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Biomedical subjects

G Agnelli

Publications and source records attributed to G Agnelli.

At least 109 records · Page 6Linked to original sources
PubMed1992

A randomised, double-blind, placebo-controlled trial of dermatan sulphate for prevention of deep vein thrombosis in hip fracture.

Dermatan sulphate (MF 701) is a natural glycosaminoglycan that catalyses thrombin inhibition by heparin cofactor II. The aim of the study was to evaluate the efficacy and safety of MF 701 for prevention of deep vein thrombosis (DVT) in patients with hip fracture. A randomised, double-blind, placebo-controlled design was used to assess two dose regimens of MF 701 in two consecutive study phases. Treatment was started within 48 h from the trauma and continued for 14 days for non-operated patients or until the 10th postoperative day. Bilateral mandatory venography was used to assess the end-point. Eighty patients were included in the first phase (40 MF 701, 40 placebo). MF 701, 100 mg IM b.i.d., did not reduce incidence of DVT from that on placebo and did not induce any bleeding. In the second phase 126 patients were included, with a randomisation ratio of 2:1 (84 MF 701, 300 mg IM b.i.d., 42 placebo). Bilateral venography was obtained for 110 patients. The incidence of DVT was 64% (23/36) in the placebo group and 38% (28/74) in the MF 701 group (p = 0.01; odds ratio [OR] = 0.34, 95% confidence limits [CL] = 0.15-0.80p; proximal DVTs were 42% (15/36) and 20% (15/74), respectively (p = 0.02; OR = 0.36, CL = 0.15-0.89). No significant differences were found in haemorrhagic complications (2.4% in each group), blood loss from drains, blood transfusions, haemoglobin and haematocrit values. This study is the first demonstration that dermatan sulphate is a clinically effective antithrombotic agent without bleeding effects. It also provides evidence of the biological role of heparin cofactor II.

Aged↗
PubMed1992

PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2.

BACKGROUND: The effect of alteplase versus heparin in pulmonary embolism has not been studied extensively with serial pulmonary angiograms. OBJECTIVES: The aim of this randomized, open trial was to evaluate the efficacy and safety of alteplase followed by heparin, versus heparin alone, in 36 patients with angiographically documented pulmonary embolism. METHODS: Twenty patients were allocated randomly to a 2-h infusion of alteplase (10 mg bolus, then 90 mg over 2 h) followed by heparin; the other 16 patients were given intravenous heparin at a continuous infusion rate of 1,750 IU/h. RESULTS: The vascular obstruction, assessed by the Miller index at pulmonary angiography, decreased significantly in alteplase-treated patients (p less than 0.01) from a baseline of 28.3 +/- 2.9 to a value of 24.8 +/- 5.2 2 h after the start of infusion; in the heparin group there was no change (from 25.3 +/- 5.3 to 25.2 +/- 5.4). Mean pulmonary artery pressure decreased significantly from a baseline of 30.2 +/- 7.8 mm Hg to 21.4 +/- 6.7 in the alteplase group and increased in the heparin group (from 22.3 +/- 10.5 to 24.8 +/- 11.2 mm Hg). For a subset of patients, lung scans were performed at baseline and on days 7 and 30. There were no differences between the two groups in the follow-up lung scans, but there were significant decreases from the baseline values. Bleeding occurred in 14 of 20 alteplase-treated patients and in 6 of 16 in the heparin group (p = NS). There were three major bleeding episodes in the alteplase group and two in the heparin group. Two patients died after fibrinolysis (one of acute renal failure after cardiac tamponade and one of cardiac arrest after cerebral hemorrhage) and one patient in the heparin group died of recurrent pulmonary embolism. CONCLUSIONS: Alteplase resulted in a greater and faster improvement of the angiographic and hemodynamic variables compared with heparin. However, the high frequency of bleeding observed with alteplase in this trial suggests that patients should be carefully selected before thrombolytic therapy is given.

Acute Disease↗
PubMed1992

Fibrin clots obtained from plasma containing heparin show a higher sensitivity to t-PA-induced lysis.

