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1.
Ann Pharm Fr ; 67(4): 291-4, 2009 Jul.
Article in French | MEDLINE | ID: mdl-19596104

ABSTRACT

Salt abuse in nutrition may exert harmful effects on health, increasing arterial hypertension and its cardiovascular consequences. It is a risk factor, particularly for older subjects and those having chronic diseases such as arterial hypertension, some renal diseases, and obesity. In subjects more particularly vulnerable, the maintenance of sodium balance, which is mainly aldosterone dependent, is perturbed. Although the use of salt for food preservation has greatly declined, it remains a serious risk factor. Excessive salt intake however results more often from poor dietary habits. The WHO and AFSSA have advised to reduce daily salt intake to 5 g, whereas it is currently about 9-10 g. In spite of repeated warnings, salt abuse remains the causal agent for many disease conditions, mainly arterial hypertension. That is why legislative measures should be taken in order to limit the salt content of food industry products, particularly as a preservative in foods. A large-scale public information campaign would be necessary with participation of public health partners, particularly physicians and pharmacists.


Subject(s)
Sodium, Dietary/adverse effects , Diet , Food Preferences , Food Preservation , Humans , Legislation, Food , Risk Factors
2.
Eur Surg Res ; 37(4): 191-8, 2005.
Article in English | MEDLINE | ID: mdl-16260867

ABSTRACT

OBJECTIVE: The effect of enoxaparin and fibroblast growth factor-1 (FGF-1) on post-infarction capillary density and regional myocardial blood flow (RMBF) was examined. METHODS: New Zealand White rabbits received an intramyocardial injection of either physiological saline, FGF-1 + enoxaparin, FGF-1 or enoxaparin directly after ligation of the left anterior descending artery. RMBF and capillary density were investigated using fluorescent microspheres and histological examination. RESULTS: One week after infarction a significant difference in the number of capillaries could be demonstrated within the FGF-1 + enoxaparin group (p < 0.001 versus the control group), the FGF-1 group (p < 0.01) and the enoxaparin group (p < 0.05). Treatment with FGF-1 + enoxaparin resulted in a significantly increased number of capillaries compared to treatment with FGF-1 (p < 0.05) and enoxaparin (p < 0.05) alone. Additionally, all groups treated with FGF-1 and/or enoxaparin showed a significant increase of microvessel density in the treated ischemic border zone compared to the non-treated ischemic border zone (p < 0.001 for FGF-1 + enoxaparin, p < 0.01 for FGF-1, p < 0.05 for enoxaparin). RMBF was significantly increased within the FGF-1 + enoxaparin group compared to the control group (p < 0.05). Moreover, perfusion rates within the FGF-1 + enoxaparin-treated area did not significantly differ from the pre-infarction values. CONCLUSION: Treatment with either enoxaparin or FGF-1 or FGF-1 + enoxaparin resulted in increased microvessel growth. However, only the combination of enoxaparin with FGF-1 promotes capillary growth and RMBF. Thus, we conclude that enoxaparin enhances the angiogenic potential of intramyocardially injected FGF-1 in the acutely infarcted rabbit heart.


Subject(s)
Capillaries/metabolism , Coronary Circulation/drug effects , Enoxaparin/pharmacology , Fibrinolytic Agents/pharmacology , Fibroblast Growth Factor 1/pharmacology , Heart/drug effects , Animals , Capillaries/drug effects , Cell Line , Cell Proliferation , Humans , Myocardial Infarction/metabolism , Neovascularization, Physiologic , Pilot Projects , Rabbits , Regional Blood Flow
3.
Ann Pharm Fr ; 63(2): 110-3, 2005 Mar.
Article in French | MEDLINE | ID: mdl-15976675

ABSTRACT

As members of the pharmacology training group set up by the committee of pharmacological science of the French Academy of Pharmacy, we examine the situation of pharmacology in drug discovery. Today, it is obvious that by integrating genome sequencing, cellular and molecular biology, and bioinformatics, pharmacology has become a cross-disciplinary science. Pharmacologists must become knowledgeable in a wide range of domains, using the major points in each to direct them towards the discovery and development of new therapeutic agents. It is also clear that pharmacology remains a major factor in the different steps of drug discovery, from the molecular and cellular stages, to clinical and pharmaceutical developments.


