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Biomedical subjects

E Seifried

Publications and source records attributed to E Seifried.

At least 109 records · Page 6Linked to original sources
PubMed1990

[Local lysis of peritoneovenous shunt thrombosis with rt-PA].

We report five instances of local lysis with rt-PA (recombinant tissue type plasminogen activator) in three patients with thrombotic occlusions of their peritoneovenous Denver shunts (PVS). In all cases liver cirrhosis was alcohol-induced and ascites was refractory to all medical measures. Because of rethrombosis two patients were treated again after 13 months. The occlusion had occurred 2-30 days before treatment. In four of the five instances the local lysis was successful. Complications were rare. This scintigraphic visualization of the catheter system allowed assessment of shunt patency under physiological flow conditions. The local lysis of a thrombotic shunt with rt-PA and scintigraphic monitoring is a low-risk alternative to reoperation. Possible benefits compared to other fibrinolytics must be confirmed by a greater patient collective.

Adult↗
PubMed1989

Single-bolus injection of recombinant tissue-type plasminogen activator in acute myocardial infarction.

Recombinant tissue-type plasminogen activator (rt-PA) has hitherto been administered in acute myocardial infarction as an intravenous infusion with an initial bolus of about 10% of the total dose, both due to its short half-life and to avoid possible early reocclusions. A single-bolus dose would simplify the therapeutic regimen. Therefore, 20 patients with symptom duration of 125 +/- 58 minutes were given a single bolus of 50 mg of rt-PA over 2 minutes. Coronary angiography 60 minutes after the rt-PA bolus revealed a patent infarct-related artery in 15 of 20 patients (patency rate 75%, 95% confidence limits 51 to 91%). In the remaining patients, reperfusion was achieved by coronary angioplasty and intracoronary fibrinolysis; in 2 patients coronary artery bypass grafting was necessary. Control angiograms at 24 hours showed reocclusions in 4 of 18 patients. One woman died due to an intracranial hemorrhage 48 hours after the rt-PA bolus injection. Circulating fibrinogen decreased from 2.7 +/- 0.5 to 1.5 +/- 0.9 g/liter after 2 to 4 hours and reached the initial value within 24 hours. Pharmacokinetic parameters were obtained in 7 patients by measuring rt-PA antigen levels in multiple plasma samples. Mean peak rt-PA concentration was 9.8 +/- 3.6 micrograms/ml, total plasma clearance 476 +/- 148 ml/min and dominant half-life 4.8 +/- 1.0 minutes. Thus, rt-PA administered as a 50-mg single bolus appears to provide similar patency rates and shows similar kinetics in comparison with the conventional infusion regimen. Assessment of the incidence of bleeding complications requires further studies.

Adult↗
PubMed1989

Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases.

Of 501 patients with chronic myeloproliferative diseases (c-MPD) 18 developed thrombosis of major abdominal vessels including 6 with hepatic vein thrombosis (Budd-Chiari syndrome). The complication was seen in 14 of 140 (10%) patients with polycythemia vera (PV), 3 of 23 (13%) patients with essential thrombocythemia (ET), 1 of 106 (1%) patients with idiopathic myelofibrosis (IMF), and none of 232 patients with chronic myelogenous leukemia (CML). Leading symptoms and signs were abdominal pain, progressive splenomegaly, widening abdominal girth, ascites, venous collaterals, and nausea and vomiting. The diagnostic modalities with highest specificity were angiography and explorative laparotomy. A causal relationship between the thrombotic event and hematocrit, thrombocyte count, or hemostatic abnormalities at the time of diagnosis could not be established. Detailed laboratory tests of platelet function and coagulation and fibrinolytic parameters of 5 surviving patients did not show any specific defect. Despite medical and surgical intervention, 39% of the patients died within 2 months after diagnosis of the thrombosis. The majority of the survivors developed further complications like liver cirrhosis with portal hypertension and esophageal varices or the short bowel syndrome after extensive bowel resection for mesenterial infarction.

Blood Coagulation Tests↗
PubMed1989

Pharmacokinetics and haemostatic status during consecutive infusions of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction.