Although heparin is currently used in concomitance with thrombolytic agents to improve their efficacy, its effect on fibrinolysis is controversial. We have evaluated the sensitivity to t-PA-induced lysis of clots prepared from plasma preincubated in vitro with therapeutic concentrations of heparin. The extent of t-PA-induced lysis was significantly increased by preincubation of plasma with 0.5 and 1.0 U/ml heparin. The concentration of t-PA required to give similar lysis rates were reduced by up to five times after adding 1.0 U/ml heparin to plasma prior to clot formation. Heparin added to the t-PA-containing medium after clot formation did not exert any significant effect. The effect of heparin was not mediated by the inhibition of thrombin as preincubation of plasma with hirudin did not modify clot sensitivity to t-PA. We also found that heparin significantly modified fibrin assembly and clot structure as assessed by a turbidimetric assay. Pre-incubation of fibrinogen with heparin caused an increase in the speed of fibrin fibre polymerization and in the turbidity of the final fibrin gel; changes known to be associated with the formation of thicker fibrin fibres. Thus the effect of heparin on clot sensitivity to lysis appears to be due to an increased permeability of these clots to fibrinolytic components. This may contribute to the antithrombotic activity and to the haemorrhagic risk of heparin. These findings could be particularly important for clinical thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Synergism↗
PubMed1992

Bolus thrombolysis in venous thromboembolism.

Thrombolytic therapy is rarely used in venous thromboembolism because of the fear of hemorrhagic complications. Preliminary clinical experiences with recombinant tissue-type plasminogen activator (rt-PA) in patients with deep vein thrombosis have shown that even this fibrin-specific plasminogen activator causes an unacceptable rate of hemorrhagic complications. Theoretical considerations and the available experimental and clinical data suggest that infusion of rt-PA over a short period of time would result in a more favorable risk-benefit ratio. Shortening the period of rt-PA infusion results in higher peak plasma levels, thus allowing a higher concentration of the plasminogen activator on the surface and inside the occluding thrombus. In addition, a bolus infusion can prevent or minimize the interaction between rt-PA and the hemostatic system, reducing the likelihood of a systemic lytic state, of a platelet function defect, and, possibly, of bleeding side effects. In venous thromboembolism animal models, the efficacy of bolus rt-PA can be further increased by the adjunctive administration of an effective antithrombotic treatment. This is because the accretion of new fibrin on the thrombi counteracts the lysis of preformed fibrin and influences negatively the final thrombus size. Effective adjunctive antithrombotic treatment includes either high doses of heparin, producing an unclottable activated partial thromboplastin time (aPTT), or doses of recombinant hirudin, doubling the aPTT. When used as an alternative to rt-PA, bolus doses of a hybrid plasminogen activator with prolonged half-life efficiently reduce thrombus size by lysing preformed and newly formed fibrin. Preliminary clinical experience in patients with pulmonary embolism seems to confirm that rt-PA infused as a bolus is at least as effective as, and probably more effective than, rt-PA infused over a longer period.

Animals↗
PubMed1991

Affects of hirudin and heparin on the binding of new fibrin to the thrombus in t-PA treated rabbits.

The aim of this study was to compare the ability of heparin and recombinant hirudin (r-hirudin) in preventing accretion of new fibrin on thrombi during and after treatment with tissue-type plasminogen activator (t-PA) and in enhancing t-PA induced fibrinolysis in a rabbit jugular vein thrombosis model. Heparin and r-hirudin were infused at doses capable of doubling aPTT. In the fibrin accretion inhibition experiments t-PA was infused over 3 h at a dose of 0.2 mg/kg along with saline or heparin, 0.75 mg/kg or r-hirudin, 1.25 mg/kg. In rabbits treated with t-PA plus saline, heparin or r-hirudin, an accumulation of 125I-fibrinogen on the thrombi of 52.5 +/- 5.1 micrograms, 49.5 +/- 5.6 micrograms and 23.5 +/- 3.5 micrograms was observed, respectively, the difference between r-hirudin and both saline and heparin being statistically significant (p less than 0.01). The inhibition of fibrin accretion on the thrombi induced by r-hirudin persists for at least 9 h after the end of the infusion. By that time r-hirudin has been cleared from the circulation and aPTT has returned to the baseline level for at least 8 h. t-PA, 0.2, 0.4, and 1 mg/kg, infused with saline produced 34 +/- 6%, 52 +/- 5% and 79 +/- 8% lysis of pre-formed thrombi, respectively. The same doses of t-PA infused with heparin, 0.75 mg/kg, produced 32 +/- 3%, 54 +/- 5% and 78 +/- 6% fibrinolysis, respectively and infused with r-hirudin, 1.25 mg/kg, 38 +/- 3%, 57 +/- 5% and 82 +/- 8%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Thrombus resistance to lysis and reocclusion after thrombolysis: the role of platelets.

