Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study

Aims To investigate if recent technical and procedural developments in percutaneous coronary intervention (PCI) significantly influence outcomes in appropriately selected patients with three-vessel (3VD) coronary artery disease. Methods and Results The SYNTAX II study is a multicenter, all-comers, open-label, single arm study that investigated the impact of a contemporary PCI strategy on clinical outcomes in patients with 3VD in 22 centres from four European countries. The SYNTAX-II strategy includes: heart team decision-making utilizing the SYNTAX Score II (a clinical tool combining anatomical and clinical factors), coronary physiology guided revascularisation, implantation of thin strut bioresorbable-polymer drug-eluting stents, intravascular ultrasound (IVUS) guided stent implantation, contemporary chronic total occlusion revascularisation techniques and guideline-directed medical therapy. The rate of major adverse cardiac and cerebrovascular events (MACCE [composite of all-cause death, cerebrovascular event, any myocardial infarction and any revascularisation]) at one year was compared to a predefined PCI cohort from the original SYNTAX-I trial selected on the basis of equipoise 4-year mortality between CABG and PCI. As an exploratory endpoint, comparisons were made with the historical CABG cohort of the original SYNTAX-I trial. Overall 708 patients were screened and discussed within the heart team; 454 patients were deemed appropriate to undergo PCI. At one year, the SYNTAX-II strategy was superior to the equipoise-derived SYNTAX-I PCI cohort (MACCE SYNTAX-II 10.6% vs. SYNTAX-I 17.4%; HR 0.58, 95% CI 0.39–0.85, P = 0.006). This difference was driven by a significant reduction in the incidence of MI (HR 0.27, 95% CI 0.11–0.70, P = 0.007) and revascularisation (HR 0.57, 95% CI 0.37–0.9, P = 0.015). Rates of all-cause death (HR 0.69, 95% CI 0.27–1.73, P = 0.43) and stroke (HR 0.69, 95% CI 0.10–4.89, P = 0.71) were similar. The rate of definite stent thrombosis was significantly lower in SYNTAX-II (HR 0.26, 95% CI 0.07–0.97, P = 0.045). Conclusion At one year, clinical outcomes with the SYNTAX-II strategy were associated with improved clinical results compared to the PCI performed in comparable patients from the original SYNTAX-I trial. Longer term follow-up is awaited and a randomized clinical trial with contemporary CABG is warranted.</p

Abordagem do modelo transteórico no comportamento alimentar Transtheoretical model approach in eating behavior

O estudo do comportamento alimentar tem despertado grande interesse por se tratar de um elemento importante para o sucesso de intervenções nutricionais. Considerando-se a complexidade do tema e as inúmeras influências a que está submetido, sugere-se que o aprofundamento de pesquisas sobre os determinantes do comportamento alimentar possibilite maior impacto nas ações de promoção de práticas alimentares saudáveis. A adoção cada vez mais freqüente de uma alimentação inadequada no Brasil e no mundo leva a um questionamento sobre o impacto das intervenções nutricionais tradicionalmente utilizadas em âmbito populacional. Diversas estratégias de educação nutricional são atualmente descritas na literatura; contudo, alcançar a motivação da população para uma mudança efetiva do padrão alimentar ainda é um dos grandes desafios para a saúde pública. A aplicação do modelo transteórico parece ter um papel promissor em relação à melhor compreensão da mudança de comportamento alimentar, almejada nas intervenções nutricionais. Estratégias que envolvam o direcionamento para cada estágio de mudança de comportamento, identificado segundo essa teoria, podem ser mais eficazes quanto à motivação dos indivíduos a adotar práticas alimentares mais saudáveis.<br>The study of eating behavior has been much interest, as this is an essential element for the success of dietary interventions. In view of the complexity of the subject and the countless influences to which it is subject, it is suggested that an in-depth exploration of eating behavior determinants enhances the impact of programs promoting healthy dietary practices. Increasingly more frequent, the adoption of inadequate diets in Brazil and elsewhere in the world leads to questions about the impact of dietary interventions traditionally applied to population groups. Many nutritional education strategies are currently described in the literature; however, motivating people to change their eating habits is still a major public health challenge. Applying the transtheoretical model seems to have a promising role for an enhanced understanding of changes in eating habits that are targeted by dietary interventions. Strategies that are tailored to each step in these changes, as identified by this theory, can motivate people more effectively to adopt healthier eating habits

Novel treatments for drug-induced toxic epidermal necrolysis (Lyell's syndrome).

Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25-30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-alpha (TNF-alpha) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-alpha antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed