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Biomedical subjects

R W Smalling

Publications and source records attributed to R W Smalling.

At least 37 records · Page 2Linked to original sources
PubMed1998

Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase.

BACKGROUND: Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. METHODS AND RESULTS: InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. CONCLUSIONS: Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

Adolescent↗
PubMed1998

Clinical experience with the percutaneous hemopump during high-risk coronary angioplasty.

The percutaneous Hemopump showed beneficial effects during coronary angioplasty in 32 high-risk patients with unloading of the left ventricle during ischemia and maintaining cardiac output with mean aortic pressures of 50 mm Hg in case of cardiac arrest (3 patients). High procedure-related morbidity (occlusion of femoral artery in 2 patients; bleeding with need of transfusion in 4 patients) and mortality (4 of 32 patients) rates demonstrate the need for a very careful selection of patients.

Adult↗
PubMed1998

Therapy with thrombolytic agents in coronary artery disease.

Over the past two decades, new thrombolytic agents with sufficient pharmacologic potency and acceptable clinical safety profiles to treat thrombotic vascular occlusive syndromes, such as acute myocardial infarction, pulmonary embolism, acute peripheral and arterial thrombotic occlusions, and deep vein thrombosis, have been developed and evaluated. The evolution of thrombolysis and its application to clinical cardiology came as a consequence of understanding the systems of coagulation and fibrinolysis and their role in the pathogenesis of acute coronary syndromes.

Coronary Disease↗
PubMed1997

A fresh look at the molecular pharmacology of plasminogen activators: from theory to test tube to clinical outcomes.

The molecular pharmacology of plasminogen activators and its implications for thrombolytic therapy are discussed. The benefits of coronary thrombolysis were first demonstrated with intracoronary and i.v. streptokinase. Tissue plasminogen activator (t-PA) or recombinant t-PA (alteplase) proved to be superior to streptokinase with respect to speed of reperfusion and reperfusion efficacy. Since alteplase neither lessened the risk of bleeding found with streptokinase nor generated Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates above about 50%, the quest for faster-acting, safer, and more effective thrombolytic agents has continued. The ideal agent would be highly efficient at converting plasminogen to plasmin, have an intermediate half-life, have a low affinity for fibrin, and be of reasonable cost. Genetic engineering of the wild-type t-PA molecule resulted in reteplase, which has a longer half-life than alteplase and may be superior in terms of lytic activity, myocardial salvage, and survival. Also under investigation are TNK-t-PA and n-PA, which have longer half-lives and, in animal models, seem to produce more rapid and complete thrombolysis, at less risk of intracranial bleeding, than alteplase. The risk of intracranial bleeding remains a problem with all thrombolytics; the risk versus the benefit will have to be assessed in large randomized trials. An understanding of the functions of various regions of the t-PA molecule has led to genetic engineering of new and promising plasminogen activators.

Animals↗
PubMed1997

Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry.

OBJECTIVES: This study sought to determine whether infrapopliteal transcatheter interventions can salvage ischemic limbs in diabetic patients referred for below the knee amputation at our institution. BACKGROUND: The value of transcatheter interventions in diabetic crural arteries is controversial. Tissue oxygen partial pressure (TCO2) levels < 40 mm Hg predict poor wound healing. METHODS: Percutaneous interventions were performed in 29 consecutive diabetic patients in need of limb salvage. Technical success was defined as < 20% residual vessel stenosis. Clinical success was defined as the avoidance of amputation and achievement of wound healing. At hospital discharge, patients were treated with Coumadin and aspirin. Ankle-brachial index (ABI) and TCO2 measurements were obtained before and after the intervention. RESULTS: After 12-month follow-up, six patients had presistent wounds, whereas 23 experienced wound healing. Forty of the 50 infrapopliteal arteries successfully dilated were occluded, with a mean (+/-SD) lesion length of 18.0 +/- 3.5 cm. After the procedure, TCO2 improved from 27.82 +/- 9.97 mm Hg (95% confidence interval [CI] 23.95 to 31.69) to 54.5 +/- 14.73 mm Hg (95% CI 48.79 to 60.21, p < 0.0001), whereas the ABI did not (p > 0.2). TCO2 predicted procedural and clinical success (p < 0.0182). CONCLUSIONS: Infrapopliteal transcatheter interventions in diabetic patients may salvage the majority of limbs doomed to amputation. Although TCO2 measurements are valuable in predicting wound healing and success after interventions, ABI measurements are not.

Angiography↗
PubMed1997

Pharmacological and clinical impact of the unique molecular structure of a new plasminogen activator.

