Current Pharmaceutical Design - Volume 21, Issue 28, 2015

Deriving from the Greek word for “widening”, aneurysms have been a well known entity since antiquity. In the 2nd century AD, Antyllos, the Greek born surgeon who practiced in Rome, described a method for aneurysms’ surgical removal that remained a standard procedure till the 19th century. In 18th century John Hunter proposed a limb saving operation method for treating peripheral aneurysms paving thus the way for the modern surgery of aneurysms and Rudolph Matas, carried out the first aneurysmorrhaphy. During the 20th century two eminent surgeons laid the foundations of vascular surgery: Charles Dubost, who utilized the first homograft for aneurysm repair and Michael DeBakey, who performed the first radical treatment of a thoracic aneurysm.

Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.

Macrophages early invade the forming abdominal aortic aneurysm (AAA) and greatly contribute to its pathogenesis. Recent findings have shown that Ly-6Chigh and Ly-6Clow monocytes are rapidly mobilized from the splenic reservoir in response to angiotensin II infusion and sequentially infiltrate the abdominal aorta. The first wave of Ly-6Chigh monocytes prevails in the aorta and promotes the accumulation of inflammatory macrophages, which most likely cause irreversible changes in the abdominal aorta. In this review, we discuss the current knowledge on the cellular mechanisms that initiate AAA in mice. We particularly focus on the role of monocyte and macrophage subsets during the early steps of the aneurysmal process.

Abdominal aortic aneurysm is a vascular disease which, despite the fact that it shares common risk factors with atherosclerosis, develops in parallel but as a partly independent process, through different pathogenic mechanisms. The pathogenic mechanisms involve metalloproteinase and collagenase activation, median and adventitial degradation, elastin lysis, vascular smooth cells transformation and apoptosis, collagen production and lysis imbalance combined with excessive inflammatory infiltration. Endothelial cells respond to a number of stimulating factors, including smoking, hypertension and AT1 receptor stimulation and non-uniform distribution of wall stress. Their ability to produce NO is crucial in order to adapt. Endothelial cells contribute to AAA development due to increased oxidative stress which is partly mediated by impaired NO bioavailability due to endothelial dysfunction and NADPH oxidase overexpression. In addition, they express several molecules among which adherence molecules, selectins, endothelin-1, regulating inflammatory infiltration and oxidative stress. Inflammatory cells consist of monocytes, polymorphonuclear neutrophils and lymphocytes and they are involved in the degrading process in the aortic wall by secreting proteolytic enzymesor by releasing interleukins which mediate the inflammation response. Endothelial dysfunction and arterial stiffness reflect on indices like FMD, carotid-femoral PWV and augmentation index, sometimes with controversial results. At present, surgical treatment is the only option provided in patients with large AAA, in particular. Focusing on the emerging role of endothelial cells in AAA pathology may contribute in creating new therapeutic options in a disease which has not yet a well-accepted, implemented pharmaceutical treatment.

Abdominal aortic aneurysm (AAA) is a devastating disease associated with high prevalence of death due to aortic rupture. Currently the therapy is restricted to surgical procedures to prevent aortic rupture, which in turn has a risk for postoperative mortality. There are no proven pharmacological therapies available to prevent expansion or rupture of AAA due to the paucity of knowledge on the mechanisms underlying the nature and pathophysiological processes of this complex disease. Animal models are powerful tools to provide mechanistic insights into understanding the development of AAA. Numerous pharmacological approaches have been explored as potential therapies in experimental AAA in the past decade. This review overviews recent advances in mechanistic studies of AAA in angiotensin II-infused mouse models and highlights their clinical relevance for possible therapeutic targets.

Introduction. Since the initial publication in 2000, Angiotensin II-infused mice have become one of the most popular models to study abdominal aortic aneurysm in a pre-clinical setting. We recently used phase contrast X-ray based computed tomography to demonstrate that these animals develop an apparent luminal dilatation and an intramural hematoma, both related to mural ruptures in the tunica media in the vicinity of suprarenal side branches. Aims. The aim of this narrative review was to provide an extensive overview of small animal applicable techniques that have provided relevant insight into the pathogenesis and morphology of dissecting AAA in mice, and to relate findings from these techniques to each other and to our recent PCXTM-based results. Combining insights from recent and consolidated publications we aimed to enhance our understanding of dissecting AAA morphology and anatomy. Results and conclusion. We analyzed in vivo and ex vivo images of aortas obtained from macroscopic anatomy, histology, highfrequency ultrasound, contrast-enhanced micro-CT, micro-MRI and PCXTM. We demonstrate how in almost all publications the aorta has been subdivided into a part in which an intact lumen lies adjacent to a remodeled wall/hematoma, and a part in which elastic lamellae are ruptured and the lumen appears to be dilated. We show how the novel paradigm fits within the existing one, and how 3D images can explain and connect previously published 2D structures. We conclude that PCXTM-based findings are in line with previous results, and all evidence points towards the fact that dissecting AAAs in Angiotensin II-infused mice are actually caused by ruptures of the tunica media in the immediate vicinity of small side branches.

