A prospective, randomized, double-blind multicenter trial of a single bolus injection of the novel modified t-PA E6010 in the treatment of acute myocardial infarction: comparison with native t-PA. E6010 Study Group.

OBJECTIVES: This prospective, randomized, double-blind multicenter trial evaluated the efficacy and safety of a single bolus injection of the novel modified tissue-type plasminogen activator (t-PA) E6010 in the treatment of acute myocardial infarction compared with that of native t-PA. BACKGROUND: E6010 is a novel modified t-PA with a prolonged half-life (t1/2 alpha > or = 23 min) compared with native t-PA (t1/2 alpha = 4 min). E6010 can be administered in patients as a single intravenous bolus injection, and early recanalization can be expected. METHODS: The efficacy of E6010 was compared with that of native t-PA in 199 patients with acute myocardial infarction who were treated within 6 h of onset in a prospective, randomized, double-blind multicenter trial. Patients were given either 0.22 mg/kg body weight of E6010 intravenously over 2 min or native t-PA (tisokinase) 28.8 mg or 14.4 million IU (10% of the total dose over 1 to 2 min, the remainder infused over 60 min). RESULTS: The primary end point was the recanalization rate of the infarct-related coronary artery at 60 min after the start of treatment. Time to reperfusion was shorter in the E6010 group than in the native t-PA group. Thrombolysis in Myocardial Infarction flow grade 2 or 3 recanalization at 15, 30, 45 and 60 min after administration was observed in 37%, 62%, 74% and 79% (95% confidence interval [CI] 70% to 87%) of the E6010-treated patients and in 14%, 32%, 50% and 65% (95% CI 55% to 74%) of native t-PA-treated patients, respectively (p = 0.032 at 60 min). CONCLUSIONS: The present study indicates that, compared with native t-PA, a single bolus injection of E6010 over 2 min produces a higher rate of early recanalization of the infarct-related coronary artery without fatal bleeding complications.

A psychophysiological study of the development of delirium in coronary care units.

This is a longitudinal investigation of the psychophysiological mechanism for the development of delirium in coronary care units (CCUs). Ten patients satisfying DSM-III-R diagnostic criteria for delirium (group D) and 10 controls (group C) were drawn from patients admitted to CCU. Electroencephalogram (EEG) and eye movement recordings were observed over the days that patients were admitted to CCU and on a control day of admission and compared for each group and between each day. In the D group, slowing of background EEG activity, particularly on day 2, and many R (rapid) group eye movements and RS type (rapid superimposed on slow) eye movements, particularly on day 3, were observed. That is, from days 2 to 3, EEG findings showed an improvement in consciousness, and eye movement recordings manifested signs of anxiety and tension. These psychophysiological findings can be used to explain the transition from prodromal delirium to obvious delirium, and are supported by clinical features.

Platelet release reaction in vivo in patients with ischaemic heart disease after isometric exercise and its prevention with dipyridamole.

In 20 patients with ischaemic heart disease (IHD), platelet sensitivity to ADP-aggregation, plasma von Willebrand factor (vWF) and plasma beta-thromoboglobulin (beta-TG) were measured before and after isometric exercise. Effect of dipyridamole on these determinants was studied in a crossover fashion. To assess plasma vWF level, a new simple method was employed which has the advantage of not requiring an optical aggregometer and was proved to be reproducible. No significant difference was seen in platelet sensitivity to ADP-aggregation, vWF and beta-TG among healthy controls, IHD patients on placebo and on dipyridamole at rest. After exercise, platelet sensitivity to aggregation, plasma vWF and beta-TG increased significantly in IHD patients on placebo. In healthy controls, no significant changes were seen. On dipyridamole, above changes seen in IHD patients were not seen. The results suggests that isometric exercise may induce platelet release reaction in vivo and may produce hypercoagulable state in IHD patients. These phenomena may be prevented by pretreatment with dipyridamole.

Changes in platelet aggregability after ovariectomy.

