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Biomedical subjects

A Bernat

Publications and source records attributed to A Bernat.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effect of various drugs on adriamycin-enhanced venous thrombosis in the rat: importance of PAF.

In the rat, adriamycin increased stasis-induced thrombosis in a dose- and time-dependent manner. Two potent antiplatelet agents, clopidogrel (20 mg/kg, po) and aspirin (200 mg/kg, po) showed a strong antithrombotic efficacy (92 and 77% inhibition of thrombus formation respectively) therefore suggesting that platelets play a major role in the prothrombotic effect of adriamycin. Standard heparin, administered as a single bolus injection (3 mg/kg, iv), 5 min prior to stasis did not affect adriamycin-induced thrombosis whereas hirudin (1 mg/kg, iv) suppressed thrombus formation (98% inhibition). SR 27417, a potent PAF receptor antagonist injected iv, reduced venous thrombosis in a dose-dependent manner (14, 29 and 63% inhibition after 1, 3 and 6 mg/kg respectively). These results therefore demonstrate that adriamycin-induced venous thrombosis is highly dependent upon platelet activation.

Animals↗
PubMed1994

Aurin tricarboxylic acid inhibits experimental venous thrombosis.

In vitro, aurin tricarboxylic acid (ATA) inhibited ristocetin-induced human platelet agglutination in a dose-dependent manner. The IC50 value (dose which inhibits 50% of platelet agglutination) was 60 +/- 8.7 micrograms/ml. In vivo, the i.v. administration of ATA to rats reduced the thrombus formation in an arteriovenous shunt with an ED50 value of 9.0 +/- 1.6 mg/kg. In a venous thrombosis model, using a combination of a thrombogenic challenge and stasis, ATA displayed a significant, dose-dependent antithrombotic effect, the ED50 value being of 18.3 +/- 2.0 mg/kg. In an experimental model of disseminated intravascular coagulation, ATA protected mice from the lethal effect of thromboplastin-induced thromboembolism with a ED50 value of 1.1 +/- 0.15 mg/kg, being in that respect 12 times less potent than standard heparin (ED50 = 90 +/- 15 micrograms/kg). These observations therefore show that ATA is active in both arterial- or venous-type thrombosis models and suggest that von Willebrand Factor might be important not only in arterial but also in venous thrombosis.

Agglutination↗
PubMed1994

Effect of aspirin and clopidogrel on platelet-dependent tissue factor expression in endothelial cells.

Tissue factor is an ubiquitous membrane-anchored glycoprotein that initiates blood coagulation by forming a complex with circulating factors VII and VIIa. Under normal circumstances, endothelial cells do not express tissue factor but, in some pathological situations, when the endothelium or the monocytes are exposed to inflammatory mediators, they can acquire procoagulant properties. When rat platelets were incubated with cultured bovine aortic endothelial cells, a significant increase in tissue factor expression was obtained. When added simultaneously, thrombin or 2-methylthio-ADP, a stable analogue of ADP, potentiated in a time and dose-dependent manner the effect obtained with platelets alone. In order to determine if antiplatelet agents can modulate these effects, the activity of two compounds was evaluated. When administered orally at the dose of 25 mg/kg, clopidogrel, a potent and selective analogue of ticlopidine, was able to inhibit platelet-induced tissue factor expression whereas aspirin (100 mg/kg, p.o.) was ineffective. These effects were closely correlated to their respective anti-aggregatory and antithrombotic activities showing that platelet activation which has already been shown to be mainly involved in arterial-type thrombosis could also play an important role in the initiation of venous thrombosis where tissue factor expression is thought to play a major role.

Adenosine Diphosphate↗
PubMed1993

Effect of various antiplatelet agents on acute arterial thrombosis in the rat.

Electrical stimulation of the rat carotid artery causes a deep medial injury and the formation of a platelet-rich thrombus. Occlusive thrombosis at sites of vessel wall injury was significantly reduced after the oral administration of clopidogrel, a potent analogue of ticlopidine, which showed dose-dependent inhibition of the thrombus formation (ED50 = 1.0 +/- 0.2 mg/kg, p.o.). Accumulation of thrombotic material was also considerably reduced after the i.v. administration of SR 27417, a highly potent and selective platelet activating factor receptor antagonist (ED50 = 10 micrograms/kg, i.v.), nafagrel, a thromboxane A2 synthetase inhibitor (ED50 = 1.3 mg/kg, i.v.) and hirudin (ED50 = 140 micrograms/kg, i.v.). A high dose (20 mg/kg, i.v.) of the anti-adhesive tetrapeptide Arg-Gly-Asp-Ser (RGDS) showed only a slight effect on thrombus formation whereas aspirin was ineffective. These results confirm that ADP and thromboxane A2 play key roles in the initiation and progression of arterial thrombus formation and suggest that platelet activating factor may also modulate thrombosis in this experimental model.

