Administração de antibióticos por via subcutânea: uma revisão integrativa da literatura

OBJETIVO: Caracterizar os artigos científicos relacionados ao uso de antibióticos por via subcutânea em pacientes com difícil acesso venoso em cuidados paliativos quanto à tolerância local e eficácia terapêutica. MÉTODOS: Revisão integrativa da literatura realizada nas bases de dados LILACS, CINAHL, PUBMED, EMBASE e Biblioteca Cochrane, utilizando-se como referencial teórico a Prática Baseada em Evidências. RESULTADOS: 17 artigos foram selecionados com dez antibióticos diferentes, sendo o Ceftriaxona, o antibiótico mais estudado. Constatou-se a eficácia terapêutica com base nos parâmetros farmacocinéticos e clínicos. A tolerância local esteve associada à maior diluição dos antibióticos. Com administração de aminoglicosídeos, observaram-se lesões graves e necrose tecidual. A baixa tolerância reforça a restrição de uso apenas para essa classe de antibióticos. CONCLUSÃO: As previsões de eficácia terapêutica e a boa tolerância sugerem uma possibilidade a ser considerada quando se deseja uma via de administração parenteral alternativa, porém recomenda-se cautela, visto que nenhum dos estudos avaliou pacientes em cuidados paliativos.

Synthesis and characterization of the atropisomeric relationships of a substituted N-phenyl-bipyrazole derivative with anti-inflammatory properties

This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The 1H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs. Chirality 24:463470, 2012. (c) 2012 Wiley Periodicals, Inc.

Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS

Introduction: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. Methods: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. Results: The study aimed to evaluate patient compliance and determine if there was an association between non-adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 +/- 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/lamivudine was used, the patients were less compliant (chi(2) = 4.468, 1 degree of freedom, p = 0.035). Conclusions: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival.

Potent Antiretroviral Therapy for Human Immunodeficiency Virus Infection Increases Aortic Stiffness

Background: Highly active antiretroviral therapy for AIDS is known to increase cardiovascular risk, but the effects of potent antiretroviral agents according to gender are unknown. Objective: The present study evaluated the impact of HIV infection treatment on aortic stiffness according to gender. Methods: From university-affiliated hospitals, we recruited 28 AIDS patients undergoing highly active antiretroviral treatment (HAART), 28 treatment-naive HIV-infected patients, 44 patients with type 2 diabetes, and 30 controls. Aortic stiffness was determined by measuring pulse wave velocity (PWV) using a validated and non-invasive automatic device. Results: The crude mean PWV values and 95% confidence intervals (95% CI) for HAART, diabetics, and controls were 9.77 m/s (95% CI 9.17-10.36),, 9.00 m/s (95% CI 8.37-9.63), 9.90 m/s (95% CI 9.32-10.49), and 9.28 m/s (95% CI 8.61-9.95), respectively, for men (P-value for trend = 0.14), and 9.61 m/s (95% CI 8.56-10.66), 8.45 m/s (95% CI 7.51-9.39), 9.83 (95% CI 9.21-10.44), and 7.79 m/s (95% CI 6.99-8.58), respectively, for women (P-value for trend <0.001). Post-hoc analysis revealed a significant difference between the mean PWV values in the HAART group and controls in women (P-value <0.01). After adjusting for other potential covariates, including systolic blood pressure and diabetes, these results did not change. The findings indicate that the impact of HAART treatment on aortic stiffness was amplified in women with hypertension, dyslipidemia, and metabolic syndrome. Conclusion: Potent anti-retroviral agents used in the treatment of HIV infection increases aortic stiffness, mainly among women with higher cardiovascular risk. (Arq Bras Cardiol 2012;99(6):1100-1107)

TNF blockers show distinct patterns of immune response to the pandemic influenza A H1N1 vaccine in inflammatory arthritis patients

Methods. One hundred and twenty patients (RA, n = 41; AS, n = 57; PsA, n = 22) on anti-TNF agents (monoclonal, n = 94; soluble receptor, n = 26) were compared with 116 inflammatory arthritis patients under DMARDs and 117 healthy controls. Seroprotection, seroconversion (SC), geometric mean titre, factor increase in geometric mean titre and adverse events were evaluated 21 days after vaccination. Results. After immunization, SC rates (58.2% vs 74.3%, P = 0.017) were significantly lower in SpA patients receiving anti-TNF therapy, whereas no difference was observed in RA patients receiving this therapy compared with healthy controls (P = 0.067). SpA patients receiving mAbs (infliximab/adalimumab) had a significantly lower SC rate compared with healthy controls (51.6% vs 74.3%, P = 0.002) or those on DMARDs (51.6% vs 74.7%, P = 0.005), whereas no difference was observed for patients on etanercept (86.7% vs 74.3%, P = 0.091). Further analysis of non-seroconverting and seroconverting SpA patients revealed that the former group had a higher mean age (P = 0.003), a higher frequency of anti-TNF (P = 0.031) and mAbs (P = 0.001) and a lower frequency of MTX (P = 0.028). In multivariate logistic regression, only older age (P = 0.015) and mAb treatment (P = 0.023) remained significant factors for non-SC in SpA patients. Conclusion. This study revealed a distinct disease pattern of immune response to the pandemic influenza vaccine in inflammatory arthritis patients receiving anti-TNF agents, illustrated by a reduced immunogenicity solely in SpA patients using mAbs. Trial Registration: ClinicalTrials.gov, ext-link-type="uri" xlink:href="www.clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.clinicaltrials.gov, NCT01151644.

Design, synthesis and the effect of 1,2,3-triazole sialylmimetic neoglycoconjugates on Trypanosoma cruzi and its cell surface trans-sialidase

This work describes the synthesis of a series of sialylmimetic neoglycoconjugates represented by 1,4-disubstituted 1,2,3-triazole-sialic acid derivatives containing galactose modified at either C-1 or C-6 positions, glucose or gulose at C-3 position, and by the amino acid derivative 1,2,3-triazole fused threonine-3-O-galactose as potential TcTS inhibitors and anti-trypanosomal agents. This series was obtained by Cu(I)-catalysed azide-alkyne cycloaddition reaction ('click chemistry') between the azido-functionalized sugars 1-N(3)-Gal (commercial), 6-N(3)-Gal, 3-N(3)-Glc and 3-N(3)-Gul with the corresponding alkyne-based 2-propynyl-sialic acid, as well as by click chemistry reaction between the amino acid N(3)-ThrOBn with 3-O-propynyl-GalOMe. The 1,2,3-triazole linked sialic acid-6-O-galactose and the sialic acid-galactopyranoside showed high Trypanosoma cruzi trans-sialidase (TcTS) inhibitory activity at 1.0 mM (approx. 90%), whilst only the former displayed relevant trypanocidal activity (IC(50) 260 mu M). These results highlight the 1,2,3-triazole linked sialic acid-6-O-galactose as a prototype for further design of new neoglycoconjugates against Chagas' disease. (C) 2011 Elsevier Ltd. All rights reserved.

Mode of Peroxisome Proliferator-Activated Receptor gamma Activation by Luteolin

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a target for treatment of type II diabetes and other conditions. PPAR gamma full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPAR gamma but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPAR gamma agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPAR gamma target genes in 3T3-L1 cells (LPL, ORL1, and CEBP alpha) and PPAR gamma-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPAR gamma ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPAR gamma LBD conformer and occupies a space near the beta-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPAR gamma, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Omega-loop among H2', H3, and the beta-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPAR gamma-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPAR gamma modulators.

Antimicrobial Properties and Cytotoxicity of an Antimicrobial Monomer for Application in Prosthodontics

