Dehydrogenation of N-Propanol to Propionaldehyde over a copper chromite catalyst

Methyl methacrylate (MMA) is widely used for a range of polymer products. MMA can be produced from propionaldehyde via the BASF process. n-Propanol is readily available 'in South Africa as a byproduct of Fischer-Tropsch synthesis. This prompted an investigation into the production of propionaldehyde by the dehydrogenation of n-propanol. There is presently no established technology for the dehydrogenation of n-propanol to propionaldehyde and there has been very little work carried out on the effect of process variables on propionaldehyde yield. The emphasis of the current work was optimising propionaldehyde production. A commercial copper-chromite catalyst (G-13), for the dehydrogenation of ethanol to acetaldehyde, was used for the purposes of this study

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

© 2023 The Author(s). ALTEX. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four “maps” of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.Peer reviewe

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

New approach methodologies (NAMs) based on human biology enabletheassessment of adverse biological effects of pharmaceuticals and other chemicals. Currently,however, it is unclear how NAMsshould be usedduring drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists and NAMs developers) were conducted to identify feasible NAMsand to discuss how to exploit them in specific safety assessmentcontexts. Participants generated four‘maps’of how NAMs can be exploited in the safety assessment ofthe liver, respiratory, cardiovascular,and central nervous systems. Each map showsrelevant end points measured, tools used (e.g.,cells, assays, platforms), and highlights gaps where furtherdevelopment and validation of NAMs remainsnecessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the fourorgan systems, the maps providea template that could be used for additional organ safety testing contexts.Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions. 1IntroductionExtensive nonclinical safety studies are undertaken on new pharmaceuticals prior to and alongside clinical trials. Their purpose is to identify and understand the toxic effects of thecompoundin order to determine whether its anticipated benefit versusrisk profile justifies clinical evaluation and, if so, to inform the design and monitoring of clinical studies. The nonclinical safety studies are mandated by regulatory guidelines and include a variety of safety pharmacologyand toxicology investigations.Safety pharmacology studies aimto determinewhether pharmaceuticalscause on-or off-target effects on biological processes which can affect the function of critical organ systems (e.g.,cardiovascular, respiratory, gastrointestinal,and central nervous systems)and to assess potency, which is needed to assess safety margins versushuman clinical drug exposure. Safety pharmacology studiesalso help informthe selectionof follow-on investigations that can aid human risk assessmentand may provide insight into mechanismswhich underlie any effectsthat arise in humans.Multiple leading pharmaceutical companies (e.g.,AstraZeneca, GlaxoSmithKline, Novartis,and Pfizer) have outlined the advantages provided by in vitrosafety pharmacological profiling, including early identification of off-target interactionsandthe prediction ofclinical side effects that may be missed in animalstudies, and have highlighted that these studies enable much more cost-effective and rapid profiling of large numbers of compounds than animal procedures (Bowes et al., 2012).Toxicology studies evaluate systemic organ toxicities, behavioraleffects, reproductive and developmental toxicology, genetic toxicology,eye irritancy and dermal sensitization. They include single and repeat dose studies in rodent and non-rodentanimal species, which identify target organs, assessseverity andreversibility,and define dose-response and no observed adverse effect levels. These are critical parameters which are essential for regulatory decision-makingon whether the compound can be progressed into clinical trials and if so, estimation ofa suitable starting dose,maximum dose, dose escalation regime,andany non-standard clinical safety monitoringthat may be needed.Toxicity observedinnonclinical animal safety studies is an important cause of the high attrition rate of candidate drugs prior to clinicaltrials that occurs inmultiple pharmaceutical companies(Cook et al., 2014).However, many drugs cause clinically serious adverseeffects in humans which are not detectedin animals(Bailey et al., 2015). For example, human drug induced liver injury(DILI),which is not detected in animal safety studies,is animportant cause of attrition late in clinical development, failed licensing and/or of restrictive drug labelling(Watkins, 2011). Attrition due to toxicity observed in animals and/or in humans isanimportant cause of the high failure rate of clinical drug development(Cook et al., 2014; Watkins, 2011; Thomas et al., 2021).New approach methodologies (NAMs)includemethods which predict and evaluate biological processes by which pharmaceuticals may elicit desirable pharmacological effects and/or may cause undesirable toxicity. Many different types of NAMs have been described. Theseinclude simple in vitrocell-based tests, more complex organotypic or microphysiologicalsystems (MPS)/organ-on-a-chipdevices,and whole human tissuesmaintained ex vivo. Interpretation ofthe invivorelevance of the data providedby these methods is complementedbycomputational toolswhichsimulate and predict in vivodrug disposition and kinetics, in particular physiologically based pharmacokinetic (PBPK) models. Accurate in vitroto in vivoextrapolation isfurther aided by human low-dose testing and microdosing studies (phase 0 testing), which provide precise data on systemic human drug exposure and kineticsin vivo

Liver transplantation for unresectable hepatocellular carcinoma in normal livers.

BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation <12months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC