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Advanced Drug Delivery Reviews (v.58, #3)

Editorial Board (pp. ii).

Drug-eluting stents: an innovative multidisciplinary drug delivery platform by Helen M. Burt Theme Editor; William L. Hunter Theme Editor (pp. 345-346).

Drug-eluting stents: Beyond the hyperbole by William L. Hunter (pp. 347-349).

Drug-eluting stents (DES) promised to reduce the clinical and economic cost of failed bare metal stents (BMS) by locally delivering a therapeutic agent to the injured artery, reducing or eliminating the development of neointimal hyperplasia and reducing the need for repeat interventions to re-open the obstructed artery. Data from initial large-scale, comparable, U.S. pivotal trials of the first two DES to reach the American market, CYPHER from J&J using the drug rapamycin (sirolimus) and TAXUS from Boston Scientific using the drug paclitaxel (taxol), seemed to warrant the enthusiasm. By reducing the failure rate of BMS by about 4-fold, DES have changed clinical practice, reduced the rate of coronary bypass surgery, had a significant economic impact, and triggered extensive research in the areas of stent design, restenosis biology, polymeric drug-delivery and local pharmacology and toxicology.

Keywords: Drug-eluting stents; Restenosis; Cypher; TAXUS

Drug-eluting stents: A multidisciplinary success story by Helen M. Burt; William L. Hunter (pp. 350-357).

Coronary stenting is the most common form of interventional treatment for symptomatic coronary artery disease. In-stent restenosis following bare metal stent (BMS) placement is the most common cause of procedural failure and occurs as a result of vessel wall trauma secondary to balloon angioplasty and stent deployment that results in an overly aggressive healing response (neointimal hyperplasia) that overgrows the stent lumen and causes vascular narrowing. Drug-eluting stents (DES) are specialized vascular stents capable of delivering drugs to the arterial wall in a controlled manner such that neointimal hyperplasia is reduced or prevented, luminal patency is preserved, coronary blood flow is maintained and the patient is spared a repeat procedure to re-open the vessel. The objectives of the review are to provide an overview of the major contributions that a broad range of disciplines have made to the design and development of drug-eluting stents and to summarize future directions of these fields of research. Engineers and biomaterials scientists have explored relationships between stent design and stent performance and work continues to optimize stent design and biocompatibility of stent biomaterials. Pharmaceutical scientists are continually expanding the range of candidate drugs for pharmacological intervention, and improving the technology using novel coatings to modulate drug release. Clinical scientists are investigating issues such as long-term safety and efficacy, new applications of drug-eluting stents and optimal deployment techniques.

Keywords: Biomaterials; In-stent restenosis; Stent design; Anti-proliferative drugs; Polymer coatings; Drug delivery

Restenosis following implantation of bare metal coronary stents: Pathophysiology and pathways involved in the vascular response to injury by Neal A. Scott (pp. 358-376).

This review summarizes the restenotic process that occurs after the implantation of bare metal coronary stents. The pathology of in-stent restenosis is distinct from that seen after balloon angioplasty and is characterized by neointimal proliferation and extracellular matrix deposition. The degree of neointimal proliferation is proportional to the amount of injury, the intensity of the inflammatory infiltrate and the association of stent struts with lipid-filled plaque. In-stent restenosis also appears to be associated with systemic markers of inflammation. Shear stress has an important influence on restenosis as does the presence and adhesiveness of vascular progenitor cells. Clinical predictors (e.g., artery size, stent length, diabetes, and gender) may affect the incidence of restenosis seen after stent placement. A number of catheter-based interventions have been used to treat in-stent restenosis. Although preliminary data suggest that the use of drug-eluting stents may be effective, only intracoronary radiation has shown consistent efficacy in randomized trials.

Keywords: In-stent restenosis; Pathology; Bare metal stents; Vascular responses; Vascular injury

Role of stent design and coatings on restenosis and thrombosis by Hidehiko Hara; Masato Nakamura; Julio C. Palmaz; Robert S. Schwartz (pp. 377-386).

More than 15 years have passed since stent technology was introduced by Sigwart et al. [U. Sigwart, J. Puel, V. Mirkovitch, F. Joffe, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N. Engl. J. Med. 316 (1987) 701–706.] among interventional cardiologists. Recently drug eluting stents have assumed dominance in the interventional world as positive trial results revealed their efficacy for preventing restenosis. Stent design, delivery-vehicle materials, and drug properties affect the function of these stents. Stainless steel stents with tubular and multicellular design have proven superior to coil or hybrid stent models. This chapter describes stents which have subtle influences of modular design, metal coverage, strut thickness, strut shape, surface smoothness, and coating materials like an alloy composition.

Keywords: Stent; Stent design; Drug eluting stent; Restenosis

Mechanisms of controlled drug release from drug-eluting stents by Ghanashyam Acharya; Kinam Park (pp. 387-401).

