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Biomedical subjects

J Arnout

Publications and source records attributed to J Arnout.

At least 91 records · Page 5Linked to original sources
PubMed1990

R68070, a combined thromboxane/endoperoxide receptor antagonist and thromboxane synthase inhibitor, inhibits human platelet activation in vitro and in vivo: a comparison with aspirin.

We have investigated the effects of R68070 on platelet function in vitro and in vivo. The drug inhibits U46619-induced aggregation (IC50 = 1.2 x 10(-6) mol/L), blocks serum thromboxane formation (IC50 = 1 x 10(-7) mol/L), and increases serum prostaglandin (PG)E2 and 6-keto-PGF1 alpha levels, indicating that it combines thromboxane receptor blocking and thromboxane synthase inhibiting properties. The thromboxane-dependent aggregation of blood platelets is blocked by R68070, whereas no inhibition of thromboxane independent pathways occurs. A double-blind, randomized, cross-over study was performed on nine volunteers, comparing 400 mg placebo, 400 mg aspirin, and 400 mg R68070. Thromboxane-dependent aggregations were significantly inhibited by R68070 and by aspirin, the latter still having the most pronounced action. However, R68070 was clearly more powerful than aspirin (P less than .0005) in prolonging the bleeding time. Serum TxB2 formation was completely inhibited with both treatments, whereas serum 6-keto-PGF1 alpha and PGE2 and intralesional 6-keto-PGF1 alpha were inhibited after aspirin and stimulated after R68070. We conclude that R68070 inhibits platelet thromboxane synthase and its thromboxane receptor both in vitro and in vivo; local reorientation of cyclic endoperoxide metabolism toward prostacyclin induces a stronger inhibition of hemostasis than that produced by aspirin.

Aspirin↗
PubMed1990

Autotransfusion during aorto-iliac surgery.

Red blood cell (RBC) quality and function during autotransfusion with the Solcotrans system were studied. Up to 64% (mean 999.5 +/- 310 ml) of the total volume of blood lost (mean 1895 +/- 707 ml) during operation in 10 patients undergoing elective abdominal aortic surgery was salvaged. No patient received homologous blood during surgery. Haemoglobin (Hb) and Haematocrit (PCV) values decreased but within acceptable limits. No evidence of DIC was found and renal function was unaffected. Mechanical and functional damage to the RBC was minimal and erythrocyte oxygen-carrying capacity was excellent. 2,3-DPGRBC concentration and RBC reduced glutathion were normal. The device was easy to handle and technical problems were not encountered. It was accurate in salvaging blood although the need for homologous blood was not entirely eliminated since four patients received homologous blood products in the postoperative period. No adverse clinical events occurred.

Aged↗
PubMed1990

Protein C deficiency associated with venous thromboembolism.

Protein C deficiency has been reported to be associated with a high risk for thromboembolism. We report three patients with protein C deficiency: one suffered from left renal vein thrombosis, another from recurrent venous thrombosis of the legs complicated by pulmonary embolism and the third from an extensive thrombosis of the splanchnic veins with partial Budd-Chiari syndrome. We discuss the unusual sites of venous thrombosis in protein C deficient patients, the factors which may act as thrombotic trigger and the strategy of long-term prevention.

Blood Protein Disorders↗
PubMed1990

Pharmacological manipulation of the thromboxane pathway in blood platelets.

Interference with blood platelet thromboxane A2 (TxA2)-formation using aspirin has proven to be clinically efficient in the prevention of arterial thrombosis. The protection, however, is far from absolute and during recent years we have witnessed the development of new classes of drugs with more specific impact on TxA2-dependent pathways of platelet activation. Thromboxane synthase inhibitors (TSI) act on the thromboxane synthase, thus preventing the formation of TxA2, and causing a shunting of the prostaglandin cyclic endoperoxide metabolism towards other prostanoids, such as the platelet inhibitory PGD2 and PGI2, the latter when endothelial cells are present that can 'steal' platelet derived cyclic endoperoxides. TSI, however, do not block the formation of the cyclic endoperoxides. Since those products themselves can also act on the TxA2-receptor, the net effect of a TSI will be the result of a complex balance of pro- and anti-aggregatory prostanoids. Known thromboxane receptor antagonists (TRA) inhibit the interaction of both TxA2 and the cyclic endoperoxides with the receptor in a competitive way, but do not change the relative levels of the different prostaglandins formed. The combination of the two actions leads to a stronger influence on in vivo, ex vivo and in vitro laboratory tests as can be seen when a TSI and TRA are used in combination, or when a drug is studied that has both characteristics. Additional data show that such a double-action drug is able to quickly reduce levels of beta-thromboglobulin, a marker for ongoing in vivo platelet activation, in patients with obstructive arterial disease.

