Murine model of ferric chloride-induced vena cava thrombosis: evidence for effect of potato carboxypeptidase inhibitor.

BACKGROUND/OBJECTIVE: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma carboxypeptidase that renders a fibrin-containing thrombus less sensitive to lysis. In the present study, we describe the development of a murine model of vena cava thrombosis and its use to characterize the antithrombotic activity of potato carboxypeptidase inhibitor (PCI) of TAFIa (activated TAFI) in mice. METHODS/RESULTS: Vena cava thrombosis was induced by various concentrations of FeCl(3) in C57BL/6 mice. A relatively mild stimulus (3.5% FeCl(3)) induced thrombosis that was consistent and sensitive to reference antithrombotic agents such as clopidogrel and heparin. Dose-response studies identified a PCI dose (5 mg kg(-1) bolus plus 5 mg kg(-1) h(-1), i.v.) that produced a maximum 45% decrease in vena cava thrombus mass as assessed by protein content (n = 8, P < 0.01 compared to vehicle) in the 3.5% FeCl(3)-induced model without exogenous tissue plasminogen activator administration. In contrast, PCI had no effect on 3.5% FeCl(3)-induced carotid artery thrombosis in mice. In a tail transection bleeding model, the 5 mg kg(-1) bolus plus 5 mg kg(-1) h(-1) dose of PCI increased tail-bleeding time up to 3.5 times control (n = 8, P < 0.05). The ex vivo activity of antithrombotic doses of PCI was also demonstrated by the enhanced lysis of whole blood clots formed in a thrombelastograph with the addition of a sub-threshold concentration of tPA. CONCLUSION: These studies provide evidence for a role of TAFIa in venous thrombosis in mice, and describe an optimized vena cava injury model appropriate for the evaluation of antithrombotic drugs and the characterization of novel therapeutic targets.

[An unusual injury pattern in magically increased false sex crime]. / Ungewöhnliches Verletzungsmuster bei magisch überhöhtem unechtem Triebdelikt.

Case report on a rape-homicide by manual strangulation involving a 59 year old female. The autopsy disclosed a peculiar cross-shaped superficial incised wound of the abdomen, encircled by 12 stab-wounds, furthermore multiple superficial and deep incised wounds of the genitalia. The injury pattern was in good agreement with the psychiatric interpretation of the sexual behaviour as outlet of severe aggressive impulses originating from non-sexual motives.

The combined antiischemic effects of the thromboxane receptor antagonist SQ 30,741 and tissue-type plasminogen activator.

The thromboxane-receptor antagonist, SQ 30,741, may be used as adjuvant therapy for thrombolysis and has also been shown to have antiischemic activity that is independent of its thrombolytic activity. Since tissue-type plasminogen activator (t-PA) and SQ 30,741 may be administered simultaneously, we determined whether the antiischemic effects of SQ 30,741 can be potentiated by t-PA. This was accomplished by combining doses of t-PA and SQ 30,741, which alone were not cardioprotective. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes and reperfusion for 5 hours. The dogs were treated during reperfusion with a dose of t-PA that caused approximately a 30% reduction in plasma fibrinogen alone or in combination with 1.5 mg/kg + 0.4 mg/kg/hr SQ 30,741, which started 10 minutes after initiation of ischemia. At these doses, neither t-PA nor SQ 30,741 alone significantly reduced infarct size (57% +/- 6%, 50% +/- 10%, 57% +/- 6% of the left ventricular area at risk for vehicle controls, t-PA, and SQ 30,741 respectively); however, combination treatment resulted in a significant reduction in infarct size (37% +/- 5% of the left ventricular area at risk). Higher doses of t-PA and SQ 30,741 alone significantly reduced infarct size. The protective effects of t-PA and SQ 30,741 occurred without altering peripheral hemodynamic status. No differences in collateral or reperfusion blood flow were observed between groups. Thus although SQ 30,741 may act to improve the efficacy of thrombolysis, t-PA may in turn enhance the antiischemic activity of SQ 30,741 or at least reduce the threshold dose.

Characterization of the antitumor activity of hexadecylphosphocholine (D 18506).

Hexadecylphosphocholine (HPC) differs from ether lipids with known antitumor activity by its lack of the glycerol part. In the experiments described here HPC revealed outstanding antitumor activity in dimethylbenzanthracene (DMBA)-induced rat mammary tumors. A dose-response relationship was seen after daily oral treatment with complete suppression of tumor growth at doses of 46.4 mg/kg/day. There was no schedule dependence and the therapeutic efficacy was independent of the tumor weight at the initiation of therapy. Another autochthonous tumor, the benzo[a]pyrene-induced sarcoma of the rat did not respond to HPC treatment, indicating a highly selective spectrum of activity of the test compound. In comparison to an optimal single dose of cyclophosphamide, a single high dose of HPC was considerably more active against the DMBA tumor. At therapeutic dose levels no major toxicity of HPC was observed. Bone marrow suppression was not encountered, on the contrary, at high doses leukocytosis became apparent. The available pharmacological and toxicological data suggest that HPC may be useful in the treatment of human cancer.