vidarabina/farmacología , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/farmacologíaRESUMEN
A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver-targeting molecule lactosaminated human serum albumin (L-HSA) was administered by intravenous infusion for 28 days to eight patients with chronic type B hepatitis. The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis indicated that, at every dose tested, the conjugate was disposed of without accumulation. Viral DNA serum levels fell markedly during treatment; values rose again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either the neurotoxic side effects of free ara-AMP or other adverse clinical reactions. It produced a significant increase both in serum alkaline phosphatase activity and platelet number, and a small but significant decrease in erythrocyte number. These laboratory parameters returned to normal levels within 2 months after treatment. The conjugate induced the production of small amounts of antibodies (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only. In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can exert the antiviral activity of ara-AMP in chronic type B hepatitis patients without producing the neurotoxic side effects which hamper a 4-week period of treatment with the free drug.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis B/tratamiento farmacológico , Albúmina Sérica/administración & dosificación , Fosfato de Vidarabina/administración & dosificación , Viremia/tratamiento farmacológico , Adulto , Enfermedad Crónica , ADN Viral/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/farmacocinéticaRESUMEN
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 WistarAsunto(s)
Virus de la Hepatitis B/efectos de los fármacos , Albúmina Sérica/farmacología , Fosfato de Vidarabina/farmacología , Replicación Viral/efectos de los fármacos , Adulto , Anciano , Enfermedad Crónica , Femenino , Hepatitis B/tratamiento farmacológico , Virus de la Hepatitis B/fisiología , Humanos , Masculino , Persona de Mediana Edad , Albúmina Sérica/uso terapéutico , Fosfato de Vidarabina/uso terapéuticoRESUMEN
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
The fibrinolytic activity, effect on the fibrinolytic activity of plasmin, anticoagulant activity and anti platelet aggregation activity of a low molecular weight heparan sulfate (LMW HS Bal) were investigated "in vitro" on blood plasma obtained from rats and rabbits. LMW HS Bal at concentrations as low as 0.25-2 micrograms/ml prevented thrombin-induced platelet aggregation. At concentrations 25 to 50 times larger it showed no significant anticoagulant activity but a marked fibrinolytic effect. At still larger concentrations LMW HS Bal also potentiated the fibrinolytic activity of plasmin. Conversely, unfractionated heparan sulfate (UHS) at concentrations of 25 to 50 micrograms/ml, only showed anticoagulant activity with no fibrinolytic activity.
Asunto(s)
Fibrinolíticos , Heparitina Sulfato/farmacología , Animales , Sinergismo Farmacológico , Fibrinolisina/farmacología , Técnicas In Vitro , Masculino , Peso Molecular , Tiempo de Tromboplastina Parcial , Inhibidores de Agregación Plaquetaria/farmacología , Conejos , Ratas , Ratas EndogámicasRESUMEN
The diffusion of the glycosylated albumin in the retinal vascular system has been studied in male New Zealand rabbits, using fluorangiographic techniques. A first group of animals was treated for 15 days with the peptide fraction from bovine Factor VIII (Vueffe); a second group, used as control group, was treated with physiological solution. At the end of treatment, glycosylated albumin was made fluorescent and then injected into the marginal vein of the rabbit. The direct observation and the photometric measurements performed on the digitized photograms with an image processing system showed a considerable reduction in retinic capillary diffusion of glycosylated albumin in the animals treated with the peptide fraction. The substance used in the study might therefore be of importance in the treatment of systemic disease with retinic vascular damage.
Asunto(s)
Factor VIII/farmacología , Péptidos/farmacología , Retina/metabolismo , Albúmina Sérica/metabolismo , Angiografía , Animales , Bovinos , Difusión , Fluorescencia , Masculino , Microcirculación , Fotometría , Conejos , Retina/anatomía & histología , Retina/irrigación sanguínea , Espectrometría de FluorescenciaRESUMEN
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.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Factor VIII/análisis , Fragmentos de Péptidos/farmacología , Animales , Aspirina/farmacología , Tiempo de Sangría , Relación Dosis-Respuesta a Droga , Heparina/farmacología , Ratones , Fragmentos de Péptidos/aislamiento & purificación , Conejos , RatasRESUMEN
We report a new method of fluorangiography employing a polypeptide fraction from bovine factor VIII that has shown remarkable affinity to the endothelial surface of microvessels. Rabbits injected with this compound, labeled with fluorescein isothiocyanate, show a very delayed disappearance time of fluorescence in retinal vessels when compared with those injected with ordinary fluorescein. This allows a good observation of the late time, which is of great diagnostic advantage for several pathological conditions.
