Indole based antioxidants for the treatment of ischemia reperfusion injury

With the number of ischemia reperfusion (I/R) injuries on the rise, and a lack of pharmacological intervention aimed at reducing free radical damage associated with I/R, we have developed 30 indole phenolic antioxidants that were synthesized by click chemistry to couple our indole with a phenolic or anisole derivative. The total antioxidant activity of the analogues was tested in vitro using the ferric thiocyanate lipid emulsion method. Compounds containing hydroxyl or methoxy aromatics at the 3 or 4 position on the aromatic coupled to the indole exhibited increased antioxidant scavenging. 4-methoxyindole derivatives (8a-e) exhibited increased scavenging (p < 0.05) compared to the known antioxidant butylated hydroxyanisole (BHA).

A randomised controlled trial of spinal manipulative therapy in acute low back pain

OBJECTIVE: To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. METHODS: 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. RESULTS: Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. CONCLUSIONS: SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.

Prospective population-based study of RSV-related intermediate care and intensive care unit admissions in Switzerland over a 4-year period (2001-2005)

OBJECTIVES: Respiratory syncytial virus (RSV) infections are a leading cause of hospital admissions in small children. A substantial proportion of these patients require medical and nursing care, which can only be provided in intermediate (IMC) or intensive care units (ICU). This article reports on all children aged < 3 years who required admission to IMC and/or ICU between October 1, 2001 and September 30, 2005 in Switzerland. PATIENTS AND METHODS: We prospectively collected data on all children aged < 3 years who were admitted to an IMC or ICU for an RSV-related illness. Using a detailed questionnaire, we collected information on risk factors, therapy requirements, length of stay in the IMC/ICU and hospital, and outcome. RESULTS: Of the 577 cases reported during the study period, 90 were excluded because the patients did not fulfill the inclusion criteria; data were incomplete in another 25 cases (5%). Therefore, a total of 462 verified cases were eligible for analysis. At the time of hospital admission, only 31 patients (11%) were older than 12 months. Since RSV infection was not the main reason for IMC/ICU admission in 52% of these patients, we chose to exclude this subgroup from further analyses. Among the 431 infants aged < 12 months, the majority (77%) were former near term or full term (NT/FT) infants with a gestational age > or = 35 weeks without additional risk factors who were hospitalized at a median age of 1.5 months. Gestational age (GA) < 32 weeks, moderate to severe bronchopulmonary dysplasia (BPD), and congenital heart disease (CHD) were all associated with a significant risk increase for IMC/ICU admission (relative risk 14, 56, and 10, for GA < or = 32 weeks, BPD, and CHD, respectively). Compared with NT/FT infants, high-risk infants were hospitalized at an older age (except for infants with CHD), required more invasive and longer respiratory support, and had longer stays in the IMC/ICU and hospital. CONCLUSIONS: In Switzerland, RSV infections lead to the IMC/ICU admission of approximately 1%-2% of each annual birth cohort. Although prematurity, BPD, and CHD are significant risk factors, non-pharmacological preventive strategies should not be restricted to these high-risk patients but also target young NT/FT infants since they constitute 77% of infants requiring IMC/ICU admission.

Integrating fragmented evidence by network meta-analysis: relative effectiveness of psychological interventions for adults with post-traumatic stress disorder

BACKGROUND To summarize the available evidence on the effectiveness of psychological interventions for patients with post-traumatic stress disorder (PTSD). METHOD We searched bibliographic databases and reference lists of relevant systematic reviews and meta-analyses for randomized controlled trials that compared specific psychological interventions for adults with PTSD symptoms either head-to-head or against control interventions using non-specific intervention components, or against wait-list control. Two investigators independently extracted the data and assessed trial characteristics. RESULTS The analyses included 4190 patients in 66 trials. An initial network meta-analysis showed large effect sizes (ESs) for all specific psychological interventions (ESs between -1.10 and -1.37) and moderate effects of psychological interventions that were used to control for non-specific intervention effects (ESs -0.58 and -0.62). ES differences between various types of specific psychological interventions were absent to small (ES differences between 0.00 and 0.27). Considerable between-trial heterogeneity occurred (τ 2 = 0.30). Stratified analyses revealed that trials that adhered to DSM-III/IV criteria for PTSD were associated with larger ESs. However, considerable heterogeneity remained. Heterogeneity was reduced in trials with adequate concealment of allocation and in large-sized trials. We found evidence for small-study bias. CONCLUSIONS Our findings show that patients with a formal diagnosis of PTSD and those with subclinical PTSD symptoms benefit from different psychological interventions. We did not identify any intervention that was consistently superior to other specific psychological interventions. However, the robustness of evidence varies considerably between different psychological interventions for PTSD, with most robust evidence for cognitive behavioral and exposure therapies.

