Contents:

Executive Summary 1. Cardiovascular Diseases Introduction History of cardiovascular drug delivery Overview of cardiovascular disease Coronary artery disease Angina pectoris Limitations of current therapies for myocardial ischemic disease Cardiomyopathies Cardiac arrhythmias Congestive heart failure Peripheral arterial disease Current management Atherosclerosis The endothelium as a target for cardiovascular therapeutics Molecular cardiology Cardiogenomics Cardioproteomics Personalized cardiology Pharmacogenomics of cardiovascular disorders Modifying the genetic risk for myocardial infarction Management of heart failure Management of hypertension Pharmacogenomics of diuretic drugs Pharmacogenomics of ACE inhibitors Management of hypertension by personalized approach Pharmacogenetics of lipid-lowering therapies Polymorphisms in genes involved in cholesterol metabolism Role of eNOS gene polymorphisms Important advances in cardiovascular therapeutics Drug delivery, biotechnology and the cardiovascular system 2. Methods for Drug Delivery to the Cardiovascular System Introduction Routes of drug delivery to the cardiovascular system Local administration of drugs to the cardiovascular system Intramyocardial drug delivery Drug delivery via coronary venous system Intrapericardial drug delivery Formulations for drug delivery to the cardiovascular system Sustained and controlled release Programming the release at a defined time Dosage formulation of calcium channel blockers Sustained and controlled release verapamil Methods of administration of proteins and peptides Delivery of peptides by subcutaneous injection Depot formulations and implants Poly(ethylene glycol) technology Microencapsulation for protein delivery Localized delivery of biomaterials for tissue engineering Oral delivery of proteins and peptides DDS to improve systemic delivery of cardiovascular drugs Nanotechnology-based drug delivery Targeted drug delivery to the cardiovascular system Immunotargeting of liposomes to activated vascular endothelial cells PEGylated biodegradable particles targeted to inflamed endothelium Devices for cardiovascular drug delivery Local drug delivery by catheters Microneedle for periarterial injection Nanotechnology-based devices for the cardiovascular system Liposomal nanodevices for targeted cardiovascular drug delivery Nanotechnology approach to the problem of “vulnerable plaque” Role of cardiovascular imaging in cardiovascular therapeutics Chronopharmacotherapy of cardiovascular diseases Drug delivery in the management of cardiovascular disease Drug delivery in the management of hypertension Transnasal drug delivery for hypertension Transdermal drug delivery for hypertension Oral extended and controlled release preparations for hypertension Long-acting hypertensives for 24 h blood pressure control Drug delivery to control early morning blood pressure peak Role of drug delivery in improving compliance with antihypertensive therapy Drug delivery for congestive heart failure Oral human brain-type natriuretic peptide Nitric oxide-based therapies for congestive heart failure Automated drug delivery system for cardiac failure DDS in the management of ischemic heart disease Intravenous emulsified formulations of halogenated anesthetics Injectable peptide nanofibers for myocardial ischemia Delivery of angiogenesis-inducing agents for myocardial ischemia Drug delivery for cardiac rhythm disorders Drug delivery in the treatment of angina pectoris Sustained and controlled-release nitrate for angina pectoris Transdermal nitrate therapy Controlled release calcium blockers for angina pectoris Drug delivery in the management of pulmonary hypertension Anticoagulation in cardiovascular disease Oral heparin Low molecular weight heparin-loaded polymeric nanoparticles Transdermal anticoagulants Thrombolysis for cardiovascular disorders Use of ultrasound to facilitate thrombolysis Delivery of alteplase through the AngioJet rheolytic catheter Drug delivery for peripheral arterial disease Delivery of thrombolytic agent to the clot through a catheter Immune modulation therapy for PAD NO-based therapies for peripheral arterial disease Drug delivery in the management of hypercholesterolemia Controlled/sustained release formulations of statins Combinations of statins with other drugs to increase efficacy Controlled release fenofibrate Extended release nicotinic acid Intravenous infusion of lipoprotein preparations to raise HDL Innovative approaches to hypercholesterolemia Single dose therapy for more than one cardiovascular disorder 3. Cell Therapy for Cardiovascular Disorders Introduction Inducing the proliferation of cardiomyocytes Role of stem cells in repair of the heart Cell-mediated immune modulation for chronic heart disease Cell therapy for atherosclerotic coronary artery disease Transplantation of myoblasts for myocardial infarction MyoCell™ (Bioheart) Transplantation of cardiac progenitor cells for revascularization of myocardium Methods