A associação salmeterol//fluticasona é mais eficaz do que a fluticasona e o montelukast oral na asma

RESUMO: Em todo o mundo, as taxas de morbilidade e mortalidade relacionadas com a asma têm vindo a aumentar. Segundo as normas intervencionais (Guidelines), os objectivos do manejamento da asma brônquica devem ser o controlo de sintomas e a prevenção das exacerbações e consequente melhoria da qualidade de vida do doente asmático. à amplamente aceite que a terapêutica corticosteróide inalada é o tratamento preventivo disponível mais eficaz devido ao seu papel anti-inflamatório. No caso de doentes que permanecem sintomáticos sob corticoterapia por via inalatória, a associação de β2 agonista de longa acção com o salmeterol traduzse numa melhoria da função pulmonar e controlo dos sintomas mais significativa do que a observada com a duplicação da dose de corticosteróides. Está comprovada a eficácia da combinação de β2 agonistas de longa acção e corticosteróides inalados no tratamento da inflamação e disfunção do músculo liso â mecanismos fisiopatológicos envolvidos na asma.Não é ainda perfeitamente clara a vantagem da adição de antileucotrienos embora existam diversos estudos que evidenciam uma modesta melhoria da função pulmonar e dos sintomas diários quando esta classe de fármacos é associada à corticoterapia inalada.A análise actual compara a eficácia clínica de associação do salmeterol e do montelukast à corticoterapia por via inalatória (propionato de fluticasona) em adultos com asma que estão sintomáticas apesar da terapêutica referida.Foi efectuado um estudo multicêntrico, randomizado, duplamente cego, com um grupo controlo, englobando indivíduos asmáticos com idadeâ¥15 anos medicados com corticóides inalados durante, pelo menos, as 4 semanas que antecederam o estudo. Apresentavam obstrução das vias aéreas reversível após inalação de um β2 agonista de curta acção numa dose â¤800 μg (â FEV1â¥15%).Foram excluídos os doentes com infecções respiratórias, exacerbações requerendo hospitalização nas últimas 4 semanas, submetidos a corticoterapia oral ou endovenosa nesse período ou mais de 2 vezes nas últimas 12 semanas, fumadores UMA>10, mulheres grávidas ou em período de amamentação e doentes cuja terapêutica de manutenção foi alterada nas últimas semanas.Após um período de run-in de 4 semanas, os doentes foram submetidos durante 12 semanas à associação salmeterol/ propionato de fluticasona 50/100 μg duas vezes/dia ou propionato de fluticasona 100 μg duas vezes/dia e montelukast 10 mg uma vez/dia. Os doentes registaram diariamente os scores de sintomas, o PEF matinal e o uso de terapêutica de alívio.Foram observados às 4, 8 e 12 semanas de tratamento, tendo a função pulmonar sido avaliada nessas datas. Foi feito o levantamento das exacerbações que foram classificadas em ligeira (terapêutica de alívioâ¥3 inalações/ dia em relação ao basal em 2 dias consecutivos), moderada (requerendo CT oral e/ ou antibióticos) ou grave (necessitando de hospitalização).Foi monitorizada a segurança e tolerabilidade do tratamento através do registo dos efeitos adversos em cada visita clínica. Nestas foi efectuada observação pela ORL.Foram avaliados 1168 doentes, tendo sido 725 submetidos a terapêutica (356 salmeterol/ propionato de fluticasona e 369 a propionato de fluticasona e montelukast). A compliance foi elevada em ambos os grupos: 96% e 97%, respectivamente.Após 12 semanas de tratamento, o aumento do PEF matinal foi significativamente superior no grupo salmeterol/ fluticasona (36 L/min) em comparação com o 2.º grupo (19 L/min; p<0,001). A melhoria do FEV foi também significativamente maior no grupo salmeterol/fluticasona (p<0,001). A associação permite um melhor controlo dos sintomas diurnos e nocturnos, sendo as exacerbações mais raras e o uso da terapêutica de alívio menor. Ambos os tratamentos foram bem tolerados. A satisfação com os resultados obtidos com a terapêutica instituída foi superior no 1º grupo (92,9% versus 83,8%; p<0,005). A melhoria da função pulmonar observada após a administração de associação salmeterol/ fluticasona foi significativamente superior em relação à verificada com a corticoterapia inalada e o montelukast. COMENTÃRIO: Os resultados deste estudo revelaram que a associação salmeterol/ propionato de fluticasona (50 μg/ 100 μg) em 2 tomas/dia durante 12 semanas era mais eficaz que propionato de fluticasona 10 μg duas vezes/dia e montelukast 10 μg uma vez/dia no tratamento de doentes com asma moderada ou grave. A associação traduz-se numa melhoria significativamente superior da função pulmonar, dos scores de sintomas e numa redução da frequência das exacerbações.Este estudo foi efectuado para demonstrar os benefícios da associação de β2 agonistas de longa duração (salmeterol) ou anti-leucotrienos (montelukast) à corticoterapia por via inalatória em doentes sintomáticos.Os critérios de inclusão implicaram que se tratasse de indivíduos asmáticos com sintomatologia e requerendo aumento da terapêutica de manutenção. A reversibilidade com a administração de salbutamol podia potencialmente favorecer o grupo salmeterol/ fluticasona. No entanto, este critério de selecção é fundamental para o correcto diagnóstico de asma e foi utilizado em numerosas análises retrospectivas. O período de 12 semanas é suficiente para demonstrar o máximo efeito do salmeterol e do montelukast, o que já tinha sido provado anteriormente.A redução da frequência da exacerbação de asma é importante na diminuição da morbilidade e mortalidade dos doentes asmáticos, melhorando a sua qualidade de vida e reduzindo os custos associados à doença.Numerosos estudos revelaram que a associação de salmeterol/corticóides inalados tem maiores benefícios clínicos do que a administração deste fármaco e anti-leucotrienos, traduzindo-se num menor número de visitas ao Serviço de Urgência e diminuição do uso de terapêutica de alívio.No estudo actual, a diferente eficácia não pode ser atribuída à diferença na compliance, visto esta ter sido elevada em ambos os grupos. Está, também, provado que o uso da terapêutica múltipla em dispositivos diferentes e várias tomas diárias contribui para uma má compliance.Em resumo, nos doentes sintomáticos sob doses baixas de corticóides inalados, ambas as terapêuticas são eficazes, embora no 1.º grupo os benefícios sejam significativamente superiores. Estes resultados estão de acordo com estudos realizados anteriormente com montelukast e zafirlukast e confirma que a associação salmeterol/fluticasona é a opção preferencial para doentes não controlados com a corticoterapia inalada. Palavras-chave: Salmeterol propionato de fluticasona, associação terapêutica, asma, montelukas

