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Objectives: The primary objective of this study was to determine whether intracoronary administration of the adenoviral gene for fibroblast growth factor (Ad5FGF-4) can improve myocardial perfusion compared with placebo.Background: Animal studies and observational clinical studies have shown improvement in perfusion of the ischemic myocardium using genes encoding angiogenic growth factors; however, randomized, double-blind data in humans are lacking.Methods: We performed a randomized, double-blind, placebo-controlled trial of intracoronary injection of 10(10) adenoviral particles containing a gene encoding fibroblast growth factor (Ad5FGF-4) to determine the effect on myocardial perfusion. Fifty-two patients with stable angina and reversible ischemia comprising >9% of the left ventricle on adenosine single-photon emission computed tomography (SPECT) imaging were randomized to gene therapy (n = 35) or placebo (n = 17). Clinical follow-up was performed, and 51 (98%) patients underwent a second adenosine SPECT scan after 8 weeks.Results: Overall (n = 52), the mean total perfusion defect size at baseline was 32.4% of the left ventricle, with 20% reversible ischemia and 12.5% scar. At eight weeks, Ad5FGF-4 injection resulted in a significant reduction of ischemic defect size (4.2% absolute, 21% relative; p < 0.001) and placebo-treated patients had no improvement (p = 0.32). Although the change in reversible perfusion defect size between Ad5FGF-4 and placebo was not significant (4.2% vs. 1.6%, p = 0.14), when a single outlier was excluded a significant difference was observed (4.2% vs. 0.8%, p < 0.05). Ad5FGF-4 was well tolerated and did not result in any permanent adverse sequelae.Conclusions: Intracoronary injection of Ad5FGF-4 showed an encouraging trend for improved myocardial perfusion; however, further studies of therapeutic angiogenesis with Ad5FGF-4 will be necessary. [ABSTRACT FROM AUTHOR]

Angiogenic gene therapy for stable angina is aimed at promoting new blood vessel formation in the heart, thus providing enhanced cardiac perfusion, symptom relief, increased exercise capacity, improved quality of life, and reduced risk of coronary events. Ad5FGF-4 is a replication-deficient serotype 5 adenovirus encoding the gene for fibroblast growth factor-4 (FGF-4) driven by a cytomegalovirus promoter. In preclinical studies using a pig model of myocardial ischemia, a single intracoronary infusion of Ad5FGF-4 improved cardiac contractile function and regional blood flow in the ischemic region during stress. These effects were apparent after 2 weeks and maintained for > or =12 weeks. Histologic evidence of capillary angiogenesis was observed. FGF-4 gene expression was detected in the heart but not at extracardiac sites. Placebo-controlled trials in humans with chronic stable angina indicate that Ad5FGF-4 increases treadmill exercise duration and improves stress-related ischemia measured by perfusion sestamibi single-photon emission computed tomography. More patients receiving Ad5FGF-4 than placebo reported complete resolution of their angina and no nitroglycerin use. Ad5FGF-4 gene therapy was well tolerated. The administration procedure did not cause any adverse events, although mild, transient fever, a transient modest fall in platelet count, and a transient mild elevation in hepatic enzymes and uric acid levels occurred in a few patients. This adverse event profile concurs with other adenoviral gene trials. There was no evidence of myocarditis, retinal neovascularization, or angioma formation. FGF-4 was not detected in venous blood. Larger clinical trials will assess Ad5FGF-4 with regard to cardiovascular prognosis, symptom relief, and safety profile in patients with chronic stable angina. [ABSTRACT FROM AUTHOR]

Background: The angiogenic response to myocardial ischemia can be augmented in animal models by gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) gene., Methods and Results: The objectives of the Angiogenic GENe Therapy (AGENT) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in 2 patients in lower-dose groups. Serious adverse events during follow-up (mean, 311 days) were not different between placebo and Ad5-FGF4. Overall, patients who received Ad5-FGF4 tended to have greater improvements in exercise time at 4 weeks (1.3 versus 0.7 minutes, P=NS, n=79). A protocol-specified, subgroup analysis showed the greatest improvement in patients with baseline ETT < or =10 minutes (1.6 versus 0.6 minutes, P=0.01, n=50)., Conclusions: Results show evidence of favorable anti-ischemic effects with Ad5-FGF4 compared with placebo, and it appears to be safe. Angiogenic gene transfer with Ad5-FGF4 shows promise as a new therapeutic approach to the treatment of angina pectoris.

Objective: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma)., Methods: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary., Results: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058)., Conclusion: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Intravenous nitroglycerin (IVNG) was used in 12 instances (11 patients) to relieve pain, following myocardial infarction or unstable angina. The strength of IVNG infusion could be easily controlled and relief of pain was prompt and satisfactory. Excessive tachycardia or severe headache was not encountered and marked hypotension was seen in one patient only. This patient had three vessel coronary artery disease, extensive myocardial damage and vein graft closure. Cardiovascular stability was provided by IVNG, prior to and during cardiac catheterisation and cineangiography, transportation to another hospital and vein graft surgery. IVNG appears to be a safe and effective drug in the management of patients with acute coronary artery disease (unstable angina and myocardial infarction). In those with both right and left ventricular wall infarction, however, the usefulness of IVNG needs to be established.