Animals↗
PubMed1990

Non-receptor-mediated refractoriness in prostacyclin production by human endothelial cells in a continuous flow system is delayed by a low-molecular-weight plasma fraction devoid of reducing cofactors for peroxidase-catalysed reactions.

Using a microcarrier perfusion model, we have investigated the effects of a low-molecular-weight plasma fraction (mol. wt. less than 10,000) on the capacity of human umbilical vein endothelial cells (HUVECs) to synthesize and release prostacyclin (PGI2) during repeated stimulation with either calcium ionophore A23187 or arachidonic acid (AA). This plasma fraction (filtrate 10,000), which has recently been shown to contain most of the activity previously referred to as 'prostacyclin regulating plasma factor', delayed the exhaustion of the PGI2 generating capacity of the HUVECs during repeated stimulation with either inducer. No such effect was seen with whole plasma. The PGI2 regulatory activity of the filtrate was not significantly affected by removal of reducing cofactors for peroxidase-catalysed reduction of hydroperoxides, accumulation of which inhibits cyclooxygenase. In contrast, albumin added to the filtrate abolished its protective effect on endothelial PGI2 synthesis. We conclude that low-molecular-weight plasma constituents partially preserve the PGI2-generating capacity of human vascular endothelium during repeated stimulation. Under continuous flow conditions, as applied in our study, this effect appears not to be related to reducing cofactor activity for peroxidase-catalysed reactions. In whole plasma, this PGI2 regulatory activity may be partially masked by the presence of plasma proteins.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Urinary thromboxane B2 and 2,3-dinor-thromboxane B2 in the neonate born at full-term age.

We have developed a method for measurement of urinary 2,3-dinor-TXB2, which is a reflection of the actual rate of TXA2 synthesis by platelets in vivo. This determination was based on purification by high-pressure liquid chromatography and on measurement by RIA. After validation of the assay, we established the range of urinary Tx metabolites in healthy infants born at full-term during their first week of life. The 2,3-dinor-TXB2 levels were higher than in adults and declined gradually during the first seven days of life.

Chromatography, High Pressure Liquid↗
PubMed1989

Platelet aggregation in whole blood--studies with a platelet counting technique--methodological aspects and some applications.

We describe a method for measuring platelet aggregation in whole blood by single platelet counting. The importance of a low stirring speed (100 rpm) to obtain agonist-specific aggregation is stressed. Despite this low stirring speed, the sensitivity to agonists equals that of the turbidometric technique in platelet-rich plasma. The optimal concentration of formaldehyde for fixing the aggregates, the effects of storage times and anticoagulant are studied. Applicability to the study of platelet function inhibitors or of inherited platelet function disorders is illustrated. It is concluded that this technique, used under the appropriate conditions, combines the advantage of measuring platelet aggregation in a more physiologic environment with the advantages of the turbidometric technique such as high sensitivity.

Adenosine Diphosphate↗
PubMed1989

Characterization of N,N'-bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets.

Picotamide (G137 or N,N'-bis[3-picolyl]-4-methoxy-isophtalamide), a drug which has shown platelet inhibitory effects in vitro and ex vivo, was investigated for its mechanism of action on human platelets in vitro. This compound suppresses the aggregation of human platelets induced by arachidonic acid (IC50: 1.8 x 10(-5) M), low-dose collagen (IC50: 3.5 x 10(-4) M), U46619 (IC50: 1 1.4 x 10(-4) M) and by authentic TxA2 (IC50: 1 x 10(-4) M), without affecting the aggregation induced by A23187 or primary aggregation by ADP. Picotamide inhibits dose-dependently TxA2 synthesis by platelets (IC50: 1.5 x 10(-4) M) and enhances the formation of PGE2. Picotamide-treated platelets also favour the formation of PGI2 by aspirinated endothelial cells; in addition, the drug appears to exert a direct stimulatory effect on PGI2-synthesis, at least at high concentrations. Finally, in platelet-rich plasma stimulated with arachidonic acid, picotamide increases intraplatelet cAMP while no effects on cAMP are detected in unstimulated platelets. In conclusion, picotamide is a dual thromboxane-synthase inhibitor/thromboxane-receptor antagonist in human platelets and introduces a new class of agents potentially useful in antithrombotic therapy.