Thrombolytic therapy has been recognized as a significant improvement in the management of acute myocardial infarction. Thrombolytic agents however have been limited by short half-lives that necessitate complex administration protocols and by the potential for bleeding complications. The native t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding. Reteplase is a third-generation recombinant mutant of tissue-type plasminogen activator (t-PA) that is expressed in Escherichia coli cells and consists of the kringle 2 and the protease domains of t-PA. Compared with t-PA, reteplase has a lower fibrin binding, which may translate to improved clot penetration. As well as a longer half-life and a more rapid initiation of thrombolysis. Preclinical pharmacology studies have indicated that reteplase has potent in vivo thrombolytic activity and leads to rapid reperfusion; these findings have been confirmed by promising results obtained in large-scale clinical trials. Other new agents developed by modifying the native t-PA molecule include the n-PA and the TNK mutants of t-PA. These novel, genetically modified thrombolytic agents all lyse clots better than the native t-PA; however, they differ with respect to their half-lives and fibrin-binding activity. Although all the third-generation thrombolytic agents have shown considerable potential in improving the efficacy of thrombolytic therapy, their risk of intracranial bleeding remains problematic and is still somewhat uncertain.

Amino Acid Sequence↗
PubMed1997

Clinical trial results with a new plasminogen activator.

Thrombolysis has become an accepted form of therapy for acute myocardial infarction. As demonstrated in the Global Utilization of Streptokinase and t-PA for Occluded Arteries trial, early, complete and sustained patency of the infarct-related coronary artery is correlated with reduced mortality. However, current thrombolytic regimens are able to achieve such patency within 90 min in only 81% of cases. To improve the risk/benefit ratio of thrombolytic therapy, newer agents such as reteplase have been developed to establish more rapid, more complete and more stable coronary artery patency, thus reducing mortality. This report summarizes the pharmacological properties of reteplase. It also summarizes the findings from various animal and clinical studies in which reteplase was compared with alteplase and streptokinase and the findings from animal and clinical studies evaluating infusion, single-bolus, double-bolus, doses of reteplase.

Amino Acid Sequence↗
PubMed1997

Reteplase (r-PA): a new plasminogen activator.

Reteplase (r-PA) is a genetically engineered deletion mutant of wild-type tissue-type plasminogen activator. The structural differences lead to different functional properties, such as a prolonged half-life. The compound demonstrated good thrombolytic efficacy in in vitro as well as in animal studies. In angiographically controlled patency studies (GRECO, GRECO-2 RAPID-1, RAPID-2), the double-bolus application scheme was established, and a superior patency profile for reteplase in comparison to alteplase was demonstrated. Mortality studies established reteplase as a safe drug with a 30-day mortality at least equivalent to streptokinase (INJECT) and very similar to alteplase (GUSTO-3). A possible advantage may be the double-bolus application without a need for weight adjustment, especially in a prehospital setting. Thus, reteplase can be regarded as an excellent alternative to streptokinase or alteplase for thrombolytic therapy in acute myocardial infarction.

Journal Article↗
PubMed1996

Molecular biology of plasminogen activators: what are the clinical implications of drug design?

The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials.

Animals↗
PubMed1996

Patency trials with reteplase (r-PA): what do they tell us?

Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.

Cerebral Hemorrhage↗
PubMed1996

Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. The RAPID II Investigators.

BACKGROUND: The therapeutic benefit of thrombolytic therapy has been shown to correlate directly with completeness (TIMI grade 3 flow) and speed of reperfusion of the infarct-related coronary artery. The purpose of the RAPID II study was to determine whether a double-bolus regimen of reteplase, a recently developed deletion mutant of wild-type tissue plasminogen activator, could improve 90-minute coronary artery patency rates achieved with the most successful standard regimen, an "accelerated" front-loaded infusion of alteplase. METHODS AND RESULTS: Three hundred twenty-four patients with acute myocardial infarction were randomized to receive (along with intravenous heparin and aspirin) either a 10 plus 10 megaunits double bolus of reteplase or front-loaded alteplase. The primary end point of "patency at 90 minutes, graded according to the TIMI classification" was centrally assessed in a blinded fashion. Infarctrelated coronary artery patency (TIMI grade 2 or 3) and complete patency (TIMI grade 3) at 90 minutes after the start of thrombolytic therapy were significantly higher in the reteplase-treated patients (TIMI grade 2 or 3: 83.4% versus 73.3% for front-loaded alteplase-treated patients, P = .03; TIMI grade 3: 59.9% versus 45.2%, P = .01). At 60 minutes, the incidence of both, patency and complete patency, was also significantly higher in reteplase-treated patients (reteplase versus alteplase, TIMI grade 2 or 3: 81.8% versus 66.1%, P = .01; TIMI grade 3: 51.2% versus 37.4%, P < .03). Reteplase-treated patients required fewer acute additional coronary interventions (13.6% versus 26.5%, P < .01), and 35-day mortality was 4.1% for reteplase and 8.4% for alteplase (P = NS). There were no significant differences between reteplase and alteplase in bleedings requiring a transfusion (12.4% versus 9.7%) or hemorrhagic stroke (1.2% versus 1.9%). CONCLUSIONS: Reteplase, when given as a double bolus of 10 plus 10 megaunits to patients with acute myocardial infarction, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and requires significantly fewer acute coronary interventions than front-loaded alteplase without an apparent increased risk of complications.