of delivery of cells to the heart Cellular cardiomyoplasty IGF-1 delivery by nanofibers to improve cell therapy for MI Intracoronary infusion of bone marrow-derived cells for AMI Non-invasive delivery of cells to the heart by Morph®guide catheter Transplantation of stem cells for myocardial infarction Transplantation of embryonic stem cells Transplantation of hematopoietic stem cells Transplantation of cord blood stem cells for myocardial infarction Intracoronary infusion of mobilized peripheral blood stem cells Human mesenchymal stem cells for cardiac regeneration Cytokine preconditioning of human fetal liver CD133+ SCs Transplantation of expanded adult SCs derived from the heart Transplantation of endothelial cells Transplantation of genetically modified cells Transplantation of cells secreting vascular endothelial growth factor Transplantation of genetically modified bone marrow stem cells Cell transplantation for congestive heart failure Myoblasts for treatment of congestive heart failure Injection of adult stem cells for congestive heart failure Role of cell therapy in cardiac arrhythmias Atrioventricular conduction block Ventricular tachycardia ESCs for correction of congenital heart defects Cardiac progenitors cells for treatment of heart disease in children Stem cell therapy for peripheral arterial disease Clinical trials of cell therapy in cardiovascular disease A critical evaluation of cell therapy for heart disease Publications of clinical trials of cell therapy for CVD Future directions for cell therapy of CVD 4. Gene Therapy for Cardiovascular Disorders Introduction Techniques of gene transfer to the cardiovascular system Direct plasmid injection into the myocardium Catheter-based systems for vector delivery Ultrasound microbubbles for cardiovascular gene delivery Vectors for cardiovascular gene therapy Adenoviral vectors for cardiovascular diseases Plasmid DNA-based delivery in cardiovascular disorders Intravenous rAAV vectors for targeted delivery to the heart Hypoxia-regulated gene therapy for myocardial ischemia Angiogenesis and gene therapy of ischemic disorders Therapeutic angiogenesis vs. vascular growth factor therapy Gene painting for delivery of targeted gene therapy to the heart Gene delivery to vascular endothelium Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles Gene delivery by vascular stents Gene therapy for genetic cardiovascular disorders Genetic disorders predisposing to atherosclerosis Familial hypercholesterolemia Apolipoprotein E deficiency Hypertension Genetic factors for myocardial infarction Acquired cardiovascular diseases Coronary artery disease with angina pectoris Ad5FGF-4 Ischemic heart disease with myocardial infarction Myocardial repair with IGF-1 therapy Congestive heart failure Rationale of gene therapy in CHF Genetic manipulation of b-adrenergic receptor system in CHF Intracoronary adenovirus-mediated gene therapy for CHF AAV-mediated gene transfer for CHF AngioCell gene therapy for CHF nNOS gene transfer in CHF Gene therapy for cardiac arrhythmias Gene therapy and heart transplantation Gene therapy for peripheral arterial disease Angiogenesis by gene therapy HIF-1a gene therapy for peripheral arterial disease HGF gene therapy for peripheral arterial disease Ischemic neuropathy secondary to peripheral arterial disease Maintaining vascular patency after surgery Antisense therapy for cardiovascular disorders Antisense therapy for hypertension Antisense therapy for hypercholesterolemia RNAi for cardiovascular disorders RNAi for hypercholesterolemia microRNA and the cardiovascular system Role of miRNAs in angiogenesis Role of miRNAs in cardiac hypertrophy and failure Role of miRNAs in conduction and rhythm disorders of the heart miRNA-based approach for reduction of hypercholesterolemia miRNAs as therapeutic targets for cardiovascular diseases Future prospects of miRNA in the cardiovascular therapeutics Future prospects of gene therapy of cardiovascular disorders Companies involved in gene therapy of cardiovascular disorders 5. Drug-Eluting Stents Introduction Percutaneous transluminal coronary angioplasty Stents Restenosis Pathomechanism Treatment Nitric oxide-based therapies for restenosis Carbon monoxide inhalation for preventing restenosis Antisense approaches for prevention of restenosis after angioplasty Gene therapy to prevent restenosis after angioplasty Techniques of gene therapy for restenosis NOS gene therapy for restenosis Non-viral gene therapy to prevent intimal hyperplasia HSV-1 gene therapy to prevent intimal hyperplasia Drug delivery devices for restenosis Local drug delivery by catheter Absorbable metal stents Drug-eluting stents Various types of DES CYPHER® sirolimus-eluting coronary stent Sirolimus-eluting vs paclitaxel-eluting stents Paclitaxel-eluting stents Dexamethasone-eluting stents NO-generating stents Dexamethasone-eluting stents Novel technologies for DES Stents for delivery of gene therapy Stem cell-based stents Drug-eluting stents coated