Piperamides and their derivatives as potential anti-trypanosomal agents

We describe herein an evaluation of the trypanocidal effect of eight piperamides (1-8) isolated from Piper tuberculatum bearing dihydropyridone, piperidine, and isobutyl moieties against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas` disease. Based on such results, three hydrogenated and two hydrolyzed derivatives (10-14) were prepared and evaluated as well. The dihydropyridone amides (1-3) displayed higher anti-trypanosomal activity. The (Z)-piplartine (1) showed higher activity with a 50% inhibition concentration (IC(50)) value of 10.5 mu M, almost four times more potent than the positive control, benznidazole (IC(50) = 42.7 mu M), and should be further evaluated as a suitable hit for the design of new antiprotozoal agents.

HPLC separation, NMR and QTOF/MS/MS structure elucidation of a prominent nitric oxide donor agent based on an isomeric composition of a nitrosyl ruthenium complex

A new and promising nitrosyl ruthenium complex, [Ru(NO)(bdqi-COOH)(terpy)](PF(6))(3), bdqi-COOH is 3,4-diiminebenzoic acid and terpy is 2,2`-terpyridine, has been synthesized as a NO donor agent. The procedure used for [Ru(NO)(bdqi-COOH)(terpy)](PF(6))(3) synthesis has, apparently, yielded the formation of two isomers in which the ligand bdqi-COOH appears to be coordinated in its reduced form (bdcat-COOH), which could have differences in their pharmacological properties. Therefore, it was intended to separate the two possible isomers by high-performance liquid chromatography (HPLC) and to characterize them by high resolution mass spectrometry (QTOF MS) and by magnetic nuclear resonance spectroscopy (NMR). The results obtained by MS showed that the ESI-MS mass spectra of both HPLC column fractions, e.g. peak 1 and peak 2, are essentially equal, showing that both isomers display nearly identical gas-phase behavior with clusters of isotopologue ions centered at m/z 573, m/z 543 and m/z 513. Regarding the NMR analysis, the results showed that the positional isomerism is located in the bdqi-COOH ligand. From the observed results it can be concluded that the synthesis procedure that has been used results in the formation of two [Ru(terpy)(bdqi-COOH)NO](PF(6))(3) isomers. (c) 2009 Elsevier B.V. All rights reserved.

Antiulcerogenic Activity of the Essential Oil of Baccharis dracunculifolia on Different Experimental Models in Rats

Baccharis dracunculifolia DC (Asteraceae), a native plant from Brazil, commonly known as `Alecrim-do-campo` is widely used in folk medicine to treat inflammation, hepatic disorders and stomach ulcers, and it is the most important botanical source of Southeastern Brazilian propolis, known as green propolis. Its essential oil is composed of non-oxygenated and oxygenated terpenes. In this work, the effects of the essential oil obtained from the aerial parts of R dracunculifolia on gastric ulcers were evaluated. The antiulcer assays were undertaken using the following protocols in rats: nonsteroidal antiinflammatory drug (NSAID)-induced ulcer, ethanol-induced ulcer, stress-induced ulcer, and determination of gastric secretion using ligated pylorus. The treatment in the doses of 50, 250 and 500 mg/kg of R dracunculifolia essential oil significantly diminished the lesion index, the total lesion area and the percentage of lesions in comparison with both positive and negative control groups. With regard to the model of gastric secretion a reduction of gastric juice volume and total acidity was observed, as well as an increase in the gastric pH. No sign of toxicity was observed in the acute toxicity study. Considering the results, it is suggested that the essential oil of B. dracunculifolia could probably be a good therapeutic agent for the development of new phytotherapeutic medicine for the treatment of gastric ulcer. Copyright (C) 2009 John Wiley & Sons, Ltd.

Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B(6)

Vitamin B(6) has shown to be a potentially effective antioxidant agent, and dietary antioxidants are also frequently valuable inhibitors of clastogenesis and carcinogenesis. The purpose of the present work was to study the clastogenicity of different doses of vitamin B6 and to examine the possible modulating effect of this vitamin on chromosomal damage induced by the antitumor agent doxorubicin in Wistar rats. Experimental groups were set up for pre-and simultaneous treatment with vitamin B6 alone or in combination with DXR. The data obtained from administering diVerent doses of vitamin B(6) (12.5-100 mg/kg b. w.) showed no signigicant increase in total chromosomal aberrations when compared with the negative control. The administration of two doses of 25 mg/kg b. w. or one dose of 50 mg/kg b. w. of vitamin B6 before doxorubicin injection seemed equally effective in protecting cells against doxorubicin clastogenicity. The anticlastogenic effect of vitamin B(6) on DXR-induced chromosomal damage could be ascribed to its antioxidant properties. Vitamin B6 was not clastogenic or cytotoxic in rat bone marrow cells and it plays a role in inhibiting the clastogenicity induced by DXR.