A blinded comparison of fluticasone propionate with budesonide via powder devices in adult patients with moderate-to-severe asthma: a clinical evaluation

In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma. However, controversy still remains as to whether these differences translate into clinical benefits. This 12-week, international, randomized, doubleblind, parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate (FP) 800 μg daily, administered as a powder via the Diskhaler®, and budesonide (BUD) 1600 μg daily, administered using the Turbuhaler®, in adult patients with moderate-tosevere asthma. A total of 518 patients participated in the study, 256 of whom received FP and 262 BUD. Assessment of mean morning peak expiratory flow (PEF) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 μg daily and BUD 1600 μg daily in favour of FP (p = 0.003), with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD. Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF (p = 0.04), diurnal PEF variation (p = 0.03) and percentage predicted PEF (p = 0.003), as well as forced expiratory volume (p = 0.008), forced vital capacity (p = 0.02) and PEF (p = 0.005) measured at clinic visits. The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups, with similar changes seen for the median percentage of days with symptom score < 2, rescue medication use and exacerbations of asthma. The incidence of adverse events was found to be comparable in the two treatment groups. The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP, indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline, and 0.93 for BUD (p = 0.0002 compared with FP). In summary, FP 800 μg daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 μg daily

Recovery from Posttraumatic Stress Symptoms: A Qualitative Study of Attributions in Survivors of War

This study was funded by a grant from the European Commission, contract number INCO-CT-2004-50917

Reliability of sickness certificates in detecting potential sick leave reduction by modifying working conditions: a clinical epidemiology study

BACKGROUND: Medical sickness certificates are generally the main source for information when scrutinizing the need for aimed intervention strategies to avoid or reduce the individual and community side effects of sick leave. This study explored the value of medical sickness certificates related to daily work in Norwegian National Insurance Offices to identify sick-listed persons, where modified working conditions might reduce the ongoing sick leave. METHODS: The potential for reducing the ongoing sick leave by modifying working conditions was individually assessed on routine sickness certificates in 999 consecutive sick leave episodes by four Norwegian National Insurance collaborators, two with and two without formal medical competence. The study took place in Northern Norway in 1997 and 1998. Agreement analysed with differences against mean, kappa, and proportional-agreement analysis within and between groups of assessors was used in the judgement. Agreements between the assessors and the self-assessment of sick-listed subjects were additionally analysed in 159 sick-leave episodes. RESULTS: Both sick-listed subjects and National Insurance collaborators anticipated a potential reduction in sick leave in 20–30% of cases, and in another 20% the potential was assessed as possible. The chance corrected agreements, however, were poor (k < 0.20) within and between groups of National Insurance collaborators. The agreement between National Insurance collaborators and the sick-listed subjects was no better than chance. Neither extended medical information nor formal medical competence increased agreement in cases where modified working conditions might have reduced sick leave. CONCLUSION: Information in medical sickness certificates proved ineffective in detecting cases where modified working conditions may reduce sick leave, and focusing on medical certificates may prevent identification of needed interventions. Strategies on how to communicate directly with sick-listed subjects would enable social authorities to exploit more of the sick leave reduction potential by modifying the working conditions than strategies on improving medical information

