A retrospective analysis of the incidence, outcome and factors associated with the occurrence of euglycemic ketoacidosis in diabetic patients on sodium glucose co-transporter - 2 inhibitors undergoing cardiac surgery.

Introduction: SGLT2i is a new class of drugs used for type 2 diabetes. SGLT2i are known to cause EuKA in the perioperative period. Euglycemic ketoacidosis (EuKA) can cause life-threatening metabolic acidosis in the perioperative setting. Though the event rate of SGLT2i associated diabetic ketoacidosis in nonoperative setting is low, incidence among peri-operative patients can be very high and remains unknown. Aim: The aim of this study was to find the incidence, analyze outcome, and establish correlation between risk factors and EuKA in cardiac surgical patients on SGLT2i. Materials and Methods: This is a retrospective study analyzing 24 cardiac surgical patients who were on SGLT2i for type 2 diabetes mellitus. Data collection included age, sex, BMI, preoperative HbA1C, albumin, creatinine, type of SGLT2i and timing of stopping before surgery, insulin administration in the immediate pre-operative period; use of CPB, GI infusion and inotropes in the intraoperative period; blood ketone, duration of ventilation, hydration status and length of postoperative stay in postoperative period. Patients were diagnosed to have EuKA if any one of the serially measured postoperative ketone values was more than 0.6 mmol/L (ketone positive). The collected data were used to find an association between the risk factors and the occurrence of EuKA. Results: Of the 24 patients, 17 patients developed EuKA. (70.8.%). 10 of the 17 EuKA in our study required preoperative Insulin for diabetic control whereas none in the ketone negative patients required insulin. This was statistically significant (P = 0.019). Association of other factors to EuKA were not statistically significant. Conclusion: Though the event rate of SGLT2i associated Diabetic ketoacidosis in nonoperative setting is low, (17), the occurrence of EUKA in cardiac surgical patients on SGLT2i in our study was 70.8% (17 out of 24 patients). Patients who require insulin in addition to other oral hypoglycemic drugs for immediate preoperative glycemic control are at risk for the development of SGLT2 inhibitor-induced EuKA postoperatively. Missing the diagnosis of EuKA is fatal in these patients. We couldn't make a diagnosis in our first patient whom we lost. Since it was diagnosed in all our study patients by measuring serial ketone values, there was no mortality and insignificant morbidity. Cessation of SGLT2i before surgery, expectant watch for blood ketones, and treatment with GI infusion reduce morbidity and mortality in cardiac surgical patients.

Dietary-Induced Ketogenesis: Adults Are Not Children.

There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

The Combination of Cigarette Smoking and Alcohol Consumption Synergistically Increases Reactive Carbonyl Species in Human Male Plasma.

Cigarette smoking and alcohol consumption are major risk factors for lifestyle-related diseases. Although it has been reported that the combination of these habits worsens risks, the underlying mechanism remains elusive. Reactive carbonyl species (RCS) cause chemical modifications of biological molecules, leading to alterations in cellular signaling pathways, and total RCS levels have been used as a lipid peroxidation marker linked to lifestyle-related diseases. In this study, at least 41 types of RCS were identified in the lipophilic fraction of plasma samples from 40 subjects using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Higher levels of 10 alkanals, 5 trans-2-alkenals, 1 cis-4-alkenal, and 3 alkadienals were detected in the smoking/drinking group (N = 10) as compared to those with either habit (N = 10 each) or without both habits (N = 10) in the analysis of covariances adjusted for age and BMI. The levels of 3 alkanals, 1 trans-2-alkenal, 1 alkadienal, and 1 4-hydroxy-2-alkenal in the smoking/drinking group were significantly higher than those in the no-smoking/drinking and no-smoking/no-drinking groups. These results strongly indicate that the combination of cigarette smoking and alcohol drinking synergistically increases the level and variety of RCS in the circulating blood, and may further jeopardize cellular function.

Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil.

Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer's disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. PARTICIPANTS: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer's Disease were assessed. INTERVENTION: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. MEASUREMENTS: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. RESULTS: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). CONCLUSION: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.