Cyclooxygenase-derived mediators regulate the immunological control of Strongyloides venezuelensis infection

The aim of this study was to define the immunoregulatory role of prostaglandins in a mouse model of Strongyloides venezuelensis infection. Strongyloides venezuelensis induced an increase of eosinophils and mononuclear cells in the blood, peritoneal cavity fluid, and bronchoalveolar lavage fluid. Treatment with the dual cyclooxygenase (COX-1/-2) inhibitors indomethacin and ibuprofen, and the COX-2-selective inhibitor celecoxib partially blocked these cellular responses and was associated with enhanced numbers of infective larvae in the lung and adult worms in the duodenum. However, the drugs did not interfere with worm fertility. Cyclooxygenase inhibitors also inhibited the production of the T-helper type 2 (Th2) mediators IL-5, IgG1, and IgE, while indomethacin alone also inhibited IL-4, IL-10, and IgG2a. Cyclooxygenase inhibitors tended to enhance the Th1 mediators IL-12 and IFN-gamma. This shift away from Th2 immunity in cyclooxygenase inhibitor-treated mice correlated with reduced prostaglandin E(2) (PGE(2)) production in infected duodenal tissue. As PGE(2) is a well-characterized driver of Th2 immunity, we speculate that reduced production of this lipid might be involved in the shift toward a Th1 phenotype, favoring parasitism by S. venezuelensis. These findings provide new evidence that cyclooxygenase-derived lipids play a role in regulating host defenses against Strongyloides, and support the exploration of eicosanoid signaling for identifying novel preventive and therapeutic modalities against these infections.

TLR2-dependent mast cell activation contributes to the control of Mycobacterium tuberculosis infection

Mast Cells (MCs) express toll-like receptor 2 (TLR2), a receptor known to be triggered by several major mycobacterial ligands and involved in resistance against Mycobacterium tuberculosis (MTB) infection. This study investigated whether adoptive transfer of TLR2 positive MCs (TLR2(+/+)) corrects the increased susceptibility of TLR2(-/-) mice to MTB infection. TLR2(-/-) mice displayed increased mycobacterial burden, diminished myeloid cell recruitment and proinflammatory cytokine production accompanied by defective granuloma formation. The reconstitution of these mice with TLR2(+/+) MCs, but not TLR2(-/-), confers better control of the infection, promotes the normalization of myeloid cell recruitment associated with reestablishment of the granuloma formation. In addition, adoptive transfer of TLR2(+/+) MC to TLR2(-/-) mice resulted in regulation of the pulmonary levels of IL-beta, IL-6, TNF-alpha, enhanced Th1 response and activated CD8(+) T cell homing to the lungs. Our results suggest that activation of MCs via TLR2 is required to compensate the defect in protective immunity and inability of TLR2(-/-) mice to control MTB infection. (C) 2009 Elsevier Masson SAS. All rights reserved.

Control of experimental pulmonary tuberculosis depends more on immunostimulatory leukotrienes than on the absence of immunosuppressive prostaglandins

Prostaglandins (PGs) and leukotrienes (LTs) are produced in Mycobacterium tuberculosis (Mtb)-infected lungs and have immune suppressive and protective effects, respectively. Considering that both of these mediators are produced during mycobacterial infection, we investigated the specific and relative biological importance of each in regulating host response in experimental tuberculosis. Administration of celecoxib, which was found to reduce lung levels of PGE(2) and increase LTB(4), enhanced the 60-day survival of Mtb-infected mice in 14%. However administration of MK-886, which reduced levels of LTB(4) but did not enhance PGE(2), reduced 60-day survival from 86% to 43% in Mtb-infected mice, and increased lung bacterial burden. MK-886 plus celecoxib reduced survival to a lesser extent than MK-886 alone. MK-886- and MK-886 plus celecoxib-treated animals exhibited reduced levels of the protective interleukin-12 and gamma-interferon. Our findings indicate that in this model, the protective effect of LTs dominates over the suppressive effect of PGs. (C) 2011 Elsevier Ltd. All rights reserved.

Nuclear Quadrupole Resonance: A Technique to Control Hydration Processes in the Pharmaceutical Industry

Pharmaceuticals can exist in many solid forms, which can have different physical and chemical properties. These solid forms include polymorphs, solvates, amorphous, and hydrates. Particularly, hydration process can be quite common since pharmaceutical solids can be in contact with water during manufacturing process and can also be exposed to water during storage. In the present work, it is proved that NQR technique is capable of detecting different hydrated forms not only in the pure raw material but also in the final product (tablets), being in this way a useful technique for quality control. This technique was also used to study the dehydration process from pentahydrate to trihydrate.

Niobium to alcohol mol ratio control of the concurring esterification and etherification reactions promoted by NbCl5 and Al2O3 catalysts under microwave irradiation

Alcohols and acids can be switched to produce ethers or esters by varying the alcohol to catalyst mol ratio, in a new etherification and esterification method using NbCl5/Al2O3 catalyst under ""solvent free"" conditions and promoted by MW (microwave) irradiation. A ""two sites"" mechanism for the reaction is proposed, in an attempt to clarify the tendency of the catalyst to be dependent on the alcohol alone during the esterification process. (c) 2008 Elsevier B.V. All rights reserved.

