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Biomedical subjects

F Markwardt

Publications and source records attributed to F Markwardt.

At least 73 records · Page 4Linked to original sources
PubMed1989

Synthetic inhibitors of bovine factor Xa and thrombin comparison of their anticoagulant efficiency.

New derivatives of benzamidine (N alpha-arylsulfonylamino-acylated derivatives of 3-amidinophenylalanine) were found to be potent inhibitors of bovine factor Xa (F Xa). The methyl and ethyl esters of N alpha-Tos-Gly- and N alpha-beta Nas-Gly-substituted 3-amidinophenylalanine, inhibited F Xa more effectively (Ki values near 0.5 mumol/l) than thrombin (Ki about 50 mumol/l). Reinvestigation of inhibition of F Xa by bis-benzamidines showed that compounds containing a cycloheptanone linking bridge are tight-binding inhibitors of F Xa (Ki in the 10 nmol/l range). The use of these inhibitors enabled us to clarify whether inhibition of F Xa or inhibition of thrombin is more efficient in anticoagulation. The thrombin inhibitors and not the potent F Xa inhibitors proved to be particularly effective in anticoagulation in vitro.

Animals↗
PubMed1989

Antithrombotic effects of three thrombin inhibitors in a rat model of laser-induced thrombosis.

The antithrombotic effects of three thrombin inhibitors (hirudin, NAPAP and argidipine) were investigated in an experimental thrombosis model using laser lesions of rat mesenteric venules. Furthermore, their in vitro anticoagulant activity (partial thromboplastin time, thrombin time, Heptest, inhibition of factor IIa and factor Xa) in human platelet poor plasma (PPP) and their in vitro and ex vivo activities were studied in rat plasma. All three thrombin inhibitors showed significant and dose-dependent antithrombotic effects after intravenous injection, if venules were damaged, which lasted for more than 4 but less than 8 h. The anticoagulant effect observed in vitro did not differ much between human and rat PPP. The two synthetic thrombin inhibitors NAPAP and argidipine were about as effective as hirudin in vitro; however, the ex vivo effect after intravenous injection of hirudin in rats was more pronounced than that observed with the two synthetic thrombin inhibitors. The antithrombotic effect of all three thrombin inhibitors in the laser model lasted much longer than the anticoagulant activity. This fact needs further investigations in the future.

Animals↗
PubMed1989

Ca-channel currents in isolated frog ventricular cells are increased by thrombin.

Effects of the proteolytic enzyme thrombin in the modulation of cardiac Ca-channel currents were examined in single ventricular cells from frog myocardium, using the whole-cell voltage clamp technique (1). Application of 3.8 . 10(-9) M thrombin to the bath increased the peak of the Ca-channel current by 84 +/- 35% (8 cells). Hirudin (31.10(-9)M), a specific thrombin inhibitor, blocked the thrombin-induced increase of this current. The increase in the current can be made responsible for the measured positive inotropic effects on frog heart of thrombin.

Animals↗
PubMed1989

[Synthetic inhibitors of serine proteinases. 35. Inhibition action of amidino- and guanidinophenyl derivatives against hemolysis initiated by complement activation].

Selected amidino- and guanidinophenyl derivatives which have already proved to be inhibitors of serine proteinases were tested on their inhibitory effect on complement activation. To quantitate the inhibitory action the decreasing rate of haemolysis of sensitized sheep erythrocytes was recorded continuously. Compounds exerting a more or less pronounced inhibitory effect on trypsin-like proteinases turned out to have a corresponding inhibitory influence on complement-mediated haemolysis. The inhibitory effect of some amidinobenzyliden derivatives on the complement activity was markedly higher than could be expected from their general antiproteolytic efficacy. Changing the basic structure into amidinophenyl amino acid amides with strong and selective antithrombin effect completely abolished the inhibitory influence on complement.

Amidines↗
PubMed1989

[Preparation of rat fibrinogen].