Adult↗
PubMed1996

Coronary thrombi increase PTCA risk. Angioscopy as a clinical tool.

BACKGROUND: The presence of angiographically identified intracoronary thrombus has been variably associated with complications after coronary angioplasty. Angiography has been shown to be less sensitive than angioscopy for detecting subtle details of intracoronary morphology, such as intracoronary thrombi. The clinical importance of thrombi detectable by angioscopy but not by angiography is not known. METHODS AND RESULTS: Percutaneous coronary angioscopy was performed in 122 patients undergoing conventional coronary balloon angioplasty (PTCA) at six medical centers. Unstable angina was present in 95 patients (78%) and stable angina in 27 (22%). Therapy was not guided by angioscopic findings, and no patient received thrombolytic therapy as an adjunct to angioplasty. Coronary thrombi were identified in 74 target lesions (61%) by angioscopy versus only 24 (20%) by angiography. A major in-hospital complication (death, myocardial infarction, or emergency bypass surgery) occurred in 10 of 74 patients (14%) with angioscopic intracoronary thrombus, compared with only 1 of 48 patients (2%) without thrombi (P = .03). In-hospital recurrent ischemia (recurrent angina, repeat PTCA, or abrupt occlusion) occurred in 19 of 74 patients (26%) with angioscopic intracoronary thrombi versus only 5 of 48 (10%) without thrombi (P = .03). Relative risk analysis demonstrated that angioscopic thrombus was strongly associated with adverse outcomes (either a major complication or a recurrent ischemic event) after PTCA (relative risk, 3.11; 95% CI, 1.28 to 7.60; P = .01) and that angiographic thrombi were not associated with these complications (relative risk, 0.85; 95% CI, 0.36 to 2.00; P = .91). CONCLUSIONS: The presence of intracoronary thrombus associated with coronary stenoses is significantly underestimated by angiography. Angioscopic intracoronary thrombi, the majority of which were not detected by angiography, are associated with an increased incidence of adverse outcomes after coronary angioplasty.

Adult↗
PubMed1996

Rotational atherectomy with a new device: initial clinical experience.

The Bard Atherectomy Catheter is a new rotational atherectomy device that consists of a flexible, hollow, thin-walled cutting catheter that, while rotated at 1,500 revolutions per minute, is advanced across the lesion over a special spiral guidewire system. We report the initial clinical experience with this device in 20 peripheral lesions in ten patients. The majority of patients were treated for limb salvage. All lesions were successfully intervened on by atherectomy followed by adjunctive balloon angioplasty. A reduction to less than 50% stenosis was achieved in 13 of the 20 lesions (65%) after atherectomy but in all 20 lesions (100%) after adjunctive angioplasty for all lesions and stenting for dissections in two. Baseline minimal lesion lumen diameter was 0.8 +/- 0.7 mm with a reference vessel diameter of 4.2 +/- 1.7 mm (75 +/- 21% stenosis). The lumen improved to 2.0 +/- 0.8 mm (45 +/- 19% stenosis) (P < 0.001) following atherectomy and to 3.9 +/- 1.9 mm (13 +/- 16% stenosis) (P < 0.001) after adjunctive angioplasty. The average weight of removed atheroma was 45 +/- 58 mg. All ten patients had initial improvement in symptoms. At 6 months follow-up there was persistent improvement in eight patients and two subjects had undergone amputations. Our early clinical experience with this low profile, flexible atherectomy device, that enables extraction of a large amount of atheroma, suggests that it will become a valuable addition to current atherectomy technologies in small- and medium-sized vessels. The value of this device in coronary vessels is under investigation.

Angioplasty, Balloon↗
PubMed1996

Comparison of angioscopy, intravascular ultrasound imaging and quantitative coronary angiography in predicting clinical outcome after coronary intervention in high risk patients.