Subject(s)
Drug Therapy/trends , Pharmacology/trends , France , Molecular Biology/trends , Pharmacology, Clinical/trends
5.
Arch Mal Coeur Vaiss ; 95 Spec No 7: 31-5, 2002 Nov.
Article in French | MEDLINE | ID: mdl-12500602

ABSTRACT

Thrombosis and ischaemia are often linked to an atherosclerotic arterial lesion. An inflammatory process implicating leucocytes and inflammation mediators (cytokines) as well as atheroma plaque rupture liberating tissue factor are at the origin of this pathology. Equally, blood platelets play an important role, not only with the formation of platelet aggregates, but also by their procoagulant action resulting from the exposure of membrane phospholipids. Apoptotic cells release procoagulant microparticles from the plaque, favouring thrombogenesis. In this context reperfusion would a priori restore blood flow, but it is also the origin of cytotoxicity due to the sudden release of necrotising factors. Various animal models are used to experimentally reproduce arterial thrombosis either following or not following ischaemia/reperfusion. Among them the model of progressive coronary occlusion by intraluminal electrical stimulation, the model of quasi-instantaneous thrombosis by the introduction of a copper coil, and the model of ischaemia/reperfusion by occlusion of the left descending coronary for 90 minutes followed by reperfusion have been studied more precisely in the dog. In the rat, cerebral ischaemia followed by reperfusion has been provoked with occlusion of the middle cerebral artery. The studies in dogs show that Enoxaparine significantly reduces the formation of coronary thrombus induced progressively by an anodal current and potentiates the action of the tissular activator plasminogen (t-PA) on a recently formed thrombus. At the level of myocardial ischaemia. Enoxaparine reduces the extent of infarction as well as the neutrophil and platelet accumulation in the infarcted zone or in at risk zone. This effect seems to correlate with an anti-inflammatory type action demonstrated elsewhere in vitro with platelet/neutrophil adhesion in the presence of P-Selectin. In all of these studies standard heparin used under the same conditions proves to be inactive. In the ischaemia/reperfusion model in the dog, aspirin has been shown to be ineffective up to a dose of 6 mg/Kg. Enoxaparine is an example of a possible double anti-thrombotic and anti-ischaemic component in the prevention of disorders caused by the thrombosis-ischaemia-reperfusion triad.


Subject(s)
Coronary Thrombosis/physiopathology , Inflammation/pathology , Myocardial Ischemia/physiopathology , Reperfusion Injury/physiopathology , Animals , Apoptosis , Coronary Thrombosis/complications , Disease Models, Animal , Dogs , Enoxaparin/pharmacology , Fibrinolytic Agents/pharmacology , Humans , Myocardial Ischemia/complications , Rats , Risk Factors
6.
Gastroenterol Clin Biol ; 25(3): 239-42, 2001 Mar.
Article in French | MEDLINE | ID: mdl-11395669

ABSTRACT

AIMS: To examine by a case-control study the relationship between appendectomy and subsequent ulcerative colitis development in a French population. METHODS: A total of 150 patients with ulcerative colitis were matched for age (+/- 5 years) and sex, with 150 controls recruited in a preventive medicine center. The following data were collected from medical records and by standardised questionnaire in consultation or by phone: appendectomy and tonsillectomy before the onset of ulcerative colitis, smoking habits and area of residence. RESULTS: The rate of previous appendectomy in patients with ulcerative colitis was 8% (12/150) compared with 30.6% (46/150) in the control group (P=0.001). There was no significant association between ulcerative colitis and tonsillectomy (25.3 and 27.3% in the control and the ulcerative colitis groups, respectively). Smoking was more frequent in the control group (36%) than in the ulcerative colitis group (25.3%) but the difference was not significant (P=0.07). In multivariate analysis, the risk of developing ulcerative colitis was significantly lower after previous appendectomy (odds ratio=0.26; 95% confidence interval: 0.13-0.55; P=7 x 10(-4)). CONCLUSION: Our study confirms the inverse association between appendectomy and subsequent ulcerative colitis, in a French population, after adjusting on smoking.


Subject(s)
Appendectomy , Colitis, Ulcerative/prevention & control , Adult , Case-Control Studies , Colitis, Ulcerative/epidemiology , Female , France/epidemiology , Humans , Male , Middle Aged , Risk Factors , Smoking , Tonsillectomy
7.
Stroke ; 32(4): 993-9, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11283402

