Current Pharmaceutical Design - Volume 21, Issue 30, 2015

Manufactured tobacco contains over 4, 000 toxic substances, but only a few exert adverse cardiovascular effects. Nicotine and its metabolites, carbon monoxide, thiocyanate and some aromatic amines play a strong, although different, role to determine cardiovascular damage. Of these substances, however, nicotine, acting by the double mechanism of addiction and receptor-binding, and carbon monoxide by increasing the production of carboxyhemoglobin and hypoxia, are the main determinants of the damage. The development of the alterations of heart and blood vessels follows a typical way, initially consisting of functional responses that become irreversible pathological lesions at the time. Myocardium and endothelial cells are the targets where cigarette smoking exerts its effects. The first displays functional and pathological disorders primarily related to ischemic heart disease, cardiomyopathy, including experimental cardiomyopathy from smoking, and heart failure, while the second should be interpreted as a structure, which shows early alterations caused by smoking as clearly evident, repeatable and typically depending on smoking toxicity. Cardiovascular damage has a functional onset, which, at the time, leads to irreversible morphological damage of myocardial and endothelial cells.

The incidence of renal complications including kidney failure is on the rise. Moreover, with aging of the population and the high incidence of diabetes, hypertension and obesity, this trend may prevail. An important cytoprotective enzyme that has been shown to improve renal function is heme-oxygenase (HO). HO is known to abate apoptosis and necrosis, and improves cell vitality, which in turn, may enhance tissue regeneration. Consistently, HO has been shown to restore tissue morphology by potentiating potentiate proteins of repair/regeneration and promoting neovascularization. The formation of new tissue may replace damaged or dysfunctional tissue to preserve cellular integrity and function after injury. Emerging evidence indicate that HO-inducers improve kidney function in several models including, (i) streptozotocin-induced diabetic rats, (ii) Zucker-diabetic-fatty rats, (iii) Zucker-fatty rats, (iii) spontaneously hypertensive rats, (iv) uninephrectomized deoxycorticosterone-acetate hypertensive rats, (v) Nω-nitro-l-arginine-methyl ester (L-NAME)-induced hypertensive rats, (vi) glycerol induced renal failure, (vii) nephrotoxic nephritis, (viii) sepsis-induced kidney injury, (ix) cystic renal disease, (x) cisplatin-mediated acute kidney injury, and (xi) rhabdomyolysis-induced renal injury. The mechanisms underlying the HO-mediated reno-protection include: (i) the restoration of renal morphology by enhancing proteins of regeneration, (ii) the potentiation of the HO-adiponectin-atrial natriuretic peptide axis, with corresponding suppression of oxidative/inflammatory insults and extracellular matrix/profibrotic factors, and (iii) the potentiation of podocyte cytoskeletal proteins such as nephrin, podocin, podocalyxin and CD2-associated-protein, which are fundamental for forming the glomerular filtration barrier that selectively allows small molecules to pass through but not large protein molecules. Thus, this review highlights the HO-adiponectin-atrial natriuretic peptide axis in renoprotection.

From the discovery of protease activated receptors (PARs) to the development of first clinically available PAR1 antagonist (vorapaxar) more than two decades of continuous research have passed. There are four different types of PARs named as PAR1, 2, 3 and 4 having a unique mechanism of signaling. These receptors are present in different organs, including the cardiovascular system. Presence of PARs in heart and blood vessels, alteration in the level and activity of the receptors in pathological conditions along with availability of antagonists makes these receptors targetable in several cardiac diseases. Therapeutic benefits of PAR antagonist have been proven in animal model of cardiac diseases such as myocardial infarction, viral myocarditis, atherosclerosis, pulmonary arterial hypertension, etc. PAR signaling plays a vital role in mediating cardiac hypertrophy, inflammation and fibrosis. Apart from having cardiac importance PAR antagonist are also continuously experimented for their beneficial effects in improving insulin resistance in metabolic syndromes. In the present review, we have discussed the functions of individual PARs in the heart and blood vessels along with the expected usefulness of PAR modulators in cardiovascular diseases.

The rising incidence of atrial fibrillation (AF) has stimulated researches to identify novel therapeutic options for such most common and refractory cardiac arrhythmia in clinical practice. Rhythm control strategy is shown to be associated with a lower risk of progression to permanent AF and greater clinical benefit as compared with rate control. Remarkable progress has been witnessed in rhythm control strategy particularly along with the development of mapping and ablation technology, while still should pharmacological cardioversion serve as an integrated approach for the management of AF especially in the emergency department or centers not equipped with ablation professionals. Concerns regarding the safety and efficacy of existing conventional antiarrhythmic drugs (AADs) limit their clinical use. Vernakalant, with its relatively atrial selective antiarrhythmic profile, is developed as a novel AAD for pharmacological cardioversion of AF. Its mechanisms involve potassium and sodium channels blocking effects during atrial action potential. A series of clinical trials have demonstrated the rapid, efficacious and safe effect of vernakalant over placebo or conventional AADs in terminating recent-onset AF among patients with structurally normal or minimal heart disease; but current evidence does not show a superior role of vernakalant in treating long-duration AF or atrial flutter. More evidence with respect to comparisons of vernakalant with conventional AADs as well as their synergic effects is needed. Cost-effectiveness analyses of vernakalant applied in prospective and “real world” practice remain to be assessed.

