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Biomedical subjects

F Markwardt

Publications and source records attributed to F Markwardt.

At least 145 records · Page 8Linked to original sources
PubMed1984

Pharmacokinetics and anticoagulant effect of hirudin in man.

The pharmacokinetics and the effects on the haemostatic system of hirudin were assessed in six healthy subjects after single intravenous or subcutaneous dose (1000 AT-U/kg). When hirudin was given intravenously first-order elimination kinetics followed the initial distribution phase. The decline in plasma hirudin concentration was most adequately expressed by a biexponential equation describing a two compartment model. A mean elimination half-life of 0.84 hr and a mean volume of distribution of 12.9 l were calculated. After subcutaneous injection a low hirudin level (approximately 0.5 AT-U/ml) was maintained for a prolonged period of time. In the 24 hour-urine up to 50 per cent of the administered amount of hirudin was excreted in active form. Thrombin time, partial thromboplastin time and prothrombin time measured in plasma samples ex vivo were prolonged dependent on the hirudin plasma level. Platelet counts, fibrinogen level and the fibrinolytic system were unchanged. Bleeding time was prolonged twice at maximum. Subcutaneous or intravenous administration of pure hirudin was tolerated without side-effects.

Adult↗
PubMed1984

[Pharmacological potentials for activating the fibrinolytic system].

Increasing insight into the mechanism of thrombolysis has led to the development of highly effective thrombolytic agents. Further progress in thrombolytic therapy is expected by the use of extrinsic plasminogen activator from vascular endothelium and of temporarily blocked (acylated) fibrinolytic enzymes. Extensive studies on fibrinolytic/thrombolytic substances will lead to a new generation of activator of fibrinolysis that interferes with the biosynthesis and release of plasminogen activator. Such agents will be suited for treatment of hyperfibrinolytic states.

Animals↗
PubMed1984

Acyl-kallikrein; a delivery system for the kinin-liberating enzyme.

Glandular kallikrein can be temporarily acylated at the active centre by 4-amidinophenyl benzoates. The time course of reactivation depends on the nature of the acyl group introduced. Benzoyl kallikrein was used as a delivery system for kallikrein in vivo. In rabbits, bolus injection of the acylated enzyme caused a long-lasting drop in blood pressure due to sustained kinin liberation.

Acylation↗
PubMed1984

Studies on 5-hydroxytryptamine receptors on isolated human femoral veins and arteries and the influence of dihydroergotamine.

5-Hydroxytryptamine (5-HT) caused concentration-dependent contractions in human postmortem femoral venous and arterial strips. In veins, it was a more potent agonist than noradrenaline, while the reverse was true for arteries. Pizotifen and methysergide were competitive antagonists against 5-HT in femoral arteries with pA2 values of 8.18 and 8.37, while in femoral veins they exerted noncompetitive antagonism. Dihydroergotamine (DHE) antagonized the 5-HT effect in a manner which was not competitive both in veins and arteries. At concentrations employed in antagonist experiments, it increased the resting tone, particularly in veins. The contractile response of veins to DHE was inhibited when the vascular preparations were preincubated with pizotifen at nanomolar concentrations. The results suggest that 5-HT receptors on veins differ from those on arteries. DHE possesses comparatively high affinity for 5-HT receptors on veins. It is concluded that 5-HT receptors may be involved in the contractile response of veins to DHE.

Dihydroergotamine↗
PubMed1984

Inhibition of the thrombin-platelet reaction by hirudin.

The influence of hirudin on the thrombin-platelet reaction was studied by determination of thrombin-induced serotonin release from blood platelets. The dissociation constant for the thrombin-hirudin complex calculated from data obtained by measuring the platelet reaction (Ki 50 pmol/1) was in accordance with the value obtained by determination of fibrinogen clotting. Prevention of the effect of thrombin on platelets required the addition of hirudin in at least 10-fold molar excess. The release of serotonin could be immediately stopped by hirudin at any time when the special conditions for the reaction of thrombin with the tight-binding inhibitor and the receptors on the platelet surface were taken into account.

Blood Platelets↗
PubMed1984

[Pharmacologic aspects of thrombophilia].

Thrombophilic conditions are due to a failure of antithrombotic mechanisms. Starting from this fact, the possibilities of influencing pharmacologically disturbances of biosynthesis and function of prostacyclin and plasminogen activator of the vessel wall as well as of plasmatic inhibitors of clotting factors were discussed. The results of experimental and clinical studies were reported.

Anticoagulants↗
PubMed1984

[Activation of the fibrinolytic system with dehydrochlormethyltestosterone].

4-Chloro-1-dehydro-methyltestosterone (2 mg/kg/die) administered to rats and rabbits for three months increased the spontaneous fibrinolytic activity of blood, the release of plasminogen activator stimulated by venous stasis, and the activator activity in the kidney. Its effect in animal experiments corresponded to that of the steroid stanozolol tested for comparison.

Animals↗
PubMed1984

[Experimental studies of the liberation of plasminogen activator by DDAVP].

Infusion of 0,4 micrograms DDAVP/kg for 30 min increased the plasminogen activator activity in blood of experimental animals (dog, rat, rabbit). The plasminogen activator releasing effect was also demonstrated in isolated perfused vascular preparations (pig ear, rat lung) at low doses (10(-9) - 10(6) mol/l). According to these results DDAVP is believed to attack directly the endothelial cell.

Animals↗
PubMed1984

[3H]dihydroergocryptine binding to alpha-adrenoceptors in human femoral veins and arteries.

In order to characterise subtypes of alpha-adrenoceptors in human vascular tissue, radioligand binding studies with [3H]dihydroergocryptine were carried out in human femoral veins and arteries. Binding of [3H]dihydroergocryptine to venous and arterial membranes was rapid and reversible reaching steady state within 4-6 min at 25 degrees C. [3H]Dihydroergocryptine was displaced from its receptor site on vascular membranes by unlabelled alpha-adrenoceptor agonists and antagonists in a concentration-dependent manner. Yohimbine and guanfacine which possess high affinity for alpha 2-adrenoceptors were more effective in competing for [3H]dihydroergocryptine binding sites in veins than in arteries. Prazosin and phenylephrine with high affinity for alpha 1-adrenoceptors were more effective displacers in arteries than in veins. The results suggest that the alpha-adrenoceptor population differs between human femoral veins and arteries. In veins, predominantly alpha 2-adrenoceptors are present, whereas in arteries the adrenoceptor of the alpha 1 type prevails. The results show that the uneven distribution of alpha 1- and alpha 2-adrenoceptors as has been found in animal experiments and pharmacological investigations with human vessels could also be demonstrated by binding studies with [3H]dihydroergocryptine in human femoral arteries and veins.

Adrenergic alpha-Agonists↗
PubMed1984

[Synthetic inhibitors of serine proteinases. 31. The inhibition of trypsin, plasmin and thrombin by isomeric compounds of N alpha -arylsulfonylated omega-amidinophenyl-alpha-aminoalkylcarboxylic acid amides].

Isomeric compounds of N alpha-arylsulfonylated amides of omega-amidinophenyl-alpha-aminoalkylcarboxylic acids--N alpha-amidinophenylsulfonylated amides or N alpha-arylsulfonylated amidino anilides of omega-phenyl-alpha-aminoalkylcarboxylic acids, respectively--possess weak antithrombin activity as compared to the derivatives of the basic structure. Thus, the assumption is corroborated that specific enzyme-inhibitor interactions account for the high antithrombin activity of certain derivatives of omega-amidinophenyl-alpha-aminoalkylcarboxylic acids. In contrast, amidinoanilides of N alpha-substituted omega-phenyl-alpha-aminoalkylcarboxylic acids are potent inhibitors of trypsin and plasmin, their inhibitory activity approaches that of primary amides of N alpha-substituted omega-amidinophenyl-alpha-aminoalkylcarboxylic acids.

Amidines↗
PubMed1984

Animal experiments on the enhancement of fibrinolytic potential by anabolic steroids.

In animal experiments the anabolic steroids 4-chloro-17 beta-hydroxy-17-methylandrosta-1,4-dien-3-one and 4-chloro-11 beta-hydroxy-17-methylandrosta-1,4-dien-3-one were tested for their ability to enhance fibrinolysis in comparison to stanozolol. After daily administration of 2 mg/kg for 12 weeks the anabolic steroids were found to enhance spontaneous fibrinolytic activity of blood, fibrinolytic capacity and tissue plasminogen activator activity in the kidneys of rats and rabbits. Concomitantly, the AT III activity of blood increased.

Animals↗
PubMed1984

Inhibition of 5-hydroxytryptamine-potentiated aggregation of human blood platelets by 5-hydroxytryptamine receptor-blocking agents.

