Agents In Acute Myocardial Infarction Research Articles

Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. Thus we investigated effects of ivabradine, a presumably specific bradycardic agent versus metoprolol, a β-blocker, at doses offering the same heart rate (HR) reduction, on ventricular arrhythmias in the acute non-reperfused MI in the rat. Immediately after MI induction a single dose of ivabradine/ metoprolol was given. ECG was continuously recorded and ventricular arrhythmias were analyzed. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca2+ handling was assessed. Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. Both drugs reduced QTc prolongation and decreased sensitivity of ryanodine receptors in isolated cardiomyocytes, but otherwise had no effect on Ca2+ handling, velocity of conduction or repolarization. We did not find any effects of potential IKr inhibition by ivabradine in this setting. Thus Ivabradine is an equally effective antiarrhythmic agent as metoprolol in early MI in the rat. It could be potentially tested as an alternative antiarrhythmic agent in acute MI when β-blockers are contraindicated.

Treatment with 3-Bromo-4,5-Dihydroxybenzaldehyde Improves Cardiac Function by Inhibiting Macrophage Infiltration in Mice

Background and ObjectivesAppropriate inflammatory response is necessary for cardiac repairing after acute myocardial infarction (MI). Three-Bromo-4,5-dihydroxybenzaldehyde (BDB) is a potent antioxidant and natural bromophenol compound derived from red algae. Although BDB has been shown to have an anti-inflammatory effect, it remains unclear whether BDB affects cardiac remolding after MI. The aim of this study was to investigate the potential role of BDB on cardiac function recovery after MI in mice.MethodsMice were intraperitoneally injected with BDB (100 mg/kg) or vehicle control respectively 1 hour before MI and then treated every other day. Cardiac function was monitored by transthoracic echocardiography at day 7 after MI. The survival of mice was observed for 2 weeks and hematoxylin and eosin (H&E) staining was used to determine the infarct size. Macrophages infiltration was examined by immunofluorescence staining. Enzyme-linked immunosorbent assay (ELISA) was used to test the production of cytokines associated with macrophages. The phosphorylation status of nuclear factor (NF)-κB was determined by western blot.ResultsBDB administration dramatically improved cardiac function recovery, and decreased mortality and infarcted size after MI. Treatment with BDB reduced CD68+ macrophages, M1 and M2 macrophages infiltration post-MI, and suppressed the secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, and IL-6 in the injured hearts. Furthermore, BDB inhibited the phosphorylation of NF-κB in the infarcted hearts.ConclusionsThese data demonstrate, for the first time, that BDB treatment facilitated cardiac healing by suppressing pro-inflammatory cytokine secretion, and indicate that BDB may serve as a therapeutic agent for acute MI.

Early treatment with Resolvin E1 facilitates myocardial recovery from ischaemia in mice.

An appropriate inflammatory response is necessary for cardiac healing after acute myocardial infarction (MI). Resolvin E1 (RvE1) is an anti-inflammatory and pro-resolution lipid mediator derived from eicosapentaenoic acid. Here we have investigated the effects of RvE1 on the recovery of cardiac function after MI in mice. Acute MI was induced by surgical ligation of the left anterior descending artery in male C57BL/6 mice. RvE1 (5ng·g-1 ·day-1 ; i.p.) was given to mice at different times following MI. Cardiac function was monitored by transthoracic echocardiography at days 3, 7 and 14 after MI. Effects of RvE1 on the migration of subpopulations of monocytes/macrophages (Mos/Mps, Ly6Chi and Ly6Clow ) were examined by flow cytometry and transwell assay. RvE1 administration from days 1 to 7 post-MI improved cardiac function, whereas treatment from days 7 to 14 markedly inhibited recovery of cardiac function. Early treatment with RvE1 post-MI suppressed the infiltration of dominant Ly6Chi Mos/Mps and secretion of pro-inflammatory cytokines in injured hearts, which protected cardiomyocytes against apoptosis in the peri-infarct zones. Contrastingly, treatment with RvE1 1week after MI decreased infiltration of Ly6Clow Mos/Mps and expression of pro-angiogenic factors in cardiac tissue, consequently reducing neovascularization in the peri-infarct zones. Additionally, RvE1 inhibited Mp migration by activating ChemR23 receptors. Treatment with RvE1 during the initial 7days after MI facilitated cardiac healing by suppressing pro-inflammatory cytokine secretion, indicating that RvE1 may serve as an early therapeutic agent for acute MI. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Morphine Does Not Affect Myocardial Salvage in ST-Segment Elevation Myocardial Infarction.

