Evaluation of the efficacy of a posaconazole and anidulafungin combination in a murine model of pulmonary aspergillosis due to infection with Aspergillus fumigatus

Posaconazole (PSC) in combination with anidulafungin (AFG) was evaluated in a murine model of pulmonary aspergillosis. Immunosuppressed animals were infected via the nasal cavity with 2 different A. fumigatus strains. The animals received PSC (oral, 20 mg/kg per day) and/or AFG (i.p., 10 mg/kg per day) for 7 days. On Day 8, the mice were euthanized and fungal burdens were determined from the lungs. Survival curves were constructed for mortality analysis. Compared to untreated groups, groups singly treated with PSC or AFG showed a reduced fungal burden in the lungs (P = 0.0001–0.006) and prevention of mortality (66.66–83.33% of survival). Combination treatment with PSC and AFG significantly reduced the fungal burden (or sterilized the lungs) compared to the findings in the untreated and monotherapy groups and improved the survival rate to 100%. The PSC and AFG combination therapy was highly effective and should be evaluated in larger-scale experiments.     

Bis selenide alkene derivatives: A class of potential antioxidant and antinociceptive agents

Bis and tris-selenide alkene derivatives, a class of organoselenium compounds, were screened for antinociceptive and antioxidant activities. In vitro, bis-selenide alkene 1c (R=2,4,6-Me(3)C(6)H(2)), 1d (R=4-ClC(6)H(4)) and 1e (R=4-MeOC(6)H(4)) protected against lipid peroxidation about 50%, whereas 1b (R=C(6)H(5)) and 1a (R=C(4)H(9)) protected only 23%. Compound 1d presented lesser IC(50) against lipid peroxidation than other bis-selenide alkene compounds (1d>1e> or =1c>1a=1b). The maximal inhibitory effect of tris-selenide alkenes on lipid peroxidation was in the following order 2c>2a=2b. Compound 1e increased the rate of GSH, but not DTT, oxidation. Tris-selenide alkene 2c (R=4-MeOC(6)H(4)) demonstrated the higher rate of thiol oxidation, while 2a (R=C(6)H(5)) did not change DTT oxidation but oxidized GSH. Conversely, compound 2b (R=4-ClC(6)H(4)) did not change the rate of GSH oxidation, but oxidized DDT. Bis-selenide alkene derivatives 1c, 1d and 1e were the most promising compounds tested in vitro. In vivo, compounds 1c and 1d (5-50mg/kg, subcutaneously) produced significant inhibition of acetic acid- and capsaicin-induced pain. Compounds 1c and 1d increased the tail-flick response latency time. The antinociception effect of 1c and 1d was not abolished by naloxone (an antagonist of opioid receptor, 1mg/kg, subcutaneously), suggesting that the antinociceptive effect is not influenced by the opioidergic mechanism.     

Protective action of glutamine in rats with severe acute liver failure

BACKGROUND Severe acute liver failure(SALF) is a rare, but high-mortality, rapidly evolving syndrome that leads to hepatocyte degeneration with impaired liver function.Thioacetamide(TAA) is a known xenobiotic, which promotes the increase of the formation of reactive oxygen species. Erythroid 2-related factor 2(Nrf2) activates the antioxidant protection of cells. Studies have evidenced the involvement of inflammatory mediators in conditions of oxidative stress.AIM To evaluate the antioxidant effects of glutamine on Nrf2 activation and NFκBmediated inflammation in rats with TAA-induced IHAG.METHODS Male Wistar rats(n = 28) were divided into four groups: control,control+glutamine, TAA, and TAA + glutamine. Two TAA doses(400 mg/kg)were administered intraperitoneally, 8 h apart. Glutamine(25 mg/kg) was administered at 30 min, 24 h, and 36 h. At 48 h, blood was collected for liver integrity analysis [aspartate aminotransferase(AST), alanine aminotransferase(ALT), and alkaline phosphatase(ALP)]. The liver was harvested for histology and assessment of oxidative stress [thiobarbituric acid-reactive substances(TBARS), catalase(CAT), glutathione peroxidase(GPx), glutathione S-transferase(GST), glutathione(GSH), Nrf2, Kelch-like ECH-associated protein 1(Keap1),NADPH quinone oxidoreductase1(NQO1), superoxide dismutase(SOD)] and inflammatory process.RESULTS TAA caused disruption of the hepatic parenchyma, with inflammatoryinfiltration, massive necrosis, and ballooning degeneration. Glutamine mitigated this tissue damage, with visible regeneration of hepatic parenchyma; decreased TBARS(P 0.001), GSH(P 0.01), IL-1β, IL6, and TNFα levels(P 0.01) in hepatic tissue; and decreased blood levels of AST, ALT, and ALP(P 0.05). In addition, CAT, GPx, and GST activities were restored in the glutamine group(P0.01, P 0.01, and P 0.001, respectively vs TAA alone). Glutamine increased expression of Nrf2(P 0.05), NQO1, and SOD(P 0.01), as well as levels of IL-10(P 0.001), while decreasing expression of Keap1, TLR4, NFκB(P 0.001), COX-2 and iNOS,(P 0.01), and reducing NO_2 and NO_3 levels(P 0.05).CONCLUSION In the TAA experimental model of IHAG, glutamine activated the Nrf2 pathway,thus promoting antioxidant protection, and blunted the NFκB-mediated pathway, reducing inflammation.     

