Drug Delivery to the Cardiovascular System - Applications of Biotechnology in Cardiovascular Therapeutics - page 31

blood to ischemic myocardium during unstable angina or high-risk percutaneous
transluminal coronary angioplasty (PTCA). Retrograde delivery of drugs acceler-
ates coronary thrombolysis, preserves regional myocardial function, and limits
infarct size in animal models. Modifications of the coronary venous retroperfusion
technique have allowed access to smaller coronary venous branches and minimiza-
tion of systemic effects of local drug delivery. Retrograde coronary sinus perfusion
as an adjunct in high-risk coronary PTCA is limited by its inability to provide sys-
temic hemodynamic support during circulatory collapse. Targeted and specific gene
delivery to myocardium with transfection rates superior to intra-arterial or systemic
injection may be a promising new application for this technique.
Intrapericardial Drug Delivery
Pharmacologic modulation of the contents of the pericardial space has been shown
to influence the response of coronary arteries to balloon injury. Local delivery of
various drugs into the lumen of coronary arteries has been limited by short resi-
dence time, as well as by highly variable concentration of the deposited agent.
Compounds introduced into the pericardial fluid can access coronary arteries with
intramural concentrations, which typically vary by 10- to 15-fold, while endolumi-
nal delivery results in a remarkably wide intramural concentration range with up to
33,000-fold variability. Compounds placed into the pericardial space penetrate into
coronary tissue with greater consistency than seen after endoluminal delivery and
provide for prolonged coronary exposure to agents. Intrapericardial (IPC) delivery
appears to offer substantial advantages over endoluminal administration in the
coronary arteries with respect to residence time and reproducibility. This approach
has not been developed for clinical use.
Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation,
but oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and
is associated with serious extracardiac side effects. In experimental animals, IPC
delivery produces steeply decreasing drug concentrations from epicardium to endo-
cardium in both atria and ventricles with plasma drug concentrations that are sig-
nificantly lower in IPC than in IV treated animals (Bolderman et al. 2009 ). IPC
delivery of amiodarone and sotalol increases atrial drug concentration and antiar-
rhythmic effects at reduced plasma drug concentrations. These potential benefits
are particularly prominent for IPC delivered amiodarone.
Formulations for Drug Delivery to the Cardiovascular
System
Various formulations for drug delivery to the cardiovascular system are shown in
Table 2.2 .