Increased Intestinal Delivery of Viable Saccharomyces boulardii by Encapsulation in Microspheres

Purpose Although probiotics are of a major potential therapeutic interest, their efficacy is usually limited by poor bioavailability of viable microorganisms on site. The aim of this study was to protect the probiotic Saccharomyces boulardii from degradation in order to ensure a greater number of viable yeast in the colon. Methods Alginate microspheres coated with or not with chitosan were used to encapsulate the yeast by an extrusion method. The efficiency of encapsulation was assessed both in vitro and in vivo. Results In vitro, less than 1% of the non-encapsulated probiotic survived after 120 min at pH 1.1, whereas the majority of encapsulated yeast cells remained entrapped within both types of microspheres. Further exposure to a pH 6.8 allowed the release of about 35% of viable yeasts. In vivo, the percentage of viable yeast excreted over 96 h after a single oral dose of 2 × 10⁸ cfu/100 g in rats was 2.5% for non-encapsulated yeast and reached 13.3 and 9.0% of the dose administered for the uncoated and chitosan-coated microspheres, respectively. Conclusions Given the dose-dependent efficacy of S. boulardii and the efficiency of microencapsulation in protecting the yeast from degradation, alginate microspheres could be of great interest in therapeutic applications of the yeast.     

Development, validation and transfer into a factory environment of a liquid chromatography tandem mass spectrometry assay for the highly neurotoxic impurity FMTP (4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine) in paroxetine active pharmaceutical ingredient (API)

This work describes the development of a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a highly toxic impurity, FMTP (4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine), in paroxetine active pharmaceutical ingredient (API), followed by the subsequent validation of the methodology and transfer into a global production/quality control environment. The method was developed to achieve a detection limit of 10ppb mass fraction of FMTP in paroxetine API. An LC-MS/MS method was chosen because it provided the required sensitivity and selectivity with minimal sample preparation. This paper discusses the issues with transferring such complex methodology to a production environment. Linearity, repeatability and reproducibility of the method were demonstrated. This work shows that it is possible using the same approach that would be used for the transfer of any analytical method from R&D to a manufacturing environment.     

Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells

Several examples of agonist-directed trafficking of receptor signalling at 5-HT(2A) and 5-HT(2C) receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT(2A), h5-HT(2B) and h5-HT(2C-VSV) by examining two related responses, the upstream activation of Gq/11 proteins in comparison with its associated cascade of calcium mobilisation. At the h5-HT(2A) receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT(2B) and h5-HT(2C-VSV) receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT(2) receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT(2A) (and possibly h5-HT(2B) and/or h5-HT(2C-VSV)) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT(2)-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects.     

CGP12177-induced haemodynamic and vascular effects in normotensive and hypertensive rats

CGP12177 is a non-conventional partial agonist, known to have cardiostimulating and vasorelaxant properties related to its agonist action on the low affinity state of the beta(1)-adrenoceptor (beta(1LA)-adrenoceptor). In normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), CGP12177-induced vasorelaxant effects were analysed in hindquarter vessels to assess modifications in hind limb vascular resistance, and in femoral artery rings. The global haemodynamic effects induced by CGP12177 were also investigated using telemetry in conscious animals. In hindquarters vasculature precontracted with 5-hydroxytryptamine, CGP12177 (0.16 to 475 microg) produced a similar dose-dependent decrease in hindquarters perfusion pressure in both strains. Vasorelaxation was not modified by nadolol, a beta(1) and beta(2)-adrenoreceptor antagonist, nor by L748337, a beta(3)-adrenoceptor antagonist, but was concentration dependently inhibited by bupranolol, a beta(1LA)-adrenoceptor antagonist at high concentrations. In femoral artery rings from WKY rats and SHR, CGP12177 produced a concentration-dependent relaxation, which was unaffected by nitric oxide synthases inhibition but was significantly reduced in the presence of bupranolol. With double cardiac autonomic blockade (atropine plus atenolol) in conscious WKY rats and SHR, CGP12177 greatly increased heart rate with minor changes in mean arterial pressure in both strains. Conversely, in the absence of double cardiac autonomic blockade, the amplitude of CGP12177-induced heart rate increase was less pronounced and had an hypotensive effect. The reduction in tachycardia and the hypotension were significantly greater in SHR compared to WKY rats. In conclusion, in both strains, CGP12177 produced vasodilating effects in hindquarter vessels and femoral arteries that can be attributed to a beta(1LA)-adrenoceptor stimulation. In conscious WKY rats and SHR, CGP12177-induced cardiostimulation and hypotension were not significantly different after baroreflex blockade, but were decreased and increased respectively, in the presence of baroreflex activity.     

慢性阻塞性肺病稳定期患者家庭无创正压通气疗效分析

目的 研究慢性阻塞性肺病(COPD)稳定期患者长期家庭无创正压通气(NIPPV)治疗的意义.方法 回顾性分析2006～2007年法国Croix Rousse医院住院随访的接受NIPPV治疗的COPD稳定期慢性呼吸衰竭患者46例,比较患者治疗前和治疗后1、3、6、12、24和36个月的动脉血气变化;治疗前和治疗后6、12、24和36个月的肺功能改变.结果 患者应用NIPPV 1、3、6、12、24和36个月后的PaCO2较使用前皆显著下降(P均<0.05);1、3、12和36个月后的PaO2较使用前都显著升高(P均<0.05);而6、12、24和36个月后的肺功能第一秒用力呼气容积/用力呼气肺活量(FEV1/FVC)、FEV1占预计值%和FVC指标无明显改善,无统计学差异.结论 COPD稳定期长期家庭NIPPV治疗可改善血气、呼吸困难、头痛症状和提高生活质量,但在改善肺功能、延长生存期和降低死亡率方面的作用还有待进一步证实.     

