RESUMEN
Ancrod is a purified fraction of venom from the Malayan pit viper Calloselasma rhodostoma, containing a serine protease that cleaves fibrinopeptides A from fibrinogen. We report on a study that involved intravenous and subcutaneous application of ancrod in healthy subjects in which it was shown that ancrod induces the formation of desAA-fibrin complexes that are partially crosslinked by factor XIII proenzyme, and act as cofactor in tPA induced plasminogen activation. The plasmin generated degrades fibrin, as well as fibrinogen, leading to the appearance of large amounts of fibrinogen and fibrin degradation products in the circulation, including fragment D-dimer. At low concentrations of ancrod, formation of desAA-fibrin is preceded by production of desA-profibrin, lacking only one fibrinopeptide A.
Asunto(s)
Ancrod/farmacología , Factor XIII/metabolismo , Fibrina/biosíntesis , Trombina/metabolismo , Fibrina/metabolismo , Humanos , HidrólisisRESUMEN
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of ischemic stroke. The therapeutic effect is ascribed to a lowering of plasma fibrinogen. Thirty-two healthy volunteers received subcutaneous ancrod at doses of 1.0, 1.5 and 2.0 IU/kg body weight or placebo. Blood samples were drawn before the injection and at various time points until 96 h after the injection. Ancrod leads to the formation of desAA-fibrin, which serves as cofactor in tissue plasminogen activator activity (tPA)-induced plasminogen activation. Unchanged concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex (TAT) indicate that fibrin formation occurs independent of thrombin. Plasmin generation is independent of an increase in tPA activity or changes in plasminogen activator inhibitor-1 (PAI-1) concentration in plasma. Subcutaneous injection of ancrod leads to a generalized fibrino(geno)lytic response caused solely by providing tPA with soluble fibrin as its cofactor in plasminogen activation. Maximal plasmin activity is present 12 h after subcutaneous injection.
Asunto(s)
Ancrod/farmacología , Fibrinolíticos/farmacología , Plasminógeno/efectos de los fármacos , Adulto , Ancrod/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Fibrina/efectos de los fármacos , Fibrina/metabolismo , Fibrinolíticos/administración & dosificación , Humanos , Inyecciones Subcutáneas , Cinética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Plasminógeno/metabolismo , Inhibidor 1 de Activador Plasminogénico/sangre , Protrombina/efectos de los fármacos , Protrombina/metabolismo , Activador de Tejido Plasminógeno/sangreRESUMEN
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of acute ischemic stroke. Treatment with ancrod leads to fibrinogen depletion. The present study investigated the mechanisms leading to the reduction of plasma fibrinogen concentration. Twelve healthy volunteers received an intravenous infusion of 0.17 U/kg body weight of ancrod for 6 hours. Blood samples were drawn and analyzed before and at various time points until 72 hours after start of infusion. Ancrod releases fibrinopeptide A from fibrinogen, leading to the formation of desAA-fibrin monomer. In addition, a considerable proportion of desA-profibrin is formed. Production of desA-profibrin is highest at low concentrations of ancrod, whereas desA-profibrin is rapidly converted to desAA-fibrin at higher concentrations of ancrod. Both desA-profibrin and desAA-fibrin monomers form fibrin complexes. A certain proportion of complexes carries exposed fibrin polymerization sites E(A), indicating that the terminal component of the protofibril is a desAA-fibrin monomer unit. Soluble fibrin complexes potentiate tissue-type plasminogen activator-induced plasminogen activation. Significant amounts of plasmin are formed when soluble fibrin in plasma reaches a threshold concentration, leading to the proteolytic degradation of fibrinogen and fibrin. In the present setting, high concentrations of soluble fibrin are detected after 1 hour of ancrod infusion, whereas a rise in fibrinogen and fibrin degradation products, and plasmin-alpha(2)-plasmin inhibitor complex levels is first detected after 2 hours of ancrod infusion. Ancrod treatment also results in the appearance of cross-inked fibrin degradation product D-dimer in plasma. (Blood. 2000;96:2793-2802)
Asunto(s)