Changes in platelets in 48 patients with uterine myoma before and after hysterectomy with and without ovariectomy were examined. Bilateral ovariectomy in 25 cases (ovariectomized group) and unilateral or non-ovariectomy in 23 cases (control group) were performed at the hysterectomy. Platelet count and an appearance rate of secondary aggregation decreased at one day after and increased at one week after the operation, similarly in both the ovariectomized and the control group. The appearance rate of secondary aggregation was reflected in an intensity of aggregation at 5 min after the addition of reagent to PRP. At one month after the operation, the appearance rate of secondary aggregation induced by 3 microM ADP showed a statistically significant decrease in comparison with the preoperation value (P less than 0.05) and the enhancement of 5-min aggregation was still observed in the control group, while ceased in the ovariectomized group. The difference between the two groups was significant (P less than 0.05). There was almost no change in the speed and intensity of primary and secondary aggregation during the observation period. No significant differences in collagen-induced aggregation were noted between the two groups. The results suggest that ovarian hormones, mainly estrogen, facilitate platelet activation which is mediated by the so-called secondary aggregation.

Enhancement of platelet sensitivity to ADP-aggregation by isometric exercise in arteriosclerosis patients and its prevention.

A new method for assessment of platelet sensitivity to ADP-aggregation was devised. Its reproducibility and the correlations between the values obtained by this method, the optical density (O. D.) method, and the screen filtration pressure (SFP) method were assessed. In summary, this method may be said to have three main points: 1. It can be performed without centrifugation, avoiding mechanical stress to platelets, using only 0.8 ml. of blood and inexpensive equipment. 2. It may reflect different aspects of platelet function from the O. D. method and the SFP method, despite the positve significant correlations between the values obtained by these three methods. 3. It was proved to be highly reproducible and is thought to be useful clinically. By using this method, the effect of sustained isometric exercise by handgripping on platelet aggregability was assessed in coronary sclerotic and cerebral arteriosclerotic patients on placebo and EG-626, a newly synthesized cyclic AMP phosphodiesterase inhibitor. On placebo, an enhancement platelet sensitivity was observed after isometric exercise in coronary and cerebral arteriosclerotic patients but not in healthy control subjects. The enhancement was prevented by pretreatment of EG-626, administered orally 1.5 hours prior to exercise.

Platelet aggregation and cyclic nucleotide phosphodiesterase activity in arteriosclerotic patients.

Although roles of roles of cyclic AMP and cyclic GMP in platelets are though to be important on platelet aggregation, little information on their phosphodiesterase (PDE) is available. Cyclic AMP and cyclic GMP hydrolytic activities of platelets (cAMPPDE and cGMPPDE in platelets) and platelet aggregation by ADP and adrenaline were measured in 22 healthy volunteers, 26 arteriosclerotic patients and other 20 miscellaneous patients excluding vascular diseases. Activities of cAMPPDE and cGMPPDE of platelets were 2.37 +/- 0.52, 7.23 +/- 1.84 in the healthy, 2.50 +/- 0.85, 7.53 +/- 2.60 in the arteriosclerotics and 2.38 +/- 1.02, 6.98 +/- 2.59 pmol/min/10(7) platelets in the miscellaneous patients, respectively. No significant difference was observed among these three groups. Platelet aggregabilities also showed no significant difference. However, there was a significant inverse correlation between the aggregability by 1 microgram/ml of adrenaline and the PDE activities only in the arteriosclerotic patients. The correlation coefficient were-0.61 between the primary aggregation and cAMPPDE,-0.65 between the primary aggregation and cGMPPDE,-0.58 between the 5 min aggregation and cAMPPDE and -0.76 between the 5 min aggregation and cGMPPDE. The inverse correlation between platelet aggregation and cyclic nucleotide metabolism in circulating platelts of the arteriosclerotic patients may suggest that interaction of platelets with arteriosclerotiv vessel walls would produce a certain change in platelets.

The increase of the electrophoretic mobility of platelets after laparotomy.

A fully automatic instrument for the determination of electrophoretic mobility of colloidal particles was applied to human platelets. A significant increase in platelet electrophoretic mobility was observed one day after a laparotomy. This suggests that a selective consumption of platelets with smaller surface negative charge may occur during postoperative hemostatic plug formation or under surgical stress. In addition, the difference in electrophoretic mobility observed between males and females suggests an effect of estrogen on platelets.

Factors for transient entrainment of ventricular tachycardias by rapid atrial pacing.

