Current Pharmaceutical Design - Volume 24, Issue 37, 2018

High blood pressure in children and adolescents may have an adverse impact on the heart, the vessels, the kidney, and the central nervous system causing early functional or structural changes. The most prevalent subclinical hypertensive target organ damage in children and adolescents is left ventricular hypertrophy, and echocardiographic assessment of left ventricular mass is suggested in all hypertensive children. There is evolving evidence that antihypertensive treatment in children and adolescents could lead to regression of target organ damage, emphasizing also the importance of adequate blood pressure control. Assessment of subclinical organ damage could guide clinical decisions from diagnosis with regard to intensity non-pharmacological treatment, time to wait for initiation of pharmacological treatment, and choice of drug. Longitudinal studies are needed to relate the effectiveness of antihypertensive treatment and blood pressure targets in childhood with future cardiovascular or renal events. This review summarizes evidence on the associations of hypertension with target organ damage in children and adolescents and the role of antihypertensive therapy on the regression of target organ damage in the pediatric age group.

Artery disease can be identified from ankle-brachial index (peripheral artery disease), pulse wave velocity (arterial stiffness), carotid intima media thickness (atherosclerosis) and flow-mediated dilation (endothelial dysfunction). Arterial stiffness is a marker of cardiovascular disease associated with cardiovascular events. Increased vascular ageing is the acceleration of arterial stiffness inappropriate for the given chronological age. Treatment of early vascular ageing seems to be important if we target primary cardiovascular prevention. Known factors that postpone the progression of vascular ageing may include lifestyle interventions such as physical exercise, moderate alcohol consumption, reduced salt consumption and weight reduction, factors that may preserve the vessels healthier than what expected for the chronological age. Hypertension, diabetes mellitus, obstructive sleep apnea and dyslipidemia are factors accelerating vessels damage and should be treated and maintained over time well controlled. In the future, trials are needed in order to identify the best combination of treatment as well as to identify drugs targeting on the vessels ageing.

Background: The development and risk potential of hypertension-induced left ventricular (LV) hypertrophy has been well described in epidemiological studies. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. However, the best treatment strategy is still debated, as well as the appropriate blood pressure target in these patients. Objective: We here review the treatment of LV hypertrophy and the potential benefit on clinical outcomes, against a background of the epidemiology and pathophysiology. Results: Both hemodynamic and non-hemodynamic mechanisms contribute to hypertensive LV hypertrophy, which is characterized by an inappropriate myocardial fibrosis. Stringent blood pressure control reduces LV hypertrophy. Blockers of the renin-angiotensin-aldosterone system may have valuable effects on cardiac and electrophysiological remodelling beyond the effects of blood pressure reduction. Thus, they represent a cornerstone in the treatment of hypertensive LV hypertrophy, but most often other antihypertensive drug classes need to be added. Current guidelines indicate a blood pressure target in most patients with hypertensive LV hypertrophy of 120–130/80 mmHg. Conclusions: LV hypertrophy and myocardial fibrosis are important characteristics of hypertensive heart disease and associated with untoward prognosis. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. New drugs under development may add additional benefit.

Atrial fibrillation (AF) and hypertension (HT) are expected to rapidly rise worldwide in the next few years. Important improvements in AF therapy are hampered by pro-arrhythmic and bleeding risks of current medications. Prevention of AF is an important matter as it will not only prevent the disease but also medications side effects, and it is likely to be cost effective. HT is a major contributor to AF. As a modifiable risk factor, its treatment might reduce new-onset AF, and recurrent AF after cardioversion or ablation as well. We review here the effect of HT treatment to prevent AF. Renin-angiotensin system (RAS) blockers prevent new-onset AF in patients at high cardiovascular risk, and especially so in heart failure patients. The evidence is less strong among hypertensive patients, except in the presence of left ventricular hypertrophy or if at high cardiovascular risk. In such circumstances, losartan or valsartan were more effective than atenolol or amlodipine. After medical or electrical cardioversion, RAS blockers favourably affect AF recurrence and this class of drug should figure among the prescribed antihypertensive medications. Last, the addition of renal denervation to pulmonary vein isolation may provide even further therapeutic opportunities in patients with refractory HT and AF.