Thrombolytic therapy reduces the mortality rate in patients with acute myocardial infarction. However, thrombolytic agents, which are primarily directed toward the lysis of fibrin, fail to achieve reperfusion in at least 20% of patients and an early reocclusion occurs in up to 25% of cases. The role of platelets in both thrombus resistance to lysis and early reocclusion is demonstrated by experimental and clinical observations. Platelets and the fibrinolytic system interact in numerous ways. Platelet activation can potentiate or inhibit the fibrinolytic process. The activation of the fibrinolytic system has been found to induce either an activation or an inhibition of platelet function. In animal models it has been shown that platelet-rich thrombi are resistant to lysis, and that platelets and fibrin still accumulate on lysing thrombi during effective thrombolysis. One of the most attractive strategies to optimize thrombolytic therapy is adjunctive treatment with pharmacological agents which inhibit platelet function.

Animals↗
PubMed1991

Strategies for administration of tissue plasminogen activator.

Since the first patient was treated with recombinant tissue plasminogen activator (t-PA) in 1984, there has been remarkable progress in our understanding of optimal methods for administration of this thrombolytic agent. As a background and foundation to clinical trials, the experimental data for bolus t-PA, adjunctive treatments and new plasminogen activators for more optimal thrombolysis are reviewed. The major findings in clinical evaluation for acute myocardial infarction to date include (1) substantial mortality reduction and improvement in cardiac function; (2) an excess of serious bleeding complications at high doses (150 mg) of t-PA; (3) rapid infarct vessel recanalization with an accelerated "front-loaded" regimen; (4) the importance of conjunctive intravenous heparin; and (5) the potential for new, combined plasminogen activator therapies. The recent data, collectively, have set the stage for a new greater than 30,000 patient mortality reduction trial entitled Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO).

Animals↗
PubMed1991

Impedance plethysmography in the diagnosis of asymptomatic deep vein thrombosis in hip surgery. A venography-controlled study.

We prospectively evaluated the accuracy of computerized impedance plethysmography (CIP) in the diagnosis of asymptomatic deep vein thrombosis (DVT) in 246 consecutive high-risk patients scheduled for hip surgery, with bilateral venography used for comparison. The CIP was performed as a surveillance program every third day. If the CIP remained negative, bilateral venography was performed on postoperative day 10 +/- 1 or on day of treatment 14 +/- 1 in nonoperated-on patients. If the CIP became positive, venography was performed within 24 hours. The sensitivity and specificity of CIP for proximal and distal DVT were 19% (confidence interval [CI], 13% to 24%) and 91% (CI, 87% to 94%), respectively. The positive and negative predictive values were 52% (CI, 38% to 65%) and 70% (CI, 65% to 74%), respectively. The sensitivity and specificity of CIP for proximal DVT were 24% (CI, 13% to 34%) and 90% (CI, 87% to 94%), respectively; the positive and negative predictive values were 31% (CI, 20% to 51%) and 87% (CI, 83% to 90%), respectively. We conclude that, because of its low sensitivity, CIP cannot be used in the surveillance of DVT in high-risk patients or for outcome measurements in clinical trials on DVT prophylaxis.

Aged↗
PubMed1990

Effects of therapeutic doses of heparin on thrombolysis with tissue-type plasminogen activator in rabbits.

