[Systematic evaluation on efficacy and safety of Gingko Ketone Ester Dropping Pills in treatment of angina pectoris and coronary heart disease].

To systemically evaluate the efficacy and safety of Gingko Ketone Ester Dropping Pills in treating angina pectoris and co-ronary heart disease. CNKI, Wanfang, SinoMed, PubMed, Cochrane Library and EMbase databases were retrieved on computer, and the randomized clinical trial(RCT) on Gingko Ketone Ester Dropping Pills in treating angina pectoris and coronary heart disease, which were published from the database establishment to December 31, 2019, were comprehensively collected. Literature screening, data extraction and quality evaluation were conducted independently by two researchers according to inclusion and exclusion criteria. Literature methodology quality evaluation was conducted with use of the Cochrane Handbook 5.3.0(bias risk assessment tool). Meta-analysis was performed with RevMan 5.3.0 software. A total of 10 RCTs were included. The results of the Meta-analysis showed that as compared with conventional Western medicine alone, the application of Gingko Ketone Ester Dropping Pills combined with conventional Western medicine treatment further improved the total effective rate and electrocardiogram effect(RR=1.43,95%CI[1.20,1.71],P<0.000 1). There were statistically significant differences in the number of angina attacks, the duration of angina and the amount of nitroglycerin used. In terms of safety indicators, four studies reported adverse reactions in the experimental group, including facial flu-shing, tachycardia, dizziness, dyspnea, nausea and other symptoms. Based on the existing findings, in the treatment of angina pectoris and coronary heart disease, Gingko Ketone Ester Dropping Pills combined with conventional Western medicine can improve the clinical total effective rate, electrocardiogram effect, number of angina attacks, duration of angina and the amount of nitroglycerin used. However, in the included studies, due to some methodological quality problems which would impact the reliability of literature results more high-quality randomized controlled trials are still needed for further verification.

Bicarbonate Unlocks the Ergogenic Action of Ketone Monoester Intake in Endurance Exercise.

PURPOSE: We recently reported that oral ketone ester (KE) intake before and during the initial 30 min of a 3 h 15 min simulated cycling race (RACE) transiently decreased blood pH and bicarbonate without affecting maximal performance in the final quarter of the event. We hypothesized that acid-base disturbances due to KE overrules the ergogenic potential of exogenous ketosis in endurance exercise. METHODS: Nine well-trained male cyclists participated in a similar RACE consisting of 3 h submaximal intermittent cycling (IMT180') followed by a 15-min time trial (TT15') preceding an all-out sprint at 175% of lactate threshold (SPRINT). In a randomized crossover design, participants received (i) 65 g KE, (ii) 300 mg·kg-1 body weight NaHCO3 (BIC), (iii) KE + BIC, or (iv) a control drink (CON), together with consistent 60 g·h-1 carbohydrate intake. RESULTS: KE ingestion transiently elevated blood D-ß-hydroxybutyrate to ~2-3 mM during the initial 2 h of RACE (P < 0.001 vs CON). In KE, blood pH concomitantly dropped from 7.43 to 7.36 whereas bicarbonate decreased from 25.5 to 20.5 mM (both P < 0.001 vs CON). Additional BIC resulted in 0.5 to 0.8 mM higher blood D-ß-hydroxybutyrate during the first half of IMT180' (P < 0.05 vs KE) and increased blood bicarbonate to 31.1 ± 1.8 mM and blood pH to 7.51 ± 0.03 by the end of IMT180' (P < 0.001 vs KE). Mean power output during TT15' was similar between KE, BIC, and CON at ~255 W but was 5% higher in KE + BIC (P = 0.02 vs CON). Time to exhaustion in the sprint was similar between all conditions at ~60 s (P = 0.88). Gastrointestinal symptoms were similar between groups. DISCUSSION: The coingestion of oral bicarbonate and KE enhances high-intensity performance at the end of an endurance exercise event without causing gastrointestinal distress.

Acute Ketogenic Diet and Ketone Ester Supplementation Impairs Race Walk Performance.