Regardless of having a similar antihypertensive effect, different antihypertensive drug classes have a different effect on albuminuria. Patients with albuminuria will usually need more than one drug to achieve blood pressure control, particularly if the aim is also to reduce albuminuria. Albuminuria is independently associated with cardiovascular and renal risk regardless of diabetes status. The recent ESC/ESH guidelines listed microalbuminuria among the hypertension-mediated organ damages. Albumin-to-creatinine ratio was suggested to be included in routine workup for evaluation of every hypertensive patient and changes in albuminuria were considered to have moderate prognostic value. Because of its specific effects on renal hemodynamic and glomerular structure, the ACEIs and ARBs should be prescribed in maximum tolerated doses. The MRAs can be considered in uncontrolled hypertensive patients. The CCBs can be used in addition to the RAAS blockade. Data on antialbuminuric effect of the new CCBs generation (T-type and N-type calcium channel blockers) is promising and they might be preferential CCBs when available. In case of resistant hypertension, thiazide or thiazide-like diuretic has to be added into the combination with RAAS blockers and other antihypertensive drugs. Low-salt intake has to be recommended for all hypertensive patients, particularly those with albuminuria. A multifactorial and early antialbuminuric approach should be started even when albuminuria values are below the cut-off value for microalbuminuria.

Introduction: Neuronal nicotinic acetylcholine receptors are ligand-gated ion channel receptors, distributed throughout central nervous system, as well as in peripheral ganglia and some non-neuronal cells. Cytisine, a qulinolizidine alkaloid, could be considered a high affinity ligand of those receptors. It is a partial agonist of β2*-containing receptors and a full agonist of α7 and β4*-containing receptors. Current indication: At present, pharmacodynamic properties of cytisine are leveraged only in a few European countries where it is available as medicinal product (Desmoxan and Tabex) indicated in the pharmacotherapy of nicotine addiction. Cytisine mimics the influence of nicotine on α4β2* receptors, but with higher affinity and lower activity. It lowers rewarding and reinforcing effects of nicotine in smoking persons and reduces withdrawal symptoms and craving in quitting ones. Potential indications: The results of non-clinical studies suggest that cytisine could affect ethanol consumption, has an antidepressant and neuroprotective effect and could be useful in reducing body mass and preventing weight gain. Although there is a lack of research on cytisine in the treatment of areca nuts usage, the preliminary data suggest its usefulness. The combination of cytisine and Trolox C was selected as a possible effective treatment for type 2 diabetes. Though these drugs alone are not effective, their theoretical usefulness was confirmed in animal models. Summary: Treatment with cytisine is an effective, cost-efficient, affordable and well tolerated nicotine addiction therapy. Potential new indications for cytisine include the treatment of alcoholism, areca nuts usage, Parkinson’s disease, an autonomic-system failure. Further studies are necessary.

Background: Chemotherapy regimens have improved prognosis and mortality of patients with malignant diseases. The development of therapies, however, has widened the cardiotoxic spectrum and the cardiacrelated effects of antineoplastic drugs. Methods: A review of the literature under the search terms anthracyclines, oncology, cardiotoxicity, cardiooncology, chemotherapy and heart failure was used for the identification of the most relevant articles. Results: Considerable variability exists in patients' characteristics, in mechanisms involved in cardiomyopathy progression and in its physical history, as well as in modalities used to screen myocardial competence. The anthracyclines and particularly doxorubicin are the most widely used antineoplastic drugs. Monoclonal antibodies, tyrosine kinase inhibitors and other targeted therapies have been associated with cardiovascular side-effects, such as cardiomyopathy and congestive heart failure. Moreover, some of these agents are associated with an increased risk of coronary artery disease with or without myocardial infarction. The current standard for the detection of cardiac toxicity is serial echocardiography. Biomarkers though could be proved helpful, they can be tested at closer intervals and are highly accurate and reproducible. Of note, a growing body of data has emerged suggesting that some agents could have cardioprotective properties. Conclusion: Since the number of long-term survivors following the diagnosis and treatment of malignant disease will continue to increase, cardio-oncology will continue to evolve. Therefore, a better understanding of potential cardiovascular effects of chemotherapeutic regiments and the earlier identification and treatment of high-risk patients would be the focus of research in the future.