The objective of the study was to evaluate the ability of heparin to enhance the thrombolytic effect of recombinant tissue type plasminogen activator (rt-PA) and to prevent thrombus growth during and after thrombolysis with rt-PA. In the thrombolysis studies, three groups of rabbits were infused with rt-PA at a dose of 0.5 mg, 1 mg, or 2.5 mg over 3 hours, respectively. Rabbits in each group were randomized to receive, in addition to rt-PA, heparin, 20 or 60 antifactor Xa U/kg/h, or saline over 6 hours. The three doses of rt-PA produced the same extent of thrombolysis both in the two groups treated with heparin (34% +/- 6%, 52% +/- 7%, and 79% +/- 8% in the lower dose group; 39% +/- 6%, 49% +/- 4%, and 81% +/- 6% in the higher dose group) and in the group treated with saline (37% +/- 4%, 47% +/- 5%, and 84% +/- 7%). In the thrombus growth inhibition studies 0.5 mg of rt-PA was infused over 3 hours in each rabbit. In addition, the rt-PA-treated rabbits were randomized to receive heparin, 20 or 60 antifactor Xa U/kg/h over 6 hours, or saline. At the end of infusion, no statistically significant differences in thrombus growth were found in three groups of rabbits (54.8 +/- 7.4 micrograms and 52.4 +/- 12.1 micrograms in the low and high dose of heparin groups, respectively, and 59.4 +/- 10.4 micrograms in the saline group). In different experiments rabbits were randomized to receive heparin, 60 antifactor Xa U/kg/h, or saline at the end of the rt-PA infusion. In these experiments heparin inhibited thrombus growth more efficiently than saline (41.1 +/- 6.5 micrograms and 58.7 +/- 12.9 micrograms, respectively, P less than .05). In vitro experiments confirmed that heparin is unable to prevent fibrin accretion on the clots during lysis with rt-PA while both D-Phe-Pro-Arg-CH2-Cl (PPACK) and hirudin are able to prevent the accretion of fibrin. We conclude that the data obtained in these animal models do not support the concomitant use of heparin and rt-PA. However, heparin could be used successfully after rt-PA to inhibit thrombus growth.

Amino Acid Chloromethyl Ketones↗
PubMed1990

Human pharmacokinetics and pharmacodynamics of MF 701 dermatan sulfate administered by continuous intravenous infusion.

The pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i.v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 +/- 0.46 h, a plasma clearance of 2.75 +/- 0.46 l/h and a volume of distribution of 4.92 +/- 1.36 1 (means +/- SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 +/- 5.7 micrograms/ml. Maximal APTT prolongation over pre-infusion values was 42 +/- 7%; TCT performed with bovine and human thrombin was prolonged by 16 +/- 7% and 83 +/- 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i.v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.

Adolescent↗
PubMed1990

Diagnosis of deep-vein thrombosis using an objective Doppler method.

STUDY OBJECTIVE: To determine the diagnostic criteria (phase I) and to assess the accuracy (phase II) of an objective Doppler-Valsalva pressure method as compared with contrast venography for the diagnosis of acute deep-leg-vein thrombosis in symptomatic outpatients. DESIGN: A two-phase prospective study in consecutive patients. Doppler ultrasound strip-chart recordings and venograms were independently analyzed by experienced observers. SETTING: Referral-based medical clinics at university medical centers. PATIENTS: One hundred and ten (phase I) and one hundred and fifty-five (phase II) patients who had clinically suspected venous thrombosis and were referred by their general practitioners were included. METHODS AND MEASUREMENTS: A normal Doppler test result was defined as a cyclic spontaneous signal (S-signal), a continuous S-signal with a Valsalva pressure of less than 6.5 mm Hg, or an absent S-signal with flow after cessation of the Valsalva maneuver. A continuous S-signal with a Valsalva pressure of 6.5 mm Hg or more or an absent S-signal without flow after cessation of the Valsalva maneuver were defined as abnormal test results. The accuracy indices for proximal vein thrombosis in phase II (155 patients; prevalence, 31%) were sensitivity, 91% (95% CI, 79% to 98%), and specificity, 99% (CI, 97% to 100%). All 3 patients with isolated calf-vein thrombosis had normal Doppler test results. CONCLUSIONS: The objective Doppler method is an accurate, reproducible, and simple method for detection of venous thrombosis in symptomatic outpatients.

Abdomen↗
PubMed1990

The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits.