Purpose: This study aimed to investigate the antimicrobial properties and cytotoxicity of the monomer methacryloyloxyundecylpyridinium bromide (MUPB), an antiseptic agent capable of copolymerizing with denture base acrylic resins. Materials and Methods: The antimicrobial activity of MUPB was tested against the species Candida albicans, Candida dubliniensis, Candida glabrata, Lactobacillus casei, Staphylococcus aureus, and Streptococcus mutans. The minimum inhibitory and fungicidal/bactericidal concentrations (MIC, MFC/MBC) of MUPB were determined by serial dilutions in comparison with cetylpyridinium chloride (CPC). The cytotoxic effects of MUPB at concentrations ranging from 0.01 to 1 g/L were assessed by MTT test on L929 cells and compared with methyl methacrylate (MMA). The antimicrobial activity of copolymerized MUPB was tested by means of acrylic resin specimens containing three concentrations of the monomer (0, 0.3, 0.6% w/w). Activity was quantified by means of a disc diffusion test and a quantification of adhered planktonic cells. Statistical analysis employed the Mann-Whitney test for MIC and MFC/MBC, and ANOVA for the microbial adherence test (a= 0.05). Results: MUBP presented lower MIC values when compared with CPC, although differences were significant for C. dubliniensis and S. mutans only (p= 0.046 and 0.043, respectively). MFC/MBC values were similar for all species except C. albicans; in that case, MUPB presented significantly higher values (p= 0.046). MUPB presented higher cytotoxicity than MMA for all tested concentrations (p < 0.001) except at 0.01 g/L. Irrespective of the concentration incorporated and species, there was no inhibition halo around the specimens. The incorporation of MUPB influenced the adhesion of C. albicans only (p= 0.003), with lower CFU counts for the 0.6% group. Conclusions: It was concluded that non-polymerized MUPB has an antimicrobial capacity close to that of CPC and high cytotoxicity when compared with MMA. The antimicrobial activity of MUPB after incorporation within a denture base acrylic resin did not depend on its elution, but was shown to be restricted to C. albicans.

Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)coumarin derivatives: Effect on inducible nitric oxide synthase

A series of 3-(triazolyl)-coumarins were synthesized and tested as anti-inflammatory agents. It was possible to infer that these compounds do not alter the interaction of LPS with TLR-4 or TLR-2, as the intracellular pathways involved in the TNF-alpha secretion and COX-2 activity were not affected. Nevertheless, the compounds inhibited iNOS-derived NO production, without affecting the eNOS activity. The outcome of the docking studies showed that it pi center dot center dot center dot pi interactions with the heme group are important for the iNOS inhibition, thus making compound 3c a promising lead. Moreover, the efficacy of this compound was visualized by the reduced number of neutrophils in the LPS-inflamed subcutaneous tissue. Together, biological and docking data show that triazolyl-substituted coumarins, that can act on iNOS, are a good scaffold to be explored. (C) 2012 Elsevier Masson SAS. All rights reserved.

Preliminary study of Porcine circovirus type 2 and Torque teno sus virus coinfection frequencies in Brazilian pig herds

Torque teno sus virus (TTSuV) is emergent in swine herds. Recent studies have shown an increased frequency of TTSuV2 in Porcine circovirus type 2 (PCV2)-associated diseases (PCVAD), which are endemic in many swine-producing countries, including Brazil. Coinfection with several other viral and bacterial agents results in an increased incidence of more severe PCVAD. Given the limited information on TTSuV and PCV2 coinfection, especially in Brazilian swine herds, this study made a preliminary estimation of the occurrence of coinfection in swine herds by testing samples from different categories. Between 2008 and 2009, 111 samples of feces and 23 serum samples from 5 swine herds were tested for PCV2 and TTSuVs and the results analyzed for associations between these agents. No significant differences in coinfection frequency were observed for PCV2 1 + TTSuV1 or for PCV2 1 TTSuV2 between nursery piglets (P = 0.730), growing pigs (P = 0.331), or sows (P = 0.472). However, a significant difference was observed for PCV2 1 TTSuV1 1 TTSuV2 between nursery piglets and growing pigs (P = 0.004; Fisher's exact test). Phylogenetic studies agreed with the grouping of TTSuV1 and TTSuV2 into 2 different clades, with no distinct pattern of clustering of these isolates with the animal categories.

