Micheline Rosa Silveira

Effects of a BLT receptor antagonist on local and remote reperfusion injuries after transient ischemia of the superior mesenteric artery in rats.

Reperfusion of ischemic vascular beds may lead to recruitment and activation of leukocytes, release of mediators of the inflammatory process and further injury to the affected vascular bed and to remote sites. Neutrophils appear to play a major role in the pathophysiology of reperfusion injury. Amongst inflammatory mediators shown to activate neutrophils and induce their recruitment in vivo, much interest has been placed on the role of leukotriene (LT)B(4). Here, we have assessed the effects of the BLT receptor antagonist (+)-1-(3S, 4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl]-cyclopentane carboxylic acid (CP 105,696) in a model of neutrophil-dependent ischemia and reperfusion injury in the rat. The superior mesenteric artery was isolated and ischemia was induced by its total occlusion for 30 min. After 30 min of reperfusion, injury was assessed by evaluating the extravasation of Evans blue, an index of vascular permeability, and the levels of myeloperoxidase, an index of neutrophil accumulation, in the intestine, mesentery and lung. The neutrophil-dependence of the local (intestine and mesentery) and remote (lung) injury was confirmed by using fucoidin, a selectin blocker, and WT-3, an anti-CD18 monoclonal antibody. Post-ischemic treatment with CP 105,696 dose-dependently inhibited vascular permeability and neutrophil accumulation in the intestine and mesentery. CP 105,696 also blocked the vascular permeability changes, but not neutrophil accumulation, in the lungs after reperfusion injury. Virtually identical results were obtained with another BLT receptor antagonist, 1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)-heptoxy++ +)-phenyl )ethanone (LY255283). Our results suggest that post-ischemic treatment with BLT receptor antagonists may inhibit local and remote ischemia and reperfusion injury by blocking both the accumulation and/or activation of neutrophils.

Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat

The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF‐α levels. Post‐ischaemic treatment with the selectin blocker fucoidin (10 mg kg−1) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg−1) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion‐induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF‐α levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF‐α. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF‐α. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.

Changes in Pulmonary Function and Parasite Burden in Rats Infected with Strongyloides venezuelensis Concomitant with Induction of Allergic Airway Inflammation

ABSTRACT The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.

Infection with Strongyloides venezuelensis Induces Transient Airway Eosinophilic Inflammation, an Increase in Immunoglobulin E, and Hyperresponsiveness in Rats

ABSTRACT Infection by nematode parasites with a pulmonary migration in their life cycle and allergic asthma are two highly prevalent diseases in humans; therefore, one may expect both may occur concomitantly. There is a predominant and essential role of Th2 lymphocytes in the mechanisms underlying the control of parasite elimination as well as in the pathology observed in the asthmatic lung. The consequences of such situations have been explored, with controversial results, justifying the development of experimental models in which the relationship between allergic airway inflammation and helminth infection might be evaluated. The present work describes the inflammatory, humoral, and functional changes that occur in the lung of rats after single (subcutaneous inoculation of 1,500 L3 larvae) or multiple (five weekly subcutaneous inoculations of 1,500 L3 larvae) Strongyloides venezuelensis infections. The results show that the migration of S. venezuelensis larvae through the lungs of infected rats induces a local eosinophilic inflammation process which is mostly focal and parenchymal for rats infected a single time and which is peribronchial after multiple infections. The inflammatory process is accompanied by mucus hypersecretion, thickening of bronchial epithelial and muscle layers, and local increase in immunoglobulin E concentrations that peak after 5 to 7 days and are resolved after 12 days of single or multiple infections. The peak of lung immunopathologic changes observed in infected rats coincides with lung airway hyperresponsiveness (AHR), a key functional alteration in asthma. We propose that this experimental model is ideal to carry out further studies on immunoprotection against nematode infection versus immunopathology of allergic airway inflammation.