Therapeutic modalities influencing neuropathic pain in hand surgery patients

The treatment of neuropathic pain challenges not only doctors but also hand therapists, since a majority of patients don't experience a significant pain relief despite systemic pain treatment. Early diagnosis of neuropathic pain and a therapeutic concept is crucial to meet the individual needs of the patient. The complexity of a pain syndrome calls for a multidisciplinary approach using patient education, pharmacological and non-pharmacological therapies, such as graded motor imagery or somatosensory rehabilitation, behavioral therapy and physical measures. The evidence of the above mentioned therapies with regards to neuropathic pain is not yet completely established. Possible reasons are the lack of complete understanding of the pain causing mechanisms and the fact of treating the symptoms rather than the cause.

Motive-oriented therapeutic relationship building for patients diagnosed with schizophrenia

Treatment options for patients with schizophrenia demand further improvement. One way to achieve this improvement is the translation of findings from basic research into new specific interventions. Beyond that, addressing the therapy relationship has the potential to enhance both pharmacological and non-pharmacological treatments. This paper introduces motive-oriented therapeutic relationship (MOTR) building for schizophrenia. MOTR enables therapists to proactively adapt to their patient’s needs and to prevent problematic behaviors. For example, a patient might consider medication as helpful in principle, but the rejection of medication might be one of his few remaining means for his acceptable motive to stay autonomous despite hospitalization. A therapist who is motiveoriented proactively offers many degrees of freedom to this patient in order to satisfy his need for autonomy and to weaken the motivational basis for not taking medication. MOTR makes use of findings from basic and psychotherapy research and is generic in this respect, but at the same time guides therapeutic action precisely and flexibly in a patient oriented way.

The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood–brain barrier disruption: Implications for multiple sclerosis treatment

Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood–brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor α and IFN-γ mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents.

A three-hybrid system for detecting small ligand–protein receptor interactions

Small ligand–receptor interactions underlie many fundamental processes in biology and form the basis for pharmacological intervention of human diseases in medicine. We report herein a genetic system, named the yeast three-hybrid system, for detecting ligand–receptor interactions in vivo. This system is adapted from the yeast two-hybrid system with which a third synthetic hybrid ligand is combined. The feasibility of this system was demonstrated using as the hybrid ligand a heterodimer of covalently linked dexamethasone and FK506. Yeast expressing fusion proteins of the hormone binding domain of the rat glucocorticoid receptor fused to the LexA DNA-binding domain and of FKBP12 fused to a transcriptional activation domain activated reporter genes when plated on medium containing the dexamethasone–FK506 heterodimer. The reporter gene activation is completely abrogated in a competitive manner by the presence of excess FK506. Using this system, we screened a Jurkat cDNA library fused to the transcriptional activation domain in yeast expressing the hormone binding domain of rat glucocorticoid receptor–LexA DNA binding domain fusion protein in the presence of dexamethasone–FK506 heterodimer. We isolated overlapping clones of human FKBP12. These results demonstrate that the three-hybrid system can be used to discover receptors for small ligands and to screen for new ligands to known receptors.

