Design,synthesis and biological evaluation of ambenonium derivatives as AChE inhibitors

Ambenonium (1), an old AChE inhibitor, is endowed with an outstanding affinity and a peculiar mechanism of action that, taken together, make it a very promising pharmacological tool for the treatment of Alzheimer's disease (AD). Unfortunately, the bisquaternary structure of 1 prevents its passage through the blood brain barrier. In a search of centrally active ambenonium derivatives, we planned to synthesize tertiary amines of 1, such as 2 and 3. In addition, to add new insights into the binding mechanism of the inhibitor, we designed constrained analogues of ambenonium by incorporating the diamine functions into cyclic moieties (4-12). The biological evaluation of the new compounds has been assessed in vitro against human AChE and BChE. All tertiary amine derivatives resulted more than 1000-fold less potent than 1 and, unlike prototype, did not show any selectivity between the two enzymes. This result, because of recent findings concerning the role of BChE in AD, makes our compounds, endowed with a well-balanced profile of AChE/BChE inhibition, valuable candidates for further development. To better clarify the interactions that account for the high affinity of 1, docking simulations and molecular dynamics studies on the AChE-1 complex were also carried out.     

Neuropsychiatric sequelae in TBI: a comparison across different age groups

Objective: Traumatic brain injury (TBI) is the leading cause of death and permanent disability in developmental age. Neurobehavioural symptoms are not uncommon in these patients. The aim of this study was to identify the main neuropsychiatric sequelae of TBI at different ages and study the possible correlations with clinical features in the acute phase and outcome in order to better plan rehabilitative treatment and re-entry into society.

Method: Ninety-six post-traumatic patients, ranging from 0-18 years, underwent a complete psychological evaluation protocol at 1 year from trauma. Patients were divided into three different age groups (0-6 years; 7-13 years; 14-18 years) and received a protocol made up of age-appropriate scales.

Results: Different psychological problems were found across the three groups; more frequently younger patients show internalizing problems such as withdrawal and closure, while, with age, behaviour problems become more frequent, characterized by hyperactivity and aggressiveness. Factors that were most predictive of psychological, behaviour and adjustment problems include GOS scores, the degree of impairment on the neurological examination and male gender.

Conclusions: Psychological and behavioural problems differ across the three age groups and determine a different outcome, rehabilitation plan and re-entry into society. These problems should, thus, be investigated and treated specifically according to age.     

Chronic systemic inflammation in uremia: potential therapeutic approaches

Systemic inflammation characterizes several chronic diseases including uremia. Inflammation may contribute to morbidity and mortality by enhancing protein-calorie malnutrition, infectious complications, and atherosclerosis and cardiovascular disease. Although inflammation in renal disease can be caused, at least in part, by reduced renal clearance of proinflammatory mediators (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6), several pathogenetic mechanisms are likely to contribute to direct activation of the inflammatory process under these conditions. These mechanisms include accumulation of advance glycoxidation end products, production of reactive oxygen species and oxidative damage, and chronic infection. Support for direct activation of systemic inflammation provides a strong rationale for use of anti-inflammatory treatments in uremia. The current article describes the association between uremia and inflammation, provides evidence for activation of inflammatory process, and provides potential therapeutic approaches.     

Induced oral breathing and craniocervical postural relations: an experimental study in healthy young adults

The influence of induced oral breathing on head and craniocervical posture was studied in ten healthy young adults. After a baseline recording, oral respiration was induced by using a swimmer's type nose clip. The subjects were filmed 15 and 90 minutes after wearing the nose clip, immediately and 15 minutes after taking it off. The angles C7-tragion versus the true vertical, nasion-tragion versus the vertical, and C7-tragion-nasion were calculated, and the difference between the baseline and the four experimental recordings was computed. During the experiment, head and neck positions were modified in all subjects, but with a large variability for both the direction (flexion or extension) and the extent of the modification. Overall, the mean differences were minimal with large standard deviations. Differences between baseline and the experimental recordings were significant only for the C7-tragion versus the vertical angle (analysis of variance, p=0.0083). In conclusion, induced oral respiration may have a significant role in the alteration of head and craniocervical posture, but the effect was highly variable.     

Vascular endothelial growth factor-A, vascular endothelial growth factor receptor-2 and angiopoietin-2 expression in the mouse choroid plexuses

In this study, for the first time, we investigated about the localization of VEGF-A, VEGFR-2 and Ang-2 in the choroid plexuses of the adult mouse by Western blot and immunohistochemistry. Results showed that VEGF-A stained epithelial cells, while anti-VEGFR-2 and -Ang-2 antibodies stained endothelial cells. These data suggest that Ang-2, converting blood vessels into a more plastic and immature phenotype, would provide more accessibility of VEGF-A to endothelial cells.     

Hemolytic effects of water-soluble fullerene derivatives

A series of water-soluble fullerene C(60) derivatives has been investigated for their cytotoxic and hemolytic properties, with the aim to correlate structure with toxicity. We observed that cationic chains induce significant toxicity while the presence of neutral or anionic moieties did not produce any response in our model. A validation of these experimental observations has been performed by theoretical studies in which hydrophilic and hydrophobic surface areas were correlated quantitatively with hemolytic properties.     

Current perspective. Diabetic vascular disease: from endothelial dysfunction to atherosclerosis.

Cardiovascular complications are the leading cause of death in diabetes. Over the past decade a number of studies have addressed the underlying mechanisms. Derangements of endothelial function, also referred to as endothelial dysfunction, have emerged to be the crucial early step in the development of atherosclerosis and are also involved in plaque progression and clinical emergence. Endothelial dysfunction is a condition of impaired endothelium-dependent vasodilation and most important of "endothelial activation", characterized by a proinflammatory, proliferative, and procoagulatory milieu that promotes initiation and complications of atherogenesis. A synergistic cross-talk among the conventional cardiovascular risk factors associated with diabetes contributes to disruption of endothelial integrity and accelerated atherosclerosis. This review will focus on the multifactorial nature of endothelial dysfunction in diabetes, the relationship between endothelial dysfunction, conventional cardiovascular risk factors and atherosclerosis, and the therapeutic options to improve endothelial function.     

Efficacy and safety of recombinant urate oxidase (rasburicase) for treatment and prophylaxis of hyperuricemia in children undergoing chemotherapy

Rasburicase has been defined as a potent urolytic agent for management of malignancy-associated hyperuricemia. We reviewed the data of 26 children with malignancy at risk for TLS who received rasburicase for treatment or prophylaxis of acute hyperuricemia, producing a significant decrease in uric acid level in all the patients. Tolerance of treatment was excellent. Rasburicase is a safe, highly and rapidly effective agent in the treatment and prevention of malignancies-associated acute hyperuricemia.