Hans Klaus Breddin

Cardiopulmonary effects and safety of prostaglandin E1: A review

Intraarterial and intravenous infusion of prostaglandin E1 (PGE1) is established treatment for severe peripheral arterial occlusive disease, particularly in Europe and Japan. In this critical appraisal, experimental and clinical studies are reviewed, with special emphasis on cardiopulmonary effects and drug safety. The pulmonary data all indicate dose-dependent dilation of the pulmonary vessels with a reduction in pulmonary resistance. The known hemodynamic effects of PGE1 on the heart include an increase in stroke volume, cardiac index, and left ventricular ejection fraction, and a reduction in left ventricular filling pressure. Analysis of clinical trials shows a low rate of adverse effects, in particular a low incidence of cardiopulmonary side effects. If the recommendations for high-risk patients are observed, PGE1 is both an efficacious and safe therapeutic principle.

Plasma salicylate levels and platelet function after acute and chronic administration of slow-release acetylsalicylic acid (Monobeltin).

SummaryThe relationships between the antiplatelet effects and the pharmacokinetics of a slow release formulation of acetylsalicylic acid (ASA) have been investigated. After acute intake of 750 mg ASA in a slow-release formulation (Monobeltin), a slow increase in plasma ASA was paralleled by a gradual decrease in certain platelet functions. During chronic medication (750 mg twice daily), ASA was present in plasma at all times accompanied by full inhibition of platelet aggregation. For chronic antiplatelet therapy, this slow release formulation of ASA appears to be very effective, unless rapid inhibition of platelet function must be achieved.

Reversible Hemmung der Thrombozytenstimulation durch Azetylsalizylsäure und ihre Bedeutung für die antithrombotische Therapie

SummaryIn man, a single oral dose of 100–300 mg ASA leads to irreversible and almost total inhibition of cyclo-oxygenase in the platelets. The ensuing inhibition of thromboxane-formation results in a reduction of ADP- or collagen-induced or spontaneous platelet aggregation, which lasts for up to 7–9 days. Application of ASA in small doses ranging between 50–200 mg/day are sufficient to inhibit platelet aggregation continuously.Spontaneous platelet shape change after blood sampling and tissue extract-induced platelet stimulation are inhibited after single oral ASA-dosis of 500–1000 mg for also 8–12 h.Oral administration of 500 mg ASA to four healthy volunteers resulted in a rapid increase in the blood levels of ASA, salicyluric acid (SUA) and salicylic acid (SA). SUA and SA levels remained high for several hours. Platelet shape change was inhibited 30 min after ASA ingestion and after 480 min some inhibitory effect was still present.Administration of 500 mg salicylic acid led to similar blood levels of SUa and SA, but platelet shape change was not inhibited. The inhibition of platelet shape change apparently also is a specific effect of ASA, its mechanism is not yet known.If the inhibition of platelet shape change essentially contributes to the antithrombotic effect of ASA, as is made likely by animal thrombosis studies, ASA has to be administered in much higher doses than those needed for the inhibition of thromboxane-formation in the platelets.

Plasma drug and antiplatelet profiles of the original acetylsalicylic acid preparations used in the AMIS, PARIS and German-Austrian trials for secondary prevention of myocardial infarction

SummaryIn a cross-over study 6 healthy male subjects were given for 9 days the acetylsalicylic acid (ASA) preparations used in the Aspirin Myocardial Infarction Study (AMIS), Persantine-Aspirin Reinfarction Study (PARIS) and German-Austrian secondary heart attack prevention trials, exactly according to the original study protocols. Plasma concentrations of ASA and its main metabolites salicylic acid (SA) and salicyluric acid (SUA), as well as platelet function (collagen-induced platelet aggregation; tissue extract-induced change in platelet shape) were studied repeatedly on the first day of each medication period and were again examined on the sixth and ninth days. Differences in the plasma concentrations of ASA and its metabolites were found only on the first day, probably as a result of different absorption rates. Collagen-induced platelet aggregation was more rapidly inhibited the faster the preparation was absorbed. Each ASA preparation inhibited tissue extract-induced platelet shape change from the first dose, although statistically significant inhibition was seen only with the AMIS preparation. It is concluded that differences in the antithrombotic efficiency of ASA cannot be explained by differences in the pharmacokinetic and antiplatelet profiles of the various ASA preparations tested.