PURPOSE: This study aimed to determine if LCHF and ketone ester (KE) supplementation can synergistically alter exercise metabolism and improve performance. METHODS: Elite race walkers (n = 18, 15 males and 3 females; V˙O2peak, 62 ± 6 mL·min-1·kg-1) undertook a four-stage exercise economy test and real-life 10,000-m race before and after a 5-d isoenergetic high-CHO (HCHO, ~60%-65% fat; CHO, 20% fat; n = 9) or LCHF (75%-80% fat, <50 g·d-1 CHO, n = 9) diet. The LCHF group performed additional economy tests before and after diet after supplementation with 573 mg·kg-1 body mass KE (HVMN; HVMN Inc., San Francisco, CA), which was also consumed for race 2. RESULTS: The oxygen cost of exercise (relative V˙O2, mL·min-1·kg-1) increased across all four stages after LCHF (P < 0.005). This occurred in association with increased fat oxidation rates, with a reciprocal decrease in CHO oxidation (P < 0.001). Substrate utilization in the HCHO group remained unaltered. The consumption of KE before the LCHF diet increased circulating KB (P < 0.05), peaking at 3.2 ± 0.6 mM, but did not alter V˙O2 or RER. LCHF diet elevated resting circulating KB (0.3 ± 0.1 vs 0.1 ± 0.1 mM), but concentrations after supplementation did not differ from the earlier ketone trial. Critically, race performance was impaired by ~6% (P < 0.0001) relative to baseline in the LCHF group but was unaltered in HCHO. CONCLUSION: Despite elevating endogenous KB production, an LCHF diet does not augment the metabolic responses to KE supplementation and negatively affects race performance.

Systematic evaluation on efficacy and safety of Gingko Ketone Ester Dropping Pills in treatment of angina pectoris and coronary heart disease / 中国中药杂志

To systemically evaluate the efficacy and safety of Gingko Ketone Ester Dropping Pills in treating angina pectoris and co-ronary heart disease. CNKI, Wanfang, SinoMed, PubMed, Cochrane Library and EMbase databases were retrieved on computer, and the randomized clinical trial(RCT) on Gingko Ketone Ester Dropping Pills in treating angina pectoris and coronary heart disease, which were published from the database establishment to December 31, 2019, were comprehensively collected. Literature screening, data extraction and quality evaluation were conducted independently by two researchers according to inclusion and exclusion criteria. Literature methodology quality evaluation was conducted with use of the Cochrane Handbook 5.3.0(bias risk assessment tool). Meta-analysis was performed with RevMan 5.3.0 software. A total of 10 RCTs were included. The results of the Meta-analysis showed that as compared with conventional Western medicine alone, the application of Gingko Ketone Ester Dropping Pills combined with conventional Western medicine treatment further improved the total effective rate and electrocardiogram effect(RR=1.43,95%CI[1.20,1.71],P<0.000 1). There were statistically significant differences in the number of angina attacks, the duration of angina and the amount of nitroglycerin used. In terms of safety indicators, four studies reported adverse reactions in the experimental group, including facial flu-shing, tachycardia, dizziness, dyspnea, nausea and other symptoms. Based on the existing findings, in the treatment of angina pectoris and coronary heart disease, Gingko Ketone Ester Dropping Pills combined with conventional Western medicine can improve the clinical total effective rate, electrocardiogram effect, number of angina attacks, duration of angina and the amount of nitroglycerin used. However, in the included studies, due to some methodological quality problems which would impact the reliability of literature results more high-quality randomized controlled trials are still needed for further verification.

Utility of Ketone Supplementation to Enhance Physical Performance: A Systematic Review.

Ingesting exogenous ketone bodies has been touted as producing ergogenic effects by altering substrate metabolism; however, research findings from recent studies appear inconsistent. This systematic review aimed to aggregate data from the current literature to examine the impact of consuming ketone supplements on enhancing physical performance. A systematic search was performed for randomized controlled trials that measured physical performance outcomes in response to ingesting exogenous ketone supplements compared with a control (nutritive or non-nutritive) in humans. A total of 161 articles were screened. Data were extracted from 10 eligible studies (112 participants; 109 men, 3 women ) containing 16 performance outcomes [lower-body power (n = 8) and endurance performance (n = 8)]. Ketone supplements were grouped as ketone esters (n = 8) or ketone salts/precursors (n = 8). Of the 16 performance outcomes identified by the systematic review, 3 reported positive, 10 reported null, and 3 reported negative effects of ketone supplementation on physical performance compared with controls. Heterogeneity was detected for lower-body power ( Q = 40, I2 = 83%, P < 0.01) and endurance performance (Q = 95, I2 = 93%, P < 0.01) between studies. Similarly high levels of heterogeneity were detected in studies providing ketone esters (Q = 111, I2 = 93%, P < 0.01), and to a lesser extent studies with ketone salts/precursors (Q = 25, I2 = 72%, P < 0.01). Heterogeneity across studies makes it difficult to conclude any benefit or detriment to consuming ketone supplements on physical performance. This systematic review discusses factors within individual studies that may contribute to discordant outcomes across investigations to elucidate if there is sufficient evidence to warrant recommendation of consuming exogenous ketone supplements to enhance physical performance.

