Current Pharmaceutical Design - Volume 10, Issue 4, 2004

Percutaneous transluminal coronary angioplasty (PTCA) has become the main method of coronary revascularization. However, despite technical advancement, restenosis with incidence rate of 30 to 50% remains a major limitation to the long-term success of PTCA. The introduction of stents has significantly improved capability of interventional cardiology in treatment and prevention of restenosis. Recent experimental studies in animals, clinical studies in humans and multi-center randomized clinical trials with Sirolimus-eluting stents, have demonstrated a significant reduction in vasculoproliferative response with no intimal tissue growth. Moreover, no significant adverse clinical events have been reported at long-term follow-up and first studies that explored the potential of this technology for the treatment of in-stent restenosis demonstrated safety and efficacy. Although the first clinical experiences with drug-eluting stents have produced stunning results, there are a number of theoretical limitations to these devices, including: 1) limitations of drug loading capacity and 2) ability to control drug elution that could result in unfavorable pharmacokinetics. There are also questions about the durability of the polymer coatings (deformation under mechanical stress, gaps between metal and arterial wall, etc). The thickness of some coatings makes them unsuitable for very small vessels. Finally most biodegradable coatings are prone to chronic inflammation. Since only a polymer-coated bare metal stent remains following the drug's release, the potential for long term polymer biocompatibility problems remains a concern. The potential for some drugs to produce radiation-like effects such as “black holes”, malapposed and naked struts and wall thinning are potentially the dark side of this technology and may contribute to late thrombosis, aneurysms or delayed restenosis. Long term clinical follow-up is necessary to assess the long term safety of this technology. There is a legitimate question as to whether drug-eluting stents will produce similar results across all patient subsets encountered in “real-life” interventional practice (e.g. long lesions, small diameter vessels, vein grafts, chronic total occlusions, bifurcated and ostial lesions). Cost-benefit issues also need to be addressed, especially because multivessel stenting and multistent usage is likely to increase.

Restenosis after stent implantation is mainly characterized by an inflammatory response to the procedural injury and an intense fibrocellular response including smooth muscle cell (SMC) proliferation. After angioplasty alone, the restenosis process also involves thrombus formation and negative remodeling. Due to the pleiotropic mode of action exerted by glucocorticoids which include profound anti-inflammatory and immunosuppressive effects, direct inhibition on SMC proliferation and apoptosis, their potential in the prevention of restenosis has gained widespread interest. Over the last decade, preclinical and clinical data have not been able to conclusively document a robust therapeutic effect on restenosis after angioplasty or stent implantation. Only recently, preclinical data and limited observations in humans using drug eluting stents for local drug delivery have suggested beneficial effects of dexamethasone on neointimal proliferation. Randomized clinical trials using local drug delivery are expected to start in the near future. In the light of these ongoing developments, this review summarizes the pathophysiological basis of glucocorticoid action in the context of restenosis, provides an overview of the animal data available and discusses the clinical results that have been gathered over the last decade with particular emphasis on dexamethasone.

Percutaneous coronary intervention has been hampered by restenosis since its inception. Many research projects including the use of various devices and systemic drug administration have shown disappointing results. The clinical data reported from trials with sirolimus- and paclitaxel- eluting stents have been very promising, such that stents with the capability of drug elution are currently attracting the medical community for the prevention of restenosis. Based on the mechanism of action of the drugs released from the stent and the target of the restenotic process, there may be 4 therapeutic objectives: anti-inflammatory, anti-proliferative, anti-migratory, and pro-endothelial healing. There are many candidate agents for drug-eluting stents, however, it now becomes clear that not all drug-eluting stents are equally effective. This article describe candidate agents which have been tested or currently under investigation, and summarize the latest information.