ABSTRACT

BACKGROUND AND PURPOSE: Heparin and heparinoids have long been proposed for stroke treatment. This study investigates the effect of enoxaparin (Lovenox, Clexane), a low-molecular-weight heparin, on functional outcome (neuroscore) and lesion size in stroke models with reversible and irreversible cerebral ischemia using middle cerebral artery occlusion (MCAO) in the rat. METHODS: Ischemia was induced in rats by transient occlusion for 2 hours or by permanent electrocoagulation of the left MCA. Forty-eight hours after ischemia, neurological deficit was evaluated by scoring sensorimotor functions and ischemic damage was quantified by histological evaluation of lesion volumes. RESULTS: After transient MCAO, enoxaparin at 2x1.5 mg/kg IV (2 and 24 hours after insult) significantly reduced lesion size by 30% (P<0.05) and improved neuroscore (P<0.01). This significant effect on lesion size and neuroscore was still evident when treatment was started 5 hours after insult. Administered under the same protocol with a 5 hours delay post permanent MCAO, enoxaparin reduced lesion size by 49% (P<0.05) and improved neuroscore (P<0.01). CONCLUSIONS: This study indicates that standard nonhemorrhagic doses of enoxaparin reduce ischemic damage with a wide therapeutic window. In addition to its anticoagulant properties, other properties of enoxaparin could act in synergy to explain its neuroprotective profile in ischemia. Thus clinical application of enoxaparin treatment in stroke warrants serious consideration.


Subject(s)
Enoxaparin/administration & dosage , Neuroprotective Agents/administration & dosage , Stroke/drug therapy , Animals , Blood Coagulation/drug effects , Brain/blood supply , Brain/drug effects , Brain/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Heparin/administration & dosage , Infarction, Middle Cerebral Artery/complications , Injections, Intravenous , Male , Partial Thromboplastin Time , Rats , Rats, Sprague-Dawley , Severity of Illness Index , Stroke/etiology , Time Factors , Treatment Outcome
8.
J Neurotrauma ; 17(11): 1055-65, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11101208

ABSTRACT

Traumatic brain injury (TBI) is often accompanied by secondary ischemia due, in part, to edema-induced blood vessel compression. Enoxaparin, a low-molecular weight heparin, which is efficacious in models of myocardial and brain ischemia was studied in lateral fluid percussion-induced TBI in rats. Enoxaparin was administered 2 h post-TBI at 0.5 mg/kg i.v. followed by 4 x 0.5, 4 x 1, or 4 x 2 mg/kg s.c. over 30 h. Brain edema was measured in the hippocampus, temporal cortex and parietal cortex. Edema was reduced by enoxaparin (0.5 + 4 x 0.5 mg/kg) in the hippocampus (-53%, p = 0.07) and the parietal cortex (-39%, ns). At 0.5 + 4 x 1 mg/kg edema was reduced in the hippocampus (-63%, p < 0.05) and the parietal cortex (-47%, p = 0.06). At 0.5 + 4 x 2 mg/kg, the reduction was more important in the hippocampus (-69%, p < 0.01) and in the parietal cortex (-50%, p < 0.05). No reduction was seen in the temporal cortex. The lesion size was reduced by enoxaparin at 0.5 + 4 x 1 mg/kg (-50%, p < 0.05), and at 0.5 + 4 x 2 mg/kg (-35%, ns). The neurological deficit evaluated with a 9-point scale was also improved with enoxaparin at 0.5 + 4 x 1 mg/kg 1 week post-TBI (p < 0.05). The cognitive impairment evaluated with a Lashley maze task was improved with enoxaparin (0.5 + 4 x 1 mg/kg) from 48 h (p < 0.05) to 2 weeks post-TBI (p < 0.01). Our results demonstrate for the first time that enoxaparin significantly reduces the brain contusion and edema, and improves the functional outcomes induced by a TBI. Therefore, enoxaparin could be a candidate drug to treat acute brain-injured patients.


Subject(s)
Anticoagulants/therapeutic use , Brain Edema/drug therapy , Brain Injuries/drug therapy , Brain/drug effects , Cognition Disorders/drug therapy , Enoxaparin/therapeutic use , Movement Disorders/drug therapy , Animals , Body Water/metabolism , Brain/metabolism , Brain/pathology , Brain Edema/etiology , Brain Edema/metabolism , Brain Injuries/complications , Cognition/drug effects , Cognition Disorders/etiology , Male , Movement Disorders/etiology , Movement Disorders/pathology , Nervous System Diseases/etiology , Nervous System Diseases/physiopathology , Rats , Rats, Sprague-Dawley
9.
J Cardiovasc Pharmacol ; 34(4): 575-83, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10511134

