Tricaprilin (CER-0001) for the preventive treatment of migraine: A phase 2 randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Increasing evidence indicates a metabolic etiology for migraines, with ketosis potentially rectifying metabolic and clinical features. We conducted a pilot study to evaluate CER-0001, a ketogenic agent, for migraine prevention without dietary changes. METHODS: This was a 2-part, double-blind, randomised, placebo-controlled study conducted in Australia. Adults with at least a 1-year history of migraine and ≥ 1 prior preventive treatment failure were randomised to either oral CER-0001 (up to 30 g twice a day) or placebo for 12 weeks. The primary endpoint was Month 3 change in Migraine Headache Days from baseline. RESULTS: Part 1 results are presented. 81 participants were randomised and dosed (n = 40 CER-0001, n = 41 placebo), and 61 participants had evaluable efficacy data. No statistically significant difference was observed in the primary endpoint (LSMean difference 0.92 days; p = 0.586). During Month 2, a mean improvement of -2.8 days was observed for CER-0001 (p = 0.056). Withdrawal rates were 45.0% and 53.7% (CER-0001; placebo). The proportion of participants reporting at least one treatment-emergent adverse event was similar between arms (90.0% CER-0001, 82.9% placebo), mostly gastrointestinal (85.0% CER-0001, 70.7% placebo). CONCLUSION: Results suggest positive directional promise over 2-3 months for CER-0001. A new formulation will be used for larger, fully powered phase 2/3 studies. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT04437199).

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

CONTEXT: Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD. OBJECTIVE: The aim of this systematic review was to summarize the efficacy and safety of exogenic ketones, including medium chain triglycerides (MCTs), on cognitive function in patients with mild NCD and AD. DATA SOURCES: The Embase, MEDLINE, MEDLINE In-Process, PubMed Ahead-of-Print, Cochrane Central Register of Controlled Trials, Europe PMC databases were searched from inception to April 2022. Studies reporting cognitive function efficacy and safety outcomes from randomized controlled trials of exogenic ketones in patients with mild NCD and AD were included. DATA EXTRACTION: Data were extracted by 1 reviewer and checked by a second reviewer. Risk of bias was assessed using the Cochrane risk of bias tool, version 2. DATA ANALYSIS: This review identified 13 individual trials investigating the efficacy and safety of MCT or coconut oil for patients with mild NCD or with AD. Because of the heterogeneity of the studies, a narrative synthesis was used. CONCLUSION: Overall, improvements associated with exogenic ketones were observed in multiple aspects of cognitive abilities, although the large heterogeneity between the included studies makes it difficult to draw firm conclusions from the current literature. Although some studies investigated the impact of the apolipoprotein E ε4 allele status on treatment efficacy, the current data are insufficient to conclude whether such an effect is present. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42022336664.

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,ß-unsaturated ketones.

The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,ß-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine-Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent yields (up to 97%) and high enantioselectivities (up to 98.5% ee) under mild reaction conditions. In addition, this protocol was further expanded to synthesize highly enantioenriched hybrid molecules bearing biologically relevant heterocycles.

Simultaneously Enhanced Catalytic Activity and Thermostability of a Baeyer-Villiger Monooxygenase from Oceanicola granulosus by Reshaping the Binding Pocket.

Enzymatic oxygenation of various cyclic ketones into lactones via Baeyer-Villiger monooxygenases (BVMOs) could provide a promising route for synthesizing fragrances and pharmaceutical ingredients. However, unsatisfactory catalytic activity and thermostability restricted their applications in the pharmaceutical and food industries. In this study, we successfully improved the catalytic activity and thermostability of a Baeyer-Villiger monooxygenase (OgBVMO) from Oceanicola granulosus by reshaping the binding pocket. As a result, mutant OgBVMO-Re displayed a 1.0- to 6.4-fold increase in the activity toward branched cyclic ketones tested, accompanied by a 3 °C higher melting point, and a 2-fold longer half-life time (t1/2 (45 °C)). Molecular dynamics simulations revealed that reshaping the binding pocket achieved strengthened motion correlation between amino acid residues, appropriate size of the substrate-binding pocket, beneficial surface characteristics, lower energy barriers, and shorter nucleophilic distance. This study well demonstrated the trade-off between the enzyme activity and thermostability by reshaping the substrate-binding pocket, paving the way for further engineering other enzymes.

Metabolic flux in macrophages in obesity and type-2 diabetes.

Recent literature extensively investigates the crucial role of energy metabolism in determining the inflammatory response and polarization status of macrophages. This rapidly expanding area of research highlights the importance of understanding the link between energy metabolism and macrophage function. The metabolic pathways in macrophages are intricate and interdependent, and they can affect the polarization of macrophages. Previous studies suggested that glucose flux through cytosolic glycolysis is necessary to trigger pro-inflammatory phenotypes of macrophages, and fatty acid oxidation is crucial to support anti-inflammatory responses. However, recent studies demonstrated that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully understood yet. How the metabolic flux through different metabolic pathways (glycolysis, glucose oxidation, fatty acid oxidation, ketone oxidation, and amino acid oxidation) is altered by obesity- and type 2 diabetes (T2D)-associated insulin resistance is also not fully defined. This mini-review focuses on the impact of insulin resistance in obesity and T2D on the metabolic flux through the main metabolic pathways in macrophages, which might be linked to changes in their inflammatory responses. We closely evaluated the experimental studies and methodologies used in the published research and highlighted priority research areas for future investigations.

