Occurrence of n-Alkanes in vegetable oils and their analytical determination

Vegetable oils contain endogenous linear hydrocarbons, namely n-alkanes, ranging from n-C21 to n-C35 with odd chain lengths prevalent. Different vegetable oils, as well as oils of the same type, but of different variety and provenience, show typical n-alkane patterns, which could be used as a fingerprint to characterize them. In the first part of this review, data on the occurrence of n-alkanes in different vegetable oils (total and predominant n-alkanes) are given, with a focus on obtaining information regarding variety and geographical origin. The second part aims to provide the state of the art on available analytical methods for their determination. In particular, a detailed description of the sample preparation protocols and analytical determination is reported, pointing out the main drawbacks of traditional sample preparation and possible solutions to implement the analysis with the aim to shift toward rapid and solvent-sparing methods

Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - Evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: Study protocol for a randomized controlled trial

Background: Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. Methods/design: The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. Discussion: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. Trial registration: EudractCT, 2014-004897-40. Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012. Registered on 7 September 2017

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Evaluation of the impact of olive milling on the mineral oil contamination of extra-virgin olive oils

Mineral oil saturated (MOSH) and aromatic hydrocarbons (MOAH) are environmental and processing contaminants also found in extra-virgin olive oil. Knowledge on contamination sources can help minimize them. The main objective of this work was to investigate the impact of milling operations. To this purpose, samples from 25 processing lines (at 5 different processing stages) were analyzed by online high-performance liquid chromatography—gas chromatography—flame ionization detection. A protocol for eliminating endogenous n-alkanes was tested and applied when necessary. Generally, transport to the mill had a negligible impact. The washing step had a mitigation impact, more evident on samples with higher contamination. On average, total MOSH decreased of 2.1 mg kg–1. Despite the reduction determined by washing, the entire milling process resulted in an increase in contamination (> 30%) for 20% of the processing lines. Total average MOSH and MOAH contamination increased by 2.3 and 0.6 mg kg–1, respectively. Practical Applications: This work aims to improve the knowledge on the presence and sources of mineral oil hydrocarbons (MOH), contaminants of petrogenic origin, in extra-virgin olive oil. In particular, this work investigates the impact of processing at the mill, including the transport stage, as well as the potential of the washing step in reducing the contamination. For the first time, a systematic study on this topic has been carried out. The knowledge of the contribution of individual steps in the production process to final product contamination is of paramount importance in identifying critical points on which to take action to mitigate contamination, and this is of great interest for all operators of the sector and for protecting consumer health, especially when considering possible presence of MOAH, which may include genotoxic and carcinogenic compounds

Mineral oil contamination in basil pesto from the Italian market: Ingredient contribution and market survey

Mineral oil hydrocarbons (MOH) are complex mixtures of saturated hydrocarbons (MOSH) which bioaccumulate in human tissues, and aromatic hydrocarbons (MOAH) which include genotoxic and carcinogenic substances. This work aimed to investigate these emerging food contaminants in basil pesto from the Italian market, and ingredient contribution to the final product contamination. Twelve market samples and 4 additional samples (and related ingredients) produced in a pilot plant, were analyzed by on-line high-performance liquid chromatography (HPLC)- gas chromatography (GC), preceded by matrix-tailored sample preparation. Method performance was good with recoveries from 94% to 109%, residual standard deviations (RSD) less than 10%, and a limit of quantitation (LOQ) of 0.5 mg/kg (for total MOAH). Vegetable oils, followed by cashews, which showed a similar contamination profile to foods transported in jute bags, were the major contributors to contamination, while cheese and basil contribution was negligible. Sunflower oil alone accounted for more than 80–85% of the total contamination. Samples from the Italian market had an average of 5.6 and 0.6 mg/kg of MOSH and MOAH, respectively, and a contamination profile that confirmed that the main contributors to total contamination were sunflower oil and cashews. Mitigation actions should be directed toward careful control of these two ingredients

375O - Final efficacy results from IMpower132: First-line atezolizumab + chemotherapy in patients with stage IV non-squamous NSCLC

Background The Phase III IMpower132 study, evaluating first line pemetrexed plus carboplatin/cisplatin with or without atezolizumab in Stage IV non-squamous NSCLC without EGFR or ALK driver mutations, has met its PFS endpoint with an HR of 0.60 (95% CI: 0.49, 0.72; P \u3c 0.0001; Papadimitrakopoulou, WCLC 2018). Here we present the final OS and safety results. Methods Patients were randomised 1:1 to 4 or 6 cycles of carboplatin AUC 6 mg/mL/min or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W alone (arm PP) or with atezolizumab 1200 mg Q3W (arm APP), followed by pemetrexed (PP) or atezolizumab + pemetrexed (APP) maintenance. Investigator-assessed PFS and OS were co-primary endpoints. Efficacy by PD-L1 status was an exploratory endpoint. Results At data cutoff (18 July 2019), 292 patients in arm APP and 286 patients in arm PP had a median follow-up of 28.4 mo. Updated median PFS was 7.7 months (APP) vs 5.2 months (PP); HR, 0.56 (95% CI: 0.47, 0.67). Final OS data are in the table. 38.7% (APP) vs 57.3% (PP) of patients received subsequent anti-cancer therapy, including immunotherapy in 5.5% vs 45.8%. Grade ≥ 3 treatment-related adverse events (AEs) occurred in 58.4% (APP) vs 43.1% (PP) of patients, including immune-mediated AEs in 6.9% (APP) vs 4.7% (PP) of patients. Table: 375O APP PP ITT n = 292 n = 286 mOS (95% CI), mo 17.5 (13.2, 19.6) 13.6 (11.0, 15.7) HRa (95% CI; P value) 0.86 (0.71, 1.06; P = 0.155) 12-Month OS 59.7% 55.0% 24-Month OS 39.1% 34.0% PD-L1–highb n = 25 n = 20 mOS (95% CI), mo NE (22.4, NE) 26.9 (4.7, NE) HR (95% CI) 0.73 (0.31, 1.73) PD-L1–lowb n = 63 n = 73 mOS (95% CI), mo 12.7 (8.7, 18.2) 16.2 (9.6, 22.6) HR (95% CI) 1.18 (0.80, 1.76) PD-L1–negativeb n = 88 n = 75 mOS (95% CI), mo 15.9 (11.6, 22.6) 10.5 (8.1, 13.5) HR (95% CI) 0.67 (0.46, 0.96) NE, not estimable. a Stratified. b PD-L1 status available in 60% of pts. PD-L1–high: ≥ 50% TC or ≥ 10% IC; PD-L1–low: ≥ 1% and \u3c 50% TC or ≥ 1% and \u3c 10% IC; PD-L1–negative: \u3c 1% TC and \u3c 1% IC. . Conclusions IMpower132 had met its co-primary PFS endpoint at the primary analysis but did not meet its co-primary OS endpoint in this final analysis. Atezolizumab + carboplatin/cisplatin + pemetrexed was well tolerated, and no new safety signals were identified. Clinical trial identification NCT02657434