Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo

Abstract

Drug activity is often studied in well controlled and characterized cellular environments in vitro. However, the biology of cells in culture is only a part of the tissue behavior in vivo. Quantitative studies of the dose response to drugs in vivo have been limited by the inability to reliably determine or predict the concentrations achieved in tissues. We developed a method to study the dose response of injured arteries to exogenous heparin in vivo by providing steady and predictable arterial levels of drug. Controlled-release devices were fabricated to direct heparin uniformly and at a steady rate to the adventitial surface of balloon-injured rat carotid arteries. We predicted the distribution of heparin throughout the arterial wall by using computational simulations of intravascular drug binding and transport, and we correlated these concentrations with the biologic response of the tissues. This allowed the estimation of the arterial concentration of heparin required to maximally inhibit intimal hyperplasia after injury in vivo, 0.3 mg͞ml. This estimation of the required concentration of drug seen by a specific tissue is independent of the route of administration and holds for all forms of drug release. In this way we may now be able to evaluate the potential of widely disparate forms of drug release and to finally create some rigorous criteria by which to guide the development of particular delivery strategies for local diseases.

Effect of heparin binding on Helicobacter pylori resistance to serum

“…In this study, the amounts of heparin that effectively increased survival of H. pylori are in the range available in vivo, as reported by Lovich & Edelman (1999), who concluded that approximately 0 . 3 mg ml À1 is found in arteries.…”

Neointimal formation is reduced after arterial injury in human crp transgenic mice

“…Both heparin [31] and aspirin [32] can provide an anti-proliferative effect in addition to their anti-thrombotic effect. However, suppression of neointimal formation following experimental vascular injury requires substantially higher doses and far longer durations of administration (of heparin) than applied here [32][33][34][35]. The decrease in intimal hyperplasia with increased CRP though contrary to expectations may not be surprising in retrospect.…”

Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery

“…The need for a microscopic appreciation of the forces of drug distribution and transport is substantiated by recent studies that directly correlate local concentrations of therapeutic agents with ensuing biological response. 19,20 Although it is clear that absolute concentrations can determine biological effect, gradients in concentrations may also affect biological behavior. For instance, morphogens direct tissue formation in embryos by specifying cell fates along a concentration profile, 21,22 whereas the graded distribution of cytokines leads to the directed recruitment of inflammatory cells to sites of injury, minimizing their activities elsewhere.…”