Recent studies have proposed intravenous (IV) morphine is associated with delayed action of antiplatelet agents in acute myocardial infarction. However, it is unknown whether morphine results in increased myocardial damage in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated myocardial salvage index (MSI) to determine whether IV morphine affects myocardial injury adversely in STEMI patients undergoing primary PCI. 299 STEMI patients underwent contrast-enhanced magnetic resonance imaging a median of 3 days after PCI. Infarct size was measured on delayed-enhancement imaging, and area at risk was quantified on T2-weighted imaging. MSI was calculated as ‘[area at risk–infarct size] X 100 / area at risk’. IV morphine was administrated in 32.1% of patients. Patients treated with morphine had shorter symptom to balloon time and higher prevalence of Thrombolysis in Myocardial Infarction flow grade 0 or 1. The morphine group showed a trend toward larger MSI and infarct size and significantly greater area at risk than the non-morphine group. After propensity score matching (90 pairs), MSI was similar between the morphine and non-morphine group (46.1% versus 43.5%, P = .11), and infarct size and area at risk showed no difference. In propensity score-matched analysis, IV morphine prior to primary PCI in STEMI patients did not cause adverse impacts on myocardial salvage.

Glucoseinsulin Mixture as a Cardioprotective Agent in Cardiology and Cardiac Surgery (Review)

The literature review presents an analysis of publications describing the use of a glucose%insulin mixture as a cardioprotective agent in acute myocardial infarction and in cardiac surgeries with extracorporeal circulation (ECC). It summarizes historical aspects of implementation of the glucose%insulin therapy in cardiology and car% diac surgery. Possible mechanisms of action of the glucose-insulin-potassium mixture in acute ischemia and myocardial infarction were analyzed (normalization of electrical processes on the cardiomyocyte membrane, replenishment of metabolic substrates and increased production rate of adenosine triphosphoric acid due to glycolysis, decreased intensity of non%esterified fatty acid oxidation, decreased apoptosis, etc.). It discusses results of clinical studies evaluating prescription of the mixture for acute myocardial infarction, including data from metaanalyses. It demonstrated that the role and the clinical efficacy of the preventive and therapeutic measure under consideration in acute myocardial infarction are still the subject of discussion and require further research. It also analyzed modern concepts explaining the cardioprotective effects of insulin and glucose during surgeries with ECC (decreased insulin resistance, activation of anaplerosis, stimulation of intracellular signaling pathways maintaining the viability of cells, reduction of the severity of systemic inflammatory response, immunomodulating effect, etc.). Review discusses results of clinical studies including data from randomized clinical trials and metaanalyses performed over the last 5 years that demonstrated the absence of the effect of the glucose%insulin therapy on the hospital mortality. Various studies demonstrated its positive effects including decreased incidence of peri% operative myocardial infarctions and intensity of inotropic support, increased values of postoperative cardiac index, decreased duration of postoperative mechanical ventilation and ICU stay, etc. Review concludes that the interest to the therapeutic and preventive use of the glucose%-nsulin mixture in both emergency cardiology and cardiac surgery has been revived recently.

