Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice

Tumor necrosis factor (TNF)-alpha plays an important role in the mediation of reperfusion-induced tissue injury and lethality. Here, we assessed the effects of PKF242-484 and PKF241-466, two dual inhibitors of TNF-alpha converting enzyme (TACE) and matrix metalloproteinases (MMPs), in a model of ischemia and reperfusion injury in mice. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose-dependent reduction of TNF-alpha concentrations in serum. Both drugs delayed and partially inhibited the reperfusion-associated lethality. Maximal inhibition occurred at 10 mg/kg. At this dose, both inhibitors reduced reperfusion-associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and hemorrhage. In addition, the compounds markedly reduced production of TNF-alpha, CXCL1 (keratinocyte-derived chemokine, KC) and CCL2 (monocyte chemoattractant protein-1, MCP-1) in intestine and lungs of animals which underwent reperfusion. FN-439, an inhibitor of MMPs which possesses no effect on TACE, decreased MMP-2 and MMP-3 activity, but failed to affect tissue injury, TNF-alpha production or lethality. Thus, combined TACE and MMP inhibitors might be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. The effects of these drugs on TNF-alpha production appear to be more relevant than their effects on MMP inhibition.     

Mixtures of triblock copolymers E(62)P(39)E(62) and E(137)S(18)E(137) potential for drug delivery from in situ gelling micellar formulations

The gelation behaviour of concentrated micellar solutions of mixtures of a block copolymer of ethylene oxide and styrene oxide (E(137)S(18)E(137)) with one of ethylene oxide and propylene oxide (E(62)P(39)E(62)) has been investigated. Over a wide range of compositions, up to 90 wt.% E(137)S(18)E(137) in the mixture, gelation resembled that of solutions of E(62)P(39)E(62) alone, i.e. they gelled on heating from ambient to body temperature. In related experiments, using the aromatic drug griseofulvin as a comparative standard, it was demonstrated that solubilisation efficiency of dilute micellar solutions of the mixtures with 80 wt.% or more E(137)S(18)E(137) approached that of solutions of E(137)S(18)E(137) alone. Thus it was shown that the mixed system could have both the satisfactory solubilisation capacity of micellar solutions of E(137)S(18)E(137) and the desirable gelation characteristics of E(62)P(39)E(62), and so have potential for use in drug release applications involving in situ gelation.     

Adverse events of blood-pressure-lowering drugs: evidence of high incidence in a clinical setting

Objectives  Our primary objective was to determine the incidence of AEs of antihypertensive drugs in a cohort of outpatients attending a specialized clinic. The secondary objectives were to determine the incidence of AEs by classes of blood-pressure-lowering drugs used in monotherapy and to identify risk factors for the occurrence of AEs. Methods  In a prospectively planned cohort study, patients attending a hypertension outpatient clinic were systematically interrogated about the occurrence of AEs of blood-pressure-lowering drugs. We compared the incidence of AEs by classes of drugs employed in monotherapy and identified risk factors for the occurrence of AEs in a logistic regression model. Results  Participants were followed for 12.3 ± 12.2 months. In total, 534 (35.4%) of 1,366 patients treated with blood pressure drugs complained of at least one AE during the follow-up, corresponding to an incidence of 31.3 AEs per 1,000 patients/month [95% confidence interval (CI) 28.6–33.9). The systolic blood pressure in the initial evaluation (P = 0.002) and use of two or more drugs (P < 0.001) were associated with higher incidence of AEs. The incidence of AEs was higher among patients treated with calcium channel blockers in monotherapy than in patients treated with diuretics (47.2 vs. 7.6%, P < 0.001). Conclusion  Adverse events of blood-pressure-lowering drugs are quite frequent in a clinical context, and may influence the adherence to treatment. Patients under treatment with diuretics in monotherapy have the lower incidence of AEs.     

Increase of cellular recruitment, phagocytosis ability and nitric oxide production induced by hydroalcoholic extract from Chenopodium ambrosioides leaves

The leaves and the oil from the seeds of Chenopodium ambrosioides L. (Chenopodiaceae), a plant known in Brazil as 'mastruz', have been used by native people to treat parasitic diseases. Experimentally it was shown that Chenopodium ambrosioides inhibits the Ehrlich tumor growth, what could be due to an immunomodulatory effect of this product. The aim of this study was to investigate the effect of hydroalcoholic crude extract (HCE) from leaves of Chenopodium ambrosioides on macrophage activity and on lymphoid organs cellularity. C3H/HePas mice received the HCE (5mg/kg) by intraperitoneal via and were sacrificed 2 days later. HCE treatment did not alter the cell number in bone marrow, but it increased the cell number in peritoneal cavity, spleen and lymph node. The spreading and phagocytosis activity, the PMA-induced hydrogen peroxide (H(2)O(2)) release and the nitric oxide (NO) production were also increased when compared to control group. Similar results were obtained with concanavalin A (Con A), used as a positive control, with exception of the NO production that was only detected in HCE-derived macrophages. The in vitro treatment with HCE induced a dose-dependent NO production by resident macrophages, but did not enhance the NO production by HCE-derived macrophage, which however, was enhanced by Con A, suggesting that HCE and Con A induce NO production by different routes. In conclusion, HCE-treatment was able to increase the macrophages activity and also the cellular recruitment to secondary lymphoid organs, what could explain the previously related anti-tumor activity of Chenopodium ambrosioides.     

