Comparative Bioavailability Study of Two 81 mg Coated Tablet Formulations of Acetylsalicylic Acid in Fasting Healthy Volunteers

Introduction: Low-dose acetylsalicylic acid is used as antithrombotic agent and the enteric-coated formulations are widely used to minimize the gastrointestinal side effects. Aim: To compare the bioavailability of two acetylsalicylic acid formulations (Ecasil-81®, 81 mg coated tablet) in fasting healthy volunteers. Methods: Healthy volunteers (n=16) were recruited to a monocentric, open label, randomized, two-way crossover pharmacokinetic study, with seven days washout period between the treatments. They received a single 81 mg oral dose of a test (new formulation) or a standard reference formulation of acetylsalicylic acid (Ecasil-81®) after about 8 h fasting. Blood samples were collected over a period of 36 h. The salicylic acid plasma concentration was evaluated by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Noncompartmental pharmacokinetic analysis was performed using the WinNonlin program. Results: The maximum plasma concentration (Cmax) of salicylic acid was 5433 and 5719 ng/mL reached in 3.66 and 4.02 h (tmax) for the test and the reference formulation, respectively. The 90% confidence interval of the ratios of geometric means of Cmax and area under curve of plasma concentration until the last concentration observed (AUC0- last) were within the interval 80-125%. Conclusion: The new acetylsalicylic acid formulation has a bioavailability equivalent to the reference formulation for the rate and the extent of absorption

Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins

The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of antiretrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidylanthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TARbinding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins

Heavy Metals Size Distribution in PM10 and Environmental-Sanitary Risk Analysis in Acerra (Italy)

The present research has been focused on the evaluation of seasonal changes in mass concentrations and compositions of heavy metals in Particular Matters (PM)10 collected from a typical urban-industrial site in Acerra, a city located in an area called "triangle of death". No significant (p < 0.05) seasonal variation was evidenced for the PM10 concentration, but in all the seasons (except for autumn) exceedances of daily concentrations (50 μg m−3) were observed. Airborne PM was analyzed for these heavy metals: Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Sb, V and Zn, which represented about 8% of the PM10 concentrations. None of the metals classified by IARC as carcinogenic in humans (group 1) exceeded on average the annual EU's and Italy's limit. For the mentioned heavy metals the enrichment factors (EnFs) were analyzed and highlighted high enrichment for Cd, Sb, Pb, As, Cu and Zn. Principal component analysis (PCA) for the heavy metals in PM10 identified oil combustion, vehicle and industrial emissions as major sources. To assess the health risk related to the inhalation to airborne PM10 metals, we applied the Cancer Risk (CR) and Target Hazard Quotient (THQ). The results showed that the CR was similar for a child and an adult, while the THQ proved to be higher for a child than for an adult. The low PM metals risk in the urban industrial site was in agreement with the ongoing lowering trend of metals in Italy and Europe

Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice

Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK-acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance

Caratterizzazione quali-quantitativa del PM10 nelle aree individuate come critiche nel piano regionale di tutela della qualità dell'area, al fine di comprendere con rigore scientifico la loro origine.

Il particolato atmosferico, i cui effetti negativi sulla salute umana sono ormai ben noti dalla comunità scientifica, è una matrice ambientale di grande complessità e variabilità. Pertanto, grazie alla collaborazione con l'Agenzia Regionale Protezione Ambientale Campania (ARPAC), è stato analizzato il PM10 nelle sue componenti chimiche (specie ioniche,metalli,IPA e componenti carboniose) ed è stato associato lo stesso a possibili fonti d'origine mediante l'utilizzo di un modello a recettore (PMF)

Lipophilic and polar interaction forces between acidic drugs and membrane phospholipids encoded in IAM-HPLC indexes: their role in membrane partition and relationships with BBB permeation data.

The membrane phospholipid affinity data, logkwIAM , for 18 acidic and unionized drugs spanning a wide lipophilicity range were measured by HPLC on two different phospholipid stationary phases, i.e. IAM.PC.MG and IAM.PC.DD2. These data related weakly with both log PN values, the n-octanol/water partition coefficients of the neutral forms, and log D7.4 values, the n-octanol/water partition coefficients of the mixtures of neutral and ionized forms at pH 7.4. The lack of collinearity confirms that, differently from partition in n-octanol/water, partition in phospholipids encodes not only lipophilic/hydrophobic intermolecular recognition forces but also ionic bonds, due to electrostatic interactions between electrically charged species and phospholipids, according to the ???pH-piston hypothesis???. Since, differently from bases, electrostatic interactions between acids and phospholipids take place at the surface of phospholipid layers (choline moieties), and not near their lipophilic core (phosphate moieties), they were parameterized by a new procedure yielding ?????' logkwIAM??? parameters, i.e. the difference between the IAM retention factors observed for the analytes and those of neutral compounds with the same n-octanol partition values displayed by the analytes at pH 7.4. All acidic analytes, but one, and all unionized analytes, but the unionizable ones, showed positive ??'logkwIAM values, indicating that they partition stronger in phospholipids than in n-octanol. Log BB values (capability to pass BBB) weakly related with both lipophilicity and phospholipid affinity values; in contrast they inversely related with ??'logkwIAM values. The relationships between log BB and ??'logkwIAM practically overlapped the previously found log BB/??logkwIAM relationships for bases. The excess of polar interaction component between acidic drugs and phospholipids, mainly electrostatic forces, although enhancing partition in phospholipids, hinders membrane passage, analogously to the behavior previously reported for bases. The study suggests that IAM-HPLC is an effective technique to perform simple and fast measurements of the intermolecular recognition forces related to membrane partition and permeation. This can contribute to better understand the mechanisms governing both partition of charged species in cell membranes and passage through them, also allowing the possible optimization of the pharmacokinetic properties of the drugs at the early stages of their development

Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia

Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period

Biostimulants Improve Plant Growth and Bioactive Compounds of Young Olive Trees under Abiotic Stress Conditions

The negative impacts of extreme heat and drought on olive plants have driven the quest for mitigation approaches based on the use of biostimulants, which have proved to be effective in contrasting environmental stresses. The aim of our study was to evaluate the effectiveness of six biostimulants in mitigating high temperature and water stress in young olive trees in terms of vegetative and eco-physiological parameters as well as bioactive compound content. Biostimulants based on glycine betaine and macro- and micro-algae effectively protected the plants from abiotic stress by improving their eco-physiological and vegetative parameters. At the end of the growing season, olive plants were experiencing water deficit which had built up through the summer months. At this time, the glycine betaine-treated plants had a three-fold higher stomatal conductance compared with the control, while plants sprayed with the seaweed mix had a relative water content 33% higher than the control. The kaolin treatment resulted in higher total phenolics and antioxidant activities (DPPH, FRAP and ABTS) in water stress conditions and caused an increase of 238.53 and 443.49% in leaves total polyphenols content in 100% and 50% water regime, respectively. This study showed the effectiveness of biostimulants in mitigating the damage from abiotic stress on young olive trees, by improving some vegetative, eco-physiological and leaf nutraceutical parameters. Further studies are needed to test the efficiency of these biostimulants in open field conditions on olive trees in full production

The Role of 5-HT1A Receptor in the Cancer as a New Opportunity in Medicinal Chemistry

The 5-HT1A receptor is a pharmacologically well characterized serotonin receptor subtype and it has long been investigated because of its involvement in several physio-pathological mechanisms and treatment of neurological diseases like ansia and depression. Serotonin (5-HT) also shows many non-neural functions such as essential hypertension, embryogenesis, follicle maturation and behavior. Moreover it exerts a growth factor function on different types of non-tumoral cells, and it was also found to be related to oncogenes. In fact, growth-stimulatory activity of serotonin in different human tumor cells has been reported. Recently, new chemical molecules binding the 5-HT1A receptor have been described as novel therapeutic entities useful in neuroprotection, cognitive impairment, Parkinson's Disease, pain treatment, malignant carcinoid syndrome and cancer. It was widely demonstrated that 5-HT1A receptor is involved in the carcinogenesis and consequently in many human tumor types, such as prostate, bladder, small cell lung, colonrectal and cholangiocarcinoma. Furthermore depending on the tumor type, 5-HT1A receptor antagonists were shown to be able to block the 5HT-induced increase in tumor growth. In this review we have focused our attention on each tumor type where the 5-HT1A receptor is involved, investigating the role of this molecular target and the different classes of compounds that have shown the capability to modulate it. The analyzed aspects could represent the hint for the medical chemists to develop novel molecules as selective 5-HT1A agents useful to further elucidate the role this therapeutic target

Level, potential sources of polycyclic aromatic hydrocarbons (PAHs) in particulate matter (PM10) in Naples

In Naples, particulate matter PM10 associated with polycyclic aromatic hydrocarbons (PAHs) in ambient air were determined in urban background (NA01) and urban traffic (NA02) sites.The principal objective of the study was to determine the concentration and distribution of PAHs in PM10 for identification of their possible sources (through diagnostic ratio - DR and principal component analysis - PCA) and an estimation of the human health risk (from exposure to airborne TEQ). Airborne PM10 samples were collected on quartz filters using a Low Volume Sampler (LVS) for 24 h with seasonal samples (autumn, winter, spring and summer) of about 15 days each between October 2012 and July 2013. The PM10 mass was gravimetrically determined. The PM10 levels, in all seasons, were significantly higher (P < 0.001) in the urban-traffic site (NA02) than in the urban-background site (NA01). The filters were then extracted with dichloromethane using an ultrasonicator (SONICA) to perform a detailed characterization of 12 priority PAHs proposed by the USEPA, by gas chromatography-mass spectrometer (GC-MS) analysis.The concentration of Benzo[a]Pyrene, BaP (EU and National limit value: 1 ng m-3 in PM10), varied from 0.065 ng m-3 during autumn time to 0.872 ng m-3 in spring time (NA01) and from 0.120 ng m-3 during autumn time to 1.48 ng m-3 of winter time (NA02) with four overshoots.In NA02 the trend of σ12 PAHs was comparable to NA01 but were observed higher values than NA01. In fact, the mean concentration of σ12 PAHs, in urban-traffic site was generally 2 times greater than in urban-background site in all the campaigns.PAHs with 5 and 6 ring, many of which are suspected carcinogens or genotoxic agents, (i.e Benzo[a]Pyrene, Indeno[1,2,3-cd]Pyrene, Benzo[b]Fluoranthene, Benzo[k]Fluoranthene and Benzo[g,h,i]Perylene), had a large contribution (~50-55%) of total PAHs concentration in PM10 in two sites and in each of the campaigns.Diagnostic ratio analysis and PCA suggested a substantial contributions from traffic emission with minimal influence from coal combustion and natural gas emissions. In particular diesel vehicular emissions were the major source of PAHs at the studied sites. The use of Toxicity Equivalence Quantity (TEQ) concentration provide a better estimation of carcinogenicity activities; health risk to adults and children associated with PAHs inhalation was assessed by taking into account the lifetime average daily dose and corresponding incremental lifetime cancer risk (ILCR). The ILCR was within the acceptable range (10-6-10-4), indicating a low health risk to residents in these areas