Complexidade do regime terapêutico prescrito para idosos

OBJECTIVE: To examine factors associated with therapeutic regimen complexity of drug prescriptions for elderly people in Belo Horizonte, Minas Gerais, Brazil. METHODS: A household survey of elderly people selected by simple random sampling from Brazils social security register. The medication complexity index (MCI), a direct measurement of actions required to administer medication, was derived from information in the latest prescription. Univariate and bivariate analyses were performed to identify factors associated with the MCI. RESULTS: Of the 667 interviewees, 56.5% had prescriptions meeting the inclusion criteria; most (69.2%) were females aged 72.4 years (mean); 35.5% self-rated their health good or very good; and 37.4% reported five or more diseases. In the 15 days prior to interview, 1873 drugs were used (mean=5.1), of which 942 appeared on the prescriptions examined (mean=2.5). Over the same period, 22.3% of interviewees failed to use some prescribed drug. The MCI ranged from 1 to 24 (mean=6.1). Number of drugs prescribed (>2), less schooling, worse perception of health and a lower benefit payment associated positively with greater complexity (p<0.05). An association was observed between regimen complexity and failure to use some drug in the preceding 15 days (p=0.034). CONCLUSION: Elderly people in worse socio-economic and health conditions seem more likely to receive more complex therapeutic regimens, which are associated with non-compliance to the proposed treatment. This is an important consideration in the healthcare of elderly. Simplification of therapy could aid self-care among the elderly.

Scorpion venom-induced neutrophilia is inhibited by a PAF receptor antagonist in the rat.

A dramatic blood neutrophilia is an important feature of the severe envenoming caused by the Brazilian scorpion Tityus serrulatus and may contribute to the development of lung injury in children. We examined the effects of an intravenous injection of T. serrulatus scorpion venom (TsV) on the total number of leukocytes and neutrophils in the blood of anesthetized rats. Injection of TsV (250 μg/kg) induces a significant leukocytosis 2 and 3 h after its injection, explained by an increase in the number of neutrophils. The release of catecholamines and action on adrenoceptors is responsible for most of the systemic manifestations of TsV. However, pretreatment with the β‐adreno‐ceptor antagonists metoprolol and propranolol or the α1‐adrenoceptor antagonist prazosin (0.25 mg/kg) did not prevent TsV‐induced neutrophilia. Blood neutrophilia induced by TsV occurred simultaneously with a significant reduction of mature neutrophils in bone marrow. Pretreatment with the platelet‐activating factor (PAF) receptor antagonists UK‐74505 or WEB‐2086 prevented TsV‐induced increase in blood neutrophils and reduction in the number of neutrophils in the bone marrow. It is concluded that scorpion venom induces blood neutrophilia in rats, explained by a PAF receptor‐dependent mobilization of neutrophils from the bone marrow. J. Leukoc. Biol. 67:515–519; 2000.

Safety of Immunosuppressive Drugs Used as Maintenance Therapy in Kidney Transplantation: A Systematic Review and Meta-Analysis

To evaluate the safety of regimens containing calcineurin inhibitors (CNI), proliferation signal inhibitors (TOR-I) and antimetabolites, we conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies. A total of 4,960 citations were identified in our electronic search and 14 additional articles were identified through hand searching. Forty-eight articles (11,432 participants) from 42 studies (38 RCTs and four cohorts) met the inclusion criteria. Meta-analysis results revealed the following: (i) tacrolimus was associated with an increased risk for diabetes and lower risk of dyslipidemia, compared to cyclosporine; (ii) mycophenolate mofetil (MMF) was associated with increased risk for total infections, abdominal pain, diarrhea and vomiting, compared with azathioprine; (iii) sirolimus was associated with higher risk of anemia, diabetes, dyslipidemia, lymphoceles and withdrawal compared to tacrolimus or cyclosporine, and cyclosporine was associated with an increased risk of CMV infection; (iv) the combination of CNI with antimetabolites was associated with more adverse events than CNI alone; (v) TOR-I was related to more adverse events than MMF. The data observed in this meta-analysis are similar to those describe by others authors; thus, the choice of treatment must be made by the clinical staff based on specific patient characteristics.