Postoperative serum metabolites of patients on a low carbohydrate ketogenic diet after pancreatectomy for pancreatobiliary cancer: a nontargeted metabolomics pilot study.

A ketogenic diet is a potential adjuvant cancer therapy that limits glucose availability to tumours while fuelling normal tissues with ketone bodies. We examined the effect of a low carbohydrate ketogenic diet (LCKD) (80% kcal from fat, ketogenic ratio 1.75:1, w/w) compared to a general hospital diet (GD) on serum metabolic profiles in patients (n = 18, ≥ 19 years old) who underwent pancreatectomy for pancreatobiliary cancer. Serum samples collected preoperatively (week 0) and after the dietary intervention (week 2) were analysed with a nontargeted metabolomics approach using liquid chromatography-tandem mass spectrometry. Serum ß-hydroxybutyrate and total ketone levels significantly increased after 2 weeks of LCKD compared to GD (p < 0.05). Principal component analysis score plots and orthogonal partial least squares discriminant analysis also showed significant differences between groups at week 2, with strong validation. In all, 240 metabolites differed between LCKD and GD. Pathways including glycerophospholipid and sphingolipid metabolisms were significantly enriched in the LCKD samples. LCKD decreased C22:1-ceramide levels, which are reported to be high in pancreatic cancer, while increasing lysophosphatidylcholine (18:2), uric acid, citrulline, and inosine levels, which are generally low in pancreatic cancer. Postoperative LCKD might beneficially modulate pancreatic cancer-related metabolites in patients with pancreatobiliary cancer.

Impact of angiotension I converting enzyme gene I/D polymorphism on running performance, lipid, and biochemical parameters in ultra-marathoners.

The insertion (I) or deletion (D) polymorphism in the angiotension I converting enzyme gene, (ACE I/D, rs1799752) is associated with human exercise endurance and performance. However, most of the aforementioned studies focus on marathons, swimming, and triathlons, while the ACE polymorphism in ultra-marathoners has not yet been reported. We studied the impact of ACE I/D polymorphism in ultra-marathoners and investigated its relationship with lipid profiles, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP) levels in runners before and after ultra-marathon racing.This observational study used data from a 100-km ultra-marathon in Taipei, Taiwan. Twenty-four male participants were analyzed for their ACE insertion/deletion polymorphism, lipid profiles, hs-CRP, IL-6 in serum immediately before and after ultra-marathon running.In our 24 subjects analyzed, 7, 14, and 3 subjects were of I/I, I/D, and D/D genotypes, respectively. Runners with the D polymorphism (I/D and D/D) showed a trend of better performance in the 100-km ultra-marathon (measured by completion time in minutes, P = .036). In this group, the previous best marathon performance was also significantly better than the I/I group (P = .047). After adjusting for body mass index (BMI), the difference in performance was not significant. Ketone levels, IL-6, and hs-CRP levels were highly increased at immediately and 24-hour post-race. No correlation was found between different ACE polymorphisms and common biochemical parameters examined.We report the first study in the impact of the ACE I/D (rs1799752) on ultra-marathoners. Presence of the D polymorphism in ACE gene is associated with better performance, although the BMI of the runners contribute as a major factor. There was no difference in the biochemical or lipid parameters measured among different ACE polymorphisms.

Normal Blood Glucose and High Blood Ketones in a Critically Unwell Patient with T1DM Post-Bariatric Surgery: a Case of Euglycemic Diabetic Ketoacidosis.

Obesity is a global epidemic. Obesity in those with type I diabetes (T1DM) contributes to poor glycemic control and complications. Bariatric surgery as management for obesity is increasing in those with T1DM. However, there is limited data pertaining to these patients and their potential post-operative complications. These complications include severe hyperglycemia and diabetic ketoacidosis (DKA). This case study describes a 43-year-old woman with T1DM whose post-operative period following her bariatric surgery was complicated by euglycemic DKA. Post-bariatric surgery the incidence of those with T1DM experiencing DKA can be up to 1 in 4. Clinicians should be vigilant of this atypical presentation of DKA to avoid misdiagnosis potentially resulting in delays in treatment. Close monitoring in the post-operative period is warranted.

