Current Pharmaceutical Design - Volume 22, Issue 37, 2016

Background: High blood pressure is the main risk factor worldwide for mortality and morbidity. Subjects with uncontrolled hypertension increased in the last decades. Methods: This review is based on the material searched for and obtained via MEDLINE and PubMed up to June 2016. The search terms used were “hypertension, blood pressure control” in combination with “pathophysiology, lifestyle, antihypertensive drugs, target organ damage, target values and comorbidity”. Results: This narrative review focused its attention on the diagnosis, the pathophysiology, the clinical consequences of arterial hypertension, and on the factors that must be considered for a better blood pressure control. In fact, the attainment of an adequate blood pressure control is a challenge at both a population and an individual level. Conclusion: The review will discuss the best strategy to reduce uncontrolled hypertension and cardiovascular events in hypertensive patients identifying the main conditions which determine and maintain uncontrolled hypertension also highlighting the new possible strategies for a better blood pressure control and including the results of very recent multicenter randomized controlled trials.

Background: In the last decade, the development of anti-inflammatory strategies emerged as new trend in cardiovascular (CV) pharmacotherapy. Anti-inflammatory properties have been previously identified in different classes of drugs used in primary CV prevention. However, the extent to which the modification of inflammatory profile contributes in determining CV outcome remains controversial. Methods: Focusing on potential beneficial effects in primary prevention, this narrative review provides a comprehensive and critical analysis of randomized clinical trials testing anti-inflammatory treatments in CV disease. Results: As upstream regulator of the hepatic production of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-6 and IL-1 pathways early emerged as potential targets for CV prevention. More recently, additional strategies targeting lipoprotein-associated phospholipase A2, pro-protein convertase subtilisin/kexin type 9, and intracellular pathways (such as p38 MAPK and different isoforms of NADPH oxidase) have been tested. Conclusion: Conflicting results emerged from clinical trials, emphasized the need to characterize the inflammatory profile of the patients, to minimize the heterogeneity of study populations and to clarify the true value of CRP as specific biomarker of atherosclerosis-related inflammation.

Background: Atherosclerotic Cardiovascular Disease (ASCVD) is the first cause of death in Western Countries. Several risk factors contribute to generate atherosclerosis and the preventive therapeutic approaches, in particular statin therapy, reduce the mortality. However, the residual risk in statin treated patients remains significant, despite reaching the low density lipoproteins cholesterol (LDL-C) goals. Methods: we reviewed the literature published in PUB-MED to discuss the role of residual dyslipidemia in particular high density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and lipoprotein(a) [Lp(a)], genetic factors, suboptimal implementation of lifestyle therapy, mood disorders associated to low compliance to application of evidence-based therapies or related to ASCVD. Results: we summarized the current knowledge on the topic, evidencing its contradictory aspects. Conclusion: HDL-C is an important biomarker for predicting cardiovascular risk, but the classical HDL hypothesis is no longer correct and it is now being replaced by the HDL function hypothesis, thought more studies are needed to validate it. The connection between cardiovascular risk and levels of TGs is not so definite. APOE genotype and Lp(a) levels are two genetics factors associated to CV risk. Healthy lifestyle with particular dietetic factors, connected to psychological aspects, are very important for the optimal control of the global risk.

Background: The World Health Organization has emphasized that an increased body mass index (BMI) is a major risk factor for non-communicable diseases (NCDs) such as cardiovascular disease (CVD) together with diabetes, musculoskeletal disorders and some cancers. The American Heart Association had already identified obesity as an independent risk factor in 1995. There is a significantly increased risk of CVD independently of other traditional risk factors (age, sex, physical activity, smoking, blood pressure and cholesterol levels) for patients fulfilling BMI criteria of moderate overweight, which increases with the diagnosis of obesity. Thus, both overweight and obesity are major risk factors for type 2 diabetes (T2D), hypertension, and atherogenic dyslipidemia, among others. These diseases, when clustered, form the metabolic syndrome, a condition with exponential risk for CVD as compared with its isolated components. In this scenario, obesity emerges as a major public health challenge due to its huge clinical implications, taxing not only individuals but also health-care systems and society at large. Methods: The present review focuses on: i) the link between dysfunctional fat excess and CVD; ii) the apparent controversies surrounding the obesity paradox as well as the concept of metabolically healthy obesity; iii) the known beneficial effects following weight loss; and iv) available strategies to treat obesity in order to ameliorate cardiovascular risk, which include lifestyle interventions, drug therapy, endoscopic and surgical procedures. Conclusion: Obesity is a highly heterogeneous disease that requires customized recommendations. Weight loss in different degrees is attainable via diverse procedures reducing morbidity and mortality while improving psychological well-being and social function. Therapeutic strategies should be tailored to the patient’s characteristics and need a long-term personal commitment to change.

