Resultados de investigación

The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of ≤2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35-2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy., Si

Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II., Si

Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't;, The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors., Si

Background and aims: Parenteral nutrition (PN) composition could play a role in the management of systemic inflammatory response and intestinal barrier disruption. We aimed to evaluate changes in biomarkers of inflammation, oxidative status and intestinal permeability in patients with type 2 diabetes mellitus (T2DM) who received different PN lipid formulas. Methods: This was a prospective study, including 94 patients with T2DM who received omega (n)-3 polyunsaturated fatty acids (PUFA)-enriched PN, a mixture of medium and long chain triglycerides (MCT/LCT) PN, or an olive oil-based PN. Serum levels of biomarkers of oxidative status, intestinal permeability and inflammation biomarkers were determined at day 1 and day 5 after PN initiation. Registered under ClinicalTrials.gov Identifier no. NCT02706119. Results: At day 5 after the onset of PN, the MCT/LCT group had a significant reduction of 2 proinflammatory cytokines [interleukin (IL)-15, IL-17A], elevation of the anti-inflammatory cytokine IL-13 and increase of zonulin and indoxylsulfate. The olive oil group showed a statistically significant reduction of 5 proinflammatory cytokines [IL-1β, IL-17A, IL-6, cytokine-leukemia inhibitory factor (LIF) and tumor necrosis factor alpha (TNF-α)] and reduced concentrations of the anti-inflammatory cytokine IL-1RA, while the n-3 PUFA-enriched group presented a statistically significant reduction of 8 proinflammatory cytokines (interferon-gamma, IL-1β, IL-15, IL-17A, IL-6, LIF, monocyte chemoattractant protein 1, and TNF-α). In the between-group comparisons, indoxylsulfate significantly increased in the MCT/LCT group compared to the n-3 PUFA-enriched group, while 8-isoprostane and indoxylsulfate significantly increased in the MCT/LCT group compared to the other groups and superoxide dismutase significantly decreased in the MCT/LCT group compared to the other groups. Conclusion: In patients with T2DM, PN lipid composition exerts a profound impact on proinflammatory, prooxidative and intestinal permeability biomarkers., Yes

Comparar los niveles de glucemia e incidencia de hiperglucemia en el postoperatorio de cirugía general usando sueros con diferente concentración de glucosa. Ensayo clínico aleatorizado, abierto, no ciego, en pacientes no diabéticos, que ingresan en Cuidados Intensivos Pediátricos tras cirugía electiva, de 6 meses a 14 años, peso superior a 6 kg, glucemia >60 mg/dl y firma de consentimiento informado, manteniéndose a dieta con sueroterapia de mantenimiento intravenosa mediante suero con glucosa al 3,3 o 5%. Se determinan niveles de glucemia preoperatoria, al ingreso, y a las 8, 24 y 48 h, comparando los valores medios y la incidencia de hiperglucemia (glucemia > 150 mg/dl) en ambos grupos. Un total de 60 pacientes recibieron suero glucosalino 1/3 (51 mEq/l de sodio y 33 g/l de glucosa) y 70 pacientes suero glucosalino 5/0,9% (154 mEq/l de sodio y 50 g/l de glucosa). La glucemia media fue mayor en el grupo al 5%, sin diferencia estadística. No hubo diferencia en la incidencia de hiperglucemia; 8 h: 26% del grupo 3,3% vs. 21,3% del grupo 5% (p = 0,63); 24 h: 20% vs. 22,7% (p = 0,8); 48 h: 19% vs. 23,1% (p = 0,78). En el postoperatorio de cirugía general, el uso de soluciones glucosadas al 3,3% consigue niveles de glucemia similares a los detectados en pacientes que reciben suero con glucosa 5%, con una incidencia de hiperglucemia similar., To compare plasma glucose levels and incidence of hyperglycaemia in the post-operative period after general surgery using fluids with different glucose. A randomised, open-label, non-blind, clinical trial was conducted on patients admitted to Paediatric Intensive Care Unit after elective surgery. The inclusion criteria were from 6 months to 14 years of age, with a weight greater than 6kg, onset glucose level >60mg/dL, and a signed informed consent, with no oral intake and maintenance intravenous fluid therapy using fluids with 3.3% or 5% glucose. Plasma glucose levels were measured before surgery, on admission, and 8, 24, and 48h, with the mean glucose levels and incidence of hyperglycaemia (glucose level >150mg/dL) in both groups being compared. A total of 60 patients received glucose/saline 1/3 (51mEq/L sodium and 33g/L glucose), and 70 glucose/saline 5/0.9% (154mEq/L sodium and 50g/L glucose). Mean glucose levels were higher in the group receiving glucose 5%, with no statistical difference. There was no significant difference in the incidence of hyperglycaemia; 8h: 26% in the 3.3% group vs. 21.3% in the 5% group (P=.63); 24h: 20% vs. 22.7% (P=.8); and 48h: 19% vs. 23.1% (P=.78). The use of fluids with 3.3% glucose in the post-operative period of general surgery maintains mean glucose levels in a similar range to that of patients receiving fluids with 5% glucose, with no difference in the incidence of hyperglycaemia., Si

Different effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up. From February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. A total of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n = 55), risperidone (n = 63), haloperidol (n = 56), aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy. The overall dropout rate at 3 years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine = 69.09, risperidone = 71.43, aripiprazole = 73.08%, ziprasidone = 79.03%, haloperidol = 89.28%, and quetiapine = 95.53%) (χ2 = 79.86; P = .000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank = 92.240; P = .000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea. Olanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis., This study was conducted as part of a clinical trial “ Comparative Study of Aripiprazole, Quetiapine and Ziprasidone in Treatment of First Episode Psychosis: 3-year Follow-up.” ClinicalTrials.gov Identifier: NCT02526030.The authors thank the “Programa Asistencial de las Fases Iniciales de Psicosis” (PAFIP) research team, especially Víctor Ortiz-García de la Foz, Gema Pardo, and Obdulia Martínez and all patients and family members who participated in the study. The authors are entirely responsible for the scientific content of the paper. The study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant supports: Plan Nacional de Drogas Research (2005-Orden sco/3246/2004); SENY Fundació (CI 2005–0308007); and Fundación Marqués de Valdecilla (API07/011); Gerencia Regional de Salud de Castilla y León (INT/M/04/17).Unrestricted educational and research grants from AstraZeneca, Pfizer, Bristol-Myers Squibb, and Johnson & Johnson provided support for PAFIP activities. No pharmaceutical industry or institutional sponsors participated in the study design, data collection, analysis, and interpretation of the results., Si

Carboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP. ENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). During the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3-10.8 months). Median PFS was 9.8 months (95% CI: 6.6-10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment. This study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials. EU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016., Si