Moderate exercise is an effective and economic way to prevent and treat cardiovascular diseases. Unlike pathological cardiac growth, exercise-induced cardiac growth, excluding extreme strenuous exercise, does not cause cardiac cell death, fibrosis, and cardiac dysfunction. The balanced cardiomyogenesis (cardiomyocyte hypertrophy and hyperplasia) and neo-angiogenesis are essential determinants for exercise-induced cardiac growth. In particular, exercise leads to physiological cardiac growth through regulating the IGF-1-PI3K-Akt, nitric oxide (NO), C/EBPβ, and PGC-1α signaling pathways, which might be novel therapeutic targets for cardiac diseases. The formation of new cardiomyocytes in response to exercise suggests that exercise might be a useful tool to enhance cardiac regenerative capacity. Exercise also exerts its protective effects against cardiac aging and cardiac metabolic derangement. Moreover, growing evidence reveals the regulation of cardiac and circulating microRNAs in response to exercise. A better understanding of the mechanisms underlying exercise-induced cardioprotection will lead to the development of innovative pharmacotherapies for cardiac diseases.

Antisense oligonucleotide therapy is a growing field in cardiac, metabolic, and muscular diseases. This precision therapy allows for treatment of diseases due to specific genetic defects. Antisense has few side effects and is relatively long lasting. Some major targets for antisense therapy include hyperglycemia, hyperlipidemia, and hypercholesterolemia. ISIS Pharmaceuticals recently commercialized antisense therapy with Kynamro™ (Mipomersen) for homozygous familial hypercholesterolemia, opening the door for other antisense oligonucleotides for lowering proteins. Antisense can also be used to increase proteins that are inhibited by mutant exons. Sarepta is testing exon 51 skipping in the mutated dystrophin gene, which if successful will help affected individuals walk, and may help restore some cardiac function. These antisense techniques also could be applied as antisense therapies to overcome gene defects in hypertension, heart disease, muscular defects and metabolic syndrome.

Cardiovascular diseases (CVDs), primarily myocardial infarction (MI), atherosclerosis, hypertension and congestive heart failure symbolize the foremost cause of death in almost all parts of the world. Besides the traditional therapeutic approaches for the management of CVDs, newer innovative strategies are also emerging on the horizon. Recently, gene silencing via small interfering RNA (siRNA) is one of the hot topics amongst various strategies involved in the management of CVDs. The siRNA mechanism involves natural catalytic processes to silence pathological genes that are overexpressed in a particular disease. Also the versatility of gene expression by siRNA deciphers a prospective tactic to down-regulate diseases associated gene, protein or receptor existing on a specific disease target. This article reviews the application of siRNA against CVDs with special emphasis on gene targets in combination with delivery systems such as cationic hydrogels, polyplexes, peptides, liposomes and dendrimers.

Cardiovascular disorders or cardiovascular diseases (CVD) are major illness associated with heart and blood vessels. Reactive oxygen species (ROS), generated during excessive oxidative stress, are responsible for the pathophysiology of various cardiovascular disorders including atherosclerosis, cardiac hypertrophy, cardiomyopathy, heart failure, ventricular remodeling, ischemia/reperfusion injury and myocardial infarction. Cellular “redox homeostasis” generally maintains the healthy physiology in cardiac myocytes and endothelial cells. However, during excessive oxidative stress body’s endogenous system fails to maintain normal physiology hence antioxidant supplementation is necessary, which could scavenge the free radicals and other toxic radicals. Several antioxidants such as CoQ10, beta carotene, lycopene, quercetin, reserveterol, vitamin C and vitamin E have shown preventive and therapeutic benefits in different forms of CVD. However, poor biopharmaceutical properties and variable pharmacokinetics of several antioxidants limits their use as therapeutic agents. Hence delivery of stable antioxidants at their site of action is a need of current scenario. Several novel carriers based approaches have shown considerable benefits for the systemic and site specific delivery of antioxidants for the preventive and therapeutic treatment of several cardiovascular diseases. In the present review, conventional as well as novel antioxidants have been discussed with special emphasis for the treatment of CVD. Further, the current review also highlights the critical challenges for antioxidant delivery and various novel carriers (nanoformulations) including, liposomes and nanoparticles explored for their efficient delivery in the therapeutic management of CVD.

