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Indoramin was administered as a single 50 mg oral tablet to 5 elderly (aged 68-71 years) and 6 middle-aged (aged 46-55 years) healthy female volunteers. The mean half life of indoramin in elderly subjects (14.7±4.8 h, mean±SEM) was statistically significantly longer than that seen in middle-aged subjects (5.1±1.0 h). The mean plasma concentrations of indoramin and mean area under the plasma concentration/time curve were also greater in elderly than in middle-aged subjects, although this did not achieve statistical significance. In many elderly patients, therefore, a reduction in dosage may be required due to the apparent reduction in clearance of indoramin. However, because of the wide inter-subject variability observed in the oral pharmacokinetics of indoramin, individual titration of indoramin dosage in all patients may be desirable. [ABSTRACT FROM AUTHOR]

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]