ABSTRACT

Platelet-related events being associated with the increment of infarct size at reperfusion in the presence of a residual stenosis, we tested in dogs whether intravenous aspirin (ASA) could limit infarct size. The left anterior descending coronary artery was occluded for 90 min and reperfused for 6 h in the presence of a residual critical stenosis. Controls received saline, and treated groups were given 2, 6, or 12 mg/kg ASA, i.v., 5 min before reperfusion. Infarct size did not differ significantly between groups (control, 43.80+/-6.28%; ASA, 2 mg/kg: 41.07+/-7.78%; ASA, 6 mg/kg: 37.55+/-3.44%; ASA, 12 mg/kg: 29.40+/-5.41%), as well as transmural collateral blood flow and [111In]-platelet accumulation in the infarcted myocardium (2.5-3.6 x 10(5) platelets/g). However, myocardial neutrophil accumulation was significantly reduced (p < 0.05) in groups given 6 (15.0+/-2.6 x 10(6)/g tissue) and 12 mg/kg (18.4 +/-3.8) ASA, but not in the 2-mg/kg group (21.0+/-5.2), as compared with control group (32.0+/-7.2). Ex vivo platelet aggregation to collagen was abolished during reperfusion in all treated groups (p < 0.05). Transcardiac arteriovenous differences in 6-keto-PGF1alpha were reduced significantly 1 h after reperfusion in groups given 6 or 12 mg/kg ASA (94.7+/-13.1 and 71.7+/-19.2 pg/ml, respectively) but not in the 2-mg/kg group (178.3+/-78.2 pg/ml), as compared with control (405.4+/-171.6 pg/ml). ASA-insensitive platelet activation at the site of stenosis or inhibition by ASA of prostacyclin production by jeopardized myocardium may explain the observed lack of benefit of ASA.


Subject(s)
Aspirin/therapeutic use , Coronary Disease/pathology , Infarction/pathology , Platelet Aggregation/drug effects , Reperfusion Injury/drug therapy , 6-Ketoprostaglandin F1 alpha/blood , Anesthesia , Animals , Blood Cell Count/drug effects , Cell Movement/drug effects , Dogs , Female , Infusions, Intravenous , Male , Malondialdehyde/analysis , Neutrophils/metabolism
10.
Cardiovasc Res ; 37(3): 656-66, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9659449

ABSTRACT

OBJECTIVE: Heparin (HEP) is used in the post-thrombolytic state to prevent vessel reocclusion, thereby aiding myocardial salvage. Side effects limit its benefits, but besides anticoagulant activity HEP has diffuse actions that may be potentially beneficial to jeopardized reperfused myocardium. This study compares the effect of therapeutic doses of HEP and enoxaparin (ENOX), a low molecular weight heparin, and to streptokinase (SK), on infarct size. METHODS: The left anterior descending coronary artery was occluded in dogs for 90 min, followed by 6 h of reperfusion with a residual critical stenosis in place. Five min before reperfusion, HEP (2800 IU) was injected i.v., and perfused at 500 IU/h until sacrifice in group 2, while groups 3 and 4 received ENOX (2128 anti-Xa IU i.v.) followed by 380 anti-Xa IU/h. Group 4 was also given 500,000 IU SK over 30 min before reperfusion beginning at 55 min of occlusion (ENOX + SK), while group 5 received only SK. Controls (CON, group 1) received saline. P-selectin mediated platelet-neutrophil rosettes formation was also tested in vitro in the presence of HEP and ENOX. RESULTS: The area at risk delimited by dye perfusion was statistically similar among groups. Covariance analysis between infarct size (% of area at risk) delimited with triphenyltetrazolium and collateral flow measured with radioactive microspheres confirmed that groups given ENOX (21.6 +/- 5.5%) and ENOX + SK (24.9 +/- 3.9%) developed smaller infarcts (P < 0.05) than CON (48.1 +/- 4.5%), as opposed to HEP (32.2 +/- 3.6%) and SK (46.8 +/- 3.4%) groups. 111In-platelet counts in the infarct were reduced significantly by 64% in the ENOX group as compared to CON, and to a lesser extent (42%, n.s.) in the ENOX + SK group, but were not reduced by HEP and SK treatments. Neutrophil accumulation in the infarcts was decreased significantly and by more than 75% in the ENOX and ENOX + SK groups versus CON, but not in the HEP and SK groups. Also, only ENOX (10-100 micrograms/ml) significantly inhibited platelet-neutrophil rosettes formation in a plasmatic milieu. CONCLUSIONS: The ENOX treatment, as opposed to that of HEP, reduces myocardial platelet and neutrophil accumulations, and limits infarct size when given just before and during reperfusion. The benefits of ENOX on infarct size were not modified by SK, and may be related, at least in part, to an interaction with P-selectin-mediated cell adhesion.