Association between medication regimen complexity and pharmacotherapy adherence: a systematic review.

PurposeThe purpose of this study was to systematically review evidence regarding the association between regimen complexity and adherence.MethodsArticles were searched in MEDLINE, LILACS, Cochrane, CINAHL, PsycINFO and references of included studies. Search terms included medication regimen complexity, medication adherence and their synonyms. Randomized clinical trials, cross-sectional, cohort or case-control studies published until March 2016 in English, Portuguese or Spanish were eligible if quantitatively examined the association between complexity and adherence in patients of any age and sex, under any type of medication therapy. Complexity was defined according to the strategy used to assess it in the individual studies. All types of instruments used to assess complexity and adherence were considered. Data extraction was performed using an electronic spreadsheet. Quality assessment was conducted independently using standard scales. The data were qualitatively synthesized.ResultsFifty-four studies were included: 37 cross-sectional and 17 cohorts. Most were conducted in outpatient setting. Most frequently, studies were carried out with HIV-infected individuals or patients with chronic conditions. The most frequent methods used to assess complexity and adherence were complexity index (19) and self-report (27), respectively. Complexity was associated with adherence in 35 studies. Most of them (28) identified that participants with more complex regimens were less likely to adhere to pharmacotherapy; seven studies found a direct correlation. The others found inconclusive results or no association between complexity and adherence. The studies had low to moderate-methodological quality.ConclusionAlthough there was variability regarding the association between complexity and adherence, most studies showed that an increased regimen complexity reduces medication adherence.

Gender in the allocation of organs in kidney transplants: meta-analysis

OBJECTIVE To analyze whether gender influence survival results of kidney transplant grafts and patients. METHODS Systematic review with meta-analysis of cohort studies available on Medline (PubMed), LILACS, CENTRAL, and Embase databases, including manual searching and in the grey literature. The selection of studies and the collection of data were conducted twice by independent reviewers, and disagreements were settled by a third reviewer. Graft and patient survival rates were evaluated as effectiveness measurements. Meta-analysis was conducted with the Review Manager® 5.2 software, through the application of a random effects model. Recipient, donor, and donor-recipient gender comparisons were evaluated. RESULTS : Twenty-nine studies involving 765,753 patients were included. Regarding graft survival, those from male donors were observed to have longer survival rates as compared to the ones from female donors, only regarding a 10-year follow-up period. Comparison between recipient genders was not found to have significant differences on any evaluated follow-up periods. In the evaluation between donor-recipient genders, male donor-male recipient transplants were favored in a statistically significant way. No statistically significant differences were observed in regards to patient survival for gender comparisons in all follow-up periods evaluated. CONCLUSIONS The quantitative analysis of the studies suggests that donor or recipient genders, when evaluated isolatedly, do not influence patient or graft survival rates. However, the combination between donor-recipient genders may be a determining factor for graft survival.

Factors associated to antidepressant prescription for civil servants of Belo Horizonte, MG

Selecting the most suitable drug for the treatment of depression has clinical and economic implications, since both safety and cost of antidepressants (AD) vary among therapeutic subgroups. This study aimed to evaluate the prescription of antidepressants for users of the pharmacy for civil servants of PBH (FARMASERV) in 2005. Univariate, bivariate and multivariate analyzes using logistic regression were performed. Of the total prescriptions analyzed (652), the majority were for women (81.7%) and individuals aged between 19 and 59 years (81.7%). The variables independently associated with the selection of AD were gender, age and the specialty of the prescriber. Women and young adults were more likely to be prescribed an SSRI compared to their congeners, with statistically significant differences. Psychiatrists were more likely to prescribe an SSRI than neurologists or general physicians. The determinant factors for selecting antidepressants may aid the planning of interventions aimed at patients and prescribers which can enable rationalization of the use of antidepressants.