Chitosan as a Bioadhesive Agent Between Porphyrins and Phospholipids in a Biomembrane Model

Porphyrins are currently used in photodynamic therapy as photosensitizers. In this paper we studied the interaction of two charged porphyrins, 5, 10, 15, 20-mesotetrakis(N-metyl-4-pyridyl) porphyrin, (TMPyP/chloride salt) cationic, and 5, 10, 15, 20-meso-tetrakis(sulfonatophenyl) porphyrin, (TPPS(4)/sodium salt) anionic, nanoassembled in phospholipid Langmuir monolayers and Langmuir-Blodgett films. Furthermore, we used chitosan to mediate the interaction between the porphyrins and the model membrane, aiming to understand the role of the polysaccharide in a molecular level. The effect of the interaction of the photosensitizers on the fluidity of the lipid monolayer was investigated by using dilatational surface elasticity. We also used photoluminescence (PL) spectroscopy to identify the porphyrins adsorbed in the phospholipid films. We observed an expansion of the monolayer promoted by the adsorption of the porphyrins into the lipid-air interface which was more pronounced in the case of TMPyP, as a consequence of a strong electrostatic interaction with the anionic monolayer. The chitosan promoted a higher adsorption of the porphyrins on the phospholipid monolayers and enabled the porphyrin to stay in its monomeric form (as confirmed by PL spectroscopy), thus demonstrating that chitosan can be pointed out as a potential photosensitizer delivery system in photodynamic therapy.

Soil morphological control on saline and freshwater lake hydrogeochemistry in the Pantanal of Nhecolandia, Brazil

Joint pedological, geochemical, hydrological and geophysical investigations were performed to study the coexistence or saline and freshwater lakes in close proximity and similar climatic conditions in the Nhecolandia region, Pantanal wetlands in Brazil. The saline lakes are concentrically surrounded by green sandy loam horizons, which cause differential hydrological regimes. Mg-calcite, K-silicates, and amorphous silica precipitate in the soil cover, whereas Mg-silicates and more soluble Na-carbonates are concentrated in the topsoil along the shore of the saline lake. In saline solutions, some minor elements (As, Se) reach values above the water quality recommendations, whereas others are controlled and incorporated in solid phases (Ba, Sr). Locally, the destruction of the sandy loam horizons generates very acidic soil solution (pH similar to 3.5) through a process not yet understood. The soil distributions indicate that some freshwater lakes are former saline lakes. They are invaded by freshwater after destruction of the sandy loam green horizons, then the freshwater becomes enriched in K(+), SO(4)(2-), Fe, Al, and a stream of minor and trace elements. The formation of these green sandy loam horizons in the saline environment and their destruction in the non-saline one emphasizes the dynamic nature of this environment (C) 2008 Elsevier B.V. All rights reserved.

Icelandic Control Really Is A-Movement: Reply to Bobaljik and Landau

This article discusses the challenges that Bobaljik and Landau (2009) pose to Boeckx and Hornstein`s (2006) movement-based analysis of control in Icelandic. We show in detail that contrary to what Bobaljik and Landau claim, the movement theory of control (with a modification to accommodate quirky Case, a specialty of Icelandic) makes the right empirical cuts regarding the issues they raise, namely, (a) the differences in Case agreement between control and raising constructions, (b) the different patterns of Case transmission (un)available, and (c) the fact that allegedly Case-marked PROs are phonetically null. We argue that rather than being problematic, the data bearing on these issues actually provide independent support to the movement theory of control.

What Brazilian Portuguese Says about Control: Remarks on Boeckx & Hornstein

In an article in this journal, Boeckx & Hornstein (2006a) present data from Brazilian Portuguese (BP) as an argument in favor of the Movement Theory of Control (MTC). In this reply, I show that the data presented by those authors do not necessarily argue for a movement analysis of BP finite subjects nor of nonfinite control. I also show that BP provides arguments against the MTC when inflected infinitives are considered. Inflected infinitives may be used in BP in partial control structures, which makes it explicit that a singular matrix argument may control a syntactically plural null subject and shows that these two positions cannot be related by movement. Additionally, I show that the MTC makes the wrong predictions when a language with inflected infinitives is considered.

Evaluation of the Efficacy of a Dental Plaque Control Program in Autistic Patients

The aim of this study was to verify the efficacy of a programme for dental plaque control in autistics. Patients were evaluated on five occasions over a period of 180 days using the following instruments: OHI-S, DMF-T, the Fonnes brushing technique and diet questionnaire. Participants were divided into two groups according to level of co-operation on the programme: Group A (co-operative) and Group B (non-cooperative). A statistically significant improvement (p < 0.001) in Oral Hygiene was attained, with 84.2% showing regular or satisfactory hygiene at study end-point. Conclusion: Groups A and B both showed improvement in hygiene (p < 0.001 and p = 0.004), but improvement was significantly higher among co-operative patients (p < 0.001 at 180 days), who also had a higher mean age (p = 0.02).

Early Control of PTH and FGF23 in Normophosphatemic CKD Patients: A New Target in CKD-MBD Therapy?

Background and objectives: Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. Design, setting, participants, and measurements: Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). Results: At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. Conclusions: This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes. Clin J Am Soc Nephrol 5: 286-291, 2010. doi: 10.2215/CJN.05420709