Acute Disease↗
PubMed1993

Aprotinin reduces clopidogrel-induced prolongation of the bleeding time in the rat.

High doses of aprotinin have been shown to reduce blood loss and blood transfusion requirements in patients undergoing open heart surgery and recent studies in animals have shown that aprotinin was able to reduce bleeding associated with rt-PA administration. Our study was designed to demonstrate an effect of aprotinin (Iniprol) on the prolongation of the bleeding time associated with the treatment with a potent analogue of ticlopidine: clopidogrel. Bleeding time was determined in rats by transection of the tip of the tail. 2 hours after a single oral administration, clopidogrel (5 mg/kg, p.o.), induced a 4-fold increase in the bleeding time. Aprotinin administered as a bolus iv injection followed by continuous infusion strongly reduced bleeding time prolongation associated with clopidogrel treatment. This effect was dose-related and reached a maximum (congruent to 50% inhibition--P < 0.001) at and above the total dose of 40 U Ph Eur/kg (80,000 KIU/kg). After administration of a total dose of 60 U Ph Eur/kg (120,000 KIU/kg), aprotinin modified neither the antiaggregating effect of clopidogrel nor its antithrombotic activity, as determined in various experimental models. For this reason, aprotinin might constitute a useful antagonist of the haemorrhagic risk associated with interventional therapy under treatment with ticlopidine or clopidogrel.

Animals↗
PubMed1993

Antithrombotic activity of SR 46349, a novel, potent and selective 5-HT2 receptor antagonist.

SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophe nyl) propen-1-yl] phenol, hemifumarate) is the first member of a newly-developed 5-HT2 antagonist series. SR 46349 potently inhibited serotonin-induced aggregation of rabbit and human platelets (IC50 = 1 and 3.9 nM respectively) but had no effect on the action of other platelet aggregating agents. SR 46349 was 118 and 25 times more potent than ketanserin against 5-HT+epinephrine-induced aggregation of rabbit and human platelets respectively. A single per os administration of SR 46349 (1 mg/kg) resulted in a strong inhibition of 5-HT+epinephrine-induced platelet aggregation in the rabbit as measured ex vivo (67% inhibition, 6 h after the administration). Intravenous or oral administration of SR 46346 inhibited in a dose-dependent manner venous thrombosis induced by ligature of the jugular vein of rabbits whose blood was made hypercoagulable by i.v. administration of tissue thromboplastin. The doses of SR 46349 which inhibited 50% of thrombus formation were 1.5 +/- 0.8 mg/kg and 17 +/- 0.5 mg/kg after i.v. or oral administration respectively. When given i.v. to rabbits, SR 46349 exhibited a dose-dependent antithrombotic effect in an arterio-venous shunt model. Significant increase of the bleeding time was observed after the i.v. administration of 5 mg/kg of SR 46349 (3-fold increase). In dogs, SR 46349 inhibited cyclic coronary artery blood flow variations, complete abolition of CFVs being achieved after the i.v. administration of 0.5 mg/kg. In conclusion, SR 46349 is a highly potent, selective antagonist of serotonin in vitro and is to be considered as a potent, orally active antithrombotic agent.

Animals↗
PubMed1993

Potentiating effect of clopidogrel and SR 46349, a novel 5-HT2 antagonist, on streptokinase-induced thrombolysis in the rabbit.

Current thrombolytic strategies have a number of important shortcomings including resistance to recanalization and development of acute reocclusion. The purpose of this study was to investigate whether the lysis of venous thrombi by streptokinase could be enhanced by SR 46349, a novel 5-HT2 receptor antagonist, or clopidogrel, an analogue of ticlopidine. The activity of these compounds was evaluated by following the lysis of radiolabelled fibrin under a continuous infusion of streptokinase (4,000 IU kg-1 h-1 over 4 h). Streptokinase alone induced 42% thrombolysis when compared to saline. The i.v. co-administration of SR 46349 or clopidogrel (10 mg/kg) enhanced significantly streptokinase-induced thrombolysis. Thrombolysis measured by [125I]-fibrinogen lysis increased to 65 and 59% respectively. This efficacy was achieved without additional prolongation of the template bleeding time observed with streptokinase alone. Thus, the concomitant use of a 5-HT2 receptor antagonist or an anti-ADP agent during streptokinase therapy may facilitate clot lysis.