In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review highlights the recent approaches for management of cardiovascular disease using different vesicular and particulate carriers, including liposomes, nanoparticles, and nanoemulsions, with a primary emphasis on those which are expected to enhance the antioxidants level.

The increasing prevalence and complexity of cardiovascular diseases demand innovative strategies for diagnostic and therapeutic applications to improve patient care/prognoses. Additionally, various factors constrain present cardiovascular therapies, including low aqueous drug solubility, early metabolism, short half-life and drug delivery limitations. The efficient treatment of cardiovascular diseases requires improvement of traditional drug delivery systems. This can be accomplished by using novel nanomaterial that can incorporate diverse bio-actives along with diagnostic agents in a single carrier, referred to as theranostics. This review discusses the state of the art in the applications to diagnosis and therapy of innovative, nanomaterial- based strategies such as lipid based carriers, nanocapsules, magnetic nanoparticles, gold nanoparticles, protein conjugated nanoparticles, dendrimers and carbon-based nanoformulations with a special emphasis on how they can contribute to improving the management of cardiovascular disease.

Cardiovascular disease (CVD), accounting around 30% of deaths worldwide, collectively comprised of disorders affecting the heart and blood vessels as well as their associated adverse conditions. Despite outstanding progress in the area of the treatments of CVDs, significant challenges remain in designing of efficient delivery systems for myocardial therapy. Moreover, current therapy for CVDs is limited due to various clinical complications such as systemic toxicity, stent thrombosis, etc. Molecular and nanotechnology approaches provide the tools to explore such frontiers of biomedical science at the cellular level and thus offer unique features for potential application in the field of cardiac therapy. In this review, recent advances in CVD related risk factors, chronic inflammation, and their therapeutic modalities such as stem cell therapy, gene delivery, tissue factor (TF) inhibitors, miRNAs, leukotriene modifiers, thrombolytic agents etc., in modern molecular aspects are discussed. Moreover, nanoparticle based drug delivery, nanocarriers as molecular imaging, and the various challenges of myocardial tissue engineering aspects have been summarized. All these aspects may provide additional therapeutic substitutes in clinical trials for the registration of new drugs.

Cardiovascular diseases (CVDs) are the leading cause of death and morbidity worldwide. Atherosclerotic situations such as acute myocardial infarction(MI) and stroke are still major causes of death worldwide. Present therapeutic approaches based on conventional drug delivery systems are not efficient to control these disorders. With the technological advancement and intervention of nanotechnology, several fascinating areas are explored for the management of these disorders. Targeted drug delivery approaches and diagnostic tools presented by nanotechnology, certainly took the atherosclerotic disease management to next level. Criticality lies in the rationale selection of an appropriately designed nanocarrier for targeting a specific zone of disease. Manuscript provides a descriptive view of disease targets; nanotechnology based therapeutic and diagnostic approaches and different nanocarriers to accomplish this task. It is important to have the understanding of different classes of these nanosystems along with their specific merits and demerits. Mechanisms and approaches for improving the selectivity or targeting potential are also discussed. There is no doubt that nanotechnology is having great impact in this area, but it is equally important to rationalize its scale up aspects for a real world success.

Heparin, a well known drug for anticoagulant therapy and prophylaxis of deep vein thrombosis and coronary syndromes, is also involved in numerous pathological processes such as inflammation, immune cell migration, tumor cell metastasis, smooth muscle cell proliferation etc. Though heparin is a clinically used anticoagulant with minimal side effects and drug interactions, its clinical use is limited due to parenteral administration. Alternatively, noninvasive delivery approaches such as oral, nasal, pulmonary or transdermal route are being explored that may deal with problems associated with parenteral heparin without compromising therapeutic benefits. For the successful noninvasive delivery of such a large drug candidate, the biological and biochemical barriers must be overcome to achieve a clinically acceptable therapeutic advantage. Nanocarriers significantly improve the pharmacokinetics and clinical effectiveness of the loaded therapeutics by either protecting them from unfavorable bioenvironment or modifying their release at the target site. Novel carriers such as liposomes, nanoparticles, dendrimers etc. have been developed to improve the bioavailability of heparin through various routes of delivery. Overall, the present review provides complete insight to the research that has been carried out for heparin delivery through various routes.

In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Several key features of dendrimers such as excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them as a superior choice over available polymers. The diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug-loaded dendrimers is the delayed and sustained-release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as a versatile carrier for drug delivery. Collectively, this review focuses on detailed note on the delivery and improved solubility of poorly soluble anti-cardiovascular bioactives, nitric oxide (NO) donor for anti-thrombosis, gene delivery and delivery of receptor agonists for cardio-protective action of the receptors using dendrimers.