Subject(s)
Anticoagulants/therapeutic use , Enoxaparin/therapeutic use , Myocardial Reperfusion Injury/prevention & control , Thrombolytic Therapy , Analysis of Variance , Animals , Blood Platelets/pathology , Cells, Cultured , Dogs , Erythrocytes/pathology , Female , Heparin/therapeutic use , Male , Myocardial Ischemia/drug therapy , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Neutrophils/pathology , Platelet Adhesiveness/drug effects , Streptokinase/therapeutic use
11.
Haemostasis ; 28(2): 78-85, 1998.
Article in English | MEDLINE | ID: mdl-10087432

ABSTRACT

This study investigates the effect of enoxaparin (Lovenox, Klexane), a low-molecular-weight heparin, on edema following a photothrombotic lesion using rose bengal dye in the rat. An area of cerebral ischemia was provoked in the right hemisphere of rats. Edema developed over 24 h after the lesion, as seen comparing water content of a core sample from the right hemisphere to that of a similar sample from the left hemisphere of each rat. Enoxaparin at 0. 5 mg/kg i.v. plus 2 mg/kg s.c. reduced edema 24 h after lesion induction by 32% (p < 0.01) when the treatment was started 2 h after photothrombotic insult, with maintenance doses of 2 mg/kg s.c. enoxaparin at 6 and 18 h. When the same initial treatment with enoxaparin was started 18 h after insult, there was still a significant reduction of 20% (p < 0.01) in cerebral edema. Administration of enoxaparin 18 h after insult reduced cerebral edema in a dose-dependent manner. There was no evidence of intracranial hemorrhages in any of the animal groups and when the hemoglobin content of the brain samples was assayed by the method of Drabkin, no increase in hemoglobin content was seen compared to sham-operated animals.


Subject(s)
Brain Edema/drug therapy , Enoxaparin/administration & dosage , Fibrinolytic Agents/administration & dosage , Intracranial Embolism and Thrombosis/physiopathology , Animals , Fluorescent Dyes , Injections, Intravenous , Intracranial Embolism and Thrombosis/chemically induced , Male , Rats , Rats, Sprague-Dawley , Rose Bengal
12.
Biochem Biophys Res Commun ; 241(2): 548-52, 1997 Dec 18.
Article in English | MEDLINE | ID: mdl-9425308

ABSTRACT

The mechanisms involved in the maintenance or loss of the asymmetric distribution of phospholipids in the cell plasma membrane remain mysterious. In the yeast Saccharomyces cerevisiae, the transmembrane migration of certain phospholipids is controlled by transcription regulators of various ATP-binding cassette (ABC) transporters. The P-glycoprotein membrane transporters encoded by the multidrug resistance (MDR) genes, members of the ABC protein family, act as lipid translocases in mammalian cells. We report here the lack of expression of MDR genes in lymphoblasts derived from the B cells of a patient with an inherited Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications. From microsatellite analysis of 7q21.1 and functional assessment, the most likely explanation accounting for Scott phenotype is a mutation in an unlinked gene coding for a regulatory protein necessary for the expression of MDR genes. Because phosphatidylserine externalization is also one of the hallmarks of cells undergoing apoptosis, these observations are suggestive of a relationship between basic processes such as multidrug transport, apoptosis and procoagulant phospholipid exposure.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B , ATP-Binding Cassette Transporters/genetics , Carrier Proteins/metabolism , Genes, MDR , Lipid Metabolism, Inborn Errors/genetics , Membrane Proteins/metabolism , Phosphatidylserines/metabolism , Phospholipid Transfer Proteins , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/metabolism , Aged , Biological Transport , Cell Membrane/metabolism , Chromosomes, Human, Pair 7 , Drug Resistance, Multiple , Gene Expression , Genetic Markers , Humans , Lipid Metabolism, Inborn Errors/metabolism , Microsatellite Repeats
13.
Thromb Res ; 83(2): 127-36, 1996 Jul 15.
Article in English | MEDLINE | ID: mdl-8837311

ABSTRACT

Antithrombotic activity of two recombinant GPIb-binding fragments of vWF, RG12986 (residues 445-733), and VCL (residues 504-728), were assessed in an ex vivo capillary perfusion chamber exposing human type III collagen to native nonanticoagulated guinea pig blood. Platelet adhesion and thrombus formation were evaluated by computer assisted morphometry for two shear rates (650 and 1800 s-1) and for two perfusion times (1.5 and 4 min). At 1800 s-1 and 4 min of perfusion, platelet adhesion decreased from 63 +/- 7% for control, to 46 +/- 4% for 20 mg/kg RG12986, and to 29 +/- 5% for 4 mg/kg VCL, and the mean thrombus height dropped from 40 +/- 8 microns to 24 +/- 3 microns and 7.5 +/- 1 microns, respectively. The two doses did not change bleeding time values. Our results suggest that guinea pig blood and the circular perfusion chamber represent a good model for the evaluation of limited amount of GPIb/IX-vWF axis inhibitors.


