Local epicardial inotropic drug delivery allows targeted pharmacologic intervention with preservation of myocardial loading conditions

doi:10.1002/jps.22681

Journal of Pharmaceutical Sciences

Volume 100, Issue 11, November 2011, Pages 4993-5006

https://doi.org/10.1002/jps.22681 Get rights and content

ABSTRACT

Local myocardial application of inotropes may allow the study of pharmacologically augmented central myocardial contraction in the absence of confounding peripheral vasodilating effects and alterations in heart loading conditions. Novel alginate epicardial (EC) drug releasing platforms were used to deliver dobutamine to the left ventricle of rats. Pressure–volume analyses indicated that although both local and systemic intravenous (i.v.) use of inotropic drugs increase stroke volume and contractility, systemic infusion does so through heart unloading. Conversely, EC application preserves heart load and systemic blood pressure. EC dobutamine increased indices of contractility with minimal rise in heart rate and lower reduction in systemic vascular resistance than i.v. infusion. Drug sampling showed that dobutamine concentration was 650‐fold higher in the anterior wall than in the inferior wall. The plasma dobutamine concentration with local delivery was about half as much as with systemic infusion. These data suggest that inotropic EC delivery has a localized effect and augments myocardial contraction by different mechanisms than systemic infusion, with far fewer side effects. These studies demonstrate a pharmacologic paradigm that may improve heart function without interference from effects on the vasculature, alterations in heart loading, and may ultimately improve the health of heart failure patients. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4993–5006, 2011

Section snippets

INTRODUCTION

Classic teaching holds that local delivery avoids the dosing inefficiency of systemic delivery. Intravascular infusion attains whole‐body drug exposure rapidly and is ideal for circulating or systemic diseases, but problematic when drug needs to be delivered to specific organs or tissues. In this latter case, systemic administration delivers drug everywhere, reducing the net amount of administered drug that reaches the desired target along with an associated potential for systemic side effects

Fabrication and In Vitro Characterization of EC Inotrope Delivery Platform

A novel system for precisely controlling the rate of dobutamine release to the EC surface of the heart over a wide range of doses allowed characterization of the dose response for comparison to i.v. infusion. EC drug releasing platforms were constructed from calcium‐cross‐linked alginate hydrogels8., 9., 10. and served to apply drug over the anterior surface of the rat heart. Alginate (#71238; Sigma–Aldrich, St. Louis, MO) disks were made by cross‐linking 45 μL of a 2% slurry in double‐distilled

In Vitro Characterization

A novel experimental platform for controlling the EC release of inotropic drugs was developed for use in rats. Alginate was chosen for its ease in shaping molds through calcium‐cross‐linking. Preliminary data showed that a 2% starting alginate concentration yielded optimal mechanical properties. The solution was poured into a transwell support, which was then immersed in calcium. The meniscus from the original alginate solution in the transwell support formed a concave surface that was used to

DISCUSSION

Local therapy has become in vogue for many applications, specifically because local infusion may reduce systemic side effects and enhances selective delivery to a target organ. Our data add another dimension to the local therapy paradigm. Plasma concentrations should not differ substantially when the same drug is infused at the same dose from different sites unless there is significant local uptake of drug. Indeed, in our system, there was a statistically significant reduction in circulating

CONCLUSIONS

We have demonstrated a novel system for controlling the EC application of inotropic compounds. This demonstration of differential local uptake and effect after local delivery even in the face of detectable plasma drug levels from clearance from myocardial capillaries may add to our understanding of targeted and directed drug delivery. In the same vein, the difference in effects on the heart and blood vessels highlights further the complexity of cardiovascular physiology and the clinical

ACKNOWLEDGEMENTS

This work was supported by the Desphpande Center for Technical Innovation at the Massachusetts Institute of Technology, a Scientist Development Grant from the American Heart Association, and a Society of Cardiovascular Anesthesiologists Starter Grant.