Pharmacokinetics and systemic effects of recombinant tissue-type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean +/- SD) of 3310 +/- 950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of 2210 +/- 470 ng/ml and 930 +/- 200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380 +/- 74 ml/min, t1/2 alpha was 3.6 +/- 0.9 min and t1/2 beta was 16 +/- 5.4 min. After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, alpha 2-antiplasmin to 25%, alpha 2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 micrograms/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

Aged↗
PubMed1989

Pharmacokinetics and systemic effects of tissue-type plasminogen activator in normal subjects.

Pharmacokinetics and systemic effects of recombinant tissue-type plasminogen activator (rt-PA) were studied in 18 healthy male volunteers after 30-minute intravenous infusions of placebo, 0.25 mg/kg rt-PA, and 0.5 mg/kg rt-PA. Highly comparable pharmacokinetic parameters were obtained after analysis of rt-PA as both an antigen and an activity. Mean clearance (antigen) was 620 +/- 70 (SD) ml/min, volume of distribution at steady state was 8.1 +/- 0.8 L, initial volume of distribution was 4.4 +/- 0.6 L, and dominant half-life was 4.4 +/- 0.3 minutes. The pharmacokinetics of rt-PA were linear, showed low interindividual variation, and are compatible with rapid hepatic elimination of the protein. Systemic plasminogen activation was minimal as assessed by hemostatic assays of plasma samples treated with anti-rt-PA Immunoglobulin G (IgG) to inhibit in vitro fibrinogenolysis. Circulating fibrinogen levels, clotting times, and coagulation factors were unchanged; plasminogen and alpha 2-antiplasmin decreased maximally to 85% and 65% of baseline values, respectively. The data are consistent with the fibrin specificity of t-PA, which is derived from its role in physiologic fibrinolysis.

Adult↗
PubMed1989

Current developments in thrombolytic therapy using novel plasminogen activators.

As a result of intensive recent research, the molecular mechanisms governing the human fibrinolytic system could be elucidated. Clinical trials using streptokinase and urokinase demonstrated that therapeutic thrombolysis is a valuable regimen in the treatment of patients with thromboembolic diseases. After unsuccessful attempts to increase the clot specificity of these agents, efforts were increased towards developing fibrin-specific substances with high thrombolytic potency and negligible effects on systemic hemostasis. Tissue-type plasminogen activator manufactured by recombinant DNA technology (rt-PA) is currently the most comprehensively investigated fibrin-specific thrombolytic agent with the most clearly understood mechanism of action in vivo. Pro-urokinase has also become available through biotechnology. A large number of clinical trials studying thrombolytic therapy of myocardial infarction have proved that intravenous rt-PA posesses superior efficacy compared to conventional fibrinolytic agents. Comparatively few clinical studies have been performed using pro-urokinase. At therapeutic doses, the fibrin specificities of these agents differ. So far it has not been possible to correlate the incidence of bleeding complications during fibrinolytic therapy with alterations in hemostasis parameters. For routine laboratory monitoring of thrombolysis the determination of fibrinogen and thrombin clotting time can be recommended. New developments with potential for yielding the next generation of thrombolytic agents are mutants and chimeras of t-PA and pro-urokinase, and conjugates of these substances with fibrin specific antibodies.

Fibrinolytic Agents↗
PubMed1988

In vivo recovery and half-life time of a steam-treated factor IX concentrate in hemophilia B patients. The influence of reagents and standards.

Factor IX (FIX) recovery and half-life was measured in ten hemophilia B patients under standardized conditions. Each patient received a steam-treated high-purity factor IX concentrate at a dose of 19-39 U/kg body weight. FIX activity was determined using a one-stage assay, which was calibrated against the international concentrate standard (reagents from Immuno, Heidelberg). The in vivo recovery ranged from 24% to 53% (mean value 37.7%) and the half-disappearance time (HDT) from 8-30 h (mean 16.7 h). In four of the ten patients, the distribution and elimination half-lives were estimated and ranged from 0.3 h to 3.9 h (mean 1.4 h) and from 28.6 h to 39.7 h (mean 33.1 h), respectively. In six patients FIX was redetermined using a different FIX deficient plasma and a plasma standard (reagents from Merz & Dade, Munich, FRG). Recoveries and HDT based on the results obtained with this method were significantly higher (68.2% vs 39.7%; p less than 0.05), and longer (14.8 h vs 10.6 h; p less than 0.05), respectively. FIX activity was also measured by both assay systems in 100 healthy subjects (50 males, 50 females). The reagents from Immuno yielded a mean value of 0.77 U/ml, while the mean FIX activity utilizing standards and reagents from Merz & Dade was 1.11 U/ml (p less than 0.000001). The coefficient of correlation between the FIX activity measurements, as determined in 100 healthy subjects and 6 hemophilia B patients using the different test systems, was r = 0.9 (N = 159; y = 0.08 +/- 1.3* chi; p less than 0.001). Our data suggest that recovery and HDT of factor IX concentrate strongly depend on the assay and calibration conditions and that an international FIX activity plasma standard is urgently required.

