Biomedical subjects
Publications and source records attributed to F Markwardt.
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alpha-Adrenoceptors of platelets seem to differ from those of other cell types. The inhibitory effect of alpha-adrenoceptor-blocking agents on adrenaline-induced aggregation of human platelets does not parallel that on adrenaline-induced contraction of rabbit aortic strips. The most potent inhibitors of adrenaline-induced platelet aggregation are the dihydrogenated ergot alkaloids of the peptide type. Among the other ergoline derivatives testes, only lisuride has a stronger inhibitory effect than those of natural ergot alkaloids.
Amidinobenzylidene derivatives of benzo-condensed cycloalkanones proved to be potent competitive inhibitors of thrombin and trypsin. On the contrary, the antiplasmin effect of these derivatives is considerably less marked. The conversion of 3-amidinochalcone to derivatives in which the carbonyl group is incorporated into a ring, does not lead to fundamental changes in the inhibitory effect on trypsin and thrombin, whereas the antiplasmin effect decreases. Compared to 4-amidinochalcone, the 2-(4-amidinobenzylidene) derivatives of indanone-(1) and tetralone-(1) exert a stronger inhibitory effect on trypsin and thrombin. The introduction of a hetero-atom to the cycloalkanone component affected the inhibitory effect on trypsin and thrombin but insignificantly. From these results it is concluded that also in amidinobenzylidene derivatives of benzo-condensed cycloalkanone derivatives, the carbonyl function shares in enzyme-inhibitor binding.
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The antitrypsin, antiplasmin and antithrombin activities of bis(amidinobenzylidene)- and bis(amidinobenzyl)cycloalkanones are not markedly affected if the amidino group is substituted by an uncharged residue (H, OCH3, Cl, Br, NO2). In contrast, mono(amidinobenzylidene)cycloalkanones exhibit considerably lower inhibitory activities than the compounds of the abovementioned classes of substances. From the results obtained it is concluded that the second aromatic residue and not the second basic amidino group is decisive of the potent inhibitory action of the bisamidino derivatives.
The blood level, distribution and elimination of ocrase, a protease from Aspergillus ochraceus, were determined in rabbits after application of the 131I labelled enzyme in therapeutic doses.
The pharmacokinetics of the synthetic protease inhibitor APPA was studied in rabbits. After intravenous or oral application of 1 and 10 mg of (carboxyl-14C)-4-amidinophenylpyruvic acid hydrochloride/kg to rabbits, the plasma concentration was determined over several days and the excretion in urine during 24 hours. The course of the plasma concentration curves showed no dose-dependence of the pharmacokinetic behaviour. A three-phase course of the plasma concentration curves was observed after intravenous application, the slowest phase having a half-life of about 20 h. This very slow elimination is considered to be caused by tubular re-absorption of APPA. There is neither accumulation in organs, tissues or erythrocytes nor binding with plasma proteins. The thin-layer chromatographic analysis of the plasma revealed no labelled metabolites, but only unchanged APPA. APPA, when applied orally (in the form of an aqueous solution), is absorbed by more than 80%, the maximum plasma level being reached within 2--3 h. Intravenous and oral applications at 24-h intervals result in a cumulative increase in APPA concentration in the plasma. If APPA is applied to pregnant rabbits, it passes into the fetal circulation.
Disseminated intravascular coagulation was induced in dogs by infusion of tissue thrombokinase. Its course was followed by coagulation tests, determination of the rate of microthrombosis, and measurement of organ functions and oxygen consumption. The therapeutic result of streptokinase administration at an early stage of pathological changes is demonstrated by improvement of the disturbed organ functions and oxygen supply as well as by the decrease in plasma-haemoglobin level. When streptokinase was administered at an advanced stage of organ damages, they remained irreversible, although repatency of the microvasculature had been reached.
Secondary generalized hyperfibrinolysis was induced by thrombin infusion or batroxobin injection in rats. To follow intravascular fibrinolysis quantitatively, an electroimmuno-assay was used for determination of the fibrin degradation products formed. Anticoagulants (heparin, hirudin), antifibrinolytics (EACA, PAMBA, AMCA), and synthetic (APPA) and naturally occurring (aprotinin) protease inhibitors were studied with regard to their influence on secondary fibrinolysis. The potency and duration of action of the antifibrinolytics tested correspond to their antifibrinolytic activity measured in vitro and to their pharmacokinetics. Formation of degradation products is initiated after the appearance of fibrin monomer or fibrin, respectively. Due to their antithrombin action heparin, hirudin, and APPA prevent the thrombin-induced fibrin formation and thus the induction of secondary fibrinolysis. In contrast, formation of fibrin monomers caused by batroxobin is not influenced by thrombin inhibitors so that in this case formation of degradation products is not prevented.
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In patients suffering from subarachnoid hemorrhage (SAH), intrathecal administration of p-aminomethylbenzoic acid (PAMBA) was found to produce hemostatically effective concentrations of the antifibrinolytic agent in the cerebrospinal fluid (CSF). The early clinical findings speak in favor of this mode of administration.
Thrombotic processes play a role not only as a sequel of arteriosclerosis, but also for its pathogenesis. Under this aspect a pharmacological regulation of the course of the reaction of thrombpcytes, the blood coagulation and the fibrinolysis gets significance. The prevention of the formation of fibrin by well-known anticoagulants, such as coumarines and heparin, seems little suited for a prophylaxis of arteriosclerosis. By a pharmacological regulation of the reaction of the blood platelets which are decisive for the initial phase of the formation of thrombi new possibilities for an intervention into the pathomechanisms of arteriosclerosis are the result. Her also realizations concerning the prostaglandin metabolism of the blood platelets and of the wall of vessels can be evaluated. The activation of fibrinolysis by means of the hitherto introduced fibrinolytics, such as streptokinase and urokinase, is used above all for the treatment of acute thrombi. In the sense of a prevention of arteriosclerosis the activation of the endogenic fibrinolysis with the help of indirect fibrinolytics, which effect a liberation of the activators of fibrinolysis localised in the wall of the vessels, is a hopful way.
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To elucidate the structural constituents of sodium nitroprusside responsible for antiaggregating effects, comparative studies were done with pentacyanoferrates possessing ligands other than nitric oxid. Among the pentacyanoferrates tested, also the nitro and thionitro compounds possess considerable antiaggregating effects. The ammine and aquo compounds are nearly ineffective. These results support the assumption that the nitrosyl cation or its secondary product, nitrous acid, is responsible for the inhibition of aggregation.
Proteolytic enzymes participate extensively in coagulation, fibrinolysis, kininogenesis, and complement activity. Synthetic low molecular weight inhibitors of these enzymes which belong to the group of serine proteinases allow pharmacological control of these processes. The development of such inhibitors and their therapeutic importance are reported, especially on the pattern of benzamidine derivatives.
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