HTUPA as a new thrombolytic agent for acute myocardial infarction: A multicenter, randomized study

BackgroundIt is necessary to develop a new thrombolytic agent which can be used by a single bolus at first aid sites to decrease the time to reperfusion in clinical practice. HTUPA, a genetically engineered new thrombolytic with a longer half-life, is well qualified. We aim to compare the thrombolytic efficacy and safety of human tissue urokinase type plasminogen activator (HTUPA) to recombinant tissue plasminogen activator (rt-PA) in Chinese patients with acute myocardial infarction (AMI). MethodsAMI patients (n=221) were randomized to rt-PA (a standard protocol) or HTUPA (25mg bolus) treatment groups. All patients also received oral aspirin and intravenous heparin. Coronary angiography was performed 90min after therapy initiation to determine infarct-related coronary artery (IRA) patency. Clinical outcomes and changes of clotting variables, heart rate, blood pressure, left ventricular ejection fraction (LVEF), and electrocardiogram were evaluated. ResultsPatent IRA [thrombolysis in myocardial infarction (TIMI) grade 2 or 3] was observed in 77% of HTUPA-treated patients, compared to 76% of rt-PA-treated patients (P=0.76). TIMI grade 3 patency rates were 52% and 44% in the HTUPA and rt-PA groups, respectively (P=0.37). The total patency rate was 77% (86/111 patients) in the HTUPA group and 73% (80/110 patients) in the rt-PA group (P=0.41). Adverse events were infrequent in both groups, and no significant differences were detected in mortality, re-occlusion rate, revascularization rate, adverse effects, clotting index, LVEF, or electrocardiogram between the two groups. ConclusionsIntravenous HTUPA had a safe and efficacious profile as good as rt-PA in patients with AMI.

Glucocorticoid Protection Against Myocardial Ischemia-Reperfusion Injury

See related article, p 80–87 Endogenous glucocorticoids have long been recognized to play a pivotal role in orchestrating an adaptive response of the host to stress, from trauma and infection to inflammation. Therefore, it is not surprising that glucocorticoids received considerable attention as potential therapeutic agents for acute myocardial infarction. Numerous studies documented their ability to protect the heart from ischemia-reperfusion injury in many animal and in vitro models.1 However, clinical trials with glucocorticoids for the treatment of acute myocardial infarction have yielded inconsistent results, with both a small beneficial effect on mortality and adverse influence on longer term remodeling being reported.2 A likely explanation for these discrepant observations is that the benefits of local anti-inflammatory actions of glucocorticoids in the ischemic heart are offset by adverse systemic effects. Thus, understanding of the mechanisms underlying local protective actions of glucocorticoids is of particular importance. In most cell types, glucocorticoids suppress prostaglandin biosynthesis that contributes to dampening of inflammation. By contrast, glucocorticoids were found to upregulate cycloxoygenase-2 expression in rodent cardiomyocytes and exert cytoprotective effects via activation of lipocalin-type prostaglandin D (PGD) synthase–mediated PGD2 synthesis.3 However, PGD2 receptors and downstream signaling pathways have not been characterized in this study. In this issue of Hypertension , Katsumata et al4 fill this important gap in our knowledge by demonstrating that the cardioprotective actions of endogenous PGD2 are mediated predominantly through activation …

Current State of Clinical Translation of Cardioprotective Agents for Acute Myocardial Infarction

There is continued interest in the concept of limiting myocardial infarct size with adjunctive agents administered along with reperfusion injury; however, there remains considerable controversy in the literature. The purpose of this article is to review the medical literature on clinical trials performed during the past 3 years that have attempted to reduce myocardial infarct size by administration of adjunctive therapies along with reperfusion therapy. A PubMed-driven literature search revealed a host of clinical trials focusing on the following prominent types of therapies: endogenous conditioning (postconditioning and remote ischemic conditioning); rapid cooling; pharmacological therapy (cyclosporine, abciximab, clopidogrel, tirofiban, erythropoietin, thrombus aspiration, adenosine, glucose-insulin-potassium, statins, antidiabetic agents, FX06, iron chelation, and ranolazine). Although there remains some controversy, quite a few of these studies showed that adjunctive therapy further reduced myocardial infarct size when coupled with reperfusion. Antiplatelet agents are emerging as some of the newest agents that seem to have cardioprotective capabilities. Postconditioning has become a bit more controversial in the clinical literature; remote conditioning, early and rapid cooling, adenosine, and ranolazine are intriguing therapies deserving of larger studies. Certain agents and maneuvers, such as erythropoietin, protein kinase C δ inhibitors, iron chelation, and intra-aortic balloon counterpulsation, perhaps should be retired. The correct adjunctive therapy administered along with reperfusion has the capability of further reducing myocardial injury during ST-segment-elevation myocardial infarction.