Real-world efficacy and safety of eribulin in advanced and pretreated HER2-negative breast cancer in a Spanish comprehensive cancer center.

BACKGROUND: Eribulin improves survival in pre-treated HER2-negative advanced breast cancer (ABC). However, limited data exist on co-morbidities and central nervous system (CNS) efficacy. The purpose of this study was to review eribulin's efficacy and safety in everyday clinical practice with special focus on age, body mass index (BMI) and central nervous system (CNS) activity. METHODS: An observational study was conducted in a series of HER2-negative ABC patients treated from January'14-December'17 outside a clinical trial. Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), and association of clinical and pathological variables with outcome were evaluated. RESULTS: Ninety-five women were treated with at least one cycle of eribulin. Median age was 57 (33-83), and 18% were obese. Median number of prior chemotherapies for ABC was 3 (2-5) and 76% of patients had visceral metastases, including 21% with CNS involvement. Most tumors were estrogen receptor-positive (79%). ORR and stable disease (SD) at 6 months were 26.2 and 37.5%, respectively. Remarkably, relevant CNS efficacy was observed with eribulin: 20% of patients obtained partial response and 25% SD. Treatment was generally well tolerated and manageable, with 29% grade 3 and 10.9% grade 4 toxicities. Median PFS and OS were 4.1 months (CI95% 3.2-4.9) and 11.1 months (CI95% 9.5-14.7), respectively. Triple-negative disease, > 2organs involved and being younger than 70 years old were independent prognosis factors for worse OS in multivariate analysis. Most patients (75%) progressed in pre-existing metastases sites. CONCLUSION: In everyday clinical practice, eribulin's efficacy seems similar to pivotal trials. CNS-efficacy was observed. TNBC, > 2 organs involved and being younger than 70 years old were independent prognosis factors for worse OS. Remarkably, less incidence of grade 4-toxicity compared to previous studies was found.

No Benefit of Ingestion of a Ketone Monoester Supplement on 10-km Running Performance.

PURPOSE: Preexercise ingestion of exogenous ketones alters the metabolic response to exercise, but effects on exercise performance have been equivocal. METHODS: On two occasions in a double-blind, randomized crossover design, eight endurance-trained runners performed 1 h of submaximal exercise at approximately 65% V˙O2max immediately followed by a 10-km self-paced time trial (TT) on a motorized treadmill. An 8% carbohydrate-electrolyte solution was consumed before and during exercise, either alone (CHO + PLA), or with 573 mg·kg of a ketone monoester supplement (CHO + KME). Expired air, HR, and RPE were monitored during submaximal exercise. Serial venous blood samples were assayed for plasma glucose, lactate, and ß-hydroxybutyrate concentrations. RESULTS: CHO + KME produced plasma ß-hydroxybutyrate concentrations of approximately 1.0 to 1.3 mM during exercise (P < 0.001), but plasma glucose and lactate concentrations were similar during exercise in both trials. V˙O2, running economy, respiratory exchange ratio, HR, and RPE were also similar between trials. Performance in the 10-km TT was not different (P = 0.483) between CHO + KME (mean, 2402 s; 95% confidence interval, 2204-2600 s) and CHO + PLA (mean, 2422 s; 95% confidence interval, 2217-2628 s). Cognitive performance, measured by reaction time and a multitasking test, did not differ between trials. CONCLUSIONS: Compared with carbohydrate alone, coingestion of KME by endurance-trained athletes elevated plasma ß-hydroxybutyrate concentrations, but did not improve 10-km running TT or cognitive performance.