Subject(s)
Peptide Fragments/pharmacology , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIb-IX Complex/metabolism , von Willebrand Factor/pharmacology , Animals , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Guinea Pigs , Humans , In Vitro Techniques , Male , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacology , von Willebrand Factor/chemistry
14.
Semin Thromb Hemost ; 22(2): 157-64, 1996.
Article in English | MEDLINE | ID: mdl-8807713

ABSTRACT

Thrombin generation is the culminating event of the coagulation cascade. It is initiated after the expression of tissue factor by endothelial cells and monocytes exposed to thrombogenic stimuli. Anionic phospholipids, chiefly phosphatidylserine, are necessary for the optimal activity of tissue factor and completion of the clotting process. They display a catalytic potential by allowing the formation of the characteristic enzyme complexes at the membrane surface. Platelets are viewed as the main source of procoagulant phospholipid referred to as platelet factor 3. The plasma membrane of resting cells presents an asymmetrical distribution of phospholipids, aminophospholipids being sequestered in the inner leaflet. Procoagulant phospholipids become available at the outer surface after cell stimulation. The collapse of the membrane asymmetry is thought to promote a phospholipid scrambling accompanied by the shedding of microparticles. The plasma membranes of such vesicles bear irreversibly externalized procoagulant phosphatidylserine and contain glycoproteins that testify to their tissue origin. Hence, microparticles could disseminate a dual procoagulant and adhesive potential. Thrombin autoamplification is exerted through feedback activation loops involving either coagulation factors or platelets. This article details the mechanisms by which procoagulant phospholipids promote the generation of an excess of thrombin. A new pharmacological approach of thrombosis is presented, based on the control of the exposure of procoagulant phospholipids and membrane microparticle shedding.


Subject(s)
Phospholipids/physiology , Thrombin/biosynthesis , Animals , Catalysis , Humans , Phospholipids/metabolism
15.
Ann Pharm Fr ; 54(1): 8-20, 1996.
Article in French | MEDLINE | ID: mdl-8702195

ABSTRACT

In spite of progress, antithrombotic therapies involve the risk of haemorrhage. Thrombolytic agents have more or less fibrin specificity which is related to the risk of bleeding. These drugs have efficient antidotes which can be administered locally or by systemic route. The usual anticoagulants are vitamin K antagonists and heparin which have propensity to be given at reduced dose. Low molecular weight heparins have demonstrated good efficacy and tolerance in the prevention and treatment of venous thrombosis. New anticoagulants, specific inhibitors of activated factor X or thrombin, are now expected but they lack of specific antidotes. Platelet aggregation inhibitors, mainly aspirin, are widely used in the prevention of arterial thrombosis. New compounds particularly GPII/IIIa fibrinogen receptor antagonists have a broad spectrum but need to be used watchfully. Research underway suggest new molecules which will likely inhibit the procoagulant, phospholipid dependent, platelet activity or block thrombin receptor. Good knowledge of properties and progress in the preparation of improved haemostat agents could significantly reduce, particularly in dental surgery, the risk of haemorrhage.


Subject(s)
Fibrinolytic Agents/classification , Anticoagulants/adverse effects , Anticoagulants/classification , Anticoagulants/pharmacology , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Forecasting , Humans , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/classification , Platelet Aggregation Inhibitors/pharmacology
16.
Arterioscler Thromb ; 13(8): 1164-70, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8343490

ABSTRACT

The effect of D-Arg-Gly-Asp-Trp (dRGDW), a synthetic RGD-containing peptide, on platelet adhesion and aggregate formation on various purified adhesive proteins and the extracellular matrix of endothelial cells was investigated with anticoagulated blood recirculating through a parallel-plate perfusion chamber. Aggregate formation on the extracellular matrix of phorbol myristate acetate (PMA)-stimulated endothelial cells and on collagen type I was more strongly inhibited by dRGDW at higher shear rates than at a low shear rate. Platelet adhesion to the extracellular matrix of nonactivated and PMA-stimulated endothelial cells was inhibited by dRGDW, especially at high shear rates, probably as a consequence of the inhibition of platelet spreading. Inhibition by dRGDW of platelet adhesion to von Willebrand factor, fibronectin, and fibrinogen was almost complete, indicating that platelet adhesion to these substrates is mediated through RGD-directed receptors. Platelet adhesion to laminin was not inhibited by the peptide, whereas platelet adhesion to collagen was increased as a consequence of the inhibition of aggregate formation. Our results show that dRGDW is a strong inhibitor of platelet adhesion and aggregate formation, especially at high shear rates.