Recent trials provide a wealth of data documenting the benefit of cholesterol-lowering therapy with statins in both primary and secondary prevention. A growing body of evidence indicates that statins possess pleiotropic effects - independent of, or at least in addition to their lipid-lowering capacity, including inhibition of smooth muscle cell proliferation and subsequently neointimal proliferation, platelet aggregation as well as antiinflammatory and direct beneficial effects on endothelial function. The current review summarizes recent findings in non-randomized and randomized trials assessing the efficacy of statin therapy following coronary interventions with or without stent implantation. It highlights the efficacy of statins in the settings of acute coronary syndromes. Current management of acute coronary syndromes requires early administration in combination with acute interventions. High risk patients which receive the greatest benefit could be identified by measuring serum markers such as preprocedural C-reactive protein levels. The present article also describes important novel actions of statins supporting the early initiation of statins post intervention, such as the stimulation of reendothelialization - a crucial step in the healing process of the vascular wall - which is mediated at least in part by mobilization of bone-marrow derived endothelial progenitor cells.

A growing body of evidence suggests that low molecular weight heparin (LMWH) is at least as effective as unfractionated heparin (UFH) in the medical management of acute coronary syndromes (ACS) including acute myocardial infarction. Several studies support an early invasive as compared to a conservative (non-invasive) approach utilizing percutaneous coronary intervention (PCI) in these patients. During coronary angiography and PCI systemic anticoagulation usually administering UFH should prevent thrombus formation at the catheter equipment and at the site of vessel injury. The widespread use of UFH as the anticoagulant of choice is explained by low costs, easy reversibility and accepted anticoagulant properties. However, the clinical support for the use of UFH in PCI is largely based on retrospective and observational data only. Compared to UFH, LMWH have distinct pharmacological advantages, including ease of administration and usually no need for monitoring. A major drawback of LMWH is the predominant renal clearance which may lead to unpredictable levels of anticoagulation in patients with impaired renal function. Since LMWH constitute an extremely heterogeneous group of drugs each LMWH should be recognized as an individual pharmaceutical compound. Consequently, pharmacodynamic and pharmacokinetic properties of one LMWH must not be extrapolated for other LMWH. A growing body of evidence supports the use of LMWH in ACS, with or without GPIIb / IIIa receptor antagonists, thrombolysis, or PCI. Although in patients undergoing PCI, LMWH have yet not been shown to be superior to UFH they can safely be administered.

Cumulative scientific evidence gathered over the past ten years has confirmed the role of platelet GP IIb / IIIa inhibitors in reducing ischemic complications of patients undergoing percutaneous coronary intervention (PCI). Recently, mortality data available on more than 20,000 patients enrolled in randomized clinical trials suggest that GP IIb / IIIa blockade also improves short and long-term survival after PCI. Despite convincing arguments, GP IIb / IIIa inhibitors are still inconsistently administered in patients undergoing coronary intervention. The following review will discuss the scientific grounds and the principal controversies surrounding the use of these compounds in patients undergoing elective percutaneous coronary intervention.

Primary PCI is an effective reperfusion strategy for acute MI patients, which has evolved significantly in the last decade. While many adjunctive therapies have contributed to its success, substantial obstacles remain before optimal reperfusion can be achieved. Anti-platelet therapy with aspirin, clopidogrel and GP IIb / IIIa inhibitors reduces early ischemic complications, improves microvascular function and, potentially, affects the inflammatory response to ischemic injury. Current anti-thrombin therapy with UFH can be improved with LMWH, and, possibly with direct thrombin inhibitors. A number of important aspects of this strategy, though, need still to be elucidated. We need to optimize microvascular protection before and during PCI in order to capitalize on the myocardial sparing effects of reperfusion therapy. This will be probably achieved with a combination of pharmacological interventions and mechanical emboli protection devices. Improved and more targeted anti-inflammatory therapy should decrease the effects of neutrophil-related reperfusion injury, while a variety of metabolic interventions might preserve myocardial function during ischemia and after reperfusion.