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis. Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

Since the first implantation of an endograft in 1991, endovascular aneurysm repair (EVAR) rapidly gained recognition. Historical trials showed lower early mortality rates but these results were not maintained beyond 4 years. Despite newer-generation devices, higher rates of reintervention are associated with EVAR during follow-up. Therefore, the best therapeutic decision relies on many parameters that the physician has to take in consideration. Patient’s preferences and characteristics are important, especially age and life expectancy besides health status. Aneurysmal anatomical conditions remain probably the most predictive factor that should be carefully evaluated to offer the best treatment. Unfavorable anatomy has been observed to be associated with more complications especially endoleak, leading to more re-interventions and higher risk of late mortality. Nevertheless, technological advances have made surgeons move forward beyond the set barriers. Thus, more endografts are implanted outside the instructions for use despite excellent results after open repair especially in low-risk patients. When debating about AAA repair, some other crucial points should be analysed. It has been shown that strict surveillance is mandatory after EVAR to offer durable results and prevent late rupture. Such program is associated with additional costs and with increased risk of radiation. Moreover, a risk of loss of renal function exists when repetitive imaging and secondary procedures are required. The aim of this article is to review the data associated with abdominal aortic aneurysm and its treatment in order to establish selection criteria to decide between open or endovascular repair.

The prevalence of abdominal aortic aneurysm (AAA) in general population is 4-9% with a high mortality rate when ruptured. Therefore, screening programs were developed in many countries to detect small and large AAA in selected patients. Indeed, prevalence of AAA increases in patients over 65 years old with cigarette smoking history. This paper reviews recent literature related to AAA screening focusing on epidemiology, screening tests and evidence based medicine to highlight not only advantages but also disadvantages of screening programs among population.

Acridine orange (AO) is an antimalarial drug that accumulates into acidic cellular compartments. Lysosomes are quite acidic in cancer cells, and on this basis we have demonstrated that photoactivated AO is selectively toxic in sarcomas. However, photodynamic therapy is only locally effective, and cannot be used to eradicate systemic residual disease. In this study, we have evaluated the activity of non-photoactivated AO on sensitive and chemoresistant osteosarcoma (OS) cells to be considered for the systemic delivery. Since lysosomes are even more acidic in chemoresistant cells (MDR), we found that AO accumulation was significantly higher in the lysosomes of MDR in respect to parental cells, and in both cell types, therapeutic doses of AO significantly inhibited cell growth. However, the level of growth inhibition was inversely related to the level of lysosomal uptake of AO, suggesting that the main target of this agent is indeed extralysosomal. A significant reduction of intracellular ATP content and of the expression of mitochondrial complex III suggests a mitochondrial targeting. Notably, MDR cells showed a lower mitochondrial activity. Finally, the combined treatment of AO with the anticancer agent doxorubicin (DXR) significantly increased chemotoxicity by promoting DXR mitochondrial targeting, as revealed by the further reduction in ATP intracellular content. In conclusion, AO is able to effectively target both sensitive and resistant OS cells through mitotoxicity.

Nanotechnology has been revealed as a fundamental approach for antibiotics delivery. In this paper, recent findings demonstrating the superiority of nanocarried-antibiotics over “naked” ones and the ways by which nanoparticles can help to overwhelm bacterial drug resistance are reviewed. The second part of this paper sheds light on nanoparticle-bacterium interaction patterns. Finally, key factors affecting the effectiveness of nanoparticles interactions with bacteria are discussed.

There is a pressing need to develop novel antimicrobials to circumvent the scourge of antimicrobial resistance. The objective of this study is to identify non-antibiotic drugs with potent antimicrobial activity, within an applicable clinical range. A library, containing 727 FDA approved drugs and small molecules, was screened against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Drugs that showed antimicrobial activity in an applicable clinical range were further tested in vitro and in vivo in an infected mouse model. The initial screening identified 24 non-antibiotic drugs and clinical molecules active against Gram-positive pathogens including methicillin- resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) isolates. Two non-antibiotic drugs showed activity against Gram-negative pathogens. Among the active non-antibiotic drugs, only ebselen (EB) and 5-fluoro-2'-deoxyuridine (FdUrd), showed bactericidal activity, in an applicable clinical range, against multi-drug-resistant Staphylococcus isolates including MRSA, vancomycin-resistant S. aureus (VRSA), and vancomycin-intermediate S. aureus (VISA). The minimum inhibitory concentration at which 90% of clinical isolates of S. aureus were inhibited (MIC90) was found to be 0.25 and 0.0039mg/L for EB and FdUrd, respectively. Treatment with EB orally significantly increased mice survival in a lethal model of septicemic MRSAinfection by (60%) compared to that of control. FdUrd oral and intraperitoneal treatment significantly enhanced mouse survival by 60% and 100%, respectively. These data encourage screening and repurposing of non-antibiotic drugs and clinical molecules to treat multidrug-resistant bacterial infections.

Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r2), explained variance (adjusted R2), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays.