Ketone monoester plus high-dose glucose supplementation before exercise does not affect immediate post-exercise erythropoietin concentrations versus glucose alone.

The objective of this study was to examine the effect of consuming ketone monoester plus a high dose of carbohydrate from glucose (KE + CHO) on the change in erythropoietin (EPO) concentrations during load carriage exercise compared with carbohydrate (CHO) alone. Using a randomized, crossover design, 12 males consumed KE + CHO (573 mg KE/kg body mass, 110 g glucose) or CHO (110 g glucose) 30 min before 4 miles of self-paced treadmill exercise (KE + CHO:51 ± 13%, CHO: 52 ± 12% V̇O2peak) wearing a weighted vest (30% body mass; 25 ± 3 kg). Blood samples for analysis were obtained under resting fasted conditions before (Baseline) consuming the KE + CHO or CHO supplement and immediately after exercise (Post). ßHB increased (p < 0.05) from Baseline to Post in KE + CHO, with no change in CHO. Glucose and glycerol increased (p < 0.05) from Baseline to Post in CHO, with no effect of time in KE + CHO. Insulin and lactate increased (p < 0.05) from Baseline to Post independent of treatment. EPO increased (p < 0.05) from Baseline to Post in KE + CHO and CHO with no difference between treatments. Although KE + CHO altered ßHB, glucose, and glycerol concentrations, results from this study suggest that KE + CHO supplementation before load carriage exercise does not enhance immediate post-exercise increases in EPO compared with CHO alone.

Influence of Carbohydrate Intake on Caprylic Acid (C8:0)-Induced Ketogenesis-A Systematic Review and Meta-Analysis.

The ketogenic diet is used worldwide to treat various diseases, especially drug-resistant epilepsies. Medium-chain triglycerides or medium-chain fatty acids, primarily the major ketogenic compound caprylic acid (C8; C8:0), can significantly support ketogenesis. This review examines the effects of concurrent carbohydrate intake on C8-induced ketogenesis. A systematic literature search (PubMed and Web of Science) with subsequent data extraction was performed according to PRISMA guidelines and the Cochrane Handbook. Studies investigating the metabolic response to C8-containing MCT interventions with carbohydrate intake were included. The studies did not include a ketogenic diet. Three intervention groups were created. The quality of the studies was assessed using the RoB II tool, and the meta-analysis was performed using the Cochrane RevMan software. A total of 7 trials, including 4 RCTs, met the inclusion criteria. Ketone production was lower when C8 was combined with carbohydrates compared to MCT intake alone. The lower C8 dose group (11 g) did not show a significantly lower ketogenic effect than the higher dose group (19 g). Forest plot analysis showed heterogeneous data. The data suggest a non-linear relationship between C8, carbohydrate intake and ketone production. Further studies are needed to investigate the influence of different carbohydrates on C8-induced ketogenesis. Limitations include heterogeneous intervention conditions, such as different types of dispersions, caffeine intake, limited number of studies and variability in study design.

Evaluation of Copanlisib in Combination with Eribulin in Triple-negative Breast Cancer Patient-derived Xenograft Models.

The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC. SIGNIFICANCE: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC.

Efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with anthracycline/taxanes.

BACKGROUND: This prospective real-world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China. PATIENTS AND METHODS: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo-/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m2) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed. RESULTS: One hundred and thirty-four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3-15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first- or second-line treatment was significantly better than those who received eribulin as ≥3-line treatment (6.9 months [95% CI: 3.2-8.8] vs. 4.0 months [95% CI: 3.4-4.6], p = 0.006). The mPFS of patients with triple-negative, HER2-positive, and HER2(-)/HR(+) was 3.4 (95% CI: 2.7-4.1), 6.2 (95% CI: 2.3-10.1) and 5.0 months (95% CI: 4.1-5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6-6.3] vs. 4.0 months [95% CI: 3.3-4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non-TNBC receiving eribulin as ≤2-line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment-related adverse events. CONCLUSION: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real-world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials.

Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats.

It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The administration of a mix of ketone diester (KE) and medium-chain triglyceride (MCT) oil, named KEMCT, abolished the isoflurane-anesthesia-induced increase in blood glucose level and prolonged the recovery time from isoflurane anesthesia in a male preclinical rodent model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. While most preclinical studies use exclusively male animals, our previous study on blood glucose changes in response to KEMCT administration showed that the results can be sex-dependent. Thus, in this study, we investigated female WAG/Rij rats, whether KEMCT gavage (3 g/kg/day for 7 days) can change the isoflurane (3%)-anesthesia-induced increase in blood glucose level and the recovery time from isoflurane-evoked anesthesia using the righting reflex. Moreover, KEMCT-induced ketosis may enhance both the extracellular level of adenosine and the activity of adenosine A1 receptors (A1Rs). To obtain information on the putative A1R mechanism of action, the effects of an A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; intraperitoneal/i.p. 0.2 mg/kg), on KEMCT-generated influences were also investigated. Our results show that KEMCT supplementation abolished the isoflurane-anesthesia-induced increase in blood glucose level, and this was abrogated by the co-administration of DPCPX. Nevertheless, KEMCT gavage did not change the recovery time from isoflurane-induced anesthesia. We can conclude that intragastric gavage of exogenous ketone supplements (EKSs), such as KEMCT, can abolish the isoflurane-anesthesia-induced increase in blood glucose level in both sexes likely through A1Rs in WAG/Rij rats, while recovery time was not affected in females, unlike in males. These results suggest that the administration of EKSs as an adjuvant therapy may be effective in mitigating metabolic side effects of isoflurane, such as hyperglycemia, in both sexes.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes. CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Effect of Acute and Chronic Ingestion of Exogenous Ketone Supplements on Blood Pressure: A Systematic Review and Meta-Analysis.

Exogenous ketone supplements have been suggested to have potential cardiovascular benefits, but their overall effect on blood pressure is unclear. Our objective was to perform a systematic review and meta-analysis on the effects of exogenous ketone supplements on blood pressure (BP) and concomitant changes in resting heart rate (HR). Five databases were searched on January 27th, 2023, for randomized and non-randomized studies. A random-effects model meta-analysis was performed including all studies jointly and separately for acute and chronic ingestion of ketone supplements. Out of 4012 studies identified in the search, 4 acute and 6 chronic studies with n = 187 participants were included. Pooled results (n = 10) showed no change in systolic (SMD [95% CI]= -0.14 [-0.40; 0.11]; I2= 30%; p = 0.17) or diastolic BP (-0.12 [-0.30; 0.05]; I2= 0%; p = 0.69), with a potential tendency observed toward increased resting heart rate (0.17 [-0.14; 0.47]; I2= 40%; p = 0.10). Similar results for systolic and diastolic BP were observed when assessing separately the effect of acute and chronic ingestion of ketone supplements (p ≥ 0.33). Supplement dosage was found to modulate the increase in resting heart rate (0.019 ± 0.006; p = 0.013; R2=100%), suggesting that higher supplement doses lead to a higher resting heart rate. Based on currently available data, acute or prolonged ingestion of ketone supplements does not seem to modulate BP. However, a tendency for HR to increase after acute ingestion was observed, particularly with higher doses. Higher quality studies with appropriate standardized measurements are needed to confirm these results.

Insecticidal activity of 2-tridecanone against the cowpea weevil Callosobruchus maculatus (Coleoptera: Bruchidae)

The effect of 2-tridecanone vapor on the cowpea weevil (Callosobruchus maculatus) development was determined. Seeds of cowpea were infested with adults and exposed to different doses of 2-tridecanone isolated from Pilocarpus microphyllus Stapf ex Holm, a plant species native from northeastern Brazil. The pure monoterpene was evaluated both undiluted as well as in the dilutions 1:10, 1:100 and 1:1,000 (v/v). The following parameters of the cowpea weevil life cycle were analyzed in response to decreasing doses of 2-tridecanone: number of eggs laid, percentage of egg hatching on seeds, percentage of adult emergence, adult weight at emergence, mean developmental time and number of adults emerged. Vapor of 2-tridecanone caused a significant (P < 0.05) reduction in the number of eggs laid, in the percentage of eggs hatched and in the number of emerged adults in infested seeds. The fumigant insecticidal effect of 2-tridecanone was mainly due to its ovicidal activity.

O efeito dos vapores da 2-tridecanona sobre o caruncho do feijão-de-corda (Callosobruchus maculatus) foi avaliado. Sementes de feijão-de-corda infestados com insetos adultos foram expostas a diferentes doses de 2-tridecanona isolada de Pilocarpus microphyllus, uma espécie nativa do Nordeste do Brasil. O monoterpeno puro foi utilizado nas diluições 1:10, 1:100 e 1:1000 (v/v). Os parâmetros da biologia do inseto foram analisados em função da resposta a doses decrescentes de 2-tridecanona: número de ovos postos por fêmea, percentagem de eclosão de ovos, percentagem de emergência de adultos, peso dos adultos recém-emergidos, tempo médio de desenvolvimento e número total de ovos emergidos. Diferenças significativas (P < 0.05) entre as doses de 2-tridecanona testadas foram observadas, para quatro dos seis parâmetros biológicos analisados. Os resultados obtidos indicaram que a 2-tridecanona é tóxica para C. maculatus, reduzindo significativamente (P < 0.05) o número de insetos emergidos após a infestação. Esse efeito foi causado principalmente pela significativa redução observada na eclosão dos ovos expostos ao vapor da substância.