Antinociceptive and anti-hypernociceptive effects of Se-phenyl thiazolidine-4-carboselenoate in mice

In this study, the antinociceptive, anti-hypernociceptive and toxic effects of orally administered (R)-Se-phenyl thiazolidine-4-carboselenoate (Se-PTC, 1-50 mg/kg) were evaluated in mice. Se-PTC did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels. Furthermore, in an open field test, Se-PTC did not alter the number of crossings and rearing. Se-PTC significantly reduced the amount of writhing when assessed by acetic acid-induced visceral nociception and attenuated the licking time of the injected paw in the early and late phases of a formalin test. In addition, Se-PTC reduced nociception produced by intra-plantar (i.pl.) injection of glutamate, capsaicin, cinnalmaldehyde, bradykinin, phorbol myristate acetate and 8-Bromo-cAMP. Se-PTC caused a significant increase in hot plate and tail-immersion response latencies, but the antinociceptive effect of Se-PTC in the tail immersion was not abolished by pretreatment with the non-selective opioid receptor antagonist, naloxone. Se-PTC (25 mg/kg) significantly inhibited nociceptive behavior induced by intrathecal (i.t.) injection of glutamate, N-methyl-D-aspartate (NMDA) and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), but failed to affect nociception induced by kainate and α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA). Mechanical hypernociception induced by carrageenan and Complete Freund's Adjuvant was attenuated by Se-PTC administration. These results indicate that Se-PTC produces antinociception in several models of nociception.     

Development of a prediction tool for low bone mass based on clinical data and periapical radiography

Objectives

This study aimed to develop and test a tool for low bone mass pre-screening by combining periapical radiographs with clinical risk factors.

Methods

The study sample consisted of 60 post-menopausal women over 40 years of age who were referred for dental radiographs. These patients also had their bone mineral density measured at the lumbar spine and proximal femur using dual-energy X-ray absorptiometry. Radiographic density measurements and 14 morphological features were obtained from each dental radiograph using digital image processing software. The clinical variables considered were age and bone mass index. Classification and regression tree analysis (CART) was used to test the predictive power of clinical and radiographic risk factors for classifying individuals.

Results

CART indicated that the most important variables for classifying patients were age, number of terminal points/periphery, periphery/trabecular area, radiographic density and bone mass index.

Conclusion

A combination of clinical and radiographic factors can be used to identify individuals with low bone mineral density, with higher accuracy than any one of these factors taken individually.     

Embryonated chicken eggs: An experimental model for Pythium insidiosum infection

Pythiosis is a severe disease caused by Pythium insidiosum. Currently, the research on the treatment of pythiosis uses rabbits as an experimental infection model. To reduce the use of animals in scientific experimentation, alternative models are increasingly necessary options. The objective of this study was to establish a new experimental infection model for pythiosis using embryonated chicken eggs. First, we tested the inoculation of 4 zoospore concentrations into the egg allantoic cavity at 3 embryonic days. We observed that increased zoospore concentration causes a decrease in survival time, and at a later embryonic day (the 14th) of infection, embryos showed delayed mortality. To confirm the reproducibility of the model, we chose the 14th embryonic day for the inoculation of 50 zoospores/egg, and the experiment was repeated twice. Mortality began with 30% embryos 48 hours after inoculation, and 95% embryos died within 72 hours. There was no mortality in the uninfected control group. The infection was confirmed by culture, PCR and histopathology. Immunohistochemistry confirmed the presence of hyphae in blood vessels in the umbilical cords in 95% of embryos and only 1 liver (5%). Our results suggest that embryonated eggs can be a very useful alternative infection model to study pythiosis.     

Questionnaires and checklists for central auditory processing screening used in Brazil: a systematic review

Introduction

The action of listening involves a complex interaction between the peripheral and central auditory systems. Central auditory processing disorder can be described as any problem in one or more auditory abilities. Literature reports that behavioral questionnaires and checklists can be applied to screen individuals at risk for central auditory processing disorder.