Arachidonic Acid↗
PubMed1989

Inherited factor XIII deficiency.

A new observation of inherited factor XIII deficiency is described. The patient had presented in the past with an umbilical haemorrhage, a cerebral haemorrhage, multiple haematomas with delayed onset after minimal trauma, and episodes of spontaneous haemarthrosis. The biological diagnosis was made at the age of 7 years. The child had undetectable transamidating activity and factor XIII a chains, while the level of b chains was reduced. The values observed in the parents were intermediate between those of the patient and those of normal plasma. Heated factor VIII concentrates were found to contain only low amounts of factor XIII, and were thus unsuitable for the prophylactic therapy of this rare disease. The patient was successfully treated with monthly injections of a factor XIII concentrate.

Blood Coagulation Factors↗
PubMed1988

Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro.

The sulfated polysaccharides dextran sulfate and heparin have proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) in vitro. Dextran sulfate (Mr 5000) and heparin (Mr 15,000) completely protected MT-4 cells against HIV-1-induced cytopathogenicity at a concentration of 25 micrograms/ml. Their 50% inhibitory concentrations were 9.1 micrograms/ml (dextran sulfate) and 7.0 micrograms/ml (heparin), respectively. No toxicity for the host cells was observed with these compounds at a concentration of 625 micrograms/ml. The anti-HIV-1 activity of heparins of various molecular weights correlated well with their anticoagulant activity. On the other hand, with dextran sulfates of low molecular weight (5000, 8000) a significant inhibitory effect on HIV-1 was achieved at a concentration that was not markedly inhibitory to the blood coagulation process. Dextran sulfate and heparin were not inhibitory to HIV-1 reverse transcriptase unless they were used at concentrations in excess of those that inhibited HIV-1 replication. They were highly effective against HIV-1 replication even when present only during the 2-hr virus adsorption period. Studies using radiolabeled HIV-1 virions indicated that dextran sulfate and heparin inhibit virus adsorption to the host cells.

Adsorption↗
PubMed1988

Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man.

1. The efficacy and tolerability of CV-3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2. The compound, in doses from 750 to 2,000 micrograms kg-1, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 +/- 162% of the basal TAC at the end and 266 +/- 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3. CV-3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4. Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can safely be administered to man and should be useful in elucidating the role of PAF in disease.

Adult↗
PubMed1988

Effect of benazepril, a converting enzyme inhibitor, on plasma levels and activity of acenocoumarol and warfarin.

The effect of benazepril (CGS 14824), 20 mg/day orally, on the steady-state pharmaco-dynamics and plasma levels of the anticoagulants, warfarin and acenocoumarol, was studied in healthy volunteers. The anticoagulant activity of acenocoumarol was not affected by benazepril; there was an apparent slight but statistically significant reduction of the anticoagulant effect of warfarin. The magnitude of the inhibitory effect was considered not to be clinically important. There was no effect of benazepril on plasma steady-state levels of either anticoagulants.

Acenocoumarol↗
PubMed1987

Continuous inhibition of serotonin-induced platelet aggregation during chronic ketanserin administration to man can be detected after plasma pH control.

Ketanserin is a well-known serotonin S2 receptor antagonist but its capacity to inhibit serotonin-induced aggregation ex vivo during chronic administration has been a matter of debate. In vitro evidence is presented that the inhibitory capacity of ketanserin is lowered by increasing plasma pH. Since the pH of plasma kept at the open air increases with time, we studied the effect of chronic administered ketanserin on serotonin-induced platelet aggregation in plasma kept at a lowered pH of 7.70, by replacing the air with 95% O2-5% CO2. Using this slightly modified technique, we could, in contrast to our previous studies, observe a complete inhibition of the serotonin-induced aggregation throughout the ketanserin treatment period.

Humans↗