In Vitro Effects of Bevacizumab Treatment on Newborn Rat Retinal Cell Proliferation, Death, and Differentiation

PURPOSE. Vascular endothelial growth factor (VEGF) is an important signal protein in vertebrate nervous development, promoting neurogenesis, neuronal patterning, and glial cell growth. Bevacizumab, an anti-VEGF agent, has been extensively used for controlling pathological retinal neovascularization in adult and newborn patients, although its effect on the developing retina remains largely unknown. The purpose of this study was to investigate the effect of bevacizumab on cell death, proliferation, and differentiation in newborn rat retina. METHODS. Retinal explants of sixty 2-day-old Lister hooded rats were obtained after eye enucleation and maintained in culture media with or without bevacizumab for 2 days. Immunohistochemical staining was assessed against proliferating cell nuclear antigen (PCNA, to detect cell proliferation); caspase-3 and beclin-1 (to investigate cell death); and vimentin and glial fibrillary acidic protein (GFAP, markers of glial cells). Gene expressions were quantified by real-time reverse-transcription polymerase chain reaction. Results from treatment and control groups were compared. RESULTS. No significant difference in the staining intensity (on immunohistochemistry) of PCNA, caspase-3, beclin-1, and GFAP, or in the levels of PCNA, caspase-3, beclin-1, and vimentin mRNA was observed between the groups. However, a significant increase in vimentin levels and a significant decrease in GFAP mRNA expression were observed in bevacizumab-treated retinal explants compared with controls. CONCLUSIONS. Bevacizumab did not affect cell death or proliferation in early developing rat retina but appeared to interfere with glial cell maturation by increasing vimentin levels and downregulating GFAP gene expression. Thus, we suggest anti-VEGF agents be used with caution in developing retinal tissue. (Invest Ophthalmol Vis Sci. 2012;53:7904-7911) DOI:10.1167/iovs.12-10283

Terapia antirretroviral altamente eficaz para infecção pelo vírus da imunodeficiência humana aumenta a rigidez aórtica

FUNDAMENTO: Sabe-se que a terapia antirretroviral altamente potente para Aids reconhecida aumenta o risco cardiovascular, mas os efeitos dos agentes antirretrovirais de acordo com o gênero ainda são desconhecidos. OBJETIVO: O presente estudo avaliou o impacto do tratamento para o vírus da imunodeficiência humana (HIV) na rigidez aórtica de acordo com o gênero. MÉTODOS: Foram recrutados 28 pacientes com Aids submetidos à terapia antirretroviral altamente potente (HAART), 28 pacientes infectados pelo HIV virgens de tratamento, 44 pacientes com diabetes tipo 2, e 30 controles. A rigidez aórtica foi determinada pela medição da Velocidade da Onda de Pulso (VOP), utilizando um equipamento automático validado e não invasivo. RESULTADOS: Os resultados médios brutos da VOP (e intervalo de confiança de 95%) para participantes nos grupos terapia antirretroviral potente, HIV virgem de tratamento, diabéticos, e controles foram 9,77 m/s (9,17-10,36), 9,00 m/s (8,37-9,63), 9,90 m/s (9,32-10,49) e 9,28 m/s (8,61-9,95), respectivamente, para os homens (p de tendência = 0,14) e 9,61 m/s (8,56-10,66), 8,45 m/s (7,51-9,39), 9,83 (9,21-10,44) e 7,79 m/s (6,99-8,58), respectivamente, para as mulheres (p valor de tendência < 0,001). Análises post-hoc revelaram uma diferença significativa entre os valores médios de VOP no grupo com HAART e controles em mulheres (p < 0,01). Ajustes para as demais covariáveis potenciais, incluindo pressão arterial sistólica e diabetes, não alteraram esses resultados. Os achados indicam que o impacto do tratamento com HAART na rigidez aórtica foi amplificado nas mulheres com hipertensão, dislipidemia e síndrome metabólica. CONCLUSÃO: Agentes antirretrovirais potentes utilizados no tratamento da infecção pelo HIV aumentam a rigidez da aorta, especialmente em mulheres com maior risco cardiovascular.

Curcumin requires tumor necrosis Factor α signaling to alleviate cognitive impairment elicited by Lipopolysaccharide

A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampusdependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl- D –aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

Renal papillary necrosis

In 1877, Dr. Nikolaus Friedreich (1825- 1882; student of Virchow who became Professor of Pathology at Heidelberg and who also described Friedreich’s ataxia) first described renal papillary necrosis (RPN) in patients with prostatic hypertrophy and secondary hydronephrosis. Thereafter in 1937, Froboese and Günther emphasized the association of this entity with diabetes mellitus. These authors also observed renal papillary necrosis in cases of urinary tract obstruction even in the absence of diabetes mellitus.