For the first time, the fibrinogen preparation according to Blombäck was used to purify rat fibrinogen. Intermediate as well as final products were compared with those of human fibrinogen. Yields of final products were about 25% of plasma fibrinogen. Thrombin clottability amounted to 96.5 +/- 1.3% for rat fibrinogen and 95.0 +/- 1.1% for human fibrinogen, respectively. The integrity and the characteristic differences in molecular mass of rat and human fibrinogen chains were demonstrated by means of SDS-PAGE.

Animals↗
PubMed1989

Pharmacological characterization of a new structural variant of 4-amidinophenylalanine amide-type synthetic thrombin inhibitor.

The synthetic thrombin inhibitor N alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanyl-proline (1) was synthesized in order to evaluate the importance of the carboxyl group in its amine portion for fundamental pharmacodynamic and pharmacokinetic properties of these benzamidine derivatives. The compound is better tolerated in mice and rats than are similar compounds lacking this carboxyl group. It has a significantly longer plasma half-life in rabbits compared to the corresponding compound bearing piperidine instead of proline in the amide moiety. The main excretory route of 1 is via the bile. Hepatic uptake and/or biliary excretion show, however, another time course than that seen for the piperidide. Lower toxicity and more suitable pharmacokinetics may compensate for the loss of thrombin inhibitory potency of this new synthetic thrombin inhibitor.

Animals↗
PubMed1988

Clinico-pharmacological studies with recombinant hirudin.

The pharmacokinetics of recombinant hirudin were studied in 9 healthy subjects after single intravenous, subcutaneous or intramuscular doses of 0.1 mg/kg. Generally, administration of r-hirudin was tolerated without side effects. An assay was used which detects the inhibitor in blood and urine by its antithrombin activity. Absorption, distribution and elimination of r-hirudin were found to be corresponding to the results obtained with native hirudin. The effects on the haemostatic system were evaluated. Thrombin time and partial thromboplastin time were prolonged dependent on the r-hirudin plasma level. Platelet counts, fibrinogen level and fibrinolytic system were unchanged. Bleeding time was not prolonged. After administration of r-hirudin in case of chronic DIC, fibrinogen level, platelet counts and fibrin monomers transiently returned to normal values.

Adult↗
PubMed1988

Effects of trapidil-derivatives on calcium channel currents in isolated ventricular cells from mice.

A single glass micropipette voltage clamp technique with intracellular dialysis was used to study the effects of the trapidil derivatives AR 12-456 and AR 12-463 on Ca channel currents carried by Ba2+ in isolated ventricular cells from mice hearts. Inspite of a more potent inhibition of the cAMP phosphodiesterase from heart (Bartel et al. 1985) a reversible Ca channel blocking action of both compounds could be observed. The concentration of half maximal block was calculated to about 50 mumol/l for both derivatives tested. Neither a shift in the current-voltage relationships nor a significant change in the potential for half maximal activation was found. The maximal Ba2+-conductance was reduced. The steady state inactivation was shifted towards more negative potentials by application of 100 mumol/l AR 12-463. The decay of the Ba currents was accelerated in the range of the applied test potentials between -20 and +20 mV. It is concluded that the new trapidil derivatives with more potent inhibitory action on cardiac phosphodiesterase than trapidil can block myocardial Ca channels.

Animals↗
PubMed1988

Thrombin stimulates Ca-channel currents in isolated frog ventricular cells.

Effects of the proteolytic enzyme thrombin in the modulation of cardiac Ca-channel currents were examined in single ventricular cells from frog myocardium, using the whole-cell voltage clamp technique (Hamill et al. 1981). Application of 3.8.10(-9) M thrombin to the bath increased the peak of the Ca-channel current by 84 +/- 35% (8 cells). Hirudin (31.10(-9) M), a specific thrombin inhibitor, blocked the thrombin-induced increase of this current. The increase in the current can be made responsible for the measured positive inotropic effects of thrombin as well as for the shift of the plateau voltage of the action potentials towards more positive values.

Action Potentials↗
PubMed1988

Modulation of calcium channel currents in guinea-pig single ventricular heart cells by the dihydropyridine Bay K 8644.

