Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Association between Dietary Phenolic Acids and Hypertension in a Mediterranean Cohort

Background: Certain foods rich in phenolic acids have been shown to reduce the risk of hypertension, but evidence from epidemiological studies focused on dietary phenolic acid intake is scarce. The aim of this study was to determine the association between dietary phenolic acid intake, as well as their major food sources, and hypertension in a Mediterranean cohort. Methods: Demographic and dietary data of 2044 adults living in Southern Italy were collected. Food frequency questionnaires and Phenol-Explorer were used to calculate dietary intake of polyphenols. Multivariate logistic regression analyses were used to test associations. Results: The mean intake of total phenolic acids in the cohort was 362.6 mg/day. Individuals in the highest quartile of phenolic acid intake (median intake = 522.2 mg/day) were less likely to have hypertension (OR (odds ratio) = 0.68, 95% CI (confidence interval): 0.46, 1.00). When taking into account individual subclasses of phenolic acids, only hydroxyphenylacetic acid was inversely associated with hypertension (highest vs. lowest quartile, OR = 0.63, 95% CI: 0.40, 0.96). Among dietary sources of phenolic acids considered in the analysis, only beer was significantly inversely associated with hypertension (highest vs. lowest quartile, OR = 0.32, 95% CI: 0.15, 0.68). Conclusions: The findings of this study suggest that dietary phenolic acids may be inversely associated with hypertension, irrespectively of their dietary source

High adherence to Mediterranean diet, but not individual foods or nutrients, is associated with lower likelihood of being obese in a Mediterranean cohort

Purpose: The aim of the present study was to evaluate the association between the Mediterranean diet and obesity in a Mediterranean cohort. Methods: The study population of MEAL (Mediterranean Healthy Eating, Ageing, and Lifestyle) study comprised 1814 men and women (18 + years) recruited in the city of Catania, southern Italy. Food intake was evaluated through a validated food frequency questionnaire and the Mediterranean diet adherence was assessed through the MEDI-LITE score. Results: Individuals highly adherent to the Mediterranean diet (highest quartile of the score) were less likely to be obese (OR 0.53, 95% CI 0.32, 0.89) despite there was no significant associations when considering men and women separately. The dietary profile of obese and non-obese individuals did not significantly differ, except for vitamin E, processed meat, and alcohol more consumed among non-obese ones. Among the food groups characterizing this dietary pattern, only satisfaction of the criterion for dairy products (< 1 serving/day) was significantly associated with lower odds of being obese. Among other covariates, current smoking was associated with obesity, while high physical activity and regular alcohol drinking were inversely associated. Some differences between men and women in the highest category of occupational status occurred, as the former were less likely, while the latter were more likely to be obese. Conclusions: Higher adherence to the Mediterranean diet as a whole dietary pattern, rather than its individual components, is associated with less likelihood of being obese. Level of evidence: Level V, cross-sectional descriptive study

Macronutrient and Major Food Group Intake in a Cohort of Southern Italian Adults

Background: Dietary intake of macronutrient and foods is considered crucial to decrease the risk of diet-related non-communicable diseases. Methods: The aim of this study was to describe the intake of major food groups and macronutrients in a random sample of 1838 southern Italian adults. Results: No significant differences of macronutrient consumption between sexes were found. By contrast, younger individuals had significantly higher intake of animal protein than older ones. Men reported consuming significantly more total processed meats and less eggs than women; egg consumption significantly increased by age groups. Significantly lower intake of fruit in the younger age group compared to older ones was found. Various patterns of correlation between food groups were described. More than half of individuals reached the suggested recommendations for carbohydrate and fiber intake, and about two-thirds met the recommendations for total protein and cholesterol intake, while only a minority met for total fat intake. Total and plant protein, monounsaturated and omega-6 fatty acids, were significantly inversely related with BMI (body mass index), while trans fatty acids and cholesterol were directly correlated. A direct association with unprocessed meats and an inverse association with processed meats was also found. Conclusions: The overall findings suggest that relatively healthy dietary habits are common in southern Italy

TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication

Abstract Background Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) – the most aggressive BC form – is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients’ response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. Methods Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. Results This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. Conclusions Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles’ heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy

Relevance of comorbidities on initial combination therapy in pulmonary arterial hypertension

Rationale Demographic characteristics of pulmonary arterial hypertension (PAH) patients have changed over time, but the effects of cardiovascular risk factors on risk status and pulmonary vascular resistance (PVR) reduction with initial oral combination therapy are not known. Therefore, we tested the relevance of cardiovascular comorbidities in this setting. Methods The study enrolled 181 treatment-naive PAH patients with a 6-month (IQR 144–363 days) right heart catheterisation and risk assessment after initial oral combination therapy. Results Group A included 96 (53.0%) patients without cardiac comorbidities; Group B included 54 (29.8%) patients with one cardiac comorbidity; Group C included 31 (17.1%) patients with two cardiac comorbidities or more. Group C patients were older with a balanced sex distribution. There was a significant difference in PVR reduction moving from the absence to one or at least two cardiac comorbidities, respectively: median −45.0%, −30.3%, −24.3%. A European Respiratory Society/European Society of Cardiology low-risk status was present at first follow-up in 50 (52.0%) patients in Group A, 19 (35.1%) in Group B and 9 (29.0%) in Group C; a REVEAL 2.0 low-risk status was present at first follow-up in 41 (42.0%) patients in Group A, 15 (27.7%) in Group B and 7 (22.6%) in Group C. Group A patients were 2.3 times more likely to achieve/maintain a low-risk status compared with Group B and C (OR 2.27, 95% CI 1.15–4.54, p=0.02). No significant difference was observed between patients with non-cardiac comorbidities and those without comorbidities. Conclusion Initial oral combination therapy seems associated with a less effective response for patients with cardiovascular comorbidities compared with the others, related to the magnitude of treatment-induced decrease in PVR

Additional file 1 of TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication

Supplementary Material 1