Hämostaseologische Parameter unter dem Einfluß von Imipenem/Cilastatin

ZusammenfassungBei sieben Patienten mit bakteriellen Infektionen wurden vor und während der Behandlung mit Imipenem/Cilastatin, einem neuen β-Laktam-Antibiotikum mit breitem Wirkungsspektrum gegen grampositive und gramnegative Bakterien, Hämostase-Parameter untersucht. Eine Beeinflussung der plasmatischen Gerinnung durch das Antibiotikum war nicht nachweisbar. Dagegen fand sich eine vorübergehende Hemmung der Kollagen-induzierten Plättchenaggregation in den ersten Behandlungstagen. Klinisch wurde keine spontane Blutungsneigung beobachtet.SummarySeven patients were treated for bacterial infections with imipenem/cilastatin. Imipenem is a new broad-spectrum β-lactam antibiotic with antimicrobial activity against gram-positive and gram-negative bacilli. Before and during treatment parameters of blood coagulation and platelet function were studied. Blood coagulation was not influenced by the antibiotic. But there was a temporary inhibition of collagen-induced platelet aggregation during the first days of treatment. No clinical signs of enhanced spontaneous bleeding tendency were observed.Seven patients were treated for bacterial infections with imipenem/cilastatin. Imipenem is a new broad-spectrum beta-lactam antibiotic with antimicrobial activity against gram-positive and gram-negative bacilli. Before and during treatment parameters of blood coagulation and platelet function were studied. Blood coagulation was not influenced by the antibiotic. But there was a temporary inhibition of collagen-induced platelet aggregation during the first days of treatment. No clinical signs of enhanced spontaneous bleeding tendency were observed.

Die Acetylsalicylsäurewirkung auf Partialfunktionen menschlicher Thrombozyten wird in vivo durch Salicylsäure nicht gehemmt

Acetylsalicylic acid inhibits platelet function. In plasma acetylsalicylic acid is rapidly deacetylated to salicylic acid which is slowly eliminated and has no direct inhibitory effects on platelet function. However, salicylic acid prevents the inhibition by acetylsalicylic acid of collagen-induced aggregation of human thrombocytes in vitro. It was suggested that salicylic acid might inhibit the antiplatelet effects of acetylsalicylic acid in vivo and therefore low-dose acetylsalicylic acid would be more effective for antithrombotic therapy. A 500-mg tablet of acetylsalicylic acid applied 90 min after oral administration of 500 mg salicylic acid to six healthy male volunteers led to the same inhibition of collagen-induced platelet aggregation and tissue-extract-induced platelet stimulation as 500 mg acetylsalicylic acid alone. These results cannot give additional support to the recommendation of low-dose acetylsalicylic acid in the prevention of thromboembolic disease.SummaryAcetylsalicylic acid inhibits platelet function. In plasma acetylsalicylic acid is rapidly deacetylated to salicylic acid which is slowly eliminated and has no direct inhibitory effects on platelet function. However, salicylic acid prevents the inhibition by acetylsalicylic acid of collagen-induced aggregation of human thrombocytes in vitro. It was suggested that salicylic acid might inhibit the antiplatelet effects of acetylsalicylic acid in vivo and therefore low-dose acetylsalicylic acid would be more effective for antithrombotic therapy.A 500-mg tablet of acetylsalicylic acid applied 90 min after oral administration of 500 mg salicylic acid to six healthy male volunteers led to the same inhibition of collagen-induced platelet aggregation and tissue-extract-induced platelet stimulation as 500 mg acetylsalicylic acid alone. These results cannot give additional support to the recommendation of low-dose acetylsalicylic acid in the prevention of thromboembolic disease.

TFPI Release by GAGs and Its Role in Their Mechanism of Action

Tissue factor pathway inhibitor (TFPI) formerly named Extrinsic Pathway Inhibitor (EPI) or Lipoprotein Associated Coagulation Inhibitor (LACI) is a Kunitz-type protein with three inhibitory domains1. The first domain binds to the tissue factor/factor VII a — complex, while the second one has been identified as the factor Xa binding site. The third domain is probably involved in the association of TFPI with plasma lipoproteins and heparins1,2. TFPI inhibitory activity as well as antigen level in plasma can be measured but there are large discrepances between TFPI results from the functional and immunologic assays. It has been recently postulated that only the free form of TFPI is biologically active3. TFPI is synthesized in endothelial cells and megakariocytes4,5. In normal individuals there is a quite broad range of TFPI activities and antigen levels ranging from 50 to 170 ng/ml6,7,8. The biggest TFPI-pool is bound to the main site of its synthesis -endothelium. About 90% of blood TFPI is associated with lipoproteins9,10. The major part with LDL, less with HDL. About 5% plasma TFPI remains in a free form. TFPI has also been found in platelets — about 8% of the whole blood TFPI5 (Fig.1). Tissue factor pathway inhibitor has a double, two step inhibitory effect. It inhibits the active factor X and in a complex with this factor TFPI binds to the tissue factor/factor VIIa complex inhibiting its enzymatic activity11,12 (Fig.2).