Background: Cardiovascular diseases (CVDs) are one of the main factors responsible for human morbidity and mortality. Since mitochondria play a critical role in the regulation of cardiac tissue homeostasis, this organelle is a critical target for the protective effects of several pharmaceuticals. Although specific mitochondria-targeted antioxidants and some pharmacological agents are described as potential cardioprotective agents, there are still a few effective mitochondrial therapies for the treatment of CVDs. Agents which have potential cardioprotective effects by directly targeting mitochondria in vitro and in vivo are still in pre-clinical or clinical trials, hence their widespread use in the clinic is still far. Also, some of these agents have a decreased bioavailability or show some intrinsic toxicity, which also limits their working mitochondrial concentrations. Methods: By initially using PubMed specific queries for literature search, we review here cardiac mitochondrial effects of specific targeted and non-targeted antioxidants and pharmacological agents, including MitoE, MitoQ, MitoSNO, Mito-TEMPOL, SkQ1, SkQR1, carvedilol, trimetazidine, ranolazine, diazoxide and propofol. Results: The present review emphasizes new mitochondrial-targeting strategies which have emerged to address difficulties arising from current approaches. We also describe the strengths and weaknesses of these cardioprotective approaches. Conclusion: Although effective therapies to target mitochondria in the context of CVDs are not under widespread clinical use, the new strategies proposed constitute a real promise for the development of therapies which may effectively prevent CVDs in the near future.

Background: There is increasing interest in cardiovascular imaging modalities in the detection of subclinical and clinically-manifested coronary artery disease (CAD) to improve cardiovascular outcome in these patients. Methods: SPECT/CT and PET/CT can be applied for the assessment of myocardial perfusion and myocardial blood flow (MBF) quantification in CAD detection and characterization, while CT is predominantly used to identify coronary plaque burden and epicardial narrowing. In addition, PET/CT plays an increasing role in the detection of the “vulnerable” plaque in the epicardial artery. Results: Imaging of myocardial perfusion with SPECT, SPECT/CT and PET/CT is a mainstay in clinical practice for the identification of flow-limiting epicardial lesions and risk stratification of patients with suspected or known CAD. In this direction, the concurrent ability of PET/CT to determine regional myocardial blood flow (MBF) in ml/g/min at rest and during pharmacologically- induced hyperemic flows allows the calculation of the myocardial flow reserve (MFR) that may unravel reductions in coronary vasodilator capacity, as functional precursor of the CAD process, monitor its response to preventive medical intervention, yield important prognostic information in subclinical – and clinically-manifested CAD, and contributes to identify the flow-limiting effect of single lesions in multivessel CAD. Adding noncontrast computed-tomography (CT) measurements of coronary artery calcifications has further improved the reclassification of cardiovascular risk in asymptomatic individuals with intermediate probability of the presence of CAD. With contrast CT, the non-invasive visualization of coronary vessels, CAD-related plaque burden and stenosis has become feasible. Yet, a definite identification of the "vulnerable plaque" is still a matter of ongoing research. PET/CT in conjunction with various positron-emitting radiotracer yields promise in the detection of the "vulnerable plaque,” that, however, needs further clinical evaluation in CAD patients. Conclusion: Multimodality imaging in cardiovascular disease is likely to further advances and refine the identification and characterization of cardiovascular pathology in the near future.

