Synthesis of novel epibatidine-related derivatives through 1,3-dipolar cycloaddition of pyridinenitrile oxides

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Frequency of left ventricular hypertrophy in non-valvular atrial fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p <0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p <0.0001), age (OR 1.03 per year, p <0.001), hypertension (OR 2.30, p <0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention

Shark-like chondroitin sulfate and process for the preparation thereof

The present invention concerns a shark-like chondroitin sulfate and a process for the prepn. thereof. In particular, the present invention relates to a shark-like chondroitin sulfate having a very low amt. of 4-sulfate, a high charge d. and a biol. activity comparable to natural chondroitin sulfates. The invention also relates to a process for the prepn. of said shark-like chondroitin sulfate affording substantially higher productivities and better reproducibility of product quality. The shark-like chondroitin sulfate of the invention shows a high mol. mass and charge d. and in vitro biol. and anti-inflammatory effectiveness, comparable to the ones of natural products make this polysaccharide potentially useful as a drug in pharmaceutical prepns. and nutraceuticals. Chondroitin sulfate was obtained by the reaction of sodium chondroitin with sulfur trioxide pyridine comple

New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: Synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations

A group of novel 4,5-dihydro-3-methylisoxitzolyl derivatives, structurally related to epiboxidine (= (1R,4S,6S)-6-(3-methylisoxazol-5-yl)-7-azzibicyclo[2.2.1]heptane), was prepared via 1,3-dipolar cyclo-addition of acetonitrile oxide to different olefins. Target compounds 1a and 1b, 2a and 2b, 3, 4, and 5 were tested for affinity at neuronal nicotinic heteromeric (alpha 4 beta 2) and homomeric (alpha 7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the alpha 4 beta 2 subtypes (K(i) values spanning the range 4.3-126 mu M), when compared with that of epiboxidine (Ki = 0.6 nM). Therefore, the replacement of the 3-methylisoxazole ring of epiboxidine with the 4.5-dihydro-3-methylisoxazole nucleus is detrimental for the affinity at alpha 4 beta 2 receptors. A comparable lack of affinity/selectivity for the two nACh R subtypes under study was evidenced for the remaining epiboxidine-related dihydroisoxazole derivatives 2a and 2b. and 3-5. Diastereoisomers 1a and 1b, and spirocyclic derivative 3 were docked into molecular models of the receptor subtypes under study, and their binding mode was compared with that of reference ligands endowed with high binding affinity

Synthesis of epibatidine-related Delta(2)-isoxazoline derivatives and evaluation of their binding affinity at neuronal nicotinic acetylcholine receptors

The group of \u3942-isoxazoline derivatives 5a\u2013c and 6a\u2013c, structurally related to epibatidine, and the simplified analogues 7a\u2013c were synthesized by means of a 1,3-dipolar cycloaddition-based strategy and tested at \u3b14\u3b22 and \u3b17 neuronal acetylcholine receptor (nAChR) subtypes. Competition binding experiments at \u3b14\u3b22 nAChR subtypes showed an overall significant reduction in affinity for the compounds under study in comparison to the reference radioligand [3H]-epibatidine. These outcomes have been rationalized by taking into account the ligand-based pharmacophore models reported in the literature and the recently proposed molecular model of the \u3b14\u3b22 receptor subtype. Conversely, compounds 5b, 5c, and 6b exhibited a noticeable affinity for the \u3b17 receptors and, in the case of 5c, also some subtype selectivit

Synthesis and binding affinity at neuronal nicotinic acetylcholine receptors of novel epibatidine-related delta2-isoxazoline derivatives

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in a number of functional processes as well as several pathological conditions of the central nervous system, thereby representing a target for the development of novel therapeutic agents [1]. In the last few years many efforts have been directed towards the discovery of potent and selective nAChR ligands, in particular agonists at alpha4beta2 or alpha7 receptor subtypes, which are the two major populations of nAChRs found in the brain. In this context, epibatidine, a naturally occurring alkaloidal toxin which is one of the most powerful nicotinic agonists known, has become a model structure for the design of new high affinity and subtype selective ligands for nAChRs [2,3]. We designed and synthesized a set of novel compounds (1a-c and 2a-c), in which the two structural elements featuring epibatidine, i.e. the 7-azabicyclo[2.2.1]heptane system and the pyridine ring, have been distanced by insertion of a Delta2-isoxazoline moiety, either spiro-condensed or fused to the azanorbornane core, respectively. In addition, we designed compounds 3a-c as simplified analogues of derivatives 2a-c, where the ethylene bridge of the bicyclic system has been removed. The overall binding data evaluated on derivatives 1-3 indicated a relevant reduction of the alpha4beta2 affinity, typical of ebipatidine, coupled to the appearance of a noticeable affinity for the alpha7 receptor subtype. The results of further structural modifications on the compounds under investigation will be presented and discussed. [1] Paterson, D.; Nordberg, A. Neuronal Nicotinic Receptors in the Human Brain. Progr. Neurobiol. 2000; 61: 75-111. [2] Carroll, F. I. Epibatidine Structure-Activity Relationships. Bioorg. Med. Chem. Lett. 2004; 14: 1889-1896. [3] Wei, Z-L.; Petukhov, Y. X.; T\ufcckmantel, W.; George, C.; Kellar, K. J.; Kozikowski, A. P. Synthesis, Nicotinic Acetylcholine Receptor Binding Affinities, and Molecular Modeling of Constrained Epibatidine Analogues. J. Med. Chem. 2003; 46: 921-924

Contribution of Water Scarcity and Sustainability Failures to Disintegration and Conflict in the Arab Region-The Case of Syria and Yemen

Economic growth and demographic change are leading factors that impact the availability of resources such as water and arable land in countries around the globe. The case of Arab countries, where both these resources have been naturally scarce, is illustrative. This chapter outlines the contribution of growing scarcity and historic negligence of sustainability of both resources in encouraging and sustaining political instability in the region. Because of failures of public policies in the area of sustainability, vulnerability to local conflicts and larger-scale instabilities and political disintegration are increasing. This chapter provides a closer look at the case of Syria and Yemen. A growing body of scientific literature now links the current Syrian conflict to climate variability, unsustainable agriculture, and consequent unemployment on the one hand and political instability on the other hand. Evidence from Yemen suggests a link between the rise of the Houthis and groundwater depletion in the North, and a link between the repatriation of Yemenis from the Gulf in the 1990s and past failures in agricultural water management. This chapter advocates the consideration of environmental factors alongside broad regional and local political, social, and economic factors in the study of current and future conflicts