Effects of salicylates and aminoglycosides on spontaneous otoacoustic emissions in the Tokay gecko

The high sensitivity and sharp frequency discrimination of hearing depend on mechanical amplification in the cochlea. To explore the basis of this active process, we examined the pharmacological sensitivity of spontaneous otoacoustic emissions (SOAEs) in a lizard, the Tokay gecko. In a quiet environment, each ear produced a complex but stable pattern of emissions. These SOAEs were reversibly modulated by drugs that affect mammalian otoacoustic emissions, the salicylates and the aminoglycoside antibiotics. The effect of a single i.p. injection of sodium salicylate depended on the initial power of the emissions: ears with strong control SOAEs displayed suppression at all frequencies, whereas those with weak control emissions showed enhancement. Repeated oral administration of acetylsalicylic acid reduced all emissions. Single i.p. doses of gentamicin or kanamycin suppressed SOAEs below 2.6 kHz, while modulating those above 2.6 kHz in either of two ways. For ears whose emission power at 2.6–5.2 kHz encompassed more than half of the total, individual emissions displayed facilitation as great as 35-fold. For the remaining ears, emissions dropped to as little as one-sixth of their initial values. The similarity of the responses of reptilian and mammalian cochleas to pharmacological intervention provides further evidence for a common mechanism of cochlear amplification.

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of the incurable early-onset recessive human retinal degenerations known as Leber congenital amaurosis. Rpe65-deficient mice, a model of Leber congenital amaurosis, have no rod photopigment and severely impaired rod physiology. We analyzed retinoid flow in this model and then intervened by using oral 9-cis-retinal, attempting to bypass the biochemical block caused by the genetic abnormality. Within 48 h, there was formation of rod photopigment and dramatic improvement in rod physiology, thus demonstrating that mechanism-based pharmacological intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.

Terapêutica na insuficiência cardíaca aguda

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Novas terapêuticas não farmacológicas da perturbação do pós-stress traumático

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Clinical practice guidelines for management of parkinson’s disease : a systematic critical appraisal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Medidas não farmacológicas no alívio da dor no trabalho de parto

Enquadramento: A dor do parto resulta de complexas interações, de caráter inibitório e excitatório e, apesar de os seus mecanismos serem análogos aos da dor aguda, há fatores próprios do trabalho de parto de natureza neurofisiológica, obstétrica, psicológica e sociológica que intervêm no seu limiar. Neste sentido, os métodos não farmacológicas podem auxiliar a parturiente no alívio da dor, reduzir os níveis de stresse e ansiedade e, consequentemente promover uma maior satisfação. Objetivos: Demonstrar evidência científica de se os métodos não farmacológicos usados no alívio da dor no trabalho de parto são mais eficazes quando comparados com a não utilização de nenhum método, placebo ou qualquer outro método; verificar o uso de medidas não farmacológicas no alívio da dor do parto; averiguar quais as variáveis sociodemográficas, variáveis contextuais da gravidez e contextuais do parto que interferem no recurso a medidas não farmacológicas no alívio da dor do parto. Métodos: No estudo empírico I seguiu-se a metodologia de revisão sistemática da literatura. Foi realizada uma pesquisa na EBSCO, PubMed, Scielo e RCAAP, de estudos publicados entre 1 janeiro de 2010 e 2 de janeiro de 2015. Os estudos encontrados foram avaliados de acordo com os critérios de inclusão previamente estabelecidos e, posteriormente, foi feita uma apreciação da qualidade dos estudos, por dois revisores, utilizando a “Grelha para avaliação crítica de um artigo descrevendo um ensaio clínico prospetivo, aleatorizado e controlado” (Bugalho & Carneiro, 2004). No final, foram incluídos no corpus do estudo 4 artigos. O estudo empírico II enquadra-se num estudo quantitativo, transversal, descritivo e retrospetivo, desenvolvido no serviço de Obstetrícia do Centro Hospitalar Cova da Beira, segundo um processo de amostragem não probabilística por conveniência (n = 382). A recolha de dados efetuou-se através da consulta de processos clínicos de mulheres com idade ≥ 18 anos, que tiveram um parto vaginal com feto vivo após as 37 semanas de gestação. Resultados: Os métodos não farmacológicos usados no alívio da dor no trabalho de parto são mais eficazes quando comparados com a não utilização de nenhum método, placebo ou qualquer outro método. Numa amostra constituída por 382 mulheres, com uma idade média de 30,95 anos (±5,451 anos), em 34,6% dos casos foram aplicadas as medidas não farmacológicas no alívio da dor no trabalho de parto, sobressaindo a respiração e o relaxamento (86,3%). Em alguns casos, ainda que em menor número, foi aplicada a hidroterapia isolada (6,9%) ou associada à respiração e ao relaxamento (5,3%), bem como a hipnose (0,8%) e a associação entre respiração e massagem (0,8%). Conclusão: De acordo com os resultados obtidos e com base na evidência científica disponível, importa referir que é essencial que os cuidados não farmacológicos de alívio da dor no parto sejam explorados, por serem mais seguros e acarretarem menos intervenções. Desta feita, os profissionais de saúde que prestam assistência às mulheres durante o trabalho de parto e parto têm de ter acesso ao conhecimento acerca desses métodos e os seus potenciais benefícios, a fim de os poderem aplicar com maior segurança, o que resultará indiscutivelmente numa maior humanização do parto, caminhando-se no sentido de uma maternidade mais segura. Palavras-chave: Trabalho de parto; dor de parto; terapias complementares; terapias alternativas