Cardiovascular disease (CVD) is the first leading cause of morbidity and mortality in developing and developed countries. Circulating exosomes have recently been identified as extracellular transporters, detectable in biological fluids. Exosomes have established a new era in diagnosing diseases, especially CVD. Determination of exosome profiles, e.g., miRNAs, for different health states such as myocardial injury still requires further studies. In this review, we will discuss the role of exosomes as a potential biomarker in CVD, with particular emphasis on recent advances in the methods to study exosomes, isolation, detection, and characterization.

Since antibiotics use is currently limited due to undesired side effects and the increasing antibiotic resistance of various bacteria strains, there is a pressing need to develop new strategies and methods preventing epidemic outbreaks. The virulent potency of bacteria relies on a number of different extracellularly secreted factors among which proteases considered as promising, novel drug targets are of special interest. The first evidence that bacterial cysteine, serine and metalloproteinases contributed to the progression of infection was found in the early 70's. This extracellular proteolytic system allows bacteria to penetrate into tissues, escape detection by the host's immune mechanisms and grow despite limited access to nutrition. A molecule able to selectively inhibit the activity of bacterial proteases in the spread of infection may lead to designing novel therapeutics. Moreover, due to their mechanism of action, bacterial protease inhibitors can be used to fight antibiotic-resistant strains. Herein, we undertake a review of various bacterial proteases together with the design and development of their inhibitors (excluding β-lactams) for the last ten years, and introduce the reader to a brief history of the subject.

Background and Objective: The evidence regarding the association between serum/plasma vitamin D (VitD) concentrations and systemic lupus erythematosus (SLE) is inconsistent. The study was based on relevant results from literatures that were identified and evaluated. The aim of this meta-analysis is to determine circulating VitD in SLE patients and explore influencing factors. Methods: Studies examining VitD levels in SLE patients were identified through targeted searches in the PubMed and EMBASE databases (up to December 2017). Data extracted from eligible studies was synthesized to calculate the standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI). A fixed or a random effects model was applied to calculate the pooled SMDs and ORs depending on heterogeneity across studies. Results: A total of 24 studies, including 6017 patients and 18,417 controls were included. The pooled analysis suggested that VitD levels were significantly lower in SLE patients compared with those in controls [SMD= −0.09, 95%CI= −0.12 to −0.06, P < 0.001]. When the studies were stratified by ethnicity, VitD concentrations were also significantly lower in Asian, Caucasian and African patients. When the studies were stratified by age, gender, VitD level was lower in patients than that in controls. Subgroup analyses stratified by measurement type (expect for radioimmunoassay) also demonstrated consistent results. Moreover, VitD insufficiency was more prevalent in SLE patients than healthy controls [OR=6.57, 95%CI=4.64−9.29]. Conclusion: Compared with healthy controls, SLE patients had lower concentration of VitD. Additionally, the prevalence of VitD insufficiency is more common in SLE patients.