Ancrod/farmacología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Fibrina/metabolismo , Fibrinólisis/efectos de los fármacos , Fibrinolíticos/farmacología , Adulto , Ancrod/administración & dosificación , Biopolímeros , Cloruro de Calcio/farmacología , Cromatografía en Gel , Activación Enzimática/efectos de los fármacos , Factor XIII/metabolismo , Femenino , Fibrina/biosíntesis , Fibrinógeno/metabolismo , Fibrinolisina/biosíntesis , Fibrinolíticos/administración & dosificación , Fibrinopéptido A/metabolismo , Hirudinas/farmacología , Humanos , Infusiones Intravenosas , Sustancias Macromoleculares , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Plasminógeno/metabolismo , Proteínas Recombinantes/farmacología , Solubilidad , Trombina/farmacología , Activador de Tejido Plasminógeno/metabolismo , alfa 2-Antiplasmina/metabolismoRESUMEN
BACKGROUND: The low molecular weight heparin Reviparin reduces smooth muscle cell proliferation in cell culture experiments. Clinical studies with systemic application of the substance did not show a reduction of the incidence of restenosis following balloon angioplasty. Local delivery, by achieving higher local concentrations of the drug, may have the potential to decrease smooth muscle cell proliferation in the treated arterial segment. OBJECTIVES: The aim of this study was to investigate the effects of local delivery of reviparin following stent implantation in the pig coronary artery. METHODS: A coronary stent was implanted in the LAD of 34 pigs. In the treatment group 5 ml reviparin was injected with the Infusasleeve catheter at a proximal pressure of 80 psi. After 28 days the animals were sacrificed. Quantitative morphometric analysis comprised the intimal area, medial area and the lumen. The extent of vessel injury and the intimal thickness were assessed separately for each stent strut region. The correlation of injury and neointimal thickness was analysed using linear regression. RESULTS: There was no relevant difference in the extent of vessel injury (1.9 +/- 0.7 vs. 1.6 +/- 0.6), the neointimal areas (2.4 +/- 0.9 vs. 2.4 +/- 1.0 mm2) and the resulting stenosis (46 +/- 18 vs. 47 +/- 17%). The medial area was larger in the animals treated with local delivery (2.2 +/- 0.4 vs. 1.6 +/- 0.4 mm2; p < 0.01). The correlation of injury and neointimal thickness was comparable in both groups. In two animals the passage of the stent area with the delivery system resulted in stent dislocation and fatal subacute thrombosis. CONCLUSION: In this animal model, local delivery of reviparin with the Infusasleeve catheter did not result in a reduction of neointimal proliferation following stent implantation. Local delivery after stent implantation carries the risk of stent dislocation as a result of the passage with the delivery system.
Asunto(s)
Anticoagulantes/administración & dosificación , Enfermedad Coronaria/terapia , Vasos Coronarios/efectos de los fármacos , Heparina de Bajo-Peso-Molecular/administración & dosificación , Stents , Animales , Anticoagulantes/uso terapéutico , Arterias/efectos de los fármacos , Arterias/patología , Cateterismo/instrumentación , Vasos Coronarios/patología , Heparina de Bajo-Peso-Molecular/uso terapéutico , Inyecciones Intraarteriales , Porcinos , Insuficiencia del Tratamiento , Túnica Media/efectos de los fármacos , Túnica Media/patologíaRESUMEN
Polyethylene glycol (PEG)-hirudin is a derivative of hirudin with a long plasma half-life. We have compared the efficacy of PEG-hirudin with unfractionated heparin (UH) in preventing arterial thrombosis. Arterial thrombus formation was induced ex vivo in 12 healthy human volunteers by exposing a tissue factor-coated coverslip positioned in a parallel-plate perfusion chamber to flowing nonanticoagulated human blood drawn directly from an antecubital vein at an arterial wall shear rate of 2600 s-1 for 3.5 minutes. PEG-hirudin, UH, or saline (as control) were administered ex vivo through a heparin-coated mixing device positioned proximal to the perfusion chamber. Platelet and fibrin deposition was quantified by immunoenzymatic measure of the P-selectin and D-dimer content of dissolved plasmin-digested thrombi, respectively. UH was administered to a plasma concentration of 0.35 IU/mL. This concentration prolonged the activated partial thromboplastin time from 32+/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent platelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 microg/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 seconds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 microg/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required to significantly prevent fibrin deposition (0.5 microg/mL) corresponded to a much shorter prolongation of activated partial thromboplastin time (48+/-2 seconds) than that needed for UH (79+/-4 seconds). Thus, our results are compatible with the view that thrombin is greatly involved in recruitment of platelets in evolving thrombi, and that PEG-hirudin is an effective agent for preventing arterial thrombosis in a human ex vivo experimental model.