Artrite reumatóide : implicações na funcionalidade das pessoas

Enquadramento: A Artrite Reumatóide (AR) é uma patologia com profundas implicações na funcionalidade das pessoas, com efeitos significativos não só ao nível do funcionamento físico, mas também a nível emocional, familiar, social e económico. Objetivos: Avaliar a funcionalidade das pessoas com artrite reumatóide e analisar a sua relação com as variáveis sócio demográficas, clínicas, dor e qualidade do sono. Métodos: Trata-se de um estudo não experimental, transversal, descritivo-correlacional e de caráter quantitativo, que foi realizado numa amostra não probabilística por conveniência, constituída por 75 pessoas com o diagnóstico de artrite reumatóide, acompanhadas na Unidade de Dor, na Consulta de Reumatologia e na Medicina Física de Reabilitação do CHTV, EPE. Para a mensuração das variáveis utilizou-se um instrumento de colheita de dados que integra uma secção de caracterização sócio demográfica e clínica, o Índice da Qualidade de Sono de Pittsburgh – PSQI e o Health Assessment Questionnaire – HAQ. Resultados: Constatou-se que 60,0% dos inquiridos apresenta dificuldades/incapacidades leves no desempenho das atividades da vida diária, 32,0% apresenta já dificuldades moderadas e 8,0% incapacidade grave, sendo que o valor médio da funcionalidade global avaliado por meio do HAQ foi de 1,48, o que revela a existência de uma incapacidade moderada na nossa amostra. Das variáveis sócio demográficas, a idade (p=0,003), a situação laboral (p=0,000), a escolaridade (p=0,006) e os rendimentos mensais (p=0,001) têm influência no estado funcional das pessoas com AR. Das variáveis clínicas, a intensidade da dor (p=0,007) e o tempo de diagnóstico da doença (p=0,013) mostraram relacionarem-se com a funcionalidade. Em relação à qualidade do sono, apenas existem diferenças estatísticamente significativas nas subescalas “levantar-se” (p=0,030) e “caminhar” (p=0,034), sendo que a má qualidade de sono configurou-se em 94,7% dos inquiridos. Conclusão: As evidências encontradas neste estudo referem que a idade, a situação laboral, a escolaridade, os rendimentos mensais, o tempo de diagnóstico, a intensidade da dor e a qualidade do sono, associam-se a uma pior funcionalidade nas pessoas com AR. O diagnóstico precoce, a adoção de medidas para a promoção da boa qualidade do sono, a aplicação de medidas farmacológicas e não farmacológicas para o alívio da dor, e ações de formação direcionadas aos doentes com AR, devem ser estratégias a desenvolver junto desta população, numa tentativa de minimizar o impacto negativo que esta doença acarreta. Palavras-chave: artrite reumatóide, estado funcional, qualidade do sono.