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Biomedical subjects

B Kaiser

Publications and source records attributed to B Kaiser.

At least 19 recordsLinked to original sources
PubMed1992

Haemostyptic effects of batroxobin with regard to hirudin treatment.

In contrast to thrombin the fibrinogen coagulant effect of the thrombin-like enzyme batroxobin in vitro and in vivo is not inhibited by the specific thrombin inhibitor hirudin. The haemostyptic effect of batroxobin has been studied in rats after bleeding had been induced by corresponding hirudin dosages. Dependent on batroxobin concentration bleeding time was shortened by local application of batroxobin containing solutions. Strong bleeding induced by i.v. injection of 5 mg r-hirudin/kg was stopped almost immediately when a batroxobin concentration of 40 BU/ml was used. Thrombin was less active to stop bleeding after r-hirudin administration than batroxobin.

Animals↗
PubMed1992

[Cholesterol--a marker for multiple risk factors? A comparison between coronary disease and coronary health].

Comparison was made in a cross-sectional study between 658 patients in whom coronary arteriography had shown (n = 304) or excluded coronary artery disease (CHD) (n = 354) and a clinically healthy group as controls (n = 1658), to assess possible risk factors. Patients aged 31-40 years with CHD had the highest total cholesterol levels (286 +/- 43 mg/dl) and the highest number of risk factors (3.6 +/- 0.9) compared to patients without CHD of the same age (204 +/- 30 mg/dl; 2.0 +/- 0.5) and healthy controls (216 +/- 45 mg/dl; 1.7 +/- 0.5) (P less than 0.001). In older patients with CHD, total cholesterol levels were lower (age group 61-70 years: 231 +/- 49 mg/dl), reaching about the same level as that of patients without CHD (232 +/- 54 mg/dl) or healthy controls of the same age (228 +/- 55 mg/dl). Furthermore, it was demonstrated that increased total cholesterol concentration can indicate the presence of other risk factors. It would thus appear that the level of total cholesterol in patients with CHD is decisively influenced by age and the presence of other risk factors.

Adult↗
PubMed1992

Influence of recombinant hirudin and unfractionated heparin on thrombin and factor Xa generation in extrinsic and intrinsic activated systems.

Using biochemically defined conditions on a fast kinetic centrifugal analyzer the effect of recombinant hirudin (rH) and unfractionated heparin (UH) on thrombin and factor Xa generation was investigated. Diluted fibrinogen deficient human plasma was incubated with increasing concentrations of the anticoagulants and protease generation was initiated either by extrinsic (EA; thromboplastin/calcium chloride) or intrinsic (IA; ellagic acid/cephaloplastin/calcium chloride) activation of the coagulation process. Generation of thrombin or factor Xa was measured continuously by amidolytic assays using the specific chromogenic substrates Spectrozyme TH and Spectrozyme FXa. By means of calibration curves for thrombin and factor Xa the IC50 values for the inhibition of the proteases were calculated. It was found that rH and UH were nearly equally effective in inhibiting both the thrombin and factor Xa formation after IA, whereas in EA system rH produced a stronger inhibition on thrombin generation than UH, which in general showed a more pronounced effect after intrinsic than after extrinsic activation. The results suggest that, with regards to thrombin and factor Xa generation, rH does not exhibit a much higher activity than UH. This may be an expression that thrombin-mediated positive feedback-reactions are not influenced by rH as strongly as expected when using a highly specific and selective thrombin inhibitor. Furthermore, it can be concluded that protease generation assays may be useful in the characterization of anticoagulants/antithrombotics.

Blood Coagulation↗
PubMed1992

Effects of growth hormone administration in pediatric renal allograft recipients.

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2 +/- 2.0 years) all of whom had bone ages less than or equal to 12 years (10.0 +/- 1.4 years), a height standard deviation score of less than -2.5 (-4.9 +/- 1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40 ml/min per 1.73 m2 (51 +/- 6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7 +/- 2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5 +/- 1.6 cm/year pre therapy, 8.5 +/- 1.4 cm/year post therapy, P less than 0.001) and percentage of expected growth velocity for bone age (67 +/- 31% pre therapy, 163 +/- 27% post therapy, P less than 0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

In vitro studies on thrombin generation in citrated, r-hirudinized and heparinized whole blood.