Asunto(s)
Arteriopatías Oclusivas/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Fibrinolíticos/farmacología , Heparina/farmacología , Hirudinas/análogos & derivados , Trombosis/tratamiento farmacológico , Antitrombina III/análisis , Pruebas de Coagulación Sanguínea , Fibrina/análisis , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Vidrio , Semivida , Hirudinas/farmacocinética , Hirudinas/farmacología , Humanos , Selectina-P/análisis , Péptido Hidrolasas/análisis , Activación Plaquetaria , Cloruro de Sodio/farmacología , Tromboplastina/farmacología , beta-Tromboglobulina/análisisRESUMEN
BACKGROUND: Adhesion and aggregation of platelets at sites of intimal injury are accompanied by local thrombin generation and conversion of fibrinogen to insoluble fibrin. As the long-acting thrombin inhibitor, polyethylene glycol-coupled hirudin (PEG-hirudin), would be expected to interrupt this process by inhibiting the action of thrombin on platelets and fibrinogen, its effect on intracoronary thrombus formation, coagulation, platelet function, and duration and intensity of bleeding events was investigated. METHODS: Cyclic coronary flow reductions (CFRs) were induced in the left anterior descending coronary artery of 24 anaesthetised mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. There were four treatment regimens (six dogs per group): Control (isotonic saline); PEG 0.08 (0.15 mg/kg bolus + 0.08 mg/kg.h infusion); PEG 0.15 (0.30 mg/kg bolus + 0.15 mg/kg.h infusion); PEG 0.30 (0.60 mg/kg bolus + 0.30 mg/kg.h infusion). RESULTS: A linear increase in steady-state plasma concentrations to 35.4 +/- 1.6 antithrombin units (ATU)/ml, 59.2 +/- 3.0 ATU/ml and 112.7 +/- 8.4 ATU/ml was achieved with the three doses of PEG-hirudin. The activated partial thromboplastin time (APTT) was increased 1.7-fold with PEG 0.08, 1.9-fold with PEG 0.15 and 2.2-fold with PEG 0.30. The frequency of CFRs during the first hour after drug administration was diminished by about 20% with all three doses of PEG. During the second hour, CFRs were decreased by 61% in all treated groups. Thrombin-induced platelet aggregation was completely abolished by all PEG-hirudin regimens. Buccal bleeding time and blood loss were not increased after either treatment. CONCLUSION: In this canine model of coronary artery stenosis, the thrombin inhibitor, PEG-hirudin, effectively reduces platelet-dependent thrombus formation without interfering with primary haemostasis.
Asunto(s)
Antitrombinas/uso terapéutico , Trombosis Coronaria/prevención & control , Hirudinas/análogos & derivados , Animales , Antitrombinas/administración & dosificación , Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/complicaciones , Trombosis Coronaria/etiología , Vasos Coronarios/lesiones , Perros , Endotelio Vascular/lesiones , Terapia con Hirudina , Hirudinas/administración & dosificación , Tiempo de Tromboplastina Parcial , Agregación Plaquetaria/efectos de los fármacosRESUMEN
The role of endogenous endothelin-1 in variant angina was investigated using two endothelin receptor antagonists: LU 135252 (ET(A)) and BQ 788 (ET(B)). Cyclic flow reductions were induced in a coronary artery of mongrel dogs by combining critical stenosis with endothelial injury. One hour after induction of cyclic coronary flow reductions the dogs were randomized to intravenous treatment with either saline, or LU 135252 (10 mg kg(-1)), or BQ 788 (0.1 mg kg(-1)). Cyclic coronary flow reductions were monitored for two hours after drug and remained constant in controls as well as after BQ 788. LU 135252 reduced the number of cyclic coronary flow reductions significantly (about 50%) without effects on hemodynamics or hemostasis.