Cardiovascular disease (CVD) is the leading cause of global mortality. Although extensive efforts have been made to identify valid biomarkers for CVD risk, relatively few are of proven clinical utility. It is recognized that genetic factors play a major role in determining the susceptibility to CVD. Recent genome-wide-association-studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CVD. Several genetic-polymorphisms have been identified in this region that are highly associated with CVD, and these are clustered around the gene loci for CDKN2B (coding for p15ink4b), CDKN2A (coding for p16ink4a and p14ARF) and the 3′ end of CDKN2BAS, which has been termed antisense noncoding RNA in the INK4 locus (ANRIL). Targeted deletion of the 9p21 locus reduces the cardiac expression of CDKN2A/B and is the most frequent mechanism for methylthioadenosine phosphorylase inactivation, leading to a less stable plaque phenotype in the artery. Further investigations will be essential to explore the clinical utility of emerging-markers in larger and multicenter setting in order to establish their values for risk stratification or prediction a chance of future CVD events. The aim of the current review was to provide an overview of the possible molecular mechanisms by which the chromosome 9p21 locus may confer CVD risk, and the consequential clinical implications with particular emphasis on preclinical/clinical trials on genetic changes of this locus and CVD risk.

High grade gliomas (HGGs) are the most frequent and highly invasive type of brain tumors, which arise from glial cells. Among HGGs, glioblastoma multiforme (GBM) is the commonest and deadliest tumor type. Standard HGG therapy that involves tumor resection followed by concomitant treatment with radiation exposure and temozolomide (TMZ) cannot prevent recurrent tumor. The median survival of treated patients after surgery does not exceed 1.5 years. Vaccination with autologous dendritic cells (DCs) pulsed with tumor-specific peptides, antigens, or lysates is considered as a promising option to induce a potent anti-tumor immune response and cytotoxicity against GBM cells. However, since the tumor microenvironment is highly immunosuppressive and immunotolerant, specialized approaches should be applied to protect DC transplants against tumor-induced functional impairment and inhibition. So far, many phase I-III clinical trials utilizing DC vaccines for HGG treatment were completed or are underway. In summary, DC vaccination was safe and well tolerated by patients. DC-induced anti-tumor immune responses correlated with prolonged overall and progression- free survival. Combination of DC therapy with other interventional strategies (i.e., radiotherapy, chemotherapy, antibodies, etc.) and multimodal approaches should improve HGG treatment outcomes. In this review, we consider strategies that provide an option to override the immune inhibitory tumor microenvironment and boost DC vaccine-based antitumor immune response.

Despite being widely used for treating cancer, chemotherapy is accompanied by numerous adverse effects as a result of systemic distribution and nonspecific interactions of the drugs with healthy tissues, eventually leading to therapeutic inefficacy and chemoresistance. Cyclophosphamide (Cyp) as one of the chemotherapeutic pro-drugs is activated in liver and used to treat breast cancer in high dose and in combination with other drugs. In an attempt to reduce the off-target effects and enhance the therapeutic efficacy, pH-sensitive carbonate apatite nanoparticles that had predominantly and size-dependently been localized in liver following intravenous administration, were employed to electrostatically immobilize Cyp and purposely deliver it to the liver for activation. Cyp-loaded particles formed by simple 30 min incubation at 37ºC of the DMEM (pH 7.4) medium containing CaCl2 and Cyp, enhanced in vitro cytotoxicity at different degrees depending on the cell types. The size of the particles could be tightly controlled by the amount of CaCl2 required to prepare the particles and thus the bio-distribution pattern inside different organs of the body. Unlike the small particles (~ 200 nm), the large size particles (~ 600 nm) which were more efficiently accumulated in liver, significantly reduced the tumor volume following intravenous injection in 4T1-induced murine breast cancer model at a very low dose (0.17 mg/Kg) of the drug initially added for complex formation, thus shedding light on the potential applications of the Cyp-loaded nano-formulations in the treatment of breast cancer.

Phthalimide and hydrazine pharmacophores have been demonstrated to be inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX) and to possess a marked analgesic and anti-inflammatory activity. A new group of hybrid analogs of phthalimide and hydrazine (2-(arylmethylideneamino) isoindolines), possessing a variety of substituents (OMe, OH, NO2, Cl, and F) at different positions of the aryl ring, were synthesized and their analgesic and anti-inflammatory effects were evaluated. In vivo screening showed that all the analogs possessed analgesic and anti-inflammatory activity and compounds 10g, 10h and 10e were the most potent as analgesic and compounds 10b, 10c and 10i were the most potent as anti-inflammatory agents.