The aim of this study was to compare the ability of standard heparin and recombinant (r-)hirudin, a specific inhibitor of thrombin, to inhibit thrombus growth in a rabbit jugular vein model. Doses of standard heparin and r-hirudin equivalent in prolonging the aPTT were first identified. The ability of these doses to inhibit 125I-fibrin accretion onto preexisting thrombi was then evaluated. 0.5 and 0.75 mg/kg of standard heparin and 0.8 and 1.25 mg/kg of r-hirudin infused over 3 h produced a mean prolongation of the aPTT of 1.5 and 2 times, respectively. In saline treated rabbits 62 +/- 7 micrograms of 125I-fibrin were accreted on the pre-formed thrombi. The lower doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 44 +/- 5 and 25 +/- 4 micrograms, respectively (p less than 0.01). The two higher doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 34 +/- 4 and 17 +/- 3 micrograms, respectively (p less than 0.01). The increase in the dose of standard heparin up to 2.5 mg/kg produced a 125I-fibrin accretion of 26 +/- 3 micrograms a 58% reduction when compared with saline. The increase in the dose of r-hirudin up to 5 mg/kg produced a 125I-fibrin accretion of 12 +/- 2 micrograms, an 81% reduction when compared with saline. No further inhibition was observed when the doses of both agents were further increased. We conclude that doses of standard heparin and r-hirudin equivalent in prolonging the aPTT have a different effect on thrombus growth inhibition, r-hirudin being twice as effective as standard heparin. Exclusive inhibition of thrombin without any other inhibiting effect on blood coagulation appears to be sufficient to inhibit thrombus growth. Our results seem to be promising in view of a clinical evaluation of r-hirudin.

Animals↗
PubMed1990

Clinical experience with low molecular weight heparins.

Low molecular weight heparins (LMWHs) have been prepared by means of different fragmentation or fractionation procedures with the aim of obtaining a more effective and/or safer antithrombotic agent than standard heparin (SH). LMWHs resulting from different production procedures are structurally heterogeneous; this could account for the different efficacy and safety observed clinically. Many clinical trials have been carried out on the prevention of deep-vein thrombosis (DVT) and pulmonary embolism in patients undergoing major abdominal or orthopedic surgery, hemodialysis or affected by non-hemorrhagic stroke. When given once daily, LMWHs are at least as effective in all indications as SH given twice or three times daily and some of them resulted even more effective than SH in general and in orthopedic surgery. The role of LMWHs in the treatment of DVT and their superiority over SH in terms of bleeding remain to be established.

Cerebrovascular Disorders↗
PubMed1990

Effects of a stable prostacyclin analogue on platelet activity and on host immunocompetence in mice.

The stable prostacyclin (PGI2) analogue, iloprost, is a potent inhibitor of both tumor cell-induced platelet aggregation and of experimental metastasis in mice. To explore possible mechanisms of antimetastatic effect of iloprost, we measured the effect of this drug on both platelet aggregation and immunocompetence in the mouse. Iloprost (4 x 10(-8) M) inhibited platelet aggregation as induced by a mixture of collagen and epinephrine for at least 180 minutes of incubation, and completely reversed platelet aggregation when added during the second wave of aggregation. In addition, aggregation of platelets obtained from iloprost-treated mice (0.2 mg/kg) was completely inhibited for at least 90 minutes of incubation. Moreover, iloprost pretreatment in vivo counteracted tumor cell-induced thrombocytopenia. Thus, mouse platelets were equally sensitive to the inhibitory effect of iloprost on aggregation as platelets of other species including humans. Effects of iloprost on parameters of host immunocompetence that may influence tumor growth and metastasis formation were also evaluated. Iloprost treatment increased significantly macrophage cytostasis to tumor cells, natural killer (NK) lytic activity of spleen cells and T-cell mediated cytotoxicity ex vivo. These results suggested that the antimetastatic effect of iloprost in the mouse may be attributable to multiple mechanisms including inhibition of platelet aggregation and stimulation of certain host immune functions.

Aging↗
PubMed1990

Effect on thrombus growth and thrombolysis of two types of osmolar contrast media in rabbits.

Thromboembolic complications have been reported after diagnostic or interventional radiological procedures. However, contrast media inhibit platelet function and blood coagulation in vitro. To investigate these characteristics in vivo, we determined the effect of nonionic and ionic low osmolar contrast media on thrombus growth and thrombolysis in rabbits in a randomized study design. Rabbits received either ionic low osmolar contrast medium (ioxaglate), nonionic low osmolar contrast medium (iohexol) or saline. Thrombus growth was determined by the accretion of 125I-labeled fibrinogen on to autologous, nonradioactive, preformed thrombi in rabbit jugular veins. Thrombolysis was assessed by measurement of the decrease in radioactivity of standard sized preformed 125I-fibrinogen labeled thrombi. Ioxaglate significantly inhibited thrombus growth (60% inhibition, P less than 0.005 vs. saline), in contrast to iohexol, which had no significant effect (33% inhibition, P less than 0.2 vs. saline). Neither ioxaglate nor iohexol affected thrombolysis.

Animals↗