HOO• as the Chain Carrier for the Autocatalytic Photooxidation of Benzylic Alcohols.

The oxidation of benzylic alcohols is an important transformation in modern organic synthesis. A plethora of photoredox protocols have been developed to achieve the aerobic oxidation of alcohols into carbonyls. Recently, several groups described that ultraviolet (UV) or purple light can initiate the aerobic oxidation of benzylic alcohols in the absence of an external catalyst, and depicted different mechanisms involving the photoinduction of •O2- as a critical reactive oxygen species (ROS). However, based on comprehensive mechanistic investigations, including control experiments, radical quenching experiments, EPR studies, UV-vis spectroscopy, kinetics studies, and density functional theory calculations (DFT), we elucidate here that HOO•, which is released via the H2O2 elimination of α-hydroxyl peroxyl radicals [ArCR(OH)OO•], serves as the real chain carrier for the autocatalytic photooxidation of benzylic alcohols. The mechanistic ambiguities depicted in the precedent literature are clarified, in terms of the crucial ROS and its evolution, the rate-limiting step, and the primary radical cascade. This work highlights the necessity of stricter mechanistic analyses on UV-driven oxidative reactions that involve aldehydes' (or ketones) generation.

Dual-Catalytic Structural Isomerisation as a Route to α-Arylated Ketones.

Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis.

Synergistic Copper-Aminocatalysis for Direct Tertiary α-Alkylation of Ketones with Electron-Deficient Alkanes.

In this study, a novel approach for the tertiary α-alkylation of ketones using alkanes with electron-deficient C─H bonds is presented, employing a synergistic catalytic system combining inexpensive copper salts with aminocatalysis. This methodology addresses the limitations of traditional alkylation methods, such as the need for strong metallic bases, regioselectivity issues, and the risk of over alkylation, by providing a high reactivity and chemoselectivity without the necessity for pre-functionalized substrates. The dual catalytic strategy enables the direct functionalization of C(sp3)─H bonds, demonstrating remarkable selectivity in the presence of conventional C(sp3)─H bonds that are adjacent to heteroatoms or π systems, which are typically susceptible to single-electron transfer processes. The findings contribute to the advancement of alkylation techniques, offering a practical and efficient route for the construction of C(sp3)─C(sp3) bonds, and paving the way for further developments in the synthesis of complex organic molecules.

Ambulance clinician use of capillary blood ketone meters to improve emergency hyperglycaemia care: A stepped-wedged controlled, mixed-methods feasibility study.

AIM: To determine whether it was feasible, safe and acceptable for ambulance clinicians to use capillary blood ketone meters for 'high-risk' diabetic ketoacidosis (DKA) recognition and fluid initiation, to inform the need for a full-powered, multi-centre trial. METHODS: Adopting a stepped-wedge controlled design, participants with hyperglycaemia (capillary blood glucose >11.0 mmol/L) or diabetes and unwell were recruited. 'High-risk' DKA intervention participants (capillary blood ketones ≥3.0 mmol/L) received paramedic-led fluid therapy. Participant demographic and clinical data were collated from ambulance and hospital care records. Twenty ambulance and Emergency Department clinicians were interviewed to understand their hyperglycaemia and DKA care experiences. RESULTS: In this study, 388 participants were recruited (Control: n = 203; Intervention: n = 185). Most presented with hyperglycaemia, and incidence of type 1 and type 2 diabetes was 18.5% and 74.3%, respectively. Ketone meter use facilitated 'high-risk' DKA identification (control: 2.5%, n = 5; intervention: 6.5%, n = 12) and was associated with improved hospital pre-alerting. Ambulance clinicians appeared to have a high index of suspicion for hospital-diagnosed DKA participants. One third (33.3%; n = 3) of Control and almost half (45.5%; n = 5) of Intervention DKA participants received pre-hospital fluid therapy. Key interview themes included clinical assessment, ambulance DKA fluid therapy, clinical handovers; decision support tool; hospital DKA management; barriers to hospital DKA care. CONCLUSIONS: Ambulance capillary blood ketone meter use was deemed feasible, safe and acceptable. Opportunities for improved clinical decision making, support and safety-netting, as well as in-hospital DKA care, were recognised. As participant recruitment was below progression threshold, it is recommended that future-related research considers alternative trial designs. CLINICALTRIALS: gov: NCT04940897.

Acute effect of an exogenous ketone monoester supplement on appetite and food intake in adults with type 2 diabetes.

The effects of exogenous ketones on appetite and food intake remain elusive, especially for people with type 2 diabetes (T2D). This study aimed to determine whether acute ingestion of an oral ketone monoester supplement (KME) affected appetite sensations, prospective food consumption and intake in T2D. Results showed that acute KME ingestion did not significantly alter appetite scores. However, there was a tendency for lower energy intake during an ad libitum meal 3 h following ketone ingestion compared to non-energetic placebo. Further research is warranted to understand the long-term effects of exogenous ketones for energy and macronutrient intake in T2D.