Blood platelets possess specific receptors for 5-hydroxytryptamine (5-HT) which differ from the carrier for the amine uptake. Activation of 5-HT receptors causes shape change and aggregation of platelets. We studied the influence of drugs with 5-HT receptor blocking properties on 5-HT-potentiated, ADP-induced aggregation of human blood platelets. The synergistic effect of 5-HT on aggregation was inhibited by the compounds tested in the order of potency: cyproheptadine, pizotifen, spiperone, methysergide, methiothepine , mianserin, ketanserin, dihydroergotamine. The IC50 values lay in the range from 14 to 40 nmol/l. Chlorpromazine and haloperidol were less effective by more than one order of magnitude. Our results indicate a certain similarity between the 5-HT receptors on platelets and the 5-HT receptors on serotonergic neurons and vascular smooth muscle which belong to the 5-HT2 receptor type.

Adenosine Diphosphate↗
PubMed1984

[Thrombin-stimulated release of serotonin from blood platelets].

The mechanism of platelet activation by thrombin was investigated using suspensions of human platelets. The assumption that the thrombin-platelet reaction shows characteristics of an agonist-receptor interaction was corroborated by an analysis of the relation between thrombin concentration and yield of 14C-serotonin secretion. However, silent thrombin binding sites that decrease the free thrombin concentration interfere with this interaction. When the influence of these binding sites is eliminated by a decrease in platelet concentration or by saturation with DIP-thrombin the concentration-response relationship can be interpreted by the adsorption isotherm of Langmuir. The binding sites interfering with the thrombin receptor interaction are identical with the high affinity binding sites of platelets. For the yield of secretion the velocity of thrombin addition is important. The platelet reaction decreases by slowing the rate of thrombin addition. In comparison with the reaction occurring at 37 degrees C, in that occurring at 0 degree C only the rate but not the yield of receptor stimulation is diminished. The results are in accordance with the assumption that the yield of platelet activation is determined by the equilibrium binding of thrombin. It is suggested that at 37 degrees C the processes of thrombin binding to the receptor, of receptor modification and of cellular response are immediately coupled with one another and that the rate-limiting step is the binding of thrombin to the receptor.

Blood Platelets↗
PubMed1983

Comparative studies on thrombin inhibitors in experimental microthrombosis.

The influence of thrombin inhibitors, which differ both in their chemical structure and type of inhibition on thrombin-induced microthrombosis was studied in rat lungs. The antithrombotically effective doses and blood levels of the compounds correlated with their kinetic constants for inhibition of thrombin. In preventing microthrombosis, some of the synthetic inhibitors tested surpassed the effectiveness of heparin and approached that of the naturally occurring inhibitor hirudin.

4-Aminobenzoic Acid↗
PubMed1983

Cyclic amides of N alpha-arylsulfonylaminoacylated 4-amidinophenylalanine--tight binding inhibitors of thrombin.

Variation of the potent thrombin inhibitors derived from N alpha-arylsulfonyl-4-amidinophenylalanine was carried out by interposition of an omega-aminoalkylcarboxylic acid between the N alpha-arylsulfonyl residue and the 4-amidinophenylalanine part. The use of glycine as spacer renders the compounds tight binding inhibitors of thrombin. The Ki of the most potent inhibitor reaches the nmol/l range. The inhibitory effect is specifically directed against thrombin, the Ki values for inhibition of trypsin, plasmin and factor Xa are some orders of magnitude higher than those for thrombin inhibition.

Animals↗
PubMed1983

Characterisation of postjunctional alpha-adrenoceptors in isolated human femoral veins and arteries.

In order to characterise the pharmacological properties of postjunctional alpha-adrenoceptors, both the contractile effects of alpha-adrenoceptor agonists and the blocking potencies of selective alpha-adrenoceptor antagonists were studied in isolated human femoral veins and arteries. The veins were more sensitive to noradrenaline than the arteries. Guanfacine had a higher intrinsic activity in veins than in arteries, whereas the reverse was true for phenylephrine. The antagonists rauwolscine and yohimbine were more potent against noradrenaline in the veins than in arteries, while corynanthine was equally potent in either tissue. They antagonised the noradrenaline response in a competitive manner. Prazosin proved to be the most potent competitive antagonist in arteries, while in veins it exerted weak and non-competitive antagonism. The results suggest that the alpha-adrenoceptor population at the postjunctional site differs between human femoral veins and arteries. The veins seem to contain more alpha 2- than alpha 1-adrenoceptors postjunctionally, whereas in the arteries the alpha 1-subtype prevails. The results indicate the possibility of influencing selectively adrenergic reactions in the capacitance and resistance vessels.

Adrenergic alpha-Agonists↗