1. A single glass micropipette voltage clamp technique with intracellular dialysis was used to study Ba2+ currents in isolated ventricular cells from guinea-pig hearts. Effects of the 1,4-dihydropyridine Bay K 8644 on whole-cell currents were evaluated at 37 degrees C. 2. Bay K 8644 increased the Ba2+ peak currents at test potentials between -50 and +20 mV and shifted the current-voltage relationships towards hyperpolarizing potentials (leftward shift for Ca2+ channel activation, 13.8 +/- 4.1 mV; n = 9; Bay K 8644, 5 mumol/l). 3. The peak times of the Ba2+ currents were diminished over the voltage range tested between -40 and +20 mV after Bay K 8644 in parallel with a shortening of the time constant of activation that was estimated from fits of the recorded currents with a d2f model. 4. The decay of the Ba2+ currents was fitted with two exponentials including a pedestal. The compound Bay K 8644 accelerated the fast decay over the whole voltage range. The amplitude of the rapidly inactivated component of the Ba2+ currents was strikingly increased after application of Bay K 8644. 5. The steady-state inactivation using a 0.5 or 5 s pre-pulse was shifted towards hyperpolarizing potentials (leftward shift 10.3 +/- 5.2 mV; n = 4; Bay K 8644, 5 mumol/l). 6. The change in the time course of Bay K 8644-modified Ba2+ currents cannot be described solely by a decrease of the backward rate coefficient from an open to a closed state of the Ca2+ channel (Sanguinetti, Krafte & Kass, 1986). The described effects of Bay K 8644 on the inactivation can be both qualitatively and quantitatively described by a model of current-dependent inactivation (Standen & Stanfield, 1982), assuming a lower affinity of an internal binding site for Ba2+ than for Ca2+.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Dual effect of dihydroergotamine at vascular 5-hydroxytryptamine receptors in pithed rats.

Dihydroergotamine (DHE), administered intravenously to pithed normotensive rats, increased the mean arterial blood pressure dose-dependently. This pressor effect was noncompetitively inhibited by the 5-hydroxytryptamine (5-HT) receptor antagonists pizotifen and cyproheptadine (0.1 mg/kg each). The alpha 1-adrenoceptor blocker prazosin (1 mg/kg) had no influence on the DHE effect whereas the alpha 2-adrenoceptor blocker yohimbine, at the same dose, proved to be a noncompetitive inhibitor of this pressor effect. The results indicate that both the 5-HT receptors and alpha 2-adrenoceptors are involved in the DHE-induced vasoconstriction. On the other hand, in pithed normotensive rats, DHE proved to be a potent inhibitor of the pressor response to 5-HT but it did not inhibit that to noradrenaline. The results obtained characterize DHE as a noncompetitive dualist at vascular 5-HT receptors.

Adrenergic alpha-Antagonists↗
PubMed1988

The comeback of hirudin--an old-established anticoagulant agent.

Early studies dating back to 1884 revealed that extracts from medicinal leeches contain a substance which is able to prevent blood from clotting. Since our successful isolation of hirudin, the pure anticoagulant substance, in the late 1950s and its characterization as a selective thrombin inhibitor with polypeptide structure, hirudin preparations have been employed for diagnostic and scientific uses in haemostaseology. As early as 25 years ago we have shown in experimental pharmacotoxicological studies that hirudin is an anticoagulant of high quality. The antithrombotic effect of hirudin was demonstrated in several thrombosis models. But the clinical use of hirudin remained limited since it was not available in adequate amounts for therapeutic purposes. One hundred years after its discovery there is a renewed interest in this naturally occurring thrombin inhibitor. Advanced methods of peptide isolation and genetic engineering are about to provide sufficient quantities of hirudin in purified form. This prompted us to resume our investigations in hirudin and to represent new experimental and clinical pharmacological studies with natural hirudin prepared from medicinal leeches and genetically engineered recombinant hirudin, thus appreciating the comeback of hirudin into the focus of interest.

Amino Acid Sequence↗