Synthesis and antituberculosis activity of new hydrazide derivatives

The increasing clinical importance of drug-resistant mycobacterial pathogens, especially Mycobacterium tuberculosis, has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new hydrazide derivatives of imidazo[1,2-a]pyridine were synthesized and evaluated for antituberculosis activity. The reaction of 2-[(2-carboxyimidazo[1,2-a]pyridine-3-yl)sulfanyl]acetic acid hydrazide with various benzaldehydes gave N-(arylidene)-2-[(2-carboxyimidazo[1,2-a]pyridine-3-yl)sulfanyl]acetic acid hydrazide derivatives. The chemical structures of the compounds were elucidated by IR,(1)H-NMR, FAB-MS spectral data and elemental analysis. Antituberculosis activities of the synthesized compounds were determined by broth microdilution assay, the Microplate Alamar Blue Assay in BACTEC 12B medium. The results were screened in vitro, using the BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/mL; the tested compounds showed significant inhibition.     

Bony labyrinth shape variation in extant Carnivora: a case study of Musteloidea

The bony labyrinth provides a proxy for the morphology of the inner ear, a primary cognitive organ involved in hearing, body perception in space, and balance in vertebrates. Bony labyrinth shape variations often are attributed to phylogenetic and ecological factors. Here we use three‐dimensional (3D) geometric morphometrics to examine the phylogenetic and ecological patterns of variation in the bony labyrinth morphology of the most species‐rich and ecologically diversified traditionally recognized superfamily of Carnivora, the Musteloidea (e.g. weasels, otters, badgers, red panda, skunks, raccoons, coatis). We scanned the basicrania of specimens belonging to 31 species using high‐resolution X‐ray computed micro‐tomography (μCT) to virtually reconstruct 3D models of the bony labyrinths. Labyrinth morphology is captured by a set of six fixed landmarks on the vestibular and cochlear systems, and 120 sliding semilandmarks, slid at the center of the semicircular canals and the cochlea. We found that the morphology of this sensory structure is not significantly influenced by bony labyrinth size, in comparisons across all musteloids or in any of the individual traditionally recognized families (Mephitidae, Procyonidae, Mustelidae). PCA (principal components analysis) of shape data revealed that bony labyrinth morphology is clearly distinguishable between musteloid families, and permutation tests of the Kmult statistic confirmed that the bony labyrinth shows a phylogenetic signal in musteloids and in most mustelids. Both the vestibular and cochlear regions display morphological differences among the musteloids sampled, associated with the size and curvature of the semicircular canals, angles between canals, presence or absence of a secondary common crus, degree of lateral compression of the vestibule, orientation of the cochlea relative to the semicircular canals, proportions of the cochlea, and degree of curvature of its turns. We detected a significant ecological signal in the bony labyrinth shape of musteloids, differentiating semi‐aquatic taxa from non‐aquatic ones (the taxa assigned to terrestrial, arboreal, semi‐arboreal, and semi‐fossorial categories), and a significant signal for mustelids, differentiating the bony labyrinths of terrestrial, semi‐arboreal, arboreal, semi‐fossorial and semi‐aquatic species from each other. Otters and minks are distinguished from non‐aquatic musteloids by an oval rather than circular anterior canal, sinuous rather than straight lateral canal, and acute rather than straight angle between the posterior and lateral semicircular canals – each of these morphological characters has been related previously to animal sensitivity for detecting head motion in space.     

Five years update on relationships between malignant pleural mesothelioma and exposure to asbestos and other elongated mineral particles

ABSTRACT

Despite the reduction of global asbestos consumption and production due to the ban or restriction of asbestos uses in more than 50 countries since the 1970s, malignant mesothelioma remains a disease of concern. Asbestos is still used, imported, and exported in several countries, and the number of mesothelioma deaths may be expected to increase in the next decades in these countries. Asbestos exposure is the main risk factor for malignant pleural mesothelioma, but other types of exposures are linked to the occurrence of this type of cancer. Although recent treatments improve the quality of life of patients with mesothelioma, malignant pleural mesothelioma remains an aggressive disease. Recent treatments have not resulted in appreciable improvement in survival, and thus development of more efficient therapies is urgently needed. The development of novel therapeutic strategies is dependent on our level of knowledge of the physiopathological and molecular changes that mesothelial cells acquired during the neoplastic process. During the past 5 years, new findings have been published on the etiology, epidemiology, molecular changes, and innovative treatments of malignant pleural mesothelioma. This review aims to update the findings of recent investigations on etiology, epidemiology, and molecular changes with a focus on (1) attributable risk of asbestos exposure in men and women and (2) coexposure to other minerals and other elongated mineral particles or high aspect ratio nanoparticles. Recent data obtained on genomic and gene alterations, pathways deregulations, and predisposing factors are summarized.