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This effect was diminished for smaller molecules. The specific function of muscle, having the ability to contract with given force and frequency, influences drug transport and efficacy in a complex manner, going beyond passive diffusion [108–110]. Several studies have investigated the uptake of drugs or model compounds connected to the metabolic activity of contracting muscle [111–113].
Pharmaceutical compounds are the main pillar in the treatment of various illnesses. To administer these drugs in the therapeutic setting, multiple routes of administration have been defined, including ingestion, inhalation, and injection. After administration, drugs need to find their way to the intended target for high effectiveness, and this penetration is greatly dependent on obstacles the drugs encounter along their path. Key hurdles include the physical barriers that are present within the body and knowledge of those is indispensable for progress in the development of drugs with increased therapeutic efficacy. In this review, we examine several important physical barriers, such as the blood-brain barrier, the gut-mucosal barrier, and the extracellular matrix barrier, and evaluate their influence on drug transport and efficacy. We explore various in vitro model systems that aid in understanding how parameters within the barrier model affect drug transfer and therapeutic effect. We conclude that physical barriers in the body restrict the quantity of drugs that can pass through, mainly as a consequence of the barrier architecture. In addition, the specific physical properties of the tissue can trigger intracellular changes, altering cell behavior in response to drugs. Though the barriers negatively influence drug distribution, physical stimulation of the surrounding environment may also be exploited as a mechanism to control drug release. This drug delivery approach is explored in this review as a potential alternative to the conventional ways of delivering therapeutics.
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The sham control and pressure overload control groups were gavaged with starch solution as a placebo and were used to account for the impact of animal handling and stress-related changes on hemodynamic indices and exercise tolerance. In vivo hemodynamic (HD) assessments were performed 8 weeks after pressure overload induction as described elsewhere.25–28 Briefly, the animals were reanesthetized and a heating pad was adjusted to maintain rectal temperature at ∼37°C.
Simultaneous angiotensin receptor (AT₁) blockade and neprilysin inhibition with the use of sacubitril/valsartan has been recently approved to treat patients with heart failure (HF). Therapeutic benefits of this therapy have been attributed to natriuretic peptide elevation and AT₁ receptor blockade. However, that pharmacologic picture may not be complete. The aims of this study were to investigate the pharmacology of sacubitril/valsartan compared with sacubitril and valsartan alone and to examine their impact on peptides up-regulated by neprilysin inhibition, such as beta-endorphin.
An HF model was induced by pressure overload via constriction of the suprarenal abdominal aorta in rats. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or placebo was administered by daily oral gavage (starting 4 weeks after pressure overload onset and continued for 4 additional weeks; n = 8 in each group). Exercise tolerance testing was conducted using a rodent treadmill and hemodynamic assessments were conducted under anesthesia with the use of Millar left ventricular (LV) conductance technology. Pressure overload led to exercise intolerance by 4 weeks and to hypertension and LV dysfunction and remodeling by 8 weeks. Both sacubitril/valsartan and sacubitril elevated beta-endorphin levels, by 40% and 54%, respectively, and improved exercise tolerance, by 93% and 112%, whereas valsartan did not. Indices of LV dysfunction persisted with the use of sacubitril/valsartan and valsartan therapies and even deteriorated in sacubitril group.
When added to valsartan, sacubitril increases beta-endorphin concentrations and improves exercise tolerance. These data suggest beta-endorphin elevation as a potential mechanism of action leading to improvement in exercise tolerance that is seen with sacubitril/valsartan. This therapeutic benefit is potentially independent from LV function.
Myocardial drug distribution generated from local epicardial application: Potential impact of cardiac capillary perfusion in a swine model using epinephrine
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While these small rodent studies clearly demonstrate the focused therapy of local EC treatments, the deposited drug may be less confineable in animal models with larger hearts such as swine due to clearance by myocardial capillaries. Myocardial drug distribution after local application is the net result of the complex interplay between diffusive spread driven by concentration gradients, transmural convection driven by the pressure gradient from endocardial to epicardial surface, bulk transport by capillary perfusion, and clearance by the same capillaries [29–31,34]. Diffusive forces, though likely augmented by LV contraction and relaxation, decline with distance from the source.
Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart not only enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively toward the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue.
Use of pressure-volume conductance catheters in real-time cardiovascular experimentation
2014, Heart Lung and Circulation
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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.
Most applications of pressure-volume conductance catheter measurements assess cardiovascular function at a single point in time after genetic, pharmacologic, infectious, nutritional, or toxicologic manipulation. Use of these catheters as a continuous monitor, however, is fraught with complexities and limitations.
Examples of the limitations and optimal use of conductance catheters as a continuous, real-time monitor of cardiovascular function are demonstrated during inotropic drug infusion in anesthetised rats.
Inotropic drug infusion may alter ventricular dimensions causing relative movement of a well-positioned catheter, generating artifacts, including an abrupt pressure rise at end-systole that leads to over estimation of indices of contractility (max dP/dt) and loss of stroke volume signal. Simple rotation of the catheter, echocardiography-guided placement to the centre of the ventricle, or ventricular expansion through crystalloid infusion may correct for these artifacts. Fluid administration, however, alters left ventricular end-diastolic pressure and volume and therefore stroke volume, thereby obscuring continuous real-time haemodynamic measurements.
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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
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At regular intervals, a 60 μl sample from the receiving chamber was removed to evaluate the amount of the released drug and 60 μl of ddH2O was added immediately to the wells to restore receiving chamber volume. The concentration of epinephrine in each sample was determined by spectrophotometric methods [19]. Metaperiodate (6 μl of 2% NaIO4 in ddH2O, #S1878, Sigma-Aldrich) and ethanol (9 μl, 100%) were added to the samples and the absorbance at 490 nm was measured to calculate the amount of released epinephrine at each time point using a standard curve (Fig. 2A).
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.
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Pharmacokinetics, Pharmacodynamics and Drug MetabolismLocal epicardial inotropic drug delivery allows targeted pharmacologic intervention with preservation of myocardial loading conditions