Evaluation of antiviral activity of South American plant extracts against herpes simplex virus type 1 and rabies virus

This paper describes the screening of different South American plant extracts and fractions. Aqueous and organic extracts were prepared and tested for antiherpetic (HSV-1, KOS and 29R strains) and antirabies (PV strain) activities. The evaluation of the potential antiviral activity of these extracts was performed by using an MTT assay for HSV-1, and by a viral cytopathic effect (CPE) inhibitory method for rabies virus (RV). The results were expressed as 50% cytotoxicity (CC(50)) for MTT assay and 50% effective (EC(50)) concentrations for CPE, and with them it was possible to calculate the selectivity indices (SI = CC(50)/EC(50)) of each tested material. From the 18 extracts/fractions tested, six extracts and four fractions showed antiviral action. Ilex paraguariensis, Lafoensia pacari, Passiflora edulis, Rubus imperialis and Slonea guianensis showed values of SI > 7 against HSV-1 KOS and 29-R strains and Alamanda schottii showed a SI of 5.6 against RV, PV strain.     

Antinociceptive activity and toxicology of the lectin from Canavalia boliviana seeds in mice

The aim of the present study was to evaluate the potential antinociceptive and toxicity of Canavalia boliviana lectin (CboL) using different methods in mice. The role of carbohydrate-binding sites was also investigated. CboL given to mice daily for 14 days at doses of 5 mg/kg did not cause any observable toxicity. CboL (1, 5, and 10 mg/kg) administered to mice intravenously inhibited abdominal constrictions induced by acetic acid and the two phases of the formalin test. In the hot plate and tail immersion tests, the same treatment of CboL induced significant increase in the latency period. In the hot plate test, the effect of CboL (5 mg/kg) was reversed by naloxone (1 mg/kg), indicating the involvement of the opioid system. In the open-field and rota-rod tests, the CboL treatment did not alter animals' motor function. These results show that CboL presents antinociceptive effects of both central and peripheral origin, involving the participation of the opioid system via lectin domain.     

Nitric oxide and potassium channels mediate GM1 ganglioside-induced vasorelaxation

Monosialotetrahexosylganglioside (GM1) is a glycosphingolipid present in most cell membranes that displays antioxidant and neuroprotective properties. It has been recently described that GM1 induces pial vessel vasodilation and increases NO _x content in cerebral cortex, which are fully prevented by the nitric oxide synthase inhibitor N^G-nitro-l-arginine methyl ester (l-NAME). However, it is not known whether GM1 relaxes larger vessels, as well as the mechanisms by which GM1 causes vasorelaxation. In this study, we demonstrate that GM1 (10, 30, 100, 300 µM, 1 and 3 mM) induces vascular relaxation determined by isometric tension studies in rat mesenteric artery rings contracted with 1 µM phenylephrine. The vasorelaxation induced by GM1 was abolished by endothelium removal, by incubation with l-NAME (1 µM), and partially inhibited by the blockade of potassium channels by 1 mM tetraethylammonium, 10 µM glibenclamide, by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (10 µM), and by 50 nM charybdotoxin, a blocker of large and intermediate conductance calcium-activated potassium channels. Moreover, GM1-induced relaxation was not affected by apamin (50 nM), a small conductance calcium-activated potassium channel blocker. The results indicate that direct and indirect nitric oxide pathways play a pivotal role in vasorelaxation induced by GM1, which is mediated mainly by potassium channels activation. We suggest that vasodilation may underlie some of the biological effects of exogenous GM1 ganglioside.     

Comparison between Measurements Obtained with three Different Perineometers

OBJECTIVE:

To analyze the results obtained in the evaluation of intra-vaginal pressure using three different brands of perineometers in nulliparous volunteers.

MATERIALS AND METHODS:

Twenty nulliparous women with no anatomical alterations and/or dysfunction of the pelvic floor were enrolled in our study. All the women had the ability to voluntarily contract their PFM (Pelvic Floor Muscles), as assessed by digital palpation. The intra-vaginal pressure was assessed using three different brands of perineometer (Neurodyn Evolution^™, SensuPower^™ and Peritron^™). Each volunteer was evaluated on three alternate days by a single examiner using a single brand of perineometer on each day. In the assessment, the volunteers were required to pull (contract) their PFM in and up as strongly as possible 3 times and to sustain the contraction for 5 seconds, with an interval of 30 seconds between each pull. For the statistical analysis, a concordance correlation coefficient was used to compare the values that were obtained with each brand of perineometer.

RESULTS:

A moderate concordance (0.51) was found between the results from the Peritron^™ and Neurodyn^™ perineometers, a fair concordance (0.21) between the Peritron^™ and SensuPower^™ brands and a poor concordance (0.19) between the Neurodyn^™ and SensuPower^™ brands.

CONCLUSION:

The concordance of the measurements of the intra-vaginal pressure ranged from poor to moderate, suggesting that perineometers of different brands generate different results.