Gene therapy is a rapidly evolving field of medicine, which potentially offers new treatments for cardiovascular diseases. With the use of gene transfer methods it is possible to modify somatic cells in blood vessels and myocardium to overexpress or inhibit pathologically important proteins and achieve therapeutic effects. Prevention of restenosis after vascular interventions such as percutanous coronary angioplasty (PTCA), percutanous peripheral angioplasty (PTA) or stent implantation, prevention of venous graft failures and therapeutic angiogenesis are the major aims of experimental studies and clinical gene therapy. The promise of gene therapy in the treatment of cardiovascular diseases remains high. Experimental studies have established the proof of principle that gene transfer to cardiovascular system can achieve therapeutic effects. First human clinical trials provided initial evidence of the feasibility and safety of the novel therapy. There are also first successful reports on the prevention of neointimal hyperplasia and promotion of therapeutic angiogenesis in clinical trials. However, there are still important questions regarding utility, efficiency and safety of gene therapy in the treatment of cardiovascular diseases. In this review we discuss the rapid progress in cardiovascular gene therapy, the development of delivery systems and vectors, most promising therapeutic genes and results of the recent human clinical trials.

Large-scale intervention trials demonstrate that treatment with statins, the most effective lipid lowering drug class, significantly reduces the risk of coronary heart disease events. Recent evidence suggests that more aggressive LDL cholesterol lowering with newly developed statins may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. There is increasing evidence that statins exert a myriad of other beneficial pleiotropic effects on the vascular wall, thus altering the course of atherosclerotic disease. In the long-term treatment, nonlife- threatening side effects may occur in up to 15% of patients receiving one statin. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously. The combination of the statins with gemfibrozil results in higher rates of drug toxicity. Reports show possible adverse effects of statins on nervous system function including mood alterations, however, statins have also been associated with improvement in central nervous system disorders. Special attention must be paid to the tolerability of the statins in children, elderly and transplant patients. Future clinical studies and surveillance information will warrant long term safety of each member of this class of lipid-lowering agents. New classes of patients with diabetes, metabolic syndrome and renal diseases may have clinical benefits from statins. New upcoming clinical trials will address the fundamental question of whether statin treatment can protect from the natural history of atherosclerotic-related diseases. This will require a more prolonged follow-up (i.e., 10 to 15 years). Finally, the basic understanding of newer pathogenic mechanisms involving the effects of statins on angiogenesis and the nitric oxide pathway should be explored in the clinical setting as well as the study of pathogenic mechanisms by which statins can affect plaque instability.

Retinoic acid and derivatives (retinoids) exert their anti-neoplastic action through three different, though partially overlapping mechanisms: growth-inhibition, cyto-differentiation and apoptosis. Retinoid related molecules (RRMs) are a promising class of synthetic retinoic acid derivatives endowed with selective apoptotic activity on a large variety of leukemic and solid tumor cells. The in vitro apoptotic activity of RRMs translates into in vivo efficacy in a number of experimental models of neoplasia. The prototype of this novel family of cytotoxic agents is CD437, a conformation restricted retinoid originally developed as a selective RARγ agonist. A number of new RRM congeners, including ST1926, MM002, MM11453 and MX-3350-1, have been recently reported in the literature. Some of these compounds have a stronger apoptotic potential, a lower level of toxicity and a better pharmacokinetic profile than CD437. RRMs have a molecular mechanism of action that is entirely different from that of many other known chemotherapeutics. These compounds induce apoptosis in retinoic acid- and multi-drug-resistant neoplastic cells. The apoptotic process triggered by RRMs is independent of p53 activation and proceeds through a novel pathway in which the mitochondrion seems to play a pivotal role. RRMs show only very limited cross-resistance with other classes of chemotherapeutic agents and show synergistic interactions with a number of classical cyto-toxic agents. The article presents a critical overview of the current knowledge on the pharmacology of RRMs focussing on such issues as the spectrum of cytotoxic activity, the molecular mechanisms of action and the pre-clinical basis of clinical development.