Abstract 223: National and Regional Trends in Hospitalizations for Hemorrhagic Stroke after Acute Myocardial Infarction in the United States: 1999-2010

Background: Elderly survivors of acute myocardial infarction (AMI) are at elevated risk for hemorrhagic stroke, which has a mortality rate of approximately 50%. Increasing use of warfarin for arterial fibrillation and anti-platelet agents for AMI combined with an increasing aging population may have influenced the risk of post-AMI strokes. We sought to characterize temporal trends in the risk for and mortality from hemorrhagic stroke over 12 years among older AMI survivors of different age, sex, race, revascularization status, and region within the US. Methods: We used 100% of Medicare inpatient claims data to identify all fee-for-service (FFS) patients aged&gt; 64 years who were hospitalized for AMI in 1999-2010. We excluded patients who died during the hospitalization or were transferred. Revascularization procedures were identified during the index admission. We used a Cox proportional-hazards regression model to estimate the risk-adjusted annual changes in one-year hemorrhagic stroke hospitalization after AMI, overall and by subgroups. Changes were adjusted by age, gender, race, medical history and comorbidities. We calculated the 30-day mortality among patients readmitted for hemorrhagic stroke. Stroke belt regions were defined as the states with high stroke hospitalization rates in the southeast United States. Results: Among 2,433,036 AMI hospitalizations and 4,852 hemorrhagic stroke readmissions, the risk-adjusted one-year post-AMI hemorrhagic stroke rate remained stable from 1999 to 2010 (range, 0.2% to 0.3%). No significant trends were found for post-AMI stroke rates across all age-sex-race groups and all treatment groups (Figure). Thirty-day mortality rates for stroke after AMI did not show significant changes (1999, 46.7%, 95% CI 39.9%-53.7%; 2010, 50.7%, 95% CI 45.3%-56.1%; range: 46.5% to 54.6%). No difference was found in post-AMI hemorrhagic stroke rates between the stroke belt and non-stroke belt regions. Conclusions: From 1999 to 2010, the overall hospitalization rates of hemorrhagic stroke after AMI were relatively stable without significant changes across all subgroups. Thirty-day mortality rates remained largely unchanged over time. Stroke risk in the stroke belt was not found significantly higher comparing with non-stroke belt states.

Response to thrombolytic agents in acute myocardial infarction in opium abusers versus non-abusers.

Objective:Coronary artery disease is one of the leading causes of morbidity and mortality in populations. In opium abusers, level of circulating coagulation factors differs from non-abusers. The aim of this study was to evaluate response to thrombolytic therapy in opium abusers vs. non-abusers.Methods:In this prospective observational study, 83 patients (36 opium abusers and 47 non-abusers) with AMI were evaluated for the presence and degree of response to thrombolytic agent. All patients were monitored for electrocardiographic changes and response to thrombolysis 2 hours before and after administration of thrombolytic agent. Serum CPK and LDH were measured 2 hours before and after thrombolysis. Quantitative and qualitative data were analyzed by independent t-test and chi-square using SPSS, respectively.Findings:ST-resolution 2 hours after thrombolysis was 63.8% and 44.4% in opium users and non-users, respectively. Serum level of CPK cardiac biomarker 2 hours after thrombolysis was 980 ± 245 and 847 ± 130 IU/L in opium users and non-users, respectively.Conclusion:Our data demonstrate that in those patients with opium abuse, electrocardiographic changes after thrombolysis were significantly lower than opium non-users (P < 0.05). Opium users showed better ST-resolution compared with non-users. Opium addiction had effect on cardiac enzymes despite their effect on response to streptokinase.