Profiling of carboxyl-containing metabolites in smokers and non-smokers by stable isotope labeling combined with LC-MS/MS.

Profiling of carboxyl-containing metabolites in smokers and non-smokers provides insight into the smoking-related biological events and causal relationships between exposure and adverse events. However, more comprehensive analysis of carboxyl-containing metabolites in bio-matrices with high sensitivity and accuracy is challenging. In this work, stable isotope labeling in combination with liquid chromatography-tandem mass spectrometry was used for untargeted profiling and relative quantification of carboxyl-containing metabolites in plasma of smokers and non-smokers. A pair of isotope labeling reagents, N, N-dimethylethylenediamine (DMED) and d4-DMED was used to label carboxyl-containing metabolites. Since the isotope labeled dimethylamino moieties of DMED and d4-DMED are easily fragmented and lost as characteristic neutral fragments of 45 and 49 Da, respectively, double neutral loss scans can be used to profiling of carboxyl-containing metabolites. Subsequently, based on the ion pair parameters obtained from double neutral loss scans, relative quantification method was developed. As a result, 269 carboxyl-containing metabolite candidates were discovered, and 88 metabolite candidates were found to have significant alterations between smokers and non-smokers. 7Z, 10Z-hexadecadienoic acid, myristic acid and 3ß-hydroxy-5-cholestenoic acid with significant differences confirmed by standard comparison are linked to smoking related inflammation, abnormal bile acid synthesis and cholesterol metabolism.

ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners.

Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia.

High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice.

There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ)-induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies.

High anion gap metabolic acidosis induced by cumulation of ketones, L- and D-lactate, 5-oxoproline and acute renal failure.

INTRODUCTION: Frequent causes of high anion gap metabolic acidosis (HAGMA) are lactic acidosis, ketoacidosis and impaired renal function. In this case report, a HAGMA caused by ketones, L- and D-lactate, acute renal failure as well as 5-oxoproline is discussed. CASE PRESENTATION: A 69-year-old woman was admitted to the emergency department with lowered consciousness, hyperventilation, diarrhoea and vomiting. The patient had suffered uncontrolled type 2 diabetes mellitus, underwent gastric bypass surgery in the past and was chronically treated with high doses of paracetamol and fosfomycin. Urosepsis was diagnosed, whilst laboratory analysis of serum bicarbonate concentration and calculation of the anion gap indicated a  HAGMA. L-lactate, D-lactate, ß-hydroxybutyric acid, acetone and 5-oxoproline serum levels were markedly elevated and renal function was impaired. DISCUSSION: We concluded that this case of HAGMA was induced by a variety of underlying conditions: sepsis, hyperglycaemia, prior gastric bypass surgery, decreased renal perfusion and paracetamol intake. Risk factors for 5-oxoproline intoxication present in this case are female gender, sepsis, impaired renal function and uncontrolled type 2 diabetes mellitus. Furthermore, chronic antibiotic treatment with fosfomycin might have played a role in the increased production of 5-oxoproline. CONCLUSION: Paracetamol-induced 5-oxoproline intoxication should be considered as a cause of HAGMA in patients with female gender, sepsis, impaired renal function or uncontrolled type 2 diabetes mellitus, even when other more obvious causes of HAGMA such as lactate, ketones or renal failure can be identified.

Caffeine intake increases plasma ketones: an acute metabolic study in humans.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Inhibitory Activities of Essential Oil Obtained from Turmeric and Its Constituents against ß-Secretase.