Ground Truth Collection for Mining Explosions in Northern Fennoscandia and Northwestern Russia

We concluded comprehensive ground truth collection at the Khibiny, Olenegorsk, Kovdor, and Zapolyarnyi mines, and have basic information on 2,052 explosions. In the past two years we used this ground truth information to extract waveform data from the ARCES array and a number of regional stations (KEV, LVZ, APA) as well as from six stations that we deployed along two lines stretching between the Khibiny Massif mines and the region around the ARCES array. We calculated P/S ratios using the ARCES array data for many of these events comprising several source types (compact underground explosions, underground ripple-fired explosions, surface ripple-fired explosions). We found that the P/S ratios of small compact underground explosions in mines of the Khibiny Massif are systematically lower than the P/S ratios of large ripple-fired surface explosions. We had anticipated that smaller underground shots would appear more like single well-coupled explosions, thus having higher P/S ratios than large ripple-fired explosions. A possible explanation for this phenomenon is that the compact underground explosions in these mines are designed to fracture and drop a large quantity of ore from the ceiling of a horizontal shaft. The potential energy released by the falling ore may express as shear wave energy, which may be considerably greater than the (P wave) energy released directly by the explosive. We concluded the deployment of the six stations along the Khibiny-ARCES lines this past summer; this year we are examining the data from these stations to see how P/S ratios vary with range from the source. We have an update on the P/S ratio analysis contrasting different source types, with the addition of an analysis of range dependence using data from the temporary stations. The portable stations were redeployed in the fall of 2004 to the Kiruna and Malmberget underground mines in northern Sweden. The stations deployed in Malmberget also record events from the surface mining operations at the Aitik mine, located some 15 km from Malmberget mine. The data from these stations will allow comparisons of seismic waveforms resulting from different types of shooting practices at different locations within the mines. These stations will provide ground truth on a large number of explosions at these mines allowing future analyses of the dependence of discriminants on source type, possibly assessing the portability of results obtained with the Khibiny explosion observations

Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol

BACKGROUND: To compare the efficacy and safety of budesonide/formoterol (Symbicort(®)) with formoterol (Oxis(®)) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting β(2)-agonist therapy. METHODS: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV(1 )40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 μg), were randomized to receive either budesonide/formoterol (320/9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 μg]) or formoterol (9 μg, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 μg]). The primary efficacy variable was the average FEV(1 )from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV(1 )at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. RESULTS: FEV(1 )increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting β(2)-agonist

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Inhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all?

In the recent years, considerable insight has been gained in to the optimal management of adult asthma. Most adult patients with asthma have mild intermittent and persistent disease, and it is acknowledged that many patients do not reach full control of all symptoms and signs of asthma. Those with mild persistent asthma are usually not well controlled without inhaled corticosteroids (ICS). Studies have provided firm evidence that these patients can be well controlled when receiving ICS, especially when disease is of recent onset. This treatment should be given on a daily basis at a low dose and when providing a good response should be maintained to prevent severe exacerbations and disease deterioration. Intermittent ICS treatment at the time of an exacerbation has also been suggested as a strategy for mild persistent asthma, but it is less effective than low-dose regular treatment for most outcomes. Adding a long-acting beta-agonist (LABA) to ICS appears to be unnecessary in most of these patients for optimising control of their asthma. Patients with moderate persistent asthma can be regarded as those who are not ideally controlled on low-dose ICS alone. The combination of an ICS and LABA is preferred in these patients, irrespective of the brand of medicine, and this combination is better than doubling or even quadrupling the dose of ICS to achieve better asthma control and reduce exacerbation risks. An ICS/LABA combination in a single inhaler represents a safe, effective and convenient treatment option for the management of patients with asthma unstable on inhaled steroids alone. Ideally, once asthma is under full control, the dose of inhaled steroids should be reduced, which is possible in many patients. The duration of treatment before initiating this dose reduction has, however, not been fully established. One of the combinations available to treat asthma (budesonide and formoterol) has also been assessed as both maintenance and rescue therapy with a further reduction in the risk for a severe exacerbation. Clinical effectiveness in the real world now has to be established, since this approach likely improves compliance with regular maintenance therapy