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Chronic kidney disease patients on hemodialysis treatment are characterized by increased levels of inflammatory markers and oxidative stress, in addition to a significant deterioration in physical function. The benefits of physical exercise on the functional capacity of this patients are well known; however, it can also improve the endogenous antioxidant defense system and the inflammatory state, but still very few studies have been carried out. This is the first study to analyze the effect of a 4-month exercise program with combined aerobic and strength training in patients undergoing hemodialysis, under two modalities.Seventy-one patients undergoing hemodialysis were enrolled and randomized in two groups, one of them performing an intra-dialysis exercise program (n = 36), and the other carrying out a home-based exercise program (n = 35). Serum levels of oxidative stress and inflammation biomarkers were determined before and after the intervention.IL-6 plasma levels showed a significant decrease in the intra-dialysis group after exercise (42.61 ± 9.21 to 26.40 ± 7.84, p = 0.03), while CRP levels decreased significantly in the home-based group (16.12 ± 24.18 to 8.50 ± 11.28, p = 0.03). MCP-1, TNF-α, ICAM-1 and the oxidative stress markers MDA, GSH and GSSG, did not undergo significant changes after the intervention.Four months of combined strength and aerobic endurance exercise improve the inflammatory status of hemodialysis patients by significantly reducing IL-6 levels in those subjects who perform intra-dialysis exercise and CRP levels in those who do it at home.

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials. Here we describe a whole-cell method to detect inhibitors of the mitochondrial electron transport chain, using oxygen consumption as high throughput readout in 384-well plate format. The usefulness of the method has been confirmed with the Tres Cantos Antimalarial Compound Set (TCAMS). The assay identified 124 respiratory inhibitors in TCAMS, seven of which were novel anti-plasmodial chemical structures never before described as mitochondrial inhibitors., Graphical abstract Image 1, Highlights • High throughput method to detect mitochondrial electron transport chain inhibitors. • 149 selective respiratory inhibitors identified among the 13,103-compound set TCAMS. • Seven new chemical entities described as anti-plasmodial cytochrome b inhibitors.

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

Insulin-like growth factor-1 (IGF-1) is responsible for many systemic growth hormone (GH) functions although it has an extensive number of inherent activities (anabolic, cytoprotective, and anti-inflammatory). The potential options for IGF-1 therapy arise as a promising strategy in a wide list of human diseases. However, deeper studies are needed from a suitable animal model. All human conditions of IGF-1 deficiency consist in partially decreased IGF-1 levels since total absence of this hormone is hardly compatible with life. The aim of this work was to confirm that heterozygous Igf-1 (+/-) mice (Hz) may be considered as an appropriate animal model to study conditions of IGF-1 deficiency, focusing on early ages. Heterozygous Igf-1 (+/-) mice were compared to homozygous Igf-1 (+/+) by assessing gene expression by quantitative PCR, serum circulating levels by ELISA, and tissue staining. Compared to controls, Hz mice (25 days old) showed a partial but significant reduction of IGF-1 circulating levels, correlating with a reduced body weight and diminished serum IGFBP-3 levels. Hz mice presented a significant decrease of IGF-1 gene expression in related organs (liver, bone, testicles, and brain) while IGF-1 receptor showed a normal expression. However, gene expression of growth hormone receptor (GHR) was increased in the liver but reduced in the bone, testicles, and brain. In addition, a significant reduction of cortical bone thickness and histopathological alterations in the testicles were found in Hz mice when compared to controls. Finally, the lifelong evolution of IGF-1 serum levels showed significant differences throughout life until aging in mice. Results in this paper provide evidence for considering heterozygous mice as a suitable experimental model, from early stages, to get more insight into the mechanisms of the beneficial actions induced by IGF-1 replacement therapy.

The aim was to study the ability of bioadhesive cyclodextrin-poly(anhydride) nanoparticles as carriers for the oral delivery of atovaquone (ATO). In order to increase the loading capacity of ATO by poly(anhydride) nanoparticles, the following oligosaccharides were assayed: 2-hydroxypropyl-β-cyclodextrin (HPCD), 2,6-di-O-methyl-β-cyclodextrin (DCMD), randomly methylated-β-cyclodextrin (RMCD) and sulfobuthyl ether-β-cyclodextrin (SBECD). Nanoparticles were obtained by desolvation after the incubation between the poly(anhydride) with the ATO-cyclodextrin complexes. For the pharmacokinetic studies, ATO formulations were administered orally in rats. Overall, ATO displayed a higher affinity for methylated cyclodextrins than for the other derivatives. However, for in vivo studies, both ATO-DMCD-NP and ATO-HPCD-NP were chosen. These nanoparticle formulations showed more adequate physicochemical properties in terms of size (260 nm), drug loading (17.8 and 16.9 μg/mg, respectively) and yield (75%). In vivo, nanoparticle formulations induced higher and more prolonged plasmatic levels of atovaquone than control suspensions of the drug in methylcellulose. Relative bioavailability of ATO when loaded in nanoparticles ranged from 52% (for ATO-HPCD NP) to 71% (for ATO-DMCD NP), whereas for the suspension control formulation the bioavailability was only about 30%. The encapsulation of atovaquone in cyclodextrins-poly(anhydride) nanoparticles seems to be an interesting strategy to improve the oral bioavailability of this lipophilic drug.

Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

Hybrid abinitio calculations (GIAO/B3LYP/6-31G*) together with new DNMR experiments (1H and 13C) have been used to clarify the problem of the conformation of 5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene. The carbon-13 chemical shifts have been assigned unambiguously to the chair C and twist-boat TB conformations. Lineshape analysis of the 1H NMR spectra has been carried out at several temperatures using an estimated set of Karplus-type vicinal coupling constants.

A reduction of the tetracyclic skeleton of sordarins and sordaricins to a cyclopentane ring bearing the pharmacophore functional groups led to new derivatives retaining part of their in vitro and whole-cell activity.

En: Bioorganic and Medicinal Chemistry Letters. ISSN 0960-894x. n. 9, 1999, págs 103-108 A reduction of the tetracyclic skeleton of sordarins and sordaricins to a cyclopentane ring bearing the pharmacophore functional groups led to new derivatives retaining part of their in vitro and whole-cell activity.

Hybrid ab initio calculations (GIAO/B3LYP/6-31G*) together with new DNMR experiments (1H and 13C) have been used to clarify the problem of the conformation of 5,6,11,12-tetrahydrodibenzo[a,e]cyclooctene. The carbon-13 chemical shifts have been assigned unambiguously to the chair C and twist-boat TB conformations. Lineshape analysis of the 1H NMR spectra has been carried out at several temperatures using an estimated set of Karplus-type vicinal coupling constants., Financial support from the Spanish DGICYT (Project No. PB96-0001-C03) is gratefully acknowledged.

BackgroundBone is one of the major target tissues for Insulin-like Growth Factor I (IGF-I). Low doses of IGF-I were able to improve liver-associated osteopenia. In the present work, a model of partial IGF-I deficiency was used in order to provide insight into the mechanisms of the beneficial actions of IGF-I replacement therapy in bone.MethodsSeveral proteins involved in osteoblastic/osteocyte and osteoclastic differentiation and activity were studied in the three experimental groups: control (CO) group (wild type mice,Igf+/+, n = 10), heterozygousIgf+/-group with partial IGF-I deficiency (Hz, n = 10), and heterozygousIgf+/-mice treated with IGF-I for 10 days (Hz + IGF-I, n = 10).ResultsData in this paper confirm that the simple partial IGF-I deficiency is responsible for osteopenia, determined by densitometry and histopathology. These findings are associated with a reduced gene expression of osteoprotegerin, sclerostin, calcitonin receptor (CTR), insulin-like growth factor binding protein 5 and RUNX2. IGF-I replacement therapy normalized CTR gene expression and reduced markers of osteoclastic activity.ConclusionsLow doses of IGF-I constituted a real replacement therapy that normalized IGF-I serum levels improving the expression of most of these proteins closely involved in bone-forming, and reducing bone resorption by mechanisms related to osteoprotegerin, RANKL and PTH receptor.

A series of eighteen substituted pyrazoles, bis- and tris-azolyl-methanes or ethanes was investigated for their interaction with the zinc enzyme carbonic anhydrase (CA). Several types of activities were detected, generally as CA activators, but CA inhibitory properties were also discovered for the very sterically-demanding derivatives of these series. Kinetic determinations by a stopped-flow technique for carbon dioxide hydration reaction allowed the determination of Michaelis-Menten constants, which are identical in the absence or in the presence of these modulators, proving a noncompetitive mechanism of activation-inhibition. MNDO calculations were used with moderate success to explain the biological results.

A correlation was found between the carbonic anhydrase II activating power and the pKa values for a series of azoles, bisazolylmethanes and bisazolylethanes. Strong activations were found for compounds with pKa's in the interval 6.5-8.0. The mechanism of action for such activators is discussed.

Translation elongation factor 2 (EF2), which in Saccharomyces cerevisiae is expressed from the EFT1 and EFT2 genes, has been found to be targeted by a new family of highly specific antifungal compounds derived from the natural product sordarin. Two complementation groups of mutants resistant to the semisynthetic sordarin derivative GM193663 were found. The major one (21 members) consisted of isolates with mutations on EFT2 . The minor one (four isolates) is currently being characterized but it is already known that resistance in this group is not due to mutations on EFT1 , pointing to the complex structure of the functional target for these compounds. Mutations on EF2 clustered, forming a possible drug binding pocket on a three-dimensional model of EF2, and mutant cell extracts lost the capacity to bind to the inhibitors. This new family of antifungals holds the promise to be a much needed and potent addition to current antimicrobial treatments, as well as a useful tool for dissection of the elongation process in ribosomal protein synthesis.

Gantrez AN nanoparticles can be obtained by desolvation of the poly(anhydride) with an aqueous medium, followed by a purification step and freeze-drying. In order to simplify this method, a spray-drying procedure was evaluated here. For this purpose, suspensions of nanoparticles were mixed with carbohydrates before their drying. Lactose, in a saccharide/polymer ratio of 2, was found to be the most suitable excipient regarding the physicochemical characteristics and stability of the resulting nanoparticles. These conditions can be successfully applied to the preparation of conventional, combined cyclodextrin/polyanhydride or pegylated nanoparticles. The capabilities of the new procedure were also studied by the characterization of nanoparticles loaded with either an antigenic extract (HS from Brucella ovis) or atovaquone. In all cases, the new formulations displayed similar physico-chemical characteristics to those of nanoparticles obtained by lyophilization. In summary, the spray-drying procedure can be an adequate alternative to lyophilization in the preparative process of poly(anhydride) nanoparticles.