The generation of thrombin in citrated, r-hirudinized and heparinized whole blood (final concentrations 10, 25, 50 micrograms/ml) was studied in the presence or absence of various activators. Whole blood from healthy volunteers was activated either by glass or dextran sulfate (contact activation; CA) as well as by thromboplastin/calcium chloride (extrinsic activation; EA) and by ellagic acid/cephaloplastin/calcium chloride (intrinsic activation; IA) and incubated 10 (CA, EA, IA) and 30 (CA) min at 37 degrees C. After the incubation period plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT) were measured utilizing ELISA methodology. After EA or IA no blood clotting occurred in all r-hirudinized samples and in heparinized blood at the highest concentration used. Despite inhibition of clotting F1 + 2 levels were increased both in r-hirudinized and in heparinized blood. However, in blood anticoagulated with heparin F1 + 2 levels after EA, IA and especially after CA were markedly lower than in r-hirudinized blood. Furthermore, in r-hirudinized blood an increase of TAT levels was found. The enhancement of F1 + 2 and TAT levels by r-hirudin was concentration-dependent and was lower in the higher r-hirudin concentration. The results indicate that in r-hirudinized whole blood significant amounts of thrombin can be generated which may elicit thrombin-mediated feedback mechanisms.

Blood Coagulation↗
PubMed1991

Anticoagulant and antithrombotic action of the synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile.

Anticoagulant and antithrombotic effects of a synthetic thrombin inhibitor of the tripeptide type, D-phenylalanyl-L-prolyl-L-arginine nitrile (1), were studied in vitro and in vivo. The anticoagulant action was investigated in common test assays such as thrombin time, activated partial thromboplastin time, prothrombin time and thrombelastography. In human plasma 1 caused a concentration-dependent prolongation of coagulation times and influenced the recalcification measured by thrombelastographic recording. In different models of experimental thrombosis in rats the antithrombotic effectiveness of 1 was shown. I.v. infusion of the thrombin inhibitor reduced or prevented the formation of stasis-induced venous thrombi and of arterial thrombi after electrically induced damage of the vessel wall as well as prolonged the time of a thrombotic occlusion of an extracorporeal arterio-venous shunt. At low doses 1 was also effective in thrombin-induced microthrombosis.

Animals↗
PubMed1991

Studies on toxicity and pharmacokinetics of the synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile.

The tripeptide-type synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile (1) was studied with respect to its toxicity and pharmacokinetics in mice, rats and rabbits. In mice the LD50 after i.v. injection was determined to be about 30-40 mg/kg. After i.v. injection and infusion in rats 1 caused a decrease in blood pressure up to 70-80% of initial values. The dose of 2 mg/kg.min led to a final outcome after about 15 min accompanied by a sharp decrease in blood pressure. The bleeding time after standardized incision of the rat tail was not significantly prolonged at doses which were tolerated. In pharmacokinetic studies the biologic half-life of 1 after i.v. injection was estimated to be about 12 min. After s.c. injection measurable plasma levels were obtained up to 5 h. Oral or intraduodenal administration of high doses of the inhibitor did not give effective plasma levels. Biliary excretion seems to be an important route of elimination. Cumulative excretion of 1 with the bile amounted to 31% of the dose within 240 min.

Administration, Oral↗
PubMed1990

Comparison of the anticoagulant and antithrombotic effects of synthetic thrombin and factor Xa inhibitors.

The anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors. In vivo, in a venous stasis thrombosis model and a thrombo-plastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar Ki value for the respective enzyme were not effective at equimolar dosage. The results are discussed in the light of the different prerequisites and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

Animals↗
PubMed1990

Antithrombotic effects of recombinant hirudin in experimental angioplasty and intravascular thrombolysis.

The effect of recombinant desulphatohirudin CGP 39393 (rH) on arterial thrombus formation and especially on thrombotic reocclusion after experimental angioplasty as well as after thrombolysis was investigated in rabbits. In the femoral artery thrombi were induced after endothelial damage of the vessel wall by a balloon catheter and following stasis. After removing the thrombus by angioplasty or after lysing it by streptokinase reocclusion of the artery was observed within a relatively short period of time. Subcutaneous injection of rH reduced the incidence of both primary thrombus formation and reocclusion in dependence on the dose administered. After a dose of rH of 2 mg/kg s.c. arterial thrombus formation was completely prevented and after administering 4 mg/kg s.c. thrombotic reocclusion did also not occur. Comparative studies with heparin showed that similar antithrombotic effects were only achieved at doses of 12 mg heparin/kg s.c. The results obtained suggest a clear potential of rH for prevention of thrombotic reocclusion in clinical states.

Angioplasty, Balloon↗
PubMed1990

Six weeks of continuous intravenous cyclosporine and short-course methotrexate as prophylaxis for acute graft-versus-host disease after allogeneic bone marrow transplantation.

The feasibility and toxicity of six-week continuous intravenous 3 mg/kg/day cyclosporine (CsA) treatment in conjunction with a short course of methotrexate (MTX) was studied in 69 consecutive patients after HLA genotypically identical bone marrow transplantation. In light of the uncertain efficacy of prolonged oral CsA immunoprophylaxis in preventing de novo chronic graft-versus-host disease (GVHD). CsA treatment was terminated three months after BMT. Sixty-one (88%) patients received the full intravenous regimen and no patient exclusions were necessary due to intolerable adverse effects. Weekly median blood CsA concentrations ranged between 820 ng/ml in the first and 648 ng/ml in the sixth week of treatment. No significant correlation existed between blood CsA concentrations and CsA dosages. Major adverse effects of the regimen included hypertension in 36%, acute nephrotoxicity in 36%, acute hepatotoxicity in 41%, and central nervous system toxicity in 4% of the patients. Since hepatotoxicity occurred predominantly in the early posttransplant period (median onset day 9), the relatively high incidence of this untoward effect might have been additionally caused by MTX and/or the preparative regimen. Blood CsA concentrations and CsA dosages did not significantly correlate with serum creatinine or total and conjugated bilirubin levels. In addition, blood CsA and serum creatinine levels did not differ between hypertensive and normotensive patients. Acute GVHD developed in 16% of the patients. Median CsA doses and blood CsA concentrations were identical for each week after BMT for patients contracting acute GVHD as compared with those without acute GVHD. In 55 patients surviving without acute or secondary chronic GVHD, the cumulative probability of de novo chronic GVHD after termination of CsA treatment was 13%. In conclusion, this regimen was tolerable and provided constant blood CsA concentrations for six posttransplant weeks that were not adversely influenced by the development of acute GVHD. Restriction of CsA treatment to the first three months after BMT appeared not to increase the risk of de novo chronic GVHD, which challenges regimens employing oral CsA immunoprophylaxis for 6-12 months after BMT.

Acute Disease↗
PubMed1990

Pharmacological studies on the low molecular weight heparin derivative CY 216.

In animal experiments pharmacological properties of the low molecular weight heparin derivative CY 216 were determined. The heparin fragment studied caused concentration-dependent anticoagulant effects in vitro. Investigations in vivo demonstrated the antithrombotic potency of the drug in experimental models of venous and arterial thrombosis in rats. In dependence on the dose administered CY 216 reduced the formation of stasis-induced thrombi of the jugular vein and prevented the thrombotic occlusion of the carotid artery after electrically induced damage of the vessel wall. An influence on primary haemostasis measured by prolongation of bleeding time after standardized incision of the rat tail could only be observed at doses which were higher than that required for antithrombotic effects.

Animals↗
PubMed1989

Studies on antithrombotic effects of recombinant hirudin.

Recombinant desulfato hirudin (rH) was studied with regard to its effects on various models of thrombosis, its pharmacokinetic behaviour as well as its influence on primary haemostasis in rats. The pharmacological behaviour of rH proved to be similar to that of native hirudin. Depending on the different models of experimental thrombosis different dosages of rH were required to prevent thrombus formation. This corresponds to rH plasma concentrations of 0.5-1.5 micrograms/ml. Primary haemostasis is influenced only after excess dosages and plasma concentrations of 4 micrograms/ml and above.

Animals↗
PubMed1989

[The pharmacology of recombinant hirudin].

A review about comprehensive studies on pharmacological properties of hirudin produced by genetic engineering is given. Anticoagulant effects, influence on platelet functions, studies on toxicity and side effects as well as the pharmacokinetic behaviour and antithrombotic actions of this highly effective thrombin inhibitor are described.

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

Experimental studies on the antithrombotic and haemorrhagic effects of heparin and a low molecular weight heparin derivative.

Antithrombotic, haemorrhagic and anticoagulant effects of unfractionated heparin (UH) and the low molecular weight heparin fragment KABI 2165 were studied in rats. In stasis-induced venous thrombosis of the jugular vein intravenous injection of both, UH and KABI 2165, either reduced significantly the size of thrombi or completely prevented thrombus formation in a dose-dependent manner. The dose of KABI 2165 required for prevention of thrombus formation showed a marked anticoagulant activity measured by APTT which was in the same range as that of the equieffective dose of UH. After administration of antithrombotically effective doses only UH caused a significant prolongation of bleeding time after standardized incision of the tail. KABI 2165 produced haemorrhagic effects at about 4-fold higher doses only than those required for the antithrombotic action.

Animals↗
PubMed1988

Antithrombotic and haemorrhagic effects of the naturally occurring thrombin inhibitor hirudin.

Haemorrhagic effects of the naturally occurring thrombin inhibitor hirudin measured by the determination of bleeding time were compared with its antithrombotic actions in different models of experimental thrombosis. In mice and rats intravenous administration of hirudin caused a plasma concentration-dependent prolongation of bleeding time after transection of the tail tip and standardized incision of the tail, respectively. In rats intravenous infusion of hirudin prevented the formation of stasis-induced venous thrombosis of the jugular vein and the occurrence of thrombotic occlusion of the carotid artery after electrically induced damage of the vessel wall. Comparison of the haemorrhagic action of hirudin with its antithrombotic effectiveness showed that it caused haemorrhagic side effects only at plasma concentrations which are not required for the antithrombotic effects.

Animals↗