Adolescent↗
PubMed1988

[Recombinant tissue-type plasminogen activator: pharmacokinetics and effect on the hemostasis system of the human].

The in vitro interaction of rt-PA with the coagulation and fibrinolytic system was investigated. After addition of rt-PA to citrated plasma prolonged clotting times for prothrombin time, partial thromboplastin time and thrombin time, decreased activities of individual clotting factors and decreases of alpha 2-antiplasmin, plasminogen and fibrinogen were measured. The alterations were dependent on incubation times and rt-PA concentrations and were mainly observed at rt-PA concentrations exceeding therapeutic levels. These in vitro phenomena could be prevented to different degrees using various inhibitors. Because of interferences with some fibrinolytic and coagulation assays aprotinin was only of limited utility as an inhibitor. PPACK lengthened clotting time assays based on generation of endogenous thrombin, but did not affect fibrinolytic assays. The most versatile inhibitor was a specific anti-rt-PA antibody which enabled correct measurements of all fibrinolytic and most coagulation assays. It is concluded that high rt-PA levels in samples taken from patients during fibrinolytic therapy induce in vitro artefacts which can be prevented by the use of suitable inhibitors. In 8 healthy male volunteers aged 32 +/- 7 years pharmacokinetic investigations were done. After infusion of 0.25 mg rt-PA/kg bw mean maximal plasma levels were 970 +/- 130 ng/ml. The elimination of rt-PA from plasma was fitted to a two compartment model and was characterized by two half lives of t1/2 alpha = 3.3 and t1/2 beta = 26 minutes.

Adult↗
PubMed1988

Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers.

Pharmacokinetics of recombinant tissue plasminogen activator (rt-PA, large-scale process) were determined based on antigen and activity after infusion of 0.25 mg/kg in 8 healthy volunteers. Plasma antigen was measured using enzyme-linked immunosorbent assay (ELISA) with and without treatment of blood at collection with D-Phe-Pro-Arg-CH2Cl (P PACK); activity was quantified in acidified plasma both on fibrin plates and in a chromogenic assay. Highest rt-PA concentrations were measured in ELISA with P PACK-treated samples, yielding the following pharmacokinetic parameters (2-compartment model, mean +/- S.D.): Cmax = 973 +/- 133 ng/ml, CL = 687 ml/min, dominant half-life t1/2 alpha = 3.3 +/- 0.4 min, t1/2 beta = 26 +/- 12 min, V1 = 3.9 +/- 0.6 l and Vss = 7.2 +/- 1.0 l. The other assays yielded lower rt-PA concentrations, which affected clearance and volume parameters but not t1/2 beta and t1/2 beta. Linear regressions of the fibrin plate and chromogenic assay results vs. ELISA yielded excellent correlations (R greater than 0.96, n = 55-57) but slopes of 0.76 and 0.64, respectively. This indicates that about 25-35% of rt-PA antigen in thawed plasma samples are not detected in activity assays, due at least partially to in vitro binding of rt-PA by proteinase inhibitors.

Chromogenic Compounds↗
PubMed1987

Comparison of specific antibody, D-Phe-Pro-Arg-CH2Cl and aprotinin for prevention of in vitro effects of recombinant tissue-type plasminogen activator on haemostasis parameters.