Management of Antiplatelet Therapy During Acute Percutaneous Coronary Intervention: New Strategies and Therapeutics

Aggressive intravenous and oral dual antiplatelet therapy has established primary percutaneous coronary intervention (PCI) as the standard of care for acute myocardial infarction. Clopidogrel is currently the thienopyridine of choice for dual antiplatelet therapy in patients treated with PCI. The dose regime and duration of therapy of clopidogrel has undergone multiple refinements. Recently, 2 novel third generation oral inhibitors of P2Y12 receptors, prasugrel and ticagrelor, have undergone clinical evaluation with promising results. This article is a non-exhaustive review of the literature, concentrating on the role of current and novel oral antiplatelet agents for acute myocardial infarction particularly highlighting the limitations and issues associated with clopidogrel use.

Recombinant expression of rt-PA gene (encoding Reteplase) in gametophytes of the seaweed Laminaria japonica (Laminariales, Phaeophyta).

The life cycle of seaweed Laminaria japonica involves a generation alternation between diploid sporophyte and haploid gametophte. The expression of foreign genes in sporophte has been proved. In this research, the recombinant expression in gametophyte was investigated by particle bombardment with the rt-PA gene encoding the recombinant human tissue-type plasminogen activator (Reteplase), which is a thrombolytic agent for acute myocardial infarction (AMI). Transgenic gametophytes were selected by their resistance to herbicide phosphiothricin (PPT), and proliferated in an established bubble column photo-bioreactor. According to the results from quantitative ELISA, Southern blotting, and fibrin agarose plate assay (FAPA) for bioactivity, it was showed that the rt-PA gene had been integrated into the genome of gametophytes of L. japonica, and the expression product showed the expected bioactivity, implying the proper post-transcript modification in haploid gametophyte.

Glucose-Insulin-Potassium for Acute Myocardial Infarction

The “holy grail” in the field of cardioprotection is to develop pharmacological agents that can be administered as adjunctive treatment to reperfusion that will reduce myocardial infarct size and improve clinical outcomes. Numerous pharmacological agents and strategies have been studied over the years with variable results in both animal models and humans. Of drugs that have been studied, only a few have shown benefit in clinical trials. Aside from agents or devices than can restore and maintain reperfusion (thrombolytics, balloons, stents, aspirin, clopidogrel, IIb/IIIa inhibitors, low–molecular-weight heparin, and others), the only commonly used adjunctive agents shown to have cardioprotective effects when administered early after coronary occlusion and in addition to reperfusion are β-blockers. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are also used, but these can be given after infarction (as late as 1 week) and must be continued long-term to reduce left ventricular remodeling. Recently, adenosine and induced hypothermia have also shown promise as early adjunctive agents. For example, when intravenous adenosine was coupled with early reperfusion therapy, myocardial infarct size by single-photon emission computed tomography analysis and the composite end point of death and heart failure were reduced at 6 months.1 Hypothermia, induced by use of a heat-exchange cooling catheter, benefited a subgroup of patients who were successfully cooled to ≤35°C before reperfusion.2 Superoxide dismutase, magnesium, inhibitors of neutrophil adhesion, complement inhibitors, fluosol, RheothRx, the KATP channel/nitrate nicorandil, and others failed to show a benefit as adjuncts to reperfusion.3 Clinical research evaluating many of these agents in acute myocardial infarction has halted. One of the most controversial of these adjunctive agents still under investigation is GIK (glucose-insulin-potassium),4,5 a “cocktail” delivered at the time of infarction that has demonstrated variable results in both the prereperfusion and postreperfusion eras. GIK was one of the first …

Risks of treatment with beta-blocking agents in acute myocardial infarction (author's transl)

Haemodynamic investigations were performed in 40 patients with acute myocardial infarction before and after intravenous application of 6 mg propranolol. Cardiac index was significantly decreased caused by reduction of cardiac frequency and stroke volume. Pulmonary capillary pressure increased significantly. As a consequence pulmonary and peripheral vascular resistance increased. Arterial blood pressure remained largely unaffected. Propranolol showed a haemodynamically beneficial decrease of left ventricular stroke work without signs of negative cardiodepression at a cardiac index of more than 3.0 l/min . m2. At a cardiac index of less than 3.0 l/min . m2 a haemodynamically detrimental lowering of cardiac index to ranges of insufficiency of 2.0 l/min . m2 on average occurred. Thus cardiac index is an important factor for the decision of use of beta-blocking agents in acute myocardial infarction. Indiscriminate use of beta-blocking substances should not be accepted.

Clinical and biochemical predictors affect the choice and the short-term outcomes of different thrombolytic agents in acute myocardial infarction

The presence of plasminogen activator inhibitor-1, angiotensin-converting enzyme and others may play a role in unsuccessful recanalization after thrombolytic therapy. To find out the clinical and biochemical predictors that may affect the choice and short-term outcomes following different thrombolytic agents in acute myocardial infarction. Angiotensin-converting enzyme and plasminogen activator inhibitor-1 plasma levels of 184 patients with acute myocardial infarction, treated with streptokinase, metalyze or reteplase, were determined. Failure of thrombolysis was assessed by noninvasive reperfusion criteria. Prolonged hospitalization, impaired left ventricular ejection fraction and reinfarction were considered as short-term outcomes. Patients who received streptokinase developed higher incidence of >50% resolution of ST-segment elevation (82.5 vs. 64.7%, P-value<0.05, in comparison with metalyze and 82.5 vs. 55.7%, P-value 0.001, in comparison with reteplase) than those who received other thrombolytic agents. High plasma angiotensin-converting enzyme was associated with prolonged hospitalization (55, 63 and 94%, P<0.02) following streptokinase, metalyze and reteplase, respectively. High plasma plasminogen activator inhibitor-1 is associated with impaired left ventricular ejection fraction (55.3, 76.7 and 68.5%, P<0.09), ST resolution<50% (13.2, 36.7 and 37.5%, P=0.03), ST resolution>50% (86.8, 63.3 and 62.5%, P=0.03) following streptokinase, metalyze and reteplase, respectively. Rapid determination of pretreatment angiotensin-converting enzyme and plasminogen activator inhibitor-1 plasma levels in patients with acute myocardial infarction may influence the choice and outcomes of the thrombolytic agents. The presence of a high plasma level of either angiotensin-converting enzyme or plasminogen activator inhibitor-1 is significantly associated with adverse short-term outcomes after treatment with reteplase or metalyze.

Comparison of carvedilol and metoprolol in patients with acute myocardial infarction undergoing primary coronary intervention