OBJECTIVES: The purpose of this study was to identify qualitative or quantitative variables present on angioscopy, intravascular ultrasound imaging or quantitative coronary arteriography that were associated with adverse clinical outcome after coronary intervention in high risk patients. BACKGROUND: Patients with acute coronary syndromes and complex lesion morphology on angiography are at increased risk for acute complications after coronary angioplasty. Newer devices that primarily remove atheroma have not improved outcome over that of balloon angioplasty. Intravascular imaging can accurately identify intraluminal and intramural histopathologic features not adequately visualized during coronary arteriography and may provide mechanistic insight into the pathogenesis of abrupt closure and restenosis. METHODS: Sixty high risk patients with unstable coronary syndromes and complex lesions on angiography underwent angioscopy (n = 40) and intravascular ultrasound imaging (n = 46) during interventional procedures. In 26 patients, both angioscopy and intravascular ultrasound were performed in the same lesion. All patients underwent off-line quantitative coronary arteriography. Coronary interventions included balloon (n = 21) and excimer laser (n = 4) angioplasty, directional (n = 19) and rotational (n = 6) atherectomy and stent implantation (n = 11). Patients were followed up for 1 year for objective evidence for recurrent ischemia. RESULTS: Patients whose clinical presentation included rest angina or acute myocardial infarction or who received thrombolytic therapy within 24 h of procedure were significantly more likely to experience recurrent ischemia after intervention. Plaque rupture or thrombus on preprocedure angioscopy or angioscopic thrombus after intervention were also significantly associated with adverse outcome. Qualitative or quantitative variables on angiography, intravascular ultrasound or off-line quantitative arteriography were not associated with recurrent ischemia on univariate analysis. Multivariate predictors of recurrent ischemia were plaque rupture on preprocedure angioscopy (p < 0.05, odds ratio [OR] 10.15) and angioscopic thrombus after intervention (p < 0.05, OR 7.26). CONCLUSIONS: Angioscopic plaque rupture and thrombus were independently associated with adverse outcome in patients with complex lesions after interventional procedures. These features were not identified by either angiography or intravascular ultrasound.

Angioplasty, Balloon, Coronary↗
PubMed1996

Reduction of canine infarct size by bolus intravenous administration of liposomal prostaglandin E1: comparison with control, placebo liposomes, and continuous intravenous infusion of prostaglandin E1.

Prostaglandin E1 (PGE1) reduces experimental infarct size when administered by prolonged low-dose left atrial infusion during coronary occlusion. Liposomal delivery of PGE1 may enhance biologic activity and limit adverse hemodynamic effects. The purpose of this study was to test the hypothesis that intravenous bolus administration of liposomal PGE1 (TLC C-53, The Liposome Company, Princeton, N.J.) during coronary occlusion would result in myocardial salvage. We compared TLC C-53 (0.5 microgram/kg intravenous bolus at 10 and 100 min of occlusion of the left anterior descending coronary artery [LAD]), free PGE1 (0.1 microgram/kg/min infused 10 min after LAD occlusion until reperfusion), placebo liposomes, and control (n = 7 for each group) in an open-chest canine model of 2 hours of LAD occlusion and reperfusion. Infarct size as a percentage of risk area (mean +/- SD) in the control group (58.4% +/- 20.0%) was similar to that in animals given placebo liposomes (53.1% +/- 12.6%) but was significantly reduced in the groups given TLC C-53 (33.5% +/- 9.2%; p < 0.01) or free PGE1 (37.2% +/- 4.8%; p < 0.05) groups. Infarct salvage was significant (p < 0.05) for the TLC C-53-and PGE1-treated dogs compared with the control dogs, independent of collateral blood flow by analysis of covariance. Moreover, the ischemic-zone blood flow during reperfusion was significantly higher in the TLC C-53 group compared with the control group or the group receiving free PGE1. Neutrophil infiltration of ischemic myocardium was significantly inhibited by TLC C-53 as determined by myeloperoxidase assay. Unlike free PGE1, TLC C-53 did not cause significant tachycardia or hypotension during therapy. In conclusion, TLC C-53 administered intravenously during coronary occlusion significantly reduced infarct size, limited neutrophil infiltration, and improved myocardial blood flow during reperfusion without adverse hemodynamic consequences.

Alprostadil↗
PubMed1996

The future of thrombolysis in the treatment of acute myocardial infarction.

The ability of thrombolytic therapy to lower mortality in patients with acute myocardial infarction was first demonstrated in 1986 by the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. In the ensuing 10 years, large efforts have been undertaken to develop more effective and safer thrombolytic agents. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes was demonstrated, and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and on genetically engineered third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients who are currently considered ineligible, and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to those of mechanical reperfusion strategies will require constant reassessment while both forms of treatment develop.

Fibrinolytic Agents↗