Efficacy of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and diphenyl diselenide on cadmium induced testicular damage in mice

The deleterious effect of acute cadmium-intoxication in mice testes was evaluated. Animals received a single dose of CdCl₂ (2.5 or 5 mg/kg, intraperitoneally) and a number of toxicological parameters in mice testes were examined, such as δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, lipid peroxidation, hemoglobin and ascorbic acid contents. Furthermore, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were also determined. Thus, a possible protective effect of 2,3-dimercapto-1-propane-sulfonic acid (DMPS) and diphenyl diselenide (PhSe)₂ were studied. The results demonstrated an inhibition of δ-ALA-D activity, a reduction of ascorbic acid and an increase of lipid peroxidation induced by cadmium, indicating testes damage. Furthermore, we observed an increase of plasma LDH, AST and ALT activities. DMPS (400 mol/kg) and (PhSe)₂ (100 μmol/kg) partially protected from the inhibitory effect of 2.5 mg/kg CdCl₂ on δ-ALA-D and from the increase of TBARS (thiobarbituric acid reactive species) levels. (PhSe)₂ therapy was effective in ameliorate ascorbic acid content when the cadmium dose was 2.5 mg/kg. Treatment with DMPS and (PhSe)₂, individually or combined, was inefficient in reducing cadmium-induced plasma LDH and ALT activity increase. The use of combined therapy (DMPS plus (PhSe)₂) proved to be efficient in decreasing cadmium levels in testes and in ameliorating plasma AST activity from animals that received the highest dose of cadmium.     

In Vitro and In Vivo Antimicrobial Activities of Minocycline in Combination with Azithromycin,Clarithromycin, or Tigecycline against Pythium insidiosum

The present study investigated the in vitro and the in vivo interactions among azithromycin, clarithromycin, minocycline, and tigecycline against Pythium insidiosum. In vitro antimicrobial activities were determined by the broth microdilution method in accordance with CLSI document M38-A2, and the antibiotic interactions were assayed using the checkerboard MIC format. In vivo efficacy was determined using a rabbit infection model. The geometric mean MICs of azithromycin, clarithromycin, minocycline, and tigecycline against P. insidiosum were, respectively, 1.91, 1.38, 0.91, and 0.79 μg/ml. By checkerboard testing, all combinations resulted in in vitro synergistic interactions (>60%). Antagonism was not observed. The in vivo studies showed that azithromycin (20 mg/kg/day twice daily) alone or in combination with minocycline (10 mg/kg/day twice daily) significantly decreased the fungal burden. This study demonstrates that azithromycin possesses potent curative efficacy against subcutaneous pythiosis in the rabbit model.     

Involvement of bradykinin and prostaglandins in the diuretic effects of Achillea millefolium L. (Asteraceae)

Ethnopharmacological relevance

Achillea millefolium L. (Asteraceae), popularly known as “mil-folhas”, is well recognized and widely used in Brazilian folk medicine to treat heart and kidney disorders. Among its popularly described effects are diuretic and hypotensive actions.

Aim of the study

The diuretic activity of Achillea millefolium L. extracts and its semi-purified fractions, as well as the mechanisms involved, were evaluated in male Wistar rats.

Material and methods

An aqueous extract (AEAM, 125–500 mg/kg), hydroethanolic extract (HEAM, 30–300 mg/kg), dichloromethane subfractions (DCM-2, 10 and 30 mg/kg), or hydrochlorothiazide (10 mg/kg), were orally administered and the animals were kept in metabolic cages for 8 h for urine collection. To evaluate the involvement of bradykinin and prostaglandins in the diuretic action of Achillea millefolium, selected groups of rats received HOE-140 (1.5 mg/kg, i.p.) or indomethacin (5 mg/kg, p.o.), before treatment with a DCM-2 subfraction (30 mg/kg). The urinary volume, conductivity, pH, density and electrolyte excretion were measured.

Results

Similar to hydrochlorothiazide, both HEAM and DCM-2, but not AEAM, increased urinary volume and the excretion of Na⁺ and K⁺ when compared with the control group (vehicle). The diuretic effect of DCM-2 was abolished by HOE-140 (a bradykinin B2 receptor antagonist), as well as by indomethacin (a cyclooxygenase inhibitor).

Conclusion

The present study reveals that extracts obtained from Achillea millefolium are able to effectively increase diuresis when orally administered in rats. This effect depends on both the activation of bradykinin B2 receptors and the activity of cyclooxygenases.