The negative charges of dextran-sulfate (DS) used for low-density-lipoprotein (LDL) apheresis initiate the intrinsic coagulation pathway in which plasma kallikrein acts on the high-molecular-weight kininogen to produce large amounts of bradykinin. This study was undertaken to assess whether bradykinin generated during DS LDL apheresis has any physiologic effects in vivo. The plasma levels of bradykinin, prostaglandins and cyclic guanosine monophosphate (cGMP) were compared, when either of two anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity, this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the plasma levels of prostaglandin E2 (PGE2) increased significantly (5.6 ± 1.2 (mean ± SE, n=4) pg/ml before apheresis and 33.4 ± 13.2 after apheresis, p < 0.05) in association with an increase in bradykinin levels (17.9 ± 2.6 pg/ml before apheresis and 470 ± 135 after apheresis, p < 0.01). Interestingly, these changes were suppressed during apheresis using NM. There were no appreciable changes in cGMP during DS LDL apheresis with either of the anticoagulants. This finding suggests that bradykinin generated during apheresis has some pathophysiological effects via activation of the prostaglandin system. Our results support the view that in patients taking angiotensin-convertingenzyme inhibitors, the anaphylactoid reaction occurring during apheresis may be caused by an excessive rise in the bradykinin levels.

No abstract

A series of noval peptidoaminobenzophenones has been prepared via several routes and was evaluated for CNS activity. The structure--activity relationships in the series are discussed. In general, dipeptido-N-methylaminobenzophenones showed higher activities than the corresponding NH derivatives. Some compounds had very high activities in antipentylenetetrazole and antifighting tests in mice when orally administered. Very weak toxicity was also found in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in vivo conversion of peptidoaminobenzophenone by enzymatic cleavage of the terminal amino acid, followed by chemical cyclization to 1,4-benzodiazepine, is also discussed. Such novel open-ring derivatives of 1,4-benzodiazepine may serve as useful CNS agents.

Abstract-The effects of S-145, a newly synthesized thromboxane A2 (TXA2) receptor antagonist, were studied on collagen-induced changes of electrocardio grams (ECG) in rats and thrombocytopenia in rats and mice. Intravenous injection of collagen induced abnormal ECG changes such as elevation or depression of the ST segment, arrhythmia and in severe cases, cardiac arrest. These changes peaked at 3-5 min and lasted for 10 min. S-145 showed remarkable improvement of the ECG changes by both intravenous and oral administration, and the action lasted over 4 hr with 10 mg/kg, p.o. Reference compounds ONO-3708, dazoxiben and aspirin also improved the ECG changes significantly, but ticlopidine was ineffective. S-145 prevented the collagen-induced thrombocytopenia in rats but did not affect the increase in plasma TXB2 levels. S-145 also prevented collagen-induced throm bocytopenia in mice after either intravenous or oral administration in a dose dependent manner. The efficacy of S-145 was 4-13 times greater than those of the reference compounds, and the duration of action was over 4 hr with 10 mg/kg, p.o. These results indicate that S-145 is a potent, orally active and long-lasting TXA2 receptor antagonist, which will be promising as a drug for thromboembolism and ischemic heart disease caused by platelet activation.

Nach der in der vorhergehenden Arbeit beschriebenen Methode werden die Thiopyranoindole (I) hergestellt.