Hyperglycaemic crises in adults with diabetes: a consensus report.

The American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE) and Diabetes Technology Society (DTS) convened a panel of internists and diabetologists to update the ADA consensus statement on hyperglycaemic crises in adults with diabetes, published in 2001 and last updated in 2009. The objective of this consensus report is to provide up-to-date knowledge about the epidemiology, pathophysiology, clinical presentation, and recommendations for the diagnosis, treatment and prevention of diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) in adults. A systematic examination of publications since 2009 informed new recommendations. The target audience is the full spectrum of diabetes healthcare professionals and individuals with diabetes.

Determination of low carbon aldehydes and ketones in cigarette smoke by MXene membrane enrichment-liquid chromatography.

Low carbon aldehydes and ketones are typical substances harmful to human body produced during cigarette smoking. Their contents in cigarette smoke are important indicators for evaluating its toxicity and the filtration effect of cigarette filter tips, which provides important guidance for its rational design. In this work, MXene membrane with unique lamellar structure was synthesized and loaded onto glass fiber filters to achieve effective enrichment of low carbon aldehydes and ketones. Compared to commercial Cambridge filters, the MXene-loaded filters exhibited higher extraction efficiency towards low-carbon aldehydes and ketones, making viable the detection of butyraldehyde, which was not detected by that enriched with Cambridge filters. Therefore, a MXene-based membrane enrichment-HPLC method was developed for the determination of low-carbon aldehydes and ketones in cigarette smoke with detection limits ranging from 0.133 µg/mL to 0.285 µg/mL. The applicability of the method was verified by analyzing three different types of filter cigarettes with the concentration in the range of 0.5-140 µg/branch for all the analytes, which were in good agreement with the manufacturer's results. The method is accurate and sensitive, and can be used for the quantitative determination of low carbon aldehydes and ketones in cigarette smoke.

Euglycemic Diabetic Ketoacidosis With Acute Renal Failure: A Challenging Case for Clinicians.

Diabetic ketoacidosis (DKA) is a severe complication of diabetes mellitus characterized by hyperglycemia, metabolic acidosis, and ketosis. We present a challenging case of euglycemic DKA secondary to fasting and urinary tract infection with acute renal failure in a 50-year-old woman. Despite normal random blood sugar levels, the patient exhibited clinical signs of DKA, leading to further investigation. High anion gap metabolic acidosis with hyperkalemia and abnormal renal function tests were identified. After hemodialysis, serum ketones were found to be highly positive, confirming the diagnosis. Prompt management led to a complete clinical and laboratory resolution. This case underscores the importance of considering DKA in patients with suggestive symptoms, even with normal blood sugar levels.

Etiology of the Neonatal Hypoglycemias.

To provide a more appropriate foundation for dealing with the problem of hypoglycemia in newborn infants, this article focuses on the mechanisms which underlie the various forms of neonatal hypoglycemia and discusses their implications for newborn care. Evidence indicates that all of the major forms of neonatal hypoglycemia are the result of hyperinsulinism due to dysregulation of pancreatic islet insulin secretion. Based on these observations, the authors propose that routine measurement of B-hydroxybutyrate should be considered an essential part of glucose monitoring in newborn infants.

Development of iron-based single atom materials for general and efficient synthesis of amines.

Heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost-effective chemical synthesis. In particular, the development of more practical, and durable iron-based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe-single atom catalysts (Fe-SACs) entrapped in N-doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines. The synthetic protocol of Fe-SACs is based on primary pyrolysis of Fe-nitrogen complexes on SiO2 and subsequent removal of silica resulting in the formation of unique mesoporous N-doped carbon support with the pore size controlled by the size of the original silica nanoparticles. The resulting stable and reusable Fe-SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N-methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.

Unveiling the Reactivity of Part Per Million Levels of Cobalt-Salen Complexes in Hydrosilylation of Ketones.

A series of air-stable cobalt(III)salen complexes Co-1 to Co-4 have been synthesized and employed in the hydrosilylation of ketones. Notably, the most intricately tailored Co-3 pre-catalyst exhibited exceptional catalytic activity under mild reaction conditions. The developed catalytic hydrosilylation protocol proceeded with an unusual ppm level (5 ppm) catalyst loading of Co-3 and achieved a maximum turnover number (TON) of 200,000. A wide variety of aromatic, aliphatic, and heterocyclic ketones encompassing both electron-donating and electron-withdrawing substituents were successfully transformed into the desired silyl ethers or secondary alcohols in moderate to excellent yields.

Synthesis, Characterization and Antimicrobial and Anticancer Evaluations of Some Novel Heteroannulated Difuro[3,2-c:3',2'-g]Chromenes.

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3',2'-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6-8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds.

Asymmetric 1,2-Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α-Keto Imines.

A carbonyl-assisted asymmetric 1,2-migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α-amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face-selective 1,2-allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram-scale synthesis, showcasing broad functional-group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.