Asunto(s)
Angina Inestable/metabolismo , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Antagonistas de los Receptores de Endotelina , Endotelina-1/efectos de los fármacos , Angina Inestable/tratamiento farmacológico , Animales , Vasos Coronarios/lesiones , Perros , Endotelina-1/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/lesiones , Oligopéptidos/farmacología , Oligopéptidos/uso terapéutico , Fenilpropionatos/farmacología , Fenilpropionatos/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptor de Endotelina B , Receptores de Endotelina/efectos de los fármacosRESUMEN
It has been reported previously that systemic application of low molecular weight heparin (LMWH) suppresses smooth muscle cell (SMC) proliferation after balloon angioplasty in experimental studies. However, the high concentration of heparin required for a beneficial effect may cause severe bleeding complications. The ideal situation to overcome the systemic side effects would be to administer LMWH locally and deep into the arterial wall, which became possible by the development of porous balloon catheters. The in vivo feasibility of local delivery of LMWH using the porous balloon has been assessed by delivering tritium-marked LMWH into rabbit carotid arteries. The efficacy of the system was investigated by using a second injury animal model. After development of an intimal plaque by electrical stimulation, 61 rabbits were treated with the porous balloon after balloon angioplasty. In 23 rabbits, local drug delivery was accomplished with a porous balloon catheter (35 holes, hole diameter 75 microns, 2.5 mm catheter diameter). LMWH was locally administered with 4 ml (solution 375 anti-Xa-units/ml) and 2 atm. To study the extent of restenosis and morphological changes, these animals were killed 3, 7, 14, 28, or 56 d after intervention. After staining (hematoxylin, van Gieson, BrdU, RAM 11, alpha-actin) procedures to quantify SMC proliferation, intimal macrophages and morphological analysis were performed. Porous balloon treatment led to an increase in intimal SMC proliferation rate in the early stage after intervention. However, during the following time period, a significant decrease of the proliferation rate as compared with the animals treated with balloon angioplasty alone could be observed, which resulted in an only moderate increase of the intimal layer after local drug delivery compared with balloon angioplasty alone.
Asunto(s)
Angioplastia Coronaria con Balón/instrumentación , Angioplastia de Balón/instrumentación , División Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/instrumentación , Fibrinolíticos/administración & dosificación , Heparina de Bajo-Peso-Molecular/administración & dosificación , Músculo Liso Vascular/efectos de los fármacos , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Diseño de Equipo , Hemostasis/efectos de los fármacos , Masculino , Músculo Liso Vascular/patología , Conejos , Túnica Media/efectos de los fármacos , Túnica Media/patologíaRESUMEN
UNLABELLED: The aim of this experimental study was to assess the safety of local delivery of low molecular weight heparin via a porous balloon in the canine coronary artery. In 16 mongrel dogs, percutaneous transluminal coronary angioplasty was performed. In addition, eight of the dogs were given 4 ml Clivarin (1500 IU) delivered locally into the coronary artery immediately after dilatation. The animals were killed after 3 or 14 days. In the animals with local administration, the results of histopathology after 3 days showed the findings to be heterogeneous with marked disruption of the internal elastic lamina in all animals, and varying degrees of medial haemorrhage, medial necrosis, perivascular haemorrhage and signs of myocardial necrosis. Similar changes, but of lesser severity, were present in the animals treated with balloon dilatation only. After 14 days, the severity of vascular and perivascular alterations (medial haemorrhage, perivascular haemorrhage, thrombus formation) was significantly lower in the local delivery group (P < 0.05), but disruption of the internal elastic lamina, as a marker of the initial trauma, was present in all the animals. The presence of residual intracoronary thrombus was only seen in the PTCA group without local delivery. CONCLUSIONS: In this safety study, both groups showed pronounced alterations in the vessel wall 3 days following percutaneous transluminal coronary angioplasty. This changed 14 days following percutaneous transluminal coronary angioplasty when intramural injection of Clivarin resulted in a marked decrease of residual thrombus and medial as well as perivascular haemorrhage. Although the additional vessel trauma by the drug delivery technique did not result in increased complications, a careful approach with this potentially harmful procedure is essential.