ABSTRACT

Section snippets

INTRODUCTION

Fabrication and In Vitro Characterization of EC Inotrope Delivery Platform

In Vitro Characterization

DISCUSSION

CONCLUSIONS

ACKNOWLEDGEMENTS

J Biol Chem

Biophys J

Biomaterials

Carbohydr Polym

J Biol Chem

Am J Cardiol

J Biomech

J Control Release

J Am Coll Cardiol

Life Sci

Distribution of drugs following controlled delivery to the brain interstitium

J Neurooncol

Vascular regeneration by local growth factor release is self‐limited by microvascular clearance

Circulation

Simultaneous determination of beta‐1 and beta‐2‐adrenergic receptors in tissues containing both receptor subtypes

Mol Pharmacol

Left ventricular pressure–volume relationship in a rat model of advanced aging‐associated heart failure

Am J Physiol Heart Circ Physiol

Measurement of cardiac function using pressure–volume conductance catheter technique in mice and rats

Nat Protoc

Compressive and shear properties of alginate gel: Effects of sodium ions and alginate concentration

J Biomed Mater Res

Spectrophotometric determination of some catecholamine drugs using metaperiodate

J Assoc Off Anal Chem

Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase

Am J Physiol Heart Circ Physiol

Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin‐induced cardiac dysfunction

Circulation

The role of poly(ADP‐ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes

Diabetes

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

Antimicrob Agents Chemother

In vitro and in vivo comparison of the anti‐staphylococcal efficacy of generic products and the innovator of oxacillin

BMC Infect Dis

The pharmacological potency of various AT(1) antagonists assessed by Schild regression technique in man

J Renin Angiotensin Aldosterone Syst

Pharmacokinetics, Pharmacodynamics and Drug Metabolism
Local epicardial inotropic drug delivery allows targeted pharmacologic intervention with preservation of myocardial loading conditions