with polymer surfaces Absorbable DES Endeavour DES Bio-absorbable low-dose DES VAN 10-4 DES Nanotechnology-based stents Drugs encapsulated in biodegradable nanoparticles Magnetic nanoparticle-coated DES Nanocoated DES Nanopores to enhance compatibility of DES The ideal DES Companies developing drug-eluting stents Clinical trials of drug-eluting stents Measurements used in clinical trials of DES TAXUS paclitaxel-eluting stents Everolimus-eluting coronary stents XIENCE™ V Everolimus-Eluting coronary stent system COSTAR II clinical trial Endeavor RESOLUTE zotarolimus-eluting stent system CUSTOM I clinical trial NOBORI CORE Trial Comparison of DES in clinical trials Comparison of DES with competing technologies DES versus coronary artery bypass graft DES versus bare metal stents Guidelines for DES vs BMS DES vs BMS for off-label indications Role of DES in cases of bare-metal in-stent restenosis DES versus balloon catheter coated with paclitaxel DES versus intracoronary radiation therapy for recurrent stenosis Cost-effectiveness of DES Safety issues of DES Adverse reactions to DES Endothelial vascular dysfunction due to sirolismus Risk of clotting with DES Clopidogrel use and long-term outcomes of patients receiving DES Effect of blood clot on release of drug from DES Use of magnetized cell lining to prevent clotting of DES Long-term safety studies of DES Regulatory issues of DES Future prospects for treatment of restenosis by DES Future role of DES in management of cardiovascular diseases Stent cost and marketing strategies Improvements in stent technology Bioabsorbale stent 6. Markets for Cardiovascular Drug Delivery Introduction Epidemiology of cardiovascular disease Cost of care of cardiovascular disorders Cardiovascular markets according to important diseases Antithrombotics Anticholesterol agents Antihypertensive agents Drugs for congestive heart failure Markets for innovative technologies for cardiovascular disorders Markets for cell therapy of cardiovascular disorders Markets for gene therapy of cardiovascular disorders Markets for drug-eluting stents Major players in DES market Impact of safety issues on future markets for DES Patenting and legal issues The financial impact of DES on cardiovascular markets Unmet needs for cardiovascular drug delivery Role of DDS in developing cardiovascular markets Markets for cardiovascular devices Marketing of innovative cardiovascular drug delivery devices Direct to consumer advertising of DES Future trends in the integration of drug delivery with therapeutics Future prospects of cardiovascular drug delivery 7. Companies involved in Cardiovascular Drug Delivery Profiles of companies Collaborations 8. References Tables Table 1-1: Landmarks in the historical evolution of cardiovascular drug delivery Table 1-2: Gene polymorphisms that alter cardiovascular response to drugs Table 2-1: Routes of drug delivery used for treatment of cardiovascular disorders Table 2-2: Formulations for drug delivery to the cardiovascular system Table 2-3: Improved methods of systemic drug delivery of cardiovascular drugs Table 2-4: Targeted delivery of therapeutic substances to the cardiovascular system Table 2-5: Classification of devices for drug delivery to the cardiovascular system Table 2-6: Various methods of delivery of therapeutic agents for hypertension Table 2-7: Marketed controlled/ extended release preparation for hypertension Table 2-8: Drug delivery in ischemic heart disease Table 2-9: Methods of delivery of nitrate therapy in angina pectoris Table 2-10: Drug delivery for peripheral arterial disorders Table 3-1: Clinical trials of cell therapy in cardiovascular disease Table 4-1: Cardiovascular disorders for which gene therapy is being considered. Table 4-2: Catheter-based systems for vector delivery to the cardiovascular system Table 4-3: Potential applications of antisense in cardiovascular disorders Table 4-4: Companies involved in gene therapy of cardiovascular diseases Table 5-1: Treatment of restenosis Table 5-2: Devices used for drug delivery in restenosis Table 5-3: Companies involved in drug-eluting stents Table 6-1: Prevalence of cardiovascular disorders in major markets: US 2007-2017 Table 6-2: Prevalence of cardiovascular disorders in major markets: Europe 2007-2017 Table 6-3: Prevalence of cardiovascular disorders in major markets: Japan 2007-2017 Table 6-4: Values of cardiovascular DDS in major markets 2007-2017 Table 6-5: Markets for innovative technologies for cardiovascular disorders 2007-2017 Table 7-1: Top 5 companies in cardiovascular drug delivery Table 7-2: Collaborations in cardiovascular drug delivery Figures Figure 1-1: Drug delivery, biotechnology and cardiovascular diseases Figure 2-1: Microneedle for periarterial injection Figure 5-1: Vicious circle of vascular occlusion following angioplasty and stenting Figure 5-2: Medtronic’s Endeavour drug-eluting stent Figure 5-3: Magnetic nanoparticle-coated stent Figure 6-1: Unmet needs for cardiovascular drug delivery