Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.     

Synthesis of Micro-Spikes and Herringbones Structures by Femtosecond Laser Pulses on a Titanium Plate—A New Material for Water Organic Pollutants Degradation

(1) Background: The shrinkage of water resources, as well as the deterioration of its quality as a result of industrial human activities, requires a comprehensive approach relative to its protection. Advanced oxidation processes show high potential for the degradation of organic pollutants in water and wastewater. TiO₂ is the most popular photocatalyst because of its oxidizing ability, chemical stability and low cost. The major drawback of using it in powdered form is the difficulty of separation from the reaction mixture. The solution to this problem may be immobilization on a support (glass beads, molecular sieves, etc.). In order to avoid these difficulties, the authors propose to prepare a catalyst as a titanium plate covered with an oxide layer obtained with laser treatment. (2) Methods: In the present work, we generated titanium oxide structures using a cheap and fast method based on femtosecond laser pulses. The structurized plates were tested in the reaction of methylene blue (MB) degradation under UVA irradiation (365 nm). The photocatalytic activity and kinetic properties for the degradation of MB are provided. (3) Results: Studies of X-ray diffraction (XRD) and scanning electron microscopy (SEM) confirm a titanium oxide layer with laser-induced generated structures that are called “spikes” and “herringbones”. The structurized plates were effective photocatalysts, and their activity depends on the structure of the oxide layer (spike and herringbone). (4) Conclusions: The immobilization of the catalyst on a solid support can be performed in a fast and reproducible manner by using the technique of laser ablation. The layers obtained with this method have been shown to have catalytic properties.     

Synthesis of Phosphoramide Mustard Analogues of Daunomycin and Carminomycin

New phosphoramide mustards ( 6–8 ) have been prepared from the antibiotics 2 and 3 , and from 5 . The mixture of cyclophosphamides could be separated by preparative layer and column chromatography. The assignments of configuration to the isomeric phosphoramidates was based on the magnetic anisotropy of the P=O bond. The synthesized compounds 6a,b–8a,b (mixture of isomers) were tested for inhibitory activity on the [³H]-thymidine incorporation into the DNA of tumor cells, using ovarian carcinoma cell line.     

Subtypes of low voltage-activated Ca2+ channels in laterodorsal thalamic neurons: possible localization and physiological roles

The macroscopic, low-voltage-activated (LVA or T-type) Ca2+ current in isolated associative (or local-circuit) neurons from the laterodorsal thalamic nucleus of 14-17-day old rats was dissected into two components ("fast" and "slow"), corresponding to the activation of two LVA channel subtypes, based on the difference in the kinetics of inactivation and recovery from inactivation. The steady-state activation and inactivation properties of the channel subtypes endowed slow channels with a substantial window current, whereas fast channels had almost no such current. Fast channels were almost 2 times more sensitive to 30 microM nifedipine (78% inhibition), 10 microM flunarizine (92% inhibition) and 1 microM La3+ (87% inhibition), but about 1.8-fold less sensitive to 100 microM Ni2+ (32% inhibition) than slow channels (40%, 52%, 46% and 56% inhibition respectively). Both channels were almost equally sensitive to 100 microM amiloride (58% and 51% inhibition of fast and slow channels respectively). Comparison of the fast and slow LVA Ca2+ current amplitudes and densities between enzymatically isolated and intact (in brain slices) neurons suggest a predominant localization of the fast channels in soma and the proximal dendrites that remain intact during isolation procedure, whereas the slow channels are more evenly distributed with some preference to the distal areas. These data, together with our previous studies, support the notion of two LVA Ca2+ channel subtypes in associative thalamic neurons and suggest a role for the slow channels in providing the constant Ca2+ influx necessary for the outgrowth of the neurites and for the fast channels in the generation of low-threshold Ca2+ spikes and bursting activity.     

Health-related quality of life and its determinants in Parkinson's disease: results of an Italian cohort study

Parkinson's disease (PD) is a common neurodegenerative disorder with a progressive disabling course. Health-related quality of life (HrQoL) in Italian patients with PD has not been evaluated. The objective of this study was to evaluate HrQol of an Italian cohort of PD patients and to provide a comprehensive analysis of HrQoL determinants. We performed a cross-sectional survey of 70 outpatients with idiopathic PD recruited in the department of Neurology, Napoli University, Italy. Clinical data included the Unified PD Rating Scale (UPDRS), motor and non-motor symptoms. The generic instrument EuroQol (EQ-5D and EQ-VAS) was used to evaluate HrQol. Factors influencing HrQol were assessed by multivariate regression analysis. Severe problems in at least one dimension of the EQ-5D were experienced by 60% of PD patients versus 4.7% in general Italian population. The dimensions most affected were mobility, pain/discomfort and anxiety/depression with only 17.4%, 18.8% and 17.4% of patients, respectively, reporting no problems in these dimensions. The mean EQ-VAS score was 54.20 ± 18.38. Independent determinants of reduced HrQoL were increased UPDRS scores, motor fluctuations, dyskinesias, depression and dementia. PD strongly affects HrQol in Italian patients. The results of this study should be considered in the development of national healthcare programmes aimed at improvement of the HrQoL in Italian patients with PD. In particular, these programmes should concentrate not only on motor but also on non-motor manifestations of PD.     

Funding agencies in low- and middle-income countries: support for knowledge translation

OBJECTIVE: The aim was to describe how selected health research funding agencies active in low- and middle-income countries promote the translation of their funded research into policy and practice. METHODS: We conducted inductive analysis of semi-structured interviews with key informants from a purposive sample of 23 national and international funding agencies that fund health research in Brazil, Colombia, India, the Philippines, South Africa and Thailand. We also surveyed web sites. FINDINGS: We found a commitment to knowledge translation in the mandate of 18 of 23 agencies. However, there was a lack of common terminology. Most of the activities were traditional efforts to disseminate to a broad audience, for example using web sites and publications. In addition, more than half (13 of 23) of the agencies encouraged linkage/exchange between researchers and potential users, and 6 of 23 agencies described "pull" activities to generate interest in research from decision-makers. One-third (9 of 23) of funding agencies described a mandate to enhance health equity through improving knowledge translation. Only 3 of 23 agencies were able to describe evaluation of knowledge translation activities. Furthermore, we found national funding agencies made greater knowledge translation efforts when compared to international agencies. CONCLUSION: Funding agencies are engaged in a wide range of creative knowledge translation activities. They might consider their role as knowledge brokers, with an ability to promote research syntheses and a focus on health equity. There is an urgent need to evaluate the knowledge translation activities of funding agencies.