The value of early therapy with beta-blocking agents in acute myocardial infarction (AMI) undergoing reperfusion is not yet well established. Newer beta-blocking agents such as carvedilol offer potential advantages in the setting of ischemia and reperfusion injury. We randomized 100 patients with acute ST-elevation myocardial infarction (STEMI) to receive either 12.5 mg carvedilol or 50 mg metoprolol tartrate orally already before percutaneous coronary intervention (PCI) of the infarct-related artery, uptitrating to a daily target dose of 50 mg carvedilol or 150 mg metoprolol during the first week. Pts. were subjected to left ventricular (LV) angiography just before reperfusion and after 14 days to compare ejection fraction (EF) and regional wall motion abnormalities by quantitative LV analysis. Furthermore, kinetics of cardiac troponin T (cTnT), NT-proANP, NT-proBNP, endothelin, argenine vasopressin, epinephrine and norepinephrine were assessed during the first 12 hours and again at 2 weeks. In addition, reperfusion-induced rhythm abnormalities like VT, triplets, couplets, and bradycardic events were assessed continuously during the first 12 hours starting at reperfusion by Holter analysis. Both groups did not differ with respect to onset of pain, target vessel, extent of coronary heart disease, age, gender, rate of stenting or use of a GP IIb/IIIa inhibitor, pre- and postinterventional TIMI flow grade, time course of heart rate or blood pressure. There were neither significant differences in the cardiac and neurohumoral markers nor in the occurrence of arrhythmias between both treatment groups. Within 14 days, EF improved by 5.8+/-2.0% (mean+/-SEM) in the metoprolol group and by 5.2+/-2.1% in the carvedilol group (n.s.). Area of infarction was reduced by 6.1+/-2.9% in the metoprolol group and by 12.8+/-3.6% of total LV outline in the carvedilol group (n.s.). Maximum hypokinesia in the central infarcted region was diminished by 0.40+/-0.11 standard deviation (SD) in the metoprolol group and by 0.34+/-0.13 SD in the carvedilol group (n.s.). In the setting of direct PCI in acute STEMI, administration of carvedilol before reperfusion appears not to be superior to metoprolol with respect to myocardial injury and improvement of global and regional LV function. The study documents equivalent improvement of LV function and similar kinetics of cardiac and neurohumoral markers in pts. with acute STEMI undergoing direct PCI if the pts. were immediately treated with either carvedilol or metoprolol. Thus, superiority of carvedilol in experimental studies did not translate into a clinical benefit.

Suspension culture of gametophytes of transgenic kelp in a photobioreactor.

Transgenic Laminaria japonica gametophytes producing a recombinant tissue-type plasminogen activator (rtPA) protein, which is an effective third-generation thrombolytic agent for acute myocardial infarction (AMI), were cultured in an illuminated bubble column bioreactor. A maximum final dry cell weight of 1120 mg l(-1) was obtained in batch culture with an initial dry cell weight of 126 mg l(-1) and with aeration rate of 1.2 l air min(-1 )l(-1) culture, nitrate at 1.5 mM: and phosphate at 0.17 mM: . The yield of rtPA was 56 microg g(-1) dry cell wt. This is the first report regarding cultivation of a transgenic macroalga in a bioreactor.

The platelet-related effects of tenecteplase versus alteplase versus reteplase

Clinical studies have investigated the combination of glycoprotein (GP) IIb/IIIa inhibitors and thrombolytic agents for acute myocardial infarction. However, thrombolytic agents alone may possess direct antiplatelet properties that could affect reperfusion. Blood from 11 patients with coronary disease and five healthy subjects was incubated for 30 min with tenecteplase (4, 12, and 24 microg/ml), alteplase (1, 4, and 10 microg/ml), reteplase (1, 5, and 10 microg/ml) or control buffer. Platelet aggregation induced by 1, 20 and 50 micromol/l adenosine diphosphate (ADP), the stimulated expression of GP IIb/IIIa and P-selectin, and plasma fibrinogen levels were determined. Platelet aggregation in patients was inhibited by medium and high concentrations of alteplase when induced by 1 micromol/l ADP [1.6 +/- 0.5%, P = 0.001 and 0.9 +/- 0.2%, P = 0.002 versus 8.3 +/- 1.6% (control)] and 20 micromol/l ADP [46.9 +/- 3.9%, P = 0.001 and 46.2 +/- 4.8%, P = 0.001 versus 65.7 +/- 2.7% (control)]. High concentration tenecteplase was associated with lower aggregation by 20 micromol/l ADP (58 +/- 2.1% versus control, P = 0.033). There were no changes in GP IIb/IIIa activation or P-selectin expression in patients or healthy subjects. Platelet aggregation (1 micromol/l ADP) in healthy subjects was inhibited only by high doses of alteplase (P = 0.001). Plasma fibrinogen levels were significantly decreased after treatment with reteplase at 1 microg/ml(1.53 +/- 0.21 versus 2.65 +/- 0.31, P = .009) and 5 microg/ml(1.55 +/- 0.16 versus 2.65 +/- 0.31, P = .005). Alteplase inhibits platelet aggregation more than tenecteplase and reteplase. The attenuation of platelet aggregation by alteplase is dissociated from the expression of activated GP IIb/IIIa and P-selectin, and by fibrinogen degradation. These results suggest that alteplase exerts its antiplatelet effect independent of GP IIb/IIIa and P-selectin expressions and fibrinogen degradation. These findings may be directly relevant to the effect of alteplase on reperfusion and to future studies using combined platelet inhibitors and thrombolytic therapy.

Diffusion of thrombolysis for acute myocardial infarction from 1981 to 2000 in England: Trend analysis and comparison with need

To describe the adoption and take up of thrombolytic agents for acute myocardial infarction since 1980 in England and compare use with the estimated ceiling of need. Data on national sales and use of thrombolysis since 1980 (supplied by IMS Health) was used to draw an adoption and diffusion curve. The epidemiological ceiling of acute myocardial infarction, from hospital activity statistics, was modified to an estimated clinical need by accounting for diagnostic difficulty and contraindications using information from published surveys of thrombolysis use in the United Kingdom. There was a rapid uptake of thrombolytic agents in the first 2 years after availability in 1987, then a plateau, followed by a rise to a peak use in 1995. The shortfall in doses resulting from the difference between estimated ceiling of clinical need and doses purchased and provided in the 14 years since availability is estimated as 167,800 (95 percent confidence range 94,000 to 241,700). Although there was a rapid initial uptake of thrombolysis in England, usage took 8 years to reach the ceiling of clinical need of 65 percent of patients with acute myocardial infarction, with many patients missing the opportunity to benefit. Monitoring of uptake of innovations known to be cost-effective is required to identify those developments that need additional stimulus for change to ensure that patients do not miss out on the opportunity to benefit.

Quality control of a detector for the calculations of radiopharmacokinetic parameters of99mTc-glucarate in rats

Good manufacturing practices specify that a well-type scintillation NaI(Tl) crystal detector has to be validated in order to detect radioactivity from any radiopharmaceutical used to obtain radiopharmacokinetic parameters. A 5 cm well-type NaI(Tl) scintillation detector was coupled to a multi-channel analyzer centered at the 140 keV 99mTc peak with a 20% window. The area represents counts per minute (cpm). All the net cpm were decay corrected. The activity source was 99mTc-glucarate developed as an imaging agent for acute myocardial infarction. Wistar rats were injected in a tail vein with 0.1 ml (3.7 MBq) of 99mTc-glucarate solution and 13 blood samples were taken. The cpm were the input data for the WINNONLN program which calculates radiopharmacokinetic parameters. The detector's efficiency for 99mTc was 15.03% and the sensitivity 1.12 kBq/ml in plasma. The response was linear between 0.31-14.3 kBq/ml of 99mTc-glucarate. The maximum assay variation coefficient was 2.79 and recovery of 99mTc-glucarate in plasma was 99.8%±0.2%. LOD was 0.31 kBq and LOQ = 1.12 kBq in plasma samples. 99mTc-glucarate follows a two-compartment model of distribution with Vd of 21.74 ml±2.71 ml; a Vdss of 74.36 ml±12.67 ml; t1/2a0.74 h±0.19 h; t1/2b 18.98 h±4.36 h; AUC = 32.75 mCi/min.ml ± 3.73 mCi/min.ml; MRT = 24.35 h±5.51 h and total clearance 3.05 ml/h±0.35 ml/h. The well-type detector fulfills the quality system requirements and the radiopharmacokinetic parameters for 99mTc-glucarate in rats are reliable.