Animals↗
PubMed1993

Normal dexamethasone suppression in obese binge and nonbinge eaters with rapid weight loss.

Natural or experimental starvation is frequently associated with hypercortisolism, reflected as incomplete suppression of serum cortisol after dexamethasone. To determine whether rapid weight loss per se or some other aspect of starvation induces disruption of the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated 2 categories of obese women (body mass index > 30 kg/m2) undergoing rapid weight loss: binge eaters (n = 12) and nonbinge eaters (n = 8). We performed psychometric evaluation and 1 mg overnight dexamethasone suppression tests in the obese subjects, as well as in 12 race- and age-matched normal-weight women. The obese women were tested before and after 12 weeks of a 3349 kJ/day (800 kcal/day) liquid formula diet, and lost an average of 19.3 kg, which represented 17.3% of their total body weight. Binge eaters, who were initially more depressed than either nonbinge eaters or normal-weight controls, had a significant amelioration of their symptoms with weight loss. Neither group had evidence of disruption of the HPA axis before or after weight loss. Thus, the rate of failure to suppress cortisol after dexamethasone was approximately 10% in each of the obese and control groups, and did not differ between the pre- and postweight loss condition or between binge eaters and nonbinge eaters. Serum free T4 was unchanged, whereas T3 fell significantly with weight loss. We conclude that weight loss may improve affect in the obese without altering HPA axis activity, and postulate that one of the concomitants of restricted energy intake, perhaps in combination with a threshold body weight, may be of greater importance in causing abnormalities of dexamethasone suppression testing than rapid weight loss per se.

Adolescent↗
PubMed1993

Circannual variations of the bleeding time in the rat.

This study was carried out to determine the annual fluctuations of the tail bleeding time in the rat. Bleeding time was determined by transection of the tail of pentobarbital-anesthetized rats. Over a 6-year period, monthly measurement of the tail bleeding time revealed highly reproducible circannual fluctuations. Bleeding times were shortened in the summer (414 +/- 18 s in July), being almost half that observed during the winter span (886 +/- 32 s in January). The difference between these two time points was highly significant (p < 0.001). This study reports for the first time circannual variations of the bleeding time in the rat.

Analysis of Variance↗
PubMed1992

Importance of platelets in experimental venous thrombosis in the rat.

Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

Animals↗
PubMed1992

Effect of SR 27417 on oedema formation induced in rabbit skin by platelet-activating factor or antigen.

SR 27417, the first member of a newly developed series of platelet activating factor (PAF) antagonists inhibited in a dose-dependent manner PAF-induced oedema formation in rabbit skin when administered i.d. premixed with PAF (ED50 = 3.3 +/- 0.15 pmol/site i.d. (intradermally) (n = 5). The effect of SR 27417 was over 660 times more potent than that of the triazolothienodiazepine, WEB-2086 (ED50 = 5.4 +/- 0.71 nmol/site i.d.) (n = 5). SR 27417 protected rabbits from PAF-induced plasma extravasation with an ED50 value of 16 +/- 3 micrograms/kg when given i.v. 1 h before PAF challenge. It was also effective when given p.o. 3 h before PAF i.d. administration (ED50 = 0.18 +/- 0.07 mg/kg p.o.) (n = 5). This effect of SR 27417 was selective for PAF since inflammatory responses induced by other mediators (bradykinin, histamine, N-formyl-L-methionyl-L-leucyl-L-phenyl-alanine, leukotriene B4) were not affected. After i.v. or oral administration (1 and 5 mg/kg respectively) SR 27417 had an extended duration of activity (between 72 and 96 h). In presensitized rabbits, SR 27417 premixed with the allergen inhibited dose-dependently allergen-induced plasma exudation (ED50 = 12 +/- 0.08 nmol/site i.d.) (n = 5) (vs. 850 +/- 98 nmol/site (n = 5) for WEB-2086). Similarly, i.v. injection of SR 27417 (1 mg/kg i.v.) inhibited allergen-induced vascular permeability. These results confirm that PAF plays a major role in the development of cutaneous anaphylaxis and that SR 27417 may be an effective prophylactic drug.

Allergens↗
PubMed1992

Protective effect of SR 27417, a novel PAF antagonist, on PAF- or endotoxin-induced hypotension in the rat and the guinea-pig.

SR 27417, the first member of a newly-developed PAF antagonist series, inhibited in a dose-dependent manner the hypotensive effect of PAF in rats. It protected rats with an ED50 = 6 micrograms/kg, when given i.v., 1 min before PAF or p.o. (ED50 = 170 micrograms/kg) 1 h before PAF administration. After i.v. or oral administration, SR 27417 (1 and 3 mg/kg, respectively) exhibited extended duration of action (between 48 and 72 h). Similarly, i.v. administration of 1 to 6 mg/kg of SR 27417 afforded complete protection of guinea-pigs against endotoxin-induced hypotension but also totally reversed established endotoxin-induced hypotension. These results therefore confirm that PAF plays a major role in septic shock and that SR 27417 may be an effective prophylactic as well as a potent curative drug.