Asunto(s)
Factor VIII/análisis , Angiografía con Fluoresceína/métodos , Péptidos , Animales , Bovinos , Fraccionamiento Químico , Fluoresceína-5-Isotiocianato , Fluoresceínas , Masculino , Conejos , Vasos Retinianos/anatomía & histología , Tiocianatos , Factores de TiempoRESUMEN
It is well known that high molecular weight bovine factor VIII is able to aggregate human platelets and possesses procoagulant activities. There is also growing body of evidence that the hydrolysis of bovine factor VIII abolishes its aggregating and coagulative properties. We have shown in this paper that a polypeptide fraction (molecular weight 1000-25000 daltons) from bovine factor VIII does not aggregate platelets nor affect blood coagulation. In this study we investigate the action of the polypeptide fraction derived from bovine factor VIII and suggest that its effect may occur only at endothelium level without an involvement of platelets as well as blood coagulation.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Factor VII/farmacología , Péptidos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Animales , Bovinos , Humanos , Técnicas In Vitro , Peso Molecular , Tiempo de Tromboplastina ParcialRESUMEN
The tripeptide ZAMI-420 has been shown by Gervasi et al. (4) to be able to prevent experimentally-induced gastric damage, possibly by interfering with the synthesis and the action of thromboxane A2 (TXA2), a potent vasoconstrictor and platelet aggregator. Further studies on a canine stomach wedge preparation, supplied with a fixed flow of 10 ml/min-1 of arterial blood from the same dog have been designed to investigate this hypothesis. Bolus injection of arachidonic acid (AA) through a 30-sec incubation coil that allows the production of TXA2 resulted in a dose-related increase in resistance to flow in the stomach wedge vasculature and blanching of the gastric mucosa. This was progressively inhibited by ZAMI-420 perfused through the delay coil. Similar results were obtained with 1-benzylimidazole (BI). ZAMI-420, but not BI, produced a partial inhibition of TXA2-induced vasoconstriction when infused close to the stomach. Investigations of the antagonistic action of ZAMI-420 on the pharmacological effect of the formed TXA2 were carried out using strips of celiac and mesenteric artery from rabbits and gastric artery from dogs. Preincubation of these vascular preparations with ZAMI-420 led to progressive inhibition of the contraction induced either by the stable endoperoxide U-46619 or by CaCl2. Whittle et al. (3) reported that TXA2 may be involved in the pathogenesis of ulcerative disorders of the stomach; if so, both the inhibition of the synthesis and the antagonism of TXA2-induced effects could be of value in the prevention of experimentally-induced gastric disorders.
Asunto(s)
Mucosa Gástrica/irrigación sanguínea , Isquemia/inducido químicamente , Oligopéptidos/farmacología , Estómago/irrigación sanguínea , Tromboxano A2/biosíntesis , Tromboxanos/biosíntesis , Vasoconstricción/efectos de los fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animales , Arteria Celíaca/efectos de los fármacos , Perros , Femenino , Masculino , Arterias Mesentéricas/efectos de los fármacos , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Conejos , Tromboxano A2/antagonistas & inhibidores , Tromboxano A2/farmacologíaRESUMEN
There is accumulating evidence that the presence of the imidazole ring is essential for the inhibition of the thromboxane synthetase activity of several compounds synthetized so far. Inhibition of arachidonic acid (AA) induced platelet aggregation was observed by us with a series of tripeptides in which the imidazole ring belongs to histidine, included in a proper aminoacid sequence. Among these compounds the N-acetyl-L-phenylalanyl-L-phenylalanyl-L-histidine methylester (ZAMI-420) was the most effective. The bioassay of the supernatant of an AA-added platelet-rich plasma (PRP) preparation, preincubated with increasing concentrations of ZAMI-420, showed a dose-related reduction in thromboxane-A2 (TXA2)-like activity, an increase of PG-like response and disappearance of the TXB2 peak in the radiochromatogram; RIA experiments led to the same results. ZAMI-420 does not influence cyclooxygenase activity as the AA-induced increase in O2-consumption by the microsomal fraction of bovine seminal vesicles was unaltered by this compound. Administered orally to the rat, ZAMI-420 was able to prevent gastric damage provoked by a variety of pharmacological agents, including ASA, 5HT and alcohol. The protective effect on experimentally-induced gastric damage is not mediated through the antisecretory properties of this compound but is more likely to be due to a cytoprotective mechanism based on blockade of TXA2 synthesis.
Asunto(s)
Oligopéptidos/farmacología , Estómago/efectos de los fármacos , Tromboxano A2/biosíntesis , Tromboxanos/biosíntesis , Animales , Ácidos Araquidónicos/metabolismo , Bioensayo , Carbenoxolona/farmacología , Cromatografía en Capa Delgada , Cimetidina/farmacología , Etanol/efectos adversos , Femenino , Cobayas , Imidazoles/farmacología , Agregación Plaquetaria/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Conejos , Radioinmunoensayo , Ratas , Ratas Endogámicas , Serotonina/efectos adversos , Úlcera Gástrica/inducido químicamente , Tromboxano A2/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacosAsunto(s)
Ácido Ascórbico/metabolismo , Glicerol/metabolismo , Animales , Combinación de Medicamentos , Cinética , Masculino , ConejosRESUMEN
The metabolic pathway of Pinazepam and Diazepam in vitro was studied with rat, guinea pig and dog liver microsomes using a chromatographic and spectrophotometric technique. Two main pathways were observed, N1-dealkylation and C3-hydroxylation. N1-dealkylation was shown to be the predominant reaction for Pinazepam in all the animal species studied, while C3-hydroxylation was the major metabolic pathway for Diazepam in the rat. No oxazepam was found when Pinazepam and Diazepam were incubated with liver microsomes.