Subject(s)
Oligopeptides/chemistry , Oligopeptides/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Amino Acid Sequence , Collagen/pharmacology , Endothelium, Vascular/physiology , Extracellular Matrix/physiology , Humans , Molecular Sequence Data , Platelet Adhesiveness/drug effects , Proteins/physiology , Stress, Mechanical
17.
Thromb Res ; 69(5): 443-52, 1993 Mar 01.
Article in English | MEDLINE | ID: mdl-8388583

ABSTRACT

In a randomized crossover study twelve healthy male volunteers (23.5 +/- of 4.8 years, 73.0 +/- 6.4 kg, 180.8 +/- 5.7 cm) received one subcutaneous injection of either enoxaparin (EN) at 40 mg or 1 mg kg-1, or unfractionated heparin (UH) at 5,000 IU at one week intervals. Area under curves (AUC) of Anti-Xa and Anti-IIa activities correlated with EN dose. The relative effectiveness of EN versus UH 5,000 U as assessed by AUC ratio (EN/UH) was 7 and 15 for Anti-Xa activity, 1.3 and 3.1 for Anti-IIa activity after sc injection of EN 40 mg (4,000 Anti-Xa IU and 1,200 Anti-IIa U) and 1 mg kg-1 (7,300 +/- 640 Anti-Xa IU and 2,190 +/- 290 Anti-IIa IU) respectively. In volunteers receiving EN, a dose dependent inhibition of thrombin generation rate in platelet depleted plasma (PDP), measured with a new and simple chromogenic thrombin generation assay, was observed when compared with baseline values. Similarly, intrinsic prothrombin activation in whole blood, evidenced by measuring residual factor II in serum 2 hours after clotting (prothrombin consumption test: PC), was inhibited in a dose dependent manner. In UH treated volunteers, although the inhibition of thrombin generation rate in PDP was similar to that observed with EN 40 mg, prothrombin consumption in whole blood was not significantly modified. Tissue factor pathway inhibitor (TFPI) activity release was increased similarly for UH and EN 40 (1.4 fold increase above baseline values) and 1.9 fold for the higher dose of EN. The discrepancy between prothrombin consumption in whole blood and inhibition of thrombin generation rate in PDP in the UH and not in the EN group strongly suggests that UH and not EN is influenced by the presence of a platelet component. This could be formed during thrombin induced platelet activation. Platelet factor 4 is a possible candidate. Another hypothesis involves the role of TFPI-UH complex anticoagulant activity which might be inhibited more during whole blood coagulation than the TFPI-EN complex.


Subject(s)
Blood Coagulation/drug effects , Heparin, Low-Molecular-Weight/pharmacology , Heparin/pharmacology , Lipoproteins/metabolism , Prothrombin/metabolism , Adult , Biological Availability , Factor Xa Inhibitors , Humans , Male , Prothrombin/antagonists & inhibitors
18.
Thromb Haemost ; 68(6): 694-700, 1992 Dec 07.
Article in English | MEDLINE | ID: mdl-1287884

ABSTRACT

We have employed synthetic peptides with sequences corresponding to the integrin receptor-recognition regions of fibrinogen as inhibitors of platelet aggregation and adhesion to fibrinogen- and fibrin-coated surfaces in flowing whole blood, using a rectangular perfusion chamber at wall shear rates of 300 s-1 and 1,300 s-1. D-RGDW caused substantial inhibition of platelet aggregation and adhesion to fibrinogen and fibrin at both shear rates, although it was least effective at blocking platelet adhesion to fibrin at 300 s-1. RGDS was a weaker inhibitor, and produced a biphasic dose-response curve; SDRG was inactive. HHLGGAKQAGDV partially inhibited platelet aggregation and adhesion to fibrin(ogen) at both shear rates. These results support the identification of an RGD-specific receptor, most likely the platelet integrin glycoprotein IIb:IIIa, as the primary receptor responsible for platelet:fibrin(ogen) adhesive interactions under flow conditions, and indicate that platelet adhesion to surface bound fibrin(ogen) is stabilized by multivalent receptor-ligand contacts.


