Direct catalytic conversion of cellulose to liquid straight-chain alkanes

High yields of liquid straight-chain alkanes were obtained directly from cellulosic feedstock in a one-pot biphasic catalytic system. The catalytic reaction proceeds at elevated temperatures under hydrogen pressure in the presence of tungstosilicic acid, dissolved in the aqueous phase, and modified Ru/C, suspended in the organic phase. Tungstosilicic acid is primarily responsible for cellulose hydrolysis and dehydration steps, while the modified Ru/C selectively hydrogenates intermediates en route to the liquid alkanes. Under optimal conditions, microcrystalline cellulose is converted to 82% n-decane-soluble products, mainly n-hexane, within a few hours, with a minimum formation of gaseous and char products. The dominant route to the liquid alkanes proceeds via 5-hydroxymethylfurfural (HMF), whereas the more common pathway via sorbitol appears to be less efficient. High liquid alkane yields were possible through (i) selective conversion of cellulose to glucose and further to HMF by gradually heating the reactor, (ii) a proper hydrothermal modification of commercial Ru/C to tune its chemoselectivity to furan hydrogenation rather than glucose hydrogenation, and (iii) the use of a biphasic reaction system with optimal partitioning of the intermediates and catalytic reactions. The catalytic system is capable of converting subsequent batches of fresh cellulose, enabling accumulation of the liquid alkanes in the organic phase during subsequent runs. Its robustness is illustrated in the conversion of the raw (soft)wood sawdust

Direct catalytic conversion of cellulose to liquid straight-chain alkanes

High yields of liquid straight-chain alkanes were obtained directly from cellulosic feedstock in a one-pot biphasic catalytic system. The catalytic reaction proceeds at elevated temperatures under hydrogen pressure in the presence of tungstosilicic acid, dissolved in the aqueous phase, and modified Ru/C, suspended in the organic phase. Tungstosilicic acid is primarily responsible for cellulose hydrolysis and dehydration steps, while the modified Ru/C selectively hydrogenates intermediates en route to the liquid alkanes. Under optimal conditions, microcrystalline cellulose is converted to 82% n-decane-soluble products, mainly n-hexane, within a few hours, with a minimum formation of gaseous and char products. The dominant route to the liquid alkanes proceeds via 5-hydroxymethylfurfural (HMF), whereas the more common pathway via sorbitol appears to be less efficient. High liquid alkane yields were possible through (i) selective conversion of cellulose to glucose and further to HMF by gradually heating the reactor, (ii) a proper hydrothermal modification of commercial Ru/C to tune its chemoselectivity to furan hydrogenation rather than glucose hydrogenation, and (iii) the use of a biphasic reaction system with optimal partitioning of the intermediates and catalytic reactions. The catalytic system is capable of converting subsequent batches of fresh cellulose, enabling accumulation of the liquid alkanes in the organic phase during subsequent runs. Its robustness is illustrated in the conversion of the raw (soft)wood sawdust

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities

Various gastrointestinal (GI) factors affect drug and formulation behavior after oral administration, including GI transfer, motility, pH and GI fluid volume and composition. An in-depth understanding of these physiological and anatomical variables is critical for a continued progress in oral drug development. In this review, different methodologies (invasive versus non-invasive) to explore the impact of physiological variables on formulation behavior in the human GI tract are presented, revealing their strengths and limitations. The techniques mentioned allow for an improved understanding of the role of following GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and intraluminal pH (intraluminal sampling and telemetry)

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Gastrointestinal behavior of itraconazole in humans - Part 1: Supersaturation from a solid dispersion and a cyclodextrin-based solution

This study evaluated the fasted state gastrointestinal behavior of the lipophilic drug itraconazole, orally administered to healthy volunteers as either a solid dispersion (Sporanox® capsules) or a cyclodextrin-based solution (Sporanox® solution). Following intake of the drug products, gastric and duodenal fluids were aspirated and analyzed for itraconazole concentration, total content and solubilizing capacity. Release of itraconazole from the solid dispersion generated high and metastable supersaturated levels in the stomach, but the dissolved fraction in the duodenum remained extremely low (median 2.5%). After intake of the itraconazole solution, precipitation was limited in the stomach but pronounced in the small intestine. Still, the dissolved fraction of itraconazole in the duodenum (median 38%) appeared much higher than after intake of the solid dispersion, possibly explaining the improved absorption of itraconazole from the solution. As for the solid dispersion, the absorption-enabling ability of the solution appeared mainly related to increased intraluminal concentrations by means of supersaturation. Cyclodextrin-based solubilization of itraconazole occurred only in the case of limited intraluminal dilution, but did not further enhance itraconazole absorption. The obtained data will help to understand critical aspects of supersaturating drug delivery systems and act as direct reference for the optimization of in vitro simulation tools for gastrointestinal drug behavior.publisher: Elsevier articletitle: Gastrointestinal behavior of itraconazole in humans – Part 1: Supersaturation from a solid dispersion and a cyclodextrin-based solution journaltitle: International Journal of Pharmaceutics articlelink: http://dx.doi.org/10.1016/j.ijpharm.2017.04.029 associatedlink: http://dx.doi.org/10.1016/j.ijpharm.2017.04.057 content_type: article copyright: © 2017 Elsevier B.V. All rights reserved.status: publishe

The effect of food on the intraluminal behavior of abiraterone acetate in man

To relate the reported positive effect of food on the oral bioavailability of abiraterone to the intraluminal behavior of abiraterone acetate, an in vivo experiment was performed, in which duodenal fluids and plasma samples were collected from healthy volunteers after the administration of abiraterone acetate in fasted and postprandial conditions. The plasma concentration-time profiles confirmed the positive food effect. Nevertheless, intraduodenal concentrations of abiraterone acetate and abiraterone did not fully reflect this observation. This apparent discrepancy was explored by performing several in vitro experiments including solubility, dissolution, and transfer studies. Gastrointestinal transfer studies illustrated a positive impact of gastric processing of the abiraterone acetate formulation on the duodenal concentrations in the fasted state, which could not be observed in the postprandial condition. As the influence of gastric dissolution on the intraluminal concentrations in the small intestine declines aborally, it is most likely the superior solubility of abiraterone acetate and abiraterone in intestinal fluids of the fed state that dictates the food effect. Furthermore, N-oxide abiraterone sulfate and abiraterone sulfate appeared in the duodenum at significantly later time points than abiraterone, suggesting biliary excretion of these abiraterone metabolites; this was confirmed by in situ biliary excretion experiments in rats.publisher: Elsevier articletitle: The Effect of Food on the Intraluminal Behavior of Abiraterone Acetate in Man journaltitle: Journal of Pharmaceutical Sciences articlelink: http://dx.doi.org/10.1016/j.xphs.2016.03.008 content_type: article copyright: © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.status: publishe