Asunto(s)
Angioplastia Coronaria con Balón/instrumentación , Cateterismo/instrumentación , Vasos Coronarios/efectos de los fármacos , Sistemas de Liberación de Medicamentos/instrumentación , Fibrinolíticos/administración & dosificación , Heparina de Bajo-Peso-Molecular/administración & dosificación , Animales , Trombosis Coronaria/patología , Trombosis Coronaria/prevención & control , Vasos Coronarios/patología , Perros , Diseño de Equipo , Hemorragia/patología , Miocardio/patología , Recurrencia , Túnica Media/patologíaRESUMEN
Cofactor-independent thrombin inhibitors as adjunctive treatment to thrombolysis have been found to enhance reperfusion and reduce the incidence of early reocclusion more effectively than heparins. However, all thrombin inhibitors presently available are rapidly cleared from the circulation which may cause rebound effects after cessation of treatment. To evaluate the effect of PEG-hirudin (LU 87981) a new, long acting derivative of hirudin as adjunctive treatment to rt-PA, a thrombotic occlusion of the carotid artery was induced in mongrel dogs by means of a copper coil. Vessel patency was continuously monitored with an electromagnetic flow probe. Thrombolysis of the occluded artery was induced by administration of 40 micrograms x kg-1 + 240 micrograms x kg-1 x h-1 rt-PA (low dose) or 80 micrograms x kg-1 + 480 micrograms x kg-1 x h1 rt-PA (high dose). With high dose rt-PA treatment, patency was achieved in all animals within 50 min (range 24 to 75), with low dose rt-PA treatment only in 6 out of 8 animals after 73 min (range 26 to 117). Concomitant administration of PEG-hirudin (0.3 mg x kg-1 bolus + 0.15 mg x kg-1 x h-1 infusion) increased the incidence of reperfusion in the low dose rt-PA group to 100% while the reperfusion time was shortened from 73 min in the corresponding control group to 38 min (range 20 to 75 min) in the group given PEG-hirudin (p = 0.065, Mann-Whitney U-test). The carotid artery blood flow, which rapidly declined to zero within 18 to 27 min after discontinuing low or high dose rt-PA infusions remained at a sustained level for the whole observation period of 4 h only in the group given PEG-hirudin. Only one animal reoccluded after 229 min. Unfractionated heparin (UFH) given at a dose of 0.3 mg x kg-1 bolus + 0.3 mg x kg-1 x h-1 infusion did not improve the incidence of reperfusion or lower the incidence of reocclusion. Buccal bleeding time was prolonged after high dose rt-PA treatment and after low dose rt-PA with adjunctive UFH- or PEG-hirudin treatment. Buccal blood loss was not significantly affected by either treatment. In conclusion, these experiments indicate that early reocclusion after thrombolysis can effectively be diminished by concomitant treatment with the long acting thrombin inhibitor PEG-hirudin with moderate effects on bleeding time and aPTT.
Asunto(s)
Trombosis de las Arterias Carótidas/tratamiento farmacológico , Heparina/uso terapéutico , Terapia con Hirudina , Terapia Trombolítica , Animales , Trombosis de las Arterias Carótidas/sangre , Perros , Femenino , Masculino , Tiempo de Tromboplastina Parcial , Agregación Plaquetaria/efectos de los fármacos , Polietilenglicoles , Protrombina/antagonistas & inhibidoresRESUMEN
Inhibition of arterial thrombus formation by ancrod, a fibrinogen depleting agent isolated from a snake venom, r-hirudin, an inhibitor of thrombin-mediated fibrinogen cleavage, or the glycoprotein (GP)IIB/IIIa-receptor antagonist Ro 43-8857 interfering with fibrinogen binding to platelets, was evaluated in two canine models. As a marker of platelet-dependent thrombus formation, cyclic blood flow reductions (CFR) were induced in the left coronary artery (LAD) of mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. In the second model CFRs were induced by thrombolysis of a copper coil-induced thrombus in the carotid artery. Blood flow rate during the reocclusion phase was used as an additional parameter of efficacy. The frequency of CFRs used a indicator of platelet aggregation and adhesion was significantly diminished by all treatments in both the carotid artery- and the LAD-model. In the LAD-model, following ancrod treatment, CFRs were correlated with plasma fibrinogen concentrations. Carotid artery blood flow after reperfusion, used as indicator of occlusive thrombus formation, rapidly declined to zero in the control group but remained at a high level after treatment with ancrod or r-hirudin. Ro 43-8857 at the selected dose improved flow rate only to a minor degree but prolonged the bleeding time from a mean value of 87.2 +/- 10.9 s (n = 24) to values > 300 s in 50% of the animals. Our results indicate that CFRs as indicator of platelet aggregation and adhesion are inhibited by either treatments. Blood flow as indicator of occlusive thrombus formation, however, is effectively improved by ancrod and r-hirudin only. Inhibition of fibrinogen binding to platelet GPIIb/IIIa receptors alone was found to be less potent antithrombotic principle in this model.
