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Biomedical subjects

F Markwardt

Publications and source records attributed to F Markwardt.

At least 127 records · Page 7Linked to original sources
PubMed1986

Inhibition of batroxobin, a serine proteinase from Bothrops snake venom, by derivatives of benzamidine.

Benzamidine derivatives which are competitive inhibitors of trypsin-like serine proteinases also inhibited the enzymatic activity of batroxobin, a thrombin-like snake venom proteinase. Structure-activity relationships showed that primary amides of 4-amidinophenyl-alpha-aminobutyric acid have pronounced, relatively selective antibatroxobin activity. Identical effects were found on batroxobin isolated from the venoms of Bothrops atrox or Bothrops moojeni. Esters containing a benzamidine moiety acylated the active centre serine hydroxyl of either batroxobin, however, the inhibition was temporary. Such compounds, especially 4-amidinophenyl esters of substituted benzoic acids, are a particularly useful tool for designing acyl-batroxobin intermediates with different deacylation rates. With 4-nitrophenyl 4'-guanidinobenzoate, the acyl enzyme was formed so rapidly that titration of the active site of batroxobin was possible. Irreversible inhibition of batroxobin was caused only by the selective thrombin inhibitor D-Phe-Pro-ArgCH2Cl.

Acylation↗
PubMed1986

[Position and developmental trends in fibrinolytic therapy].

Increasing insight into the mechanism of fibrinolysis and particularly into the formation and release of plasminogen activator has led to more effective thrombolytic therapy. The understanding of the mechanism of thrombolysis has provided the possibility to improve the therapeutic effects of the fibrinolytic agents streptokinase and urokinase. Further advances in thrombolytic therapy are expected by the use of the plasminogen activator from tissue endothelium and pro-urokinase. Acylation of fibrinolytic enzymes will lead to beneficial effects (depot effect, protection from intrinsic inhibitors). Due to the extensive research into substances with fibrinolytic and thrombolytic effects a new generation of activators of fibrinolysis is expected that interfere with the biosynthesis and release of plasminogen activator of the vessel wall and that are suited for treatment of hypofibrinolytic states.

Fibrinolysin↗
PubMed1986

Influence of dihydrolysergic acid amide on serotonergic and alpha-adrenergic receptors in human blood platelets and femoral veins in vitro.

The effect of dihydrolysergic acid amide (DLSA) on responses of human blood platelets and isolated postmortem femoral veins to serotonin and catecholamines was studied in vitro in comparison to dihydroergotamine (DHE). DLSA inhibited the 5-HT-potentiated, ADP-induced platelet aggregation in approximately the same concentration range as DHE. It was three orders of magnitude less potent in inhibiting the adrenaline-induced aggregation and specific binding of 3H-yohimbine to intact platelets than DHE. In femoral vein strips, DLSA caused an increase in tone in the same concentration range (0.01-1.0 mumol/l) as DHE; however, its efficacy was somewhat lower. At concentrations of 0.1 to 1.0 mumol/l it antagonized the 5-HT-induced contractile response in a noncompetitive manner, the antagonist potency being one order of magnitude lower than that of DHE. DLSA (1 mumol/l) did not inhibit the noradrenaline-induced venoconstriction. The results show that DLSA possesses agonist activity in femoral veins and 5-HT-antagonist activity in platelets and veins.

Binding, Competitive↗
PubMed1986

[Vasoconstrictor effects on isolated vessel segments determined by pressure-volume measurements].

A method for pressure-volume measurement in isolated segments of dog saphenous veins and femoral arteries is described. Its applicability was shown by means of the vasoconstrictor effects of noradrenaline and serotonin. By this method changes in intravascular pressure were measured in dependence upon the in- and outflowing volume of liquid. The pressure-volume diagrams allowed to estimate the intravascular pressure, work, resistance and compliance of the vascular segments. From the diagrams differences in the responses of veins and arteries to the biogenic amines could be demonstrated. The concentration-response relationships of the venous segments for noradrenaline and serotonin corresponded to those obtained in helically cut venous strips.

Animals↗
PubMed1986

[Benzoyl-kallikrein: kallikrein activity and kinin generation in plasma].

The inactive acyl-derivative benzoyl-kallikrein was prepared from porcine pancreatic kallikrein. By deacylation the enzymatically active kallikrein was generated in plasma from benzoyl-kallikrein demonstrated by means of its amidolytic activity. Benzoyl-kallikrein was protected from being inactivated by plasma inhibitors. Therefore, the kallikrein activity in plasma was higher following incubation of benzoyl-kallikrein than following incubation of the free enzyme. A comparatively high kinin activity was found in rabbit plasma. In human plasma, this effect was prevented by rapid degradation of kinin.

Animals↗
PubMed1985

On the isolation of the thrombin inhibitor hirudin.

A procedure for isolation of hirudin from crude preparations was described. By the use of ion exchange chromatography and affinity chromatography preparations were obtained with a specific activity of 10 to 15 antithrombin units/micrograms. Separation into several fractions with the same activity suggests the existence of isoinhibitors.

Animals↗
PubMed1985

Defibrinogenation with benzoyl-batroxobin.

The B. moojeni thrombic protease, batroxobin, was acylated by 4-amidinophenyl benzoate at the active site serine hydroxyl. From the enzymatically inactive benzoyl-batroxobin, batroxobin is generated with a half-life of deacylation of about one hour. The clotting activity of benzoyl-batroxobin in plasma is recovered with deacylation. The effects of batroxobin and benzoyl-batroxobin were studied following intravenous injection in rats. Compared to defibrinogenation with batroxobin, that obtained with benzoyl-batroxobin was much retarded. Batroxobin caused microthrombosis initially, which did not develop upon injection of benzoyl-batroxobin in equivalent doses.

Acylation↗
PubMed1985

Pharmacology of hirudin: one hundred years after the first report of the anticoagulant agent in medicinal leeches.

One hundred years after its discovery hirudin, the selective thrombin inhibitor from medicinal leeches, has been brought into the focus of interest again. Advanced methods of peptide isolation and gene technology are expected to provide the opportunity to obtain pure hirudin in sufficient yield for therapeutic uses. Therefore, the present state of knowledge of this naturally occurring anticoagulant is reported.

Animals↗
PubMed1985

Pharmacological characterization of a new highly effective synthetic thrombin inhibitor.

The most potent synthetic reversible thrombin inhibitor described so far, N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide (Ki = 6 nmol/l), was studied with respect to its pharmacodynamics and pharmacokinetics in mice, rats and rabbits. In mice the LD50 was 54 mg/kg i.v. and greater than 800 mg/kg p.o. Prolongation of bleeding time in mice and reduction of mean arterial blood pressure in rats were seen only at doses above the antithrombotically effective doses. After i.v. injection in rabbits the plasma half-life was estimated to be about 9 min. Subcutaneous injection resulted in measurable inhibitor plasma levels for 4 h. Administration of high does into the duodenum did not give antithrombotically effective plasma levels. The ligature of the functional and nutritive hepatic vessels prolonged the half-life of the thrombin inhibitor, whereas renal excretion seems to be of minor importance. A dose-dependent antithrombotic effect was shown in venous stasis-induced thrombosis in rabbits.

Animals↗