Intermittent Running and Cognitive Performance after Ketone Ester Ingestion.

PURPOSE: Ingestion of exogenous ketones alters the metabolic response to exercise and may improve exercise performance, but it has not been explored in variable-intensity team sport activity, or for effects on cognitive function. METHODS: On two occasions in a double-blind, randomized crossover design, 11 male team sport athletes performed the Loughborough Intermittent Shuttle Test (part A, 5 × 15-min intermittent running; part B, shuttle run to exhaustion), with a cognitive test battery before and after. A 6.4% carbohydrate-electrolyte solution was consumed before and during exercise either alone (PLA) or with 750 mg·kg of a ketone ester (KE) supplement. Heart rate, RPE, and 15-m sprint times were recorded throughout, and serial venous blood samples were assayed for plasma glucose, lactate, and ß-hydroxybutyrate. RESULTS: KE resulted in plasma ß-hydroxybutyrate concentrations of ~1.5 to 2.6 mM during exercise (P < 0.001). Plasma glucose and lactate concentrations were lower during KE compared with PLA (moderate-to-large effect sizes). Heart rate, RPE, and 15-m sprint times did not differ between trials. Run time to exhaustion was not different (P = 0.126, d = 0.45) between PLA (mean = 268 s, 95% confidence interval [CI] = 199-336 s) and KE (mean = 229 s, 95% CI = 178-280 s). Incorrect responses in a multitasking test increased from pre- to postexercise in PLA (mean = 1.8, 95% CI = -0.6 to 4.1) but not in KE (mean = 0.0, 95% CI = -1.8 to 1.8) (P = 0.017, d = 0.70). CONCLUSION: Compared with carbohydrate alone, coingestion of a KE by team sport athletes attenuated the rise in plasma lactate concentrations but did not improve shuttle run time to exhaustion or 15-m sprint times during intermittent running. An attenuation of the decline in executive function after exhausting exercise suggests a cognitive benefit after KE ingestion.

Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males.

This study investigated the impact of raising plasma beta-hydroxybutyrate (ß-OHB) through ingestion of ketone salts on substrate oxidation and performance during cycling exercise. Ten healthy adult males (age, 23 ± 3 years; body mass index, 25 ± 3 kg/m2, peak oxygen uptake, 45 ± 10 mL/(kg·min)-1) were recruited to complete 2 experimental trials. Before enrollment in the experimental conditions, baseline anthropometrics and cardiorespiratory fitness (peak oxygen uptake) were assessed and familiarization to the study protocol was provided. On experimental days, participants reported to the laboratory in the fasted state and consumed either 0.3 g/kg ß-OHB ketone salts or a flavour-matched placebo at 30 min prior to engaging in cycling exercise. Subjects completed steady-state exercise at 30%, 60%, and 90% ventilatory threshold (VT) followed by a 150-kJ cycling time-trial. Respiratory exchange ratio (RER) and total substrate oxidation were derived from indirect calorimetry. Plasma glucose, lactate, and ketones were measured at baseline, 30 min post-supplement, post-steady-state exercise, and immediately following the time-trial. Plasma ß-OHB was elevated from baseline and throughout the entire protocol in the ketone condition (p < 0.05). RER was lower at 30% and 60% VT in the ketone compared with control condition. Total fat oxidation was greater in the ketone versus control (p = 0.05). Average time-trial power output was ∼7% lower (-16 W, p = 0.029) in the ketone condition. Ingestion of ketone salts prior to exercise increases fat oxidation during steady-state exercise but impairs high-intensity exercise performance.

Trabectedin and Eribulin: Where Do They Fit in the Management of Soft Tissue Sarcoma?

OPINION STATEMENT: Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.

Repellency and oviposition deterrence of wild tomato leaf extracts to spider mites, Tetranychus urticae Koch.