Thirteen patients with sustained ventricular tachycardia (VT) were studied to elucidate predisposing factors for the development of constant and progressive fusion by rapid atrial pacing. All patients demonstrated transient entrainment by rapid ventricular pacing during VT. Constant and progressive fusion were observed in 7 patients (positive group) during rapid atrial pacing, but not in 6 (negative group). In the positive group, VT was induced by atrial pacing in 2 patients. The demonstration of constant and progressive fusion by atrial pacing was not dependent on QRS morphology or ventriculoatrial conduction during VT. VT cycle length in the positive group (363 +/- 59 ms) was longer than in the negative group (297 +/- 31 ms; p = 0.033). The maximal atrial pacing rate producing 1:1 atrioventricular (AV) conduction in the positive group was 171 +/- 18 beats/min compared with 125 +/- 22 beats/min in the negative group (p = 0.002). There were distinct differences between the positive and negative groups in the ratio of VT cycle length to minimal atrial cycle length causing 1:1 AV conduction (1.02 +/- 0.12 vs 0.61 +/- 0.12; p = 0.0001). It is concluded that AV conduction, VT cycle length and especially their ratio are important factors for the development of transient entrainment by rapid atrial pacing during VT. Therefore, atrial pacing can be used as an easy and useful method to examine transient entrainment during VT.

Effects of aspirin and trapidil on cardiovascular events after acute myocardial infarction. Japanese Antiplatelets Myocardial Infarction Study (JAMIS) Investigators.

Aspirin therapy confers conclusive net benefits in the acute phase of evolving myocardial infarction, but no clear evidence of benefit from the long-term use of aspirin after acute myocardial infarction (AMI) has been shown in any single study. This multicenter study, the Japanese Antiplatelets Myocardial Infarction Study, was performed to find out whether aspirin or trapidil would improve clinical outcome compared with no antiplatelets in postinfarction patients. The study was a multicenter, open-label, randomized controlled trial of aspirin 81 mg/day, trapidil 300 mg/day, and no antiplatelets in patients with AMI admitted within 1 month from the onset of symptoms. Seven hundred twenty-three patients were enrolled at 70 hospitals in 18 prefectures of Japan; 250 were randomly assigned to treatment with 81 mg aspirin (aspirin group), 243 to that with trapidil (trapidil group), and 230 were not given antiplatelet agents. The mean follow-up period was 475 days. This study demonstrated that long-term use of aspirin at the dose of 81 mg/day reduced the incidence of recurrent AMI compared with the group receiving no antiplatelets after AMI (p = 0.0045) and that trapidil also reduced the occurrence of reinfarction compared with the group receiving no antiplatelets, but the difference was not significant (p = 0.0810). The incidence of cardiovascular events including cardiovascular death, reinfarction, uncontrolled unstable angina requiring admission to hospital, and nonfatal ischemic stroke was reduced in the group receiving 300 mg trapidil daily compared with the group receiving no antiplatelets (p = 0.0039). The use of aspirin 81 mg/day provided almost no benefit over no antiplatelets therapy in the incidence of cardiovascular events. In conclusion, low-dose aspirin (81 mg) effectively prevented recurrent AMI in postinfarction patients after thrombolysis or coronary angioplasty when used over a long term. Furthermore, the long-term use of trapidil resulted in a significant reduction in the incidence of cardiovascular events.

Bilateral coronary ostial stenosis associated with aortitis syndrome.

A patient with aortitis syndrome showed severe stenosis of the bilateral coronary ostium. We discuss the coronary angiographic findings and the treatment.

Influence of lipids metabolism on platelet activation in vivo.

Platelet aggregability and plasma factor VIII-related antigen (F. VIIIR:AG) level in 16 ischemic heart disease (IHD) patients were increased by isometric exercise and these changes were prevented by administration of a lipid lowering agent, simfibrate, a derivative of clofibrate. Serum total cholesterol (TC) level decreased and the high density lipoprotein-cholesterol (HDL-C)/TC ratio increased with the treatment. Another 7 hyperlipidemics were administered with simfibrate. Platelet malondialdehyde (MDA) production decreased with improvement in lipid profile. In an in vitro study, platelet aggregability and the plasma level of von Willebrand factor (vWF) and F.VIIIR:AG of normal citrated blood were increased by passing it through a glass bead column. Combining above results of the three separate studies, it would be suggested that hyperlipidemia might enhance platelet activation in vivo, which occurred through contact of platelets to atherosclerotic rough vessel surface. The anti-platelet effect of simfibrate might be mediated through its effect on arachidonic pathway in platelets.

Activation of platelets in cancer, especially with reference to genesis of disseminated intravascular coagulation.

Seventy-five cancer patients were evaluated on a scale of coagulation abnormalities related to DIC, one point given for each of the following criteria fulfilled and the score (0 to 4) being used. 1. Platelet count less than 150 x 10(3)/mu 1. 2. PT prolonged more than 1 sec over control or APTT prolonged more than 10 sec over control. 3. Fibrinogen less than 250 mg/dl (mean fibrinogen value of the cancer patients minus 1SD). 4. FDP greater than or equal to 20 micrograms/ml. The patients were distributed with 27% for score 0, 38% for 1, 20% for 2, 7% for 3 and 8% for 4. Platelet mode volume in score 4 was smaller than that of the other groups. Platelet aggregation by epinephrine was decreased in score 3 and 4 (P less than 0.01), while it was increased in score 0 (P less than 0.05). ADP-induced aggregation was increased in score 0 and 1 (P less than 0.01 - 0.05). The mean value of beta-thromboglobulin in cancer patients (44 +/- 24 ng/ml) was significantly higher than that of control (22 +/- 13 ng/ml) (P less than 0.01). These results suggest the existence of hyperfunction of platelets in cancer patients and possibility of a triggering mechanism of such activated platelets in the genesis of DIC in cancer.

Activation of platelets in patients with chronic proliferative glomerulonephritis and the nephrotic syndrome.

Platelet count, volume and aggregation and plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) were measured in 54 patients with chronic glomerulonephritis (CGN). Platelet count and platelet aggregation induced by ADP, adrenaline and collagen were significantly higher in the patients than in normal subjects, and platelet aggregation was markedly increased in the cases with progressive glomerular lesions. Plasma levels of beta-TG and PF-4 were significantly higher in the patients than in the normal subjects. There was a significant inverse correlation between plasma beta-TG and creatinine clearance. Nephrotic patients showed significantly smaller platelet volume and markedly elevated plasma beta-TG levels when compared to the controls. Plasma beta-TG decreased remarkably in 3 out of 4 patients with markedly increased beta-TG levels when they were given antiplatelet drugs. The results suggest that platelet aggregation and the release reaction were increased in patients with CGN. Activated platelets may be an important factor in the genesis of the thrombotic tendency in the nephrotic syndrome.

A case of cardiac sarcoidosis with remarkable atrophy of the left ventricular septum on two-dimensional echocardiography.

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology which mainly affects the lungs, skin, the lymphoreticular system, and the heart. We report a case of cardiac sarcoidosis in which a remarkably thin ventricular septum was demonstrated on two-dimensional echocardiography.

Inhibitory effect of Urografin 76 on platelet function and thrombus formation in vascular catheters.

The effect of Urografin 76 on platelet aggregation and thrombus formation in vascular catheter was studied. In vitro experiments revealed that ADP-, epinephrine-, and collagen-induced platelet aggregation was significantly inhibited by Urografin 76 in concentrations greater than 0.3, 1, and 5% respectively. Rabbits that received 10 ml of Urografin 76 demonstrated a transient decrease in platelet aggregation for at least 3 minutes. Urografin 76 was apparently more effective than saline in preventing blood clot formation.

Effect of isometric handgrip on systolic time intervals in patients with ischemic heart disease and cyclic amp phosphodiesterase inhibitor pretreatment.

The effect of cAMP phosphodiesterase inhibitor EG626 on the left ventricular function was studied in 23 patients with ischemic heart disease at rest and during the IHG test. Administration of a single dose of the substance produced changes in STIs indicating an increase in cardiac output and a possible enhancement of myocardial contractility during the IHG test. EG626 may have a beneficial effect on impaired left ventricular function in patients with ischemic heart disease.

[Effects of oral flecainide treatment of refractory tachyarrhythmias].

Oral flecainide treatment was given to five patients who were refractory to conventional antiarrhythmic agents. The five patients included one with atrioventricular reentrant tachycardia (AVRT), one with non-sustained ventricular tachycardia (nsVT) and three with sustained VT (sVT). Flecainide produced favorable responses in patients of AVRT, nsVT and sVT with arrhythmogenic right ventricular dysplasia (ARVD). In the case of AVRT, flecainide exhibited a preventive effect on tachycardia induced by programmed electrical stimulation (PES). In the case of nsVT, flecainide markedly reduced the number of VPC and abolished the VT on the Holter ECG. In the case of sVT with ARVD, sVT was not induced by PES after the flecainide. Long-term treatment with flecainide on these three cases produced complete prevention of tachycardias. As an adverse effect of flecainide, an aggravation of congestive heart failure was recognized in one case with cardiac sarcoidosis. PQ interval and QRS interval in all the cases were prolonged after flecainide. The results indicate that flecainide is a useful antiarrhythmic agent for tachyarrhythmias refractory to treatment with conventional drugs.