High concentrations of drug in target tissues following local controlled release are utilized for both drug distribution and biologic effect: An example with epicardial inotropic drug delivery

Abstract

Local drug delivery preferentially loads target tissues with a concentration gradient from the surface or point of release that tapers down to more distant sites. Drug that diffuses down this gradient must be in unbound form, but such drug can only elicit a biologic effect through receptor interactions. Drug excess loads tissues, increasing gradients and driving penetration, but with limited added biological response. We examined the hypothesis that local application reduces dramatically systemic circulating drug levels but leads to significantly higher tissue drug concentration than might be needed with systemic infusion in a rat model of local epicardial inotropic therapy. Epinephrine was infused systemically or released locally to the anterior wall of the heart using a novel polymeric platform that provides steady, sustained release over a range of precise doses. Epinephrine tissue concentration, upregulation of cAMP, and global left ventricular response were measured at equivalent doses and at doses equally effective in raising indices of contractility. The contractile stimulation by epinephrine was linked to drug tissue levels and commensurate cAMP upregulation for IV systemic infusion, but not with local epicardial delivery. Though cAMP was a powerful predictor of contractility with local application, tissue epinephrine levels were high and variable - only a small fraction of the deposited epinephrine was utilized in second messenger signaling and biologic effect. The remainder of deposited drug was likely used in diffusive transport and distribution. Systemic side effects were far more profound with IV infusion which, though it increased contractility, also induced tachycardia and loss of systemic vascular resistance, which were not seen with local application. Local epicardial inotropic delivery illustrates then a paradigm of how target tissues differentially handle and utilize drug compared to systemic infusion.

Use of Pressure-volume Conductance Catheters in Real-time Cardiovascular Experimentation

“…PV conductance catheters can be used as a continuous real-time monitor of cardiovascular function but such use is more complicated and somewhat more limited than at specific points in time. Continuous experiments are often pharmacologic interventions that produce acute haemodynamic changes, on the order of minutes to hours, and can be performed while the PV catheter remains in situ for the duration of the treatment [10, 11]. We have found that such real-time monitoring during pharmacologic treatment can only be performed with frequent manipulation to optimise position, which can lead to disruptions in continuous signals.…”

Myocardial drug distribution generated from local epicardial application: Potential impact of cardiac capillary perfusion in a swine model using epinephrine

“…An alginate polymeric local drug releasing system, designed to precisely administer animal-weight based amounts of epinephrine to the epicardium, was fabricated from calcium-cross-linked alginate hydrogels [29, 30]. Briefly, 0.65 ml of 2% alginate (#71238; Sigma-Aldrich) slurry in double distilled water (ddH20) was pipetted onto the upper side of the permeable membrane of a transwell support (#3472, 24 mm, polyester, 3 μm pore size; Corning).…”

“…Each release rate was then linearly correlated to the applied concentration. This relationship, specific to these disks at the fixed volume and interval of applied drug solution, allows the release rate to be prescribed solely through adjustments in applied concentration [29, 30]. This novel method of controlling epicardial drug release allows for precise animal weight-based dosing without any chemical modifications to the polymer platform.…”

“…We have shown in small animals that local EC application of inotropic compounds leads to elevated myocardial drug and intracellular second messenger concentrations in target ventricular tissue, enhanced contractile response with lower systemic levels, and less atrial and peripheral vascular responses than IV infusion [29, 30]. EC epinephrine delivery in rats required only 1/3 rd of the IV dose rate to provide an equal contractile effect without raising plasma drug levels or deleterious systemic side effects such as tachycardia or peripheral vasodilation [30]. …”

Are Peripherally Inserted Central Catheters Associated With Increased Risk of Adverse Events in Status 1B Patients Awaiting Transplantation on Continuous Intravenous Milrinone?

“…Alternatives routes of milrinone therapy do not currently exist, although novel inotrope delivery by a nebulized inhaled route (NCT 02077010 and 01571037) has been studied in humans and topical milrinone administration has been reported in nonhuman models. 34 Oral milrinone and its derivatives have been assessed in several historical clinical trials but demonstrated detrimental effects or lack of efficacy. 35,36 Study Limitations…”