Asunto(s)
Acetatos/administración & dosificación , Ancrod/administración & dosificación , Antitrombinas/administración & dosificación , Benzamidas/administración & dosificación , Trombosis Coronaria/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Hirudinas/administración & dosificación , Animales , Trombosis Coronaria/fisiopatología , Perros , Femenino , Hemodinámica/efectos de los fármacos , Masculino , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidoresRESUMEN
We investigated the effects of nexopamil, a combined Ca2+/5-HT2 antagonist on thrombus formation in vivo and on platelet aggregation in vitro. In anesthetized mongrel dogs, cyclic flow reductions (CFRs) in the left anterior descending coronary artery (LAD) were induced by implanting a constrictor after the endothelium was injured mechanically. The CFRs were due to intracoronary thrombus formation. After CFRs were recorded for 1 h, the test compounds were injected intravenously (i.v.) for 2 min. Measurements were made for another hour. Nexopamil (0.05 mg/kg) completely abolished CFRs during the first 30 min after application without significantly altering hemodynamics. The same effect was noted with 0.02 mg/kg ketanserin (5-HT2/alpha 1 antagonist). The Ca2+ antagonist gallopamil reduced CFRs only in the highest hemodynamically tolerable dose by 40%. Serotonin-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro was most potently inhibited by ketanserin (IC50 0.55 x 10(-8) M), followed by nexopamil (IC50) 0.81 x 10(-7) M) and gallopamil (IC50 1.76 x 10(-6) M). Because serotonin is an important pathophysiologic mediator in unstable angina, 5-HT2 receptor antagonism should be of considerable benefit by preventing platelet activation and aggregation. The combination with calcium-antagonistic activity leads to an increase in coronary blood flow (CBF) and a decrease in cardiac oxygen demand. Therefore, the effects noted with nexopamil should be of importance in treating patients with coronary artery disease.
Asunto(s)
Calcio/antagonistas & inhibidores , Trombosis Coronaria/prevención & control , Antagonistas de la Serotonina , Verapamilo/análogos & derivados , Animales , Circulación Coronaria/efectos de los fármacos , Perros , Femenino , Galopamilo/farmacología , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Ketanserina/farmacología , Masculino , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Verapamilo/farmacologíaRESUMEN
The effect of recombinant hirudin (r-hir), unfractionated heparin (UFH) and acetylsalicylic acid (ASA) on the incidence of reocclusion after thrombolysis with plasminogen activator (rt-PA) was evaluated in anaesthetized rabbits. Formation of a platelet rich thrombus was achieved by implantation of a copper coil into the iliac artery. The occluded artery was recanalized in six of ten animals by intravenous administration of rt-PA given as a bolus injection of 0.1 mg/kg followed by infusion of 0.5 mg/kg/h. Within 1 h after termination of rt-PA infusion rethrombosis was observed in 100% of recanalized vessels. The incidence of reocclusion was diminished by r-hir in a dose-dependent manner to 50% after infusion of 0.05 mg/kg/h and to 25% after 0.1 mg/kg/h. No effect on APTT was detectable in this dosage after 3 h infusion. UFH in a dosage increasing APTT two-fold (35 U/kg/h) did not reduce the reocclusion rate. 100 U/kg/h UFH increased APTT to greater than 3 min and reduced reocclusion rates to 50%. ASA showed a minor effect on the incidence of restenosis whereas the combination of 0.1 mg/kg/h r-hir plus bolus injection of 10 mg/kg ASA led to a further reduction in reocclusion rates to only 11% and an increase in reperfusion rates from 60 to 90%. Our experiments indicate that the combination of plasminogen activator with r-hir may be a useful approach for the prophylaxis of early reocclusion.
Asunto(s)
Fibrinolíticos/uso terapéutico , Hirudinas/análogos & derivados , Terapia Trombolítica , Trombosis/prevención & control , Activador de Tejido Plasminógeno/uso terapéutico , Animales , Aspirina/farmacología , Aspirina/uso terapéutico , Relación Dosis-Respuesta a Droga , Fibrinolíticos/farmacología , Heparina/farmacología , Heparina/uso terapéutico , Terapia con Hirudina , Hirudinas/farmacología , Arteria Ilíaca , Tiempo de Tromboplastina Parcial , Conejos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Recurrencia , Reperfusión , Trombosis/tratamiento farmacológicoRESUMEN
The effect of recombinant hirudin (r-hirudin, LU 52369) and unfractionated heparin on recombinant tissue-type plasminogen activator (rt-PA; LU 50232) thrombolysis and reocclusion rates after successful thrombolysis was studied in a copper-coil-induced thrombus model in the iliac artery of anesthetized rabbits. Simultaneous administration of rt-PA and recombinant hirudin (r-hirudin) at a dose not affecting the partial thromboplastin time (PTT) increased the number of recanalized arteries significantly. The incidence of reocclusion was drastically reduced from 100% to less than 25%. At a dose increasing PTT twofold, unfractionated heparin had no effect on the incidence of reperfusion and reocclusion. These experimental data indicate that the combination of rt-PA with low-dose r-hirudin may be useful for the prevention of early reocclusion in thrombolytic therapy.
Asunto(s)
Fibrinolíticos/uso terapéutico , Terapia con Hirudina , Terapia Trombolítica , Trombosis/tratamiento farmacológico , Animales , Sinergismo Farmacológico , Quimioterapia Combinada , Fibrinógeno/análisis , Arteria Ilíaca/lesiones , Conejos , Proteínas Recombinantes/uso terapéutico , Recurrencia , Trombina/antagonistas & inhibidores , Trombosis/etiología , Trombosis/prevención & control , alfa 2-Antiplasmina/análisisRESUMEN
Short-chain fatty acid, electrolyte and water absorption from the hindgut of two arboreal marsupial species, the greater glider (Petauroides volans) and the brush-tail possum (Trichosurus vulpecula) were studied in vivo using a single perfusion technique. Qualitative and quantitative differences in the net movement of sodium, potassium and chloride were found between the different hindgut segments and between the two species. ALl transport processes exhibited active characteristics. Net Na+ transport in all segments was concentration-dependent in the range of 45-135 mmol . 1(-1) Na+. The proximal colon of the greater glider showed a net Na+, Cl- and water secretion and K+ absorption, all electrolyte movements being against the electrochemical gradient. Water followed passively the osmotic gradient generated mainly by the net movement of Na+. Short-chain fatty acids were absorbed according to their chain length in a constant ratio of 1.0:1.2:1.3 for acetate, propionate and butyrate, respectively. Our data indicate that absorptive and secretory processes in the hindgut of these marsupials are basically similar to those of eutherians, even in epithelia differing significantly in the direction of net solute transport.
Asunto(s)
Ciego/metabolismo , Colon/metabolismo , Ácidos Grasos Volátiles/metabolismo , Marsupiales/metabolismo , Equilibrio Hidroelectrolítico , Animales , Transporte Biológico , Agua Corporal/metabolismo , Cloro/metabolismo , Absorción Intestinal , Perfusión , Potasio/metabolismo , Sodio/metabolismo , Especificidad de la EspecieRESUMEN
Mucus secretion into the rat colon has been measured in situ using a single perfusion technique. Protein, sialic acid and hexose concentrations in the perfusion solution were found to give reliable estimates of mucus output if samples were homogenized prior to analysis. Mucus output as indicated by an increase in the concentration of mucus constituents was higher when the solution was hypotonic (270 mosm . kg-1) or hypertonic (370 mosm . kg-1) than when isotonic solutions (320 mosm . kg-1) were used. The proportion of hexoses and sialic acid to protein was 23 and 14% at low, 23 and 11% at high osmolality, and 21 and 13% when isotonic solutions were used. Deoxycholic acid (DCA, 4 mmol . 1(-1)) increased the net secretion of mucus constituents 3 fold, whereas short chain fatty acids (SCFA) had no effect. Mucus composition during all treatments did not change significantly, even when stimulated with DCA. When mucus was released from the epithelial surface by previous perfusion with a DCA containing solution, net water and SCFA absorption rates and mucus output were significantly lowered for 2 to 3 h. However, no correlation between mucus secretion and SCFA absorption was found, indicating that a role for mucus as a diffusion barrier to SCFA is unlikely. Mucus output, which indicates the amount of mucus released from the epithelial surface, probably depends on the direction of net water movement, which follows the osmotic gradient between colon lumen and blood.
Asunto(s)
Colon/metabolismo , Ácido Desoxicólico/farmacología , Ácidos Grasos/farmacología , Moco/metabolismo , Concentración Osmolar , Ratas/fisiología , Animales , Masculino , Ratas Endogámicas , Agua/metabolismoAsunto(s)
Damanes/fisiología , Mamíferos/fisiología , África , Animales , Metabolismo Basal , Conducta Animal , Regulación de la Temperatura Corporal , Agua Corporal/metabolismo , Sistema Digestivo/metabolismo , Fenómenos Fisiológicos del Sistema Digestivo , Ácidos Grasos Volátiles/biosíntesis , Conducta Alimentaria , Femenino , Concentración de Iones de Hidrógeno , Damanes/metabolismo , Técnicas In Vitro , Masculino , Nitrógeno/metabolismoRESUMEN
The interrelationship between the absorption of Na, H ions and short chain fatty acids (SCFA) and the secretion of HCO3 in the sheep colon was studied using an in vivo perfusion technique. 1. Under control conditions net SCFA absorption was 62.9 +/- 6.1 mmol . h-1, net Na absorption 49.8 +/- 7.6 mmol . h-1. HCO3 accumulated in the colon lumen at a rate of 5.1 +/- 2.9 mmol . h-1. 2. When 30, 50, or 70% of the Na in the perfusion solution were replaced by Li, Na transport was gradually inhibited and even abolished when 70 mmol . 1(-1) of Li were present. SCFA absorption also decreased, however, to a lower degree. 3. Net Na transport was higher in the presence than in the absence of SCFA. This difference disappeared when Na transport was inhibited by Li. 4. HCO3 accumulation in the colon lumen significantly increased with increasing Li concentrations up to a maximum of 21.7 +/- 7.1 mmol . h-1 when 50% of Na were replaced by Li, however, only in the presence of SCFA. 5. Neither increasing Li concentrations nor the presence or absence of SCFA influenced the H ion disappeared from the perfusion solution. 6. These results indicate that net absorption of Na and SCFA in sheep colon are closely linked to the availability of H ions.
Asunto(s)
Colon/metabolismo , Ácidos Grasos Volátiles/metabolismo , Hidrógeno/metabolismo , Ovinos/fisiología , Sodio/metabolismo , Absorción , Animales , Bicarbonatos/metabolismo , Transporte Biológico , Femenino , Concentración de Iones de Hidrógeno , Litio/farmacología , Potasio/metabolismoRESUMEN
Bicarbonate appearance in the lumen and its relationship to solute absorption were studied in a Pavlov pouch in the cardiac region of the first compartment of the llama forestomach. HCO3- appearance showed no diurnal variation. HCO3- accumulation was highly dependent on the pH of the solution used. The HCO3- ion probably is formed from CO2 diffusing into the lumen from the serosal side, as a result of cell metabolism and of OH- ions. HCO3- accumulation was closely related to volatile fatty acid (VFA) absorption. The ratio of HCO3- appearance to VFA absorption depended on the pH of the solution. At a pH of 6.6, about 0.1 mol HCO3- and, at a pH of 7.8, 0.9 mol HCO3- appeared per mole absorbed VFA, indicating that at slightly alkaline pH nearly all H+ ions required for the nonionic absorption of VFA appeared to be delivered from the dissociation of H2CO3. Bicarbonate gain and VFA absorption were increased when animals were not fed for 48 h. Sodium absorption was related to VFA as well as water absorption.