Administration, Oral↗
PubMed1991

Biochemical and pharmacological activities of SR 27417, a highly potent, long-acting platelet-activating factor receptor antagonist.

SR 27417 [N-(2-dimethylamino ethyl)-N-(3-pyridinyl methyl)[4- (2,4,6-triisopropylphenyl) thiazol-2-yl]amine] is the first member of a newly developed platelet-activating factor (PAF) antagonist series. It is a highly potent, competitive and selective antagonist of the binding of [3H]PAF to its receptor in rabbit platelets. It exhibits an equilibrium inhibition constant for PAF binding of 57 pM, a value that is at least 5-fold lower than that of unlabeled PAF itself. SR 27417 potently inhibited PAF-induced aggregation of rabbit and human platelets in vitro (IC50 = 0.10 and 0.50 nM, respectively) but had no effect on the action of other platelet-aggregating agents. In comparison with the triazolothienodiazepine WEB-2086, SR 27417 was 470 and 70 times more potent against PAF-induced aggregation of rabbit and human platelets, respectively. SR 27417 displayed marked in vitro inhibition of PAF-induced oxidative burst in guinea pig macrophages (IC50 = 32 nM). In an in vivo model, it protected mice from 100 micrograms/kg PAF-induced death when given i.v. (ED50 = 7.5 micrograms/kg) 5 min before PAF challenge or p.o. (ED50 = 45 micrograms/kg) 3 hr before PAF administration. SR 27417 inhibited PAF-induced death in mice with an impressive p.o. or i.v. duration of action of 30 to 48 hr. In anesthetized guinea pigs, SR 27417 inhibited i.v. and p.o. 100 ng/kg PAF-induced bronchoconstriction (ED50 = 14 and 140 micrograms/kg, respectively), hemoconcentration (ED50 = 20 and 270 micrograms/kg, respectively), thrombocytopenia (ED50 = 30 and 240 micrograms/kg, respectively) and leukopenia (ED50 = 0.1 and 1.5 mg/kg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intravascular coagulation induced by tissue factor in rats.

Antithrombotic potency of recombinant hirudins rHV2, rHV2-Lys47 and rHV2-Arg47 was studied in a model of experimental thrombosis induced by tissue factor in the rat. Venous thrombosis was induced by i.v. injection of 25 mg/kg tissue factor followed by stasis of the inferior vena cava. In this model natural recombinant hirudins, rHV2 and rHV2-Lys47 injected 5 min before thrombo-plastin totally inhibited thrombosis in the same micrograms range as heparin or natural hirudin extracted from leeches. However, the mutant variant rHV2-Arg47 gave a maximal 60% inhibition of thrombosis. Variants rHV2-Lys47 (30 micrograms/kg) and rHV2-Arg47 (157 micrograms/kg) injected 5 min before thromboplastin prevented by 90 to 100% the drop in platelet count observed during the disseminated intravascular coagulation induced by thromboplastin injection. Recombinant hirudins were less anticoagulant than heparin as measured by an APTT on rat plasma. After rat tail transection, rHV2-Lys47 caused a 2-fold smaller prolongation of the bleeding time than an equivalent antithrombotic dose of heparin. Plasmatic elimination of rHV2-Lys47 from rat plasma after i.v. injection had a fast distribution phase with a half-life of 3 min during which 90% of injected rHV2-Lys47 was lost and was followed by a slower elimination phase. Thus recombinant hirudin rHV2-Lys47 appears as a promising potent antithrombotic agent for the prevention of thrombin-dependent venous thrombosis and disseminated intravascular coagulation.

Animals↗
PubMed1989

Production and evaluation of recombinant hirudin.

Hirudin, a 65 amino acid polypeptide form the medicinal leech, is an extremely efficient and specific thrombin inhibitor whose therapeutic potential has been demonstrated in a number of animal models. We have developed protocols for the production of recombinant hirudin by secretion from S. cerevisiae and carried out a full biologic evaluation of the purified product. These studies showed that natural and recombinant hirudin was similar in structure and in biologic function in vitro. Moreover, the recombinant protein displayed strong antithrombotic activity in several experimental thrombosis models in vivo, confirming the molecule's promise in the therapy of thrombotic disorders.

Amino Acid Sequence↗