Glandular trichomes on the leaves of wild tomato, Lycopersicon hirsutum f. hirsutum Mull, also known as Solanum habrochaites (Solanaceae) synthesize and accumulate high levels of methyl ketones (MKs). The potential of using MKs as alternatives to synthetic acaricides for controlling the twospotted spider mite, Tetranychus urticae Koch, is explored in this study. Plants of L. hirsutum accession LA 407 having high concentrations of MKs were grown from seeds under greenhouse conditions. The main objective of this investigation was to conduct bioassays that are quick and easy to implement, consistent over time (repeatable) with the ability to utilize small amounts of test material for testing repellency and fecundity (number of eggs laid by a female mite) of MKs in pure forms and in LA 407 crude extracts. Four MKs (2-tridecanone, 2-undecanone, 2-dodecanone, 2-pentadecanone) and their mixture were screened for their repellency and ability to alter fecundity of spider mites. All MKs repelled spider mites at the two periods tested. Following spraying of tomato leaf extracts prepared in ethanol (ethanol extracts), average number of eggs laid per female mite on bean leaf discs dropped from 0.8 to 0.3 and from 0.9 to 0.3 at 4 and 24 h after exposure representing 65 and 68% reduction, respectively. However, spraying of tomato leaf extracts prepared in water (water extracts) reduced number of eggs laid per female mite from 1.7 to 0.7 and from 2.6 to 0.9 at 4 and 24 h after exposure representing 60 and 67% reduction, respectively. We concluded that all MKs have repellent and egg laying deterrence activities against spider mites. This investigation suggests that ethanol and water extracts of LA 407 have a potential for repelling female spider mites and reducing their laid eggs which might be explored under field conditions for managing populations of spider mites, which could reduce reliance on synthetic acaricides.

Eribulin -- a review of preclinical and clinical studies.

Eribulin mesylate is a non-taxane, structurally simplified, completely synthetic, halichondrin B derivative with an end poisoning, microtubule inhibitory action. Preclinical studies have demonstrated activity in various cancer cell lines and synergistic action with gemcitabine, epirubicin, trastuzumab, cisplatin, docetaxel and vinorelbine. Eribulin has recently been approved by United States Food and Drug Administration as a third line therapy for metastatic breast cancer patients, who have previously been treated with an anthracycline and a taxane. It has also advanced to phase II trials in non-small cell lung cancer, pancreatic, prostate, bladder, head and neck cancers, sarcomas and ovarian and other gynecological tumors. Combination trials with carboplatin, gemcitabine, pemetrexed, cisplatin, and erlotinib are currently ongoing. Eribulin potentially has a low incidence of peripheral neuropathy. The predominant side effects are neutropenia and fatigue, which are manageable. This article reviews the available information on eribulin with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, preclinical studies and clinical trials.

Eribulin mesylate for the treatment of late-stage breast cancer.

INTRODUCTION: Chemotherapy agents, particularly anthracycline and taxane, have demonstrated their significance in metastatic breast cancer. However, improving overall survival in late-stage breast cancer remains a challenge. Eribulin mesylate, a new chemotherapy agent, has a proven significance in this setting. Eribulin mesylate is a synthetic analog of a macrolide isolated from a marine sponge. It inhibits microtubule polymerization, inducing mitosis arrest and apoptosis, and aggregates soluble tubulin in nonproductive form. In Phase II studies, this drug has shown a partial and stable response. The Phase III EMBRACE study showed that eribulin mesylate improved overall survival, compared with the physician's choice of treatment, in women who had received two to five prior chemotherapy regimens, including anthracycline and taxane for advanced breast cancer (median overall survival: 13.1 versus 10.6 months HR 0.81, p = 0.041). This compound is well tolerated. The most common adverse event is neutropenia. AREAS COVERED: This paper provides an introduction to the drug, eribulin mesylate, along with an overview of the current drug market for late-stage breast cancer; it also reviews its pharmacodynamics, pharmacokinetics and clinical efficacy. EXPERT OPINION: Currently, eribulin mesylate is only the third single-agent chemotherapy that has improved overall survival (after anthracycline and taxane) in advanced breast cancer. These results, particularly in heavily pretreated breast cancer, suggest that this drug could become a new standard in the treatment of metastatic breast cancer, and should, therefore, be further developed in its earlier stages.

Successful treatment of musk ketone-induced chronic actinic dermatitis with cyclosporine and PUVA.

We describe a patient with chronic actinic dermatitis whose photopatch tests revealed reactions to musk ketone and musk ambrette, both of which were found in his aftershave lotion. Minimal erythema doses of UVA and UVB were decreased. After initial unsuccessful treatment with PUVA therapy the patient was successfully treated with a combination of cyclosporine and PUVA.