1 The haemodynamic and electrocardiographic effects of intravenous disopyramide were studied in fifteen patients with acute myocardial infarction. 2 Five minutes after drug injection a rise in heart rate, aortic mean and diastolic pressures and systemic vascular resistence was noted which persisted for at least 30 min. A small increase in pulmonary arterial diastolic pressure (mean = 1.5 mm Hg) occurred at 5 min only and no significant change of cardiac output was found throughout the period of the study (1 h). 3 Surface electrocardiograms revealed transient prolongation of the P-R interval and a sustained increase in the QTc interval. 4 The haemodynamic changes suggest an anticholinergic effect of the drug. There was no definite evidence of a negative inotropic effect in this study, however, these peripheral haemodynamic measurements might not have revealed a modest negative inotropic effect. 5 The electrocardiographic changes are similar to those previously reported in normals and in patients without acute myocardial infarction.

Disopyramide (2 mg/kg intravenously in 10 minutes) was administered to 14 patients with myocardial infarction within 36 hours of their infarct. Heart rate (HR) increased significantly five minutes after completion of the injection, but profound tachycardia was not seen. Mean wedge pressure (WP) rose and stroke volume (SV) fell. Disopyramide therefore showed a negative inotropic effect on the heart. Systemic vascular resistance (SVR) increased but blood pressure was not significantly altered. Diastolic and mean pulmonary arterial (PA) pressure was also increased by disopyramide. Peak plasma disopyramide level was reached five minutes after injection. The implications of the haemodynamic effects of disopyramide are discussed.

The acute electrophysiological and hemodynamic effects of intravenous disopyramide (1.5 mg/kg body weight) were studied in 12 patients with suspected coronary artery disease. Plasma levels of disopyramide were monitored. Disopyramide delayed conduction within the His-Purkinje system and increased the effective refractory period of the atrium. Conduction within the AV node and its refractory period, however, was not significantly altered by the drug. The corrected Q-T interval was significantly increased. Disopyramide increased systemic arterial pressure and slightly raised the left ventricular end diastolic pressure. Heart rate, cardiac and stroke index were unaltered. Peak mean levels of disopyramide were reached 5 minutes after the injection of the drug.

The electrophysiological effects of acebutolol were studied in 12 patients. Heart rate and systemic arterial pressure were monitored. Plasma acebutolol levels were estimated. The first 6 patients (group A) received 0.3 mg/kg body weight I.V. The subsequent 6 patients (group B) received 0.5 mg/kg body weight I.V. Acebutolol delayed both antegrade and retrograde conduction through the AV node. The effect was greater in group B patients. Effective and functional refractory periods of the AV node were also increased after acebutolol. Intraatrial and intraventricular conduction and the effective refractory periods of the atrium and ventricle were not affected. Acebutolol did not alter significantly the sinus node recovery time or the QTc interval. Heart rate fell, especially where initial rates were fast. Systolic arterial pressure was lowered in group B patients. Peak mean levels of acebutolol were reached 5 min after injection of the drug. In the doses used, acebutolol, although well tolerated, failed to demonstrate electrophysiological evidence of a membrane-stabilizing effect and is therefore unlikely to add to the areas of success achieved by other beta-blocking drugs in the management of arrhythmias.

In a multicenter, prospective study of step II antihypertensive therapy with indoramin, 1,847 hypertensive patients (773 men and 1,074 women) between the ages of 18 and 70 years were treated by 148 general practitioners. Patients whose blood pressure was inadequately controlled after 4 weeks of therapy with cyclopenthiazide (0.25 to 1.0 mg/day) had indoramin (25 to 200 mg/day) added to their treatment regimen. During cyclopenthiazide treatment, mean (+/- SD) blood pressure decreased from 176/105 +/- 20/7 mm Hg at baseline to 164/98 +/- 21/9 mm Hg (p less than 0.001), and only 447 (24%) patients obtained satisfactory blood pressure control. The addition of indoramin produced a further reduction in mean blood pressure from 169/102 +/- 18/6 to 152/89 +/- 18/8 mm Hg during the first 3 months of treatment (p less than 0.001); this response was maintained for up to 2 years. Satisfactory blood pressure reduction was achieved in 79% of the patients who received indoramin (mean dose, 68 mg/day) plus cyclopenthiazide. Only 25 patients (2%) discontinued indoramin treatment because of nonresponse, and 156 (12%) withdrew because of adverse effects, the most common being sedation, dizziness/giddiness, and headache. These results indicate that indoramin provides safe and effective blood pressure control when used as step II treatment for hypertensive patients who fail to respond to single-agent diuretic therapy.