Subject(s)
Fibrin/drug effects , Fibrinogen/drug effects , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Platelet Adhesiveness/drug effects , Amino Acid Sequence , Hydrolysis , Molecular Sequence Data , Serine Endopeptidases/metabolism , Solubility , Stereoisomerism , Water/chemistry
19.
Thromb Res ; 66(2-3): 191-206, 1992 May 01.
Article in English | MEDLINE | ID: mdl-1329253

ABSTRACT

An occlusive coronary thrombus was obtained in barbiturate anesthetized dogs within 60 min following the angiographic placement of a copper coil into the left descending coronary artery. This thrombus persisted for the 60 min experimental period, within which the effects of i.v. t-PA (10 micrograms/kg/min for 30 min) alone or combined with i.v. heparin (0.63 mg/kg twice) or enoxaparin (1.5 mg/kg twice) were evaluated. t-PA alone achieved recanalization for 20 min in only 2 out of the 5 dogs studied. Combination of t-PA with either heparin or enoxaparin produced this effect in all the 5 dogs studied. In dogs treated with t-PA associated to either heparin or enoxaparin, the thrombus weight was smaller (decreases of 34% and 44% respectively) than in animals given t-PA alone. The plasma amidolytic activity, expressed as t-PA activity, was greater 15 min after the beginning of t-PA infusion, in dogs pretreated with either heparin or enoxaparin than in animals given t-PA alone. Conversely, during t-PA infusion, the apparent t-PA inhibitor and antiplasmin activities were no longer measurable in the plasma, but reappeared 10 min after the end of t-PA infusion. Plasma coagulation time was not modified by t-PA, but was slightly prolonged (2-fold) by enoxaparin and markedly (7-fold) by heparin on initiation of t-PA infusion. Plasma anti-IIa activity was 3-fold higher in dogs pretreated with heparin as opposed to enoxaparin. On the contrary, both compounds increased similarly plasma anti-Xa activity. In conclusion, these results indicate that enoxaparin, like heparin, enhances the thrombolytic effects of t-PA. This favourable effect occurs independently of a plasma hypocoagulable state, which was clearly produced by heparin but not enoxaparin. Its mechanism may be the significant elevation of plasma t-PA activity produced by both heparin and enoxaparin during t-PA infusion.


Subject(s)
Coronary Thrombosis/drug therapy , Fibrinolytic Agents/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Amino Acid Sequence , Animals , Coronary Thrombosis/blood , Dogs , Drug Synergism , Factor Xa Inhibitors , Female , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/toxicity , Hemorrhagic Disorders/chemically induced , Heparin/pharmacology , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/pharmacology , Heparin, Low-Molecular-Weight/toxicity , Humans , Male , Molecular Sequence Data , Prothrombin/antagonists & inhibitors , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/pharmacology , alpha-2-Antiplasmin/analysis
20.
Thromb Haemost ; 67(5): 556-62, 1992 May 04.
Article in English | MEDLINE | ID: mdl-1325683

ABSTRACT

A low molecular weight heparin (enoxaparin, mean molecular weight approximately 4,400) was separated by gel chromatography into eight different fractions with a narrow distribution around the following mean molecular weights: 1,800, 2,400, 2,900, 4,200, 6,200, 8,600, 9,800 and 11,000. We compared the influence of enoxaparin on the generation of thrombin in plasma to that of the eight fractions. We determined: a) the % of material with high affinity to antithrombin III (HAM) and the % of HAM above the critical chain length necessary to allow for thrombin inhibition (ACLM), b) the specific catalytic activity on the decay of endogenous thrombin, and c) the inhibition of over-all thrombin formation in the extrinsic and the intrinsic pathway. From b and c we calculated the inhibition of prothrombin conversion in these pathways. We found that a) there is a gradual decrease of the HAM fraction with decreasing molecular weight; b) the specific catalytic activity for the inactivation of thrombin does not vary significantly between the fractions when expressed in terms of ACLM; c) the potency to inhibit prothrombin conversion does not vary significantly between the fractions when expressed in terms of HAM.


Subject(s)
Heparin, Low-Molecular-Weight/pharmacology , Thrombin/antagonists & inhibitors , Thromboplastin/antagonists & inhibitors , Antithrombin III/chemistry , Fluorescence , Heparin, Low-Molecular-Weight/chemistry , Humans , Molecular Weight , Thrombin/biosynthesis
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