The clinical importance of drug-eluting stents (DESs) has been demonstrated by their unparalleled success in preventing restenosis after stenting procedures. The magnitude of success is historic despite their short history. The current DESs deliver a single drug aiming to prevent or minimize proliferation of smooth muscle cells. Since the restenosis process involves several different biological responses, the ability to deliver the right drugs at the right times is critical for further development of the second generation of DESs. As the type of drugs that can be delivered from DESs varies, it is imperative to understand the drug delivery mechanisms and the approaches available for drug coating on the stents. The drug delivery mechanisms of current DESs that have been used clinically and under clinical trials are explained.

Keywords: Drug-eluting stents; Restenosis; Controlled drug delivery; Stent coating; Biocompatibility

Drug-eluting stents: Factors governing local pharmacokinetics by Chiming Yang; Helen M. Burt (pp. 402-411).

Stent-based drug delivery system is a revolutionary approach to mitigate the negative affects of balloon angioplasty, improve immune responsiveness and prevent hyperplastic growth of smooth muscle in the restenotic state. Its success is therefore empirically associated with effective delivery of potent therapeutics to the target site at a therapeutic concentration, for a sufficient time, and in a biologically active form. However, local delivery with drug-eluting stents imparts large dynamic concentration gradients across tissues that can be difficult to identify, characterize and control. This review explores the factors such as physiological transport forces, drug physicochemical properties, local biological tissue properties and stent design that governs the local pharmacokinetics within the arterial wall by drug-eluting stent. Rational design and optimization of drug-eluting stents for local delivery thus requires a careful consideration of all these factors.

Keywords: Drug-eluting stent; Drug transport; Local pharmacokinetics; Diffusion; Convection; Arterial wall structure; Stent design; Computational modeling

The Taxus™ drug-eluting stent: A new paradigm in controlled drug delivery by Kalpana R. Kamath; James J. Barry; Kathleen M. Miller (pp. 412-436).

The advent of drug-eluting stents (DES) has provided the medical community with a technology that is transforming the treatment of coronary artery disease. As the newest treatment modality available to the interventional cardiologist, drug-eluting stents have not only significantly reduced the risk of restenosis, but they are also allowing the interventionalists to treat more complex lesions in patients that would otherwise require more invasive bypass surgery. Development of these drug–device combination products has presented considerable challenges to the device industry because it involves a multi-disciplinary approach that combines conventional device design and manufacturing with the principles of controlled local drug delivery. This review article provides an in-depth discussion of the key elements of drug-eluting stents, focusing on the TAXUS™ paclitaxel-eluting stent as an example of this new class of product. Specific sections will review the drug and polymer matrix components, formulation development and evaluation, pre-clinical studies and clinical trial results.

Keywords: Restenosis; Paclitaxel; SIBS; Stents; Drug-eluting stents; Controlled drug delivery; Local drug delivery; Taxus; DES

Zotarolimus (ABT-578) eluting stents by Sandra E. Burke; Richard E. Kuntz; Lewis B. Schwartz (pp. 437-446).

Drug-eluting stents have revolutionized the field of interventional cardiology and have provided a significant innovation for preventing coronary artery restenosis. Polymer coatings that deliver anti-proliferative drugs to the vessel wall are key components of these revolutionary medical devices. This article focuses on the development of stents which elute the potent anti-proliferative agent, zotarolimus, from a synthetic phosphorylcholine-based polymer known for its biocompatible profile. Zotarolimus is the first drug developed specifically for local delivery from stents for the prevention of restenosis and has been tested extensively to support this indication. Clinical experience with the PC polymer is also extensive, since more than 120,000 patients have been implanted to date with stents containing this non-thrombogenic coating. This review provides background on pre-clinical studies with zotarolimus, on the development of the biocompatible PC polymer and on the clinical trials conducted using two stent platforms which deliver this drug to patients with coronary artery disease.

Keywords: Restenosis; Zotarolimus; Coronary stenting; Coronary artery disease

Clinical experience and applications of drug-eluting stents in the noncoronary vasculature, bile duct and esophagus by Lindsay Machan (pp. 447-462).

To review the use of drug-eluting stents outside the coronary artery.The vast majority of research and clinical data on drug-eluting stents are from their use in coronary artery atherosclerosis; however, these devices can be used outside the coronary circulation in both vascular and nonvascular structures. In noncoronary arteries the principle indication for drug-eluting vascular stents is the same as in the coronary circulation, prevention of restenosis. Human experience has been essentially limited to trials or compassionate use; two small controlled studies and a number of small observational single center reports have been published, and there are trials in progress. To date the data have not been as compelling as in the coronary circulation. The physical characteristics of each vascular bed such as external compressive forces, blood flow rates, wall thickness relative to lumen size, and vessel wall composition differ significantly from the coronary circulation and each presents unique challenges to local drug delivery. Outside the vascular bed, the principle expected use is the prevention of tissue ingrowth after stent insertion in tubular structures such as the trachea, esophagus or bile ducts.Considerable further study of drug-eluting stents will be required in each anatomic region to determine the ideal stent/drug combination and clinical appropriateness.

Keywords: Stents; Peripheral catheterization; Peripheral vascular diseases; Interventional radiology; Gastrointestinal neoplasms

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Advanced Drug Delivery Reviews (v.58, #3)