In vitro, concentration-dependent effects of rt-PA on a range of coagulation and fibrinolytic assays in thawed plasma samples were investigated. In absence of a fibrinolytic inhibitor, 2 micrograms rt-PA/ml blood (3.4 micrograms/ml plasma) caused prolongation of clotting time assays and decreases of plasminogen (to 44% of the control value), fibrinogen (to 27%), alpha 2-antiplasmin (to less than 5%), FV (to 67%), FVIII (to 41%) and FXIII (to 16%). Of three inhibitors tested, a specific polyclonal anti-rt-PA antibody prevented interferences in all fibrinolytic and most clotting assays. D-Phe-Pro-Arg-CH2Cl (PPACK) enabled correct assays of fibrinogen and fibrinolytic parameters but interfered with coagulometric assays dependent on endogenous thrombin generation. Aprotinin was suitable only for a restricted range of both assay types. Most in vitro effects were observed only with rt-PA plasma concentrations in excess of therapeutic values. Nevertheless it is concluded that for clinical application, collection of blood samples on either specific antibody or PPACK is essential for a correct assessment of in vivo effects of rt-PA on the haemostatic system in patients undergoing fibrinolytic therapy.

Amino Acid Chloromethyl Ketones↗
PubMed1986

HTLV III antibodies and immunological alterations in hemophilia patients.

The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.

Acquired Immunodeficiency Syndrome↗
PubMed1985

[Fibrin pleurodesis in malignant pleural effusions].

Fibrin pleurodesis was performed on 30 patients with malignant pleural effusions. A pleural catheter was inserted to empty the pleural space and effect the pleurodesis. When the pleural space was dry, 20 000 U of aprotinin were instilled intrapleurally for local fibrinolysis inhibition. 10 ml fibrinogen concentrate and 10 ml thrombin (500 U/ml) and 3000 KI U/ml aprotinin were then applied. Complete success was achieved in 19 of 27 patients, partial success in two. The results could not be evaluated in three patients. The only side-effect of the treatment was a subfebrile temperature in three of the 30 patients. Fibrin pleurodesis thus proved itself as an effective form of treatment with few side-effects (10%).

Adult↗
PubMed1985

Prevalence of antibodies to human T-lymphotropic virus-III (HTLV-III) in hemophiliacs and other patients chronically substituted with blood products.

The prevalence of antibodies to human T-lymphotropic virus III (HTLV-III) was determined in a total of 140 hemophiliacs and 36 polytransfused patients from three medical centers by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. 58 hemophiliacs (41.4%) were seropositive. In all instances where the origin of the coagulation factors given to these patients could be determined, blood products came from the United States. In addition, 2 of 36 polytransfused patients, mostly with acute leukemias, who were transfused with blood products from local donors were positive for HTLV-III antibodies. No HTLV-III antibodies were detected in 237 blood donors selected in part from the donor pool of the polytransfused patients.

Antibodies, Viral↗
PubMed1985

Prevalence of antibodies to HTLV-III in AIDS risk groups in West Germany.

The prevalence of antibodies to human T-lymphotropic virus III was determined in acquired immunodeficiency syndrome (AIDS) risk groups by an enzyme linked immunosorbent assay and confirmatory tests in four different areas in West Germany. Twenty-four of 28 homosexual AIDS patients (86%), 24 of 33 homosexual patients with lymphadenopathy syndrome or AIDS related complex (73%), and 44 of 113 asymptomatic homosexuals at risk for AIDS (39%) were seropositive. In three groups of hemophiliacs, 8 of 35 in 1983 (23%), 25 of 65 in early 1984 (39%), and 19 of 23 in late 1984 (83%) showed positive results. Two sera from 36 polytransfused patients were also positive, whereas 36 selected blood donors, and 32 healthy laboratory and clinical personnel were all negative. Also no human T-lymphotropic virus III antibodies were detected in sera of 187 prostitutes in the Munich area.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Low-dose Ara-C in the treatment of acute leukemia. Cytotoxicity or differentiation induction?

The differentiation inducing effect of low-dose Ara-C on human myeloid leukemic cells was studied in two patients with subacute myelocytic and subacute myelomonocytic leukemia in vivo and in vitro. By continuous i.v. administration of 10 mg Ara-C/m2 over 12 h daily for 12 or 20 days complete remissions were obtained in both patients with normalization of the incidence of the committed progenitor cells BFU-E and CFU-C in the marrow while the incidence of pluripotent CFU-GEMM remained subnormal. Parallel cultures of the patients' bone marrow cells in diffusion chambers (DC) implanted in mice demonstrated a clear cytotoxic effect of low-dose Ara-C. The greater increase of granulopoietic cells within DC in the Ara-C exposed group than in control mice after the end of drug administration is, in addition, an indication for differentiation induction by this kind of Ara-C therapy.

Adult↗