Background: Keratoconus is recognized by asymmetrical thinning and bulging of the cornea, resulting in distortion in the surface of the cornea. Keratoconus also alters the biomechanical properties of the cornea, which can be an indicator of the healthy and keratoconus eyes. This study was aimed at employing a combination of clinical data, finite element method (FEM), and artificial neural network (ANN) to establish a novel biomechanical- based diagnostic method for the keratoconus eyes. Methods: To do that, the clinical-biomechanical parameters of 40 healthy and 40 keratoconus eyes were obtained via the Pentacam and non-contact tonometer (Corvis ST, Oculus Optikgeräte, Wetzlar, Germany) devices. Intraocular pressure (IOP) was measured using a Goldmann applanation tonometer as well as Corvis. According to the geometry of the cornea, the FE model of each cornea was made and the same boundary and loading conditions were applied not only to confirm the FE model in terms of the biomechanical parameters but also to calculate the amount of von Mises stress in the apex of the cornea. The clinical-biomechanical data of the Corvis along with the von Mises stresses were then incorporated into the ANN algorithm to distinguish the healthy and keratoconus corneas on a basis of the resulted von Mises stresses. The proposed programming code, according to the input data from the Corvis, enabled to predict whether the cornea is keratoconus or not. Finally, to verify the results of the proposed method, 155 individuals were examined. Results: The clinical and biomechanical results of the Corvis revealed that the healthy corneas have a higher thickness compared to the keratoconus ones. No significant differences were observed among the IOPs, 1st applanation length, and pick distance in the highest concavity. The 2nd applanation length and radius in the highest concavity of the healthy cornea were higher than the keratoconus ones. Conversely, the 1st and 2nd applanation velocities and deformation amplitudes of the keratoconus corneas were higher than the healthy ones. The FE results also showed higher stresses for the healthy corneas compared to the keratoconus ones. The ANN was also well verified since it demonstrated more than 95.5% accuracy on diagnosing the keratoconus eyes. Conclusion: These findings have implications not only for identifying the keratoconus corneas as an important clinical and surgical tool for eye care professionals but also for providing both a quantitative and an accurate approach to the problem of understanding the biomechanical nature of keratoconus.

Background: Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN- α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have been approved or are in clinical development, the majority of currently available PIs have significant limitations related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing schedules, and shorter treatment durations. Methods: The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using a fluorescence-based enzymatic assay. Results: We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a. Conclusion: The two compounds presented in this study may be promising inhibitors against NS3/4A protease of HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of chronic HCV infection.

Background: Although several clinical and numerical studies have been conducted on plaque vulnerability assessment, it still remains a critical target for investigation. The stresses whether because of the blood pressure or stenting induce within plaque and arterial layers inside an atherosclerotic artery might exceed from their yield stresses and trigger plaque rupture or arterial layer injury. This study is aimed at conducting a comparative study to understand the vulnerability of the plaques, i.e., calcified, cellular, and hypocellular, as well as the coronary arterial layers, i.e., intima, media, and adventitia, during the stent expansion inside a patient-specific atherosclerotic coronary-artery model. Methods: To do that, a three-dimensional (3D) finite element (FE) model of the atherosclerotic coronary artery is established on a basis of CT/MRI data of a patient. The stent is then expanded inside the atherosclerotic artery and the resulted stresses and strains in the plaque components, i.e., the fibrotic capsule (FC) and necrotic core (NC), and arterial layers are computed. Results: The results revealed that the distribution and magnitude of the von Mises stresses in each component involved in stenting are different according to the plaque types and arterial layers. The stress in the calcified plaque is the highest as compared to the cellular and hypocellular. Lower stresses are observed in the adjacent medial and adventitial layers while the stress in the intima is high enough to invoke injury. The results suggest FC and plaque rupture may occur at localized regions as well as plaque shoulders. Eventually, the dogboning and foreshortening parameters found to be independent on that of the plaque types. Conclusions: The results may have implications not only for understanding the vulnerable plaques and arterial layers to rupture during the stenting, but also for providing a comprehensive information for the medical and biomechanical experts in interventions and surgeries, including balloon-angioplasty, bypass, and stenting.