The need for a preventive agent against dementia led us to screen natural plant resources. Among the herbs and spices tested, turmeric, from rhizomes of Curcuma longa, showed high potency against ß-secretase. The active principles were determined as α-turmerone, ß-turmerone and ar-turmerone, with IC(50) values of 39, 62 and 92 µM respectively. In this study, the efficiency of collecting the essential oil using steam distillation of the volatile substance was disclosed The active principles were explored, and four sesquiterpenoids and five monoterpenoids were revealed as active principles against ß-secretase; On the other hand, α-turmerone, ß-turmerone and ar-turmerone were also investigated in a pharmacokinetic absorption experiment. After oral administration, these compounds were detected in an intact form in the brain and serum. These results suggest that consumption of-turieric constituents may prevent dementia.

Role of Hyperketonemia in Inducing Oxidative Stress and Cellular Damage in Cultured Hepatocytes and Type 1 Diabetic Rat Liver.

BACKGROUND/AIMS: Type 1 diabetic (T1D) patients have a higher incidence of liver disease. T1D patients frequently experience elevated plasma ketone levels along with hyperglycemia. However, no study has examined whether hyperketonemia per se has any role in excess liver damage in T1D. This study investigates the hypothesis that hyperketonemia can induce oxidative stress and cellular dysfunction. METHODS: STZ treated diabetic rats, FL83B hepatocytes, and GCLC knocked down (GSH deficient) hepatocytes were used. RESULTS: The blood levels of ALT and AST, biomarkers of liver damage, and ketones were elevated in T1D rats. An increase in NOX4 and ROS along with a reduction in GSH and GCLC levels was observed in T1D rat livers in comparison to those seen in non-diabetic control or type 2 diabetic rats. MCP-1 and ICAM-1 were also elevated in T1D rat livers and ketone treated hepatocytes. Macrophage markers CCR2 and CD11A that interact with MCP-1, and ICAM-1 respectively, were also elevated in the T1D liver, indicating macrophage infiltration. Additionally, activated macrophages increased hepatocyte damage with ketone treatment, which was similar to that seen in GCLC knockdown hepatocytes without ketones. CONCLUSION: Hyperketonemia per se can induce macrophage mediated damage to hepatocytes and the liver, caused by GSH depletion and oxidative stress up regulation in T1D.

Pharmacodynamics (PD) and pharmacokinetics (PK) of E7389 (eribulin, halichondrin B analog) during a phase I trial in patients with advanced solid tumors: a California Cancer Consortium trial.

BACKGROUND: The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four. METHODS: This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay. RESULTS: Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]). CONCLUSIONS: E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of ß-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.

Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer.

Eribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m(2)) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m(2). Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886).

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status.

BACKGROUND: Cisplatin, a platinum-derived chemotherapeutic agent, produces antineoplastic effects coupled with toxic neuropathic pain and impaired general health status. These side-effects complicate long term studies of neuropathy or analgesic interventions in animals. We recently demonstrated that pretreatment with sodium bicarbonate (4% NaHCO3) prior to cisplatin (3 mg/kg i.p. weekly up to 5 weeks) was associated with improved health status (i.e. normal weight gain, body temperature, creatinine and ketone levels, and kidney weight ratio) in rats (Neurosci Lett 544:41-46, 2013). To reduce the nephrotoxic effects of cisplatin treatment in mice, we compared effects of sodium bicarbonate (4% NaHCO3 s.c.), vitamin C (25 mg/kg s.c.), resveratrol (25 mg/kg s.c.) and saline (0.9% NaCl) pretreatment on cisplatin-induced changes in animal health status, neuropathic pain and proinflammatory cytokine levels in spinal cord and kidney. RESULTS: Cisplatin-treated mice receiving saline pretreatment exhibited elevated ketone, creatinine and kidney weight ratios, representative of nephrotoxicity. Vitamin C and sodium bicarbonate lowered creatinine/ketone levels and kidney weight ratio whereas resveratrol normalized creatinine levels and kidney weight ratios similar to saline pretreatment. All pretreatments were associated with decreased ketone levels compared to saline pretreatment. Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in all pretreatment groups and was similarly reversed by either morphine (6 mg/kg i.p.) or ibuprofen (6 mg/kg i.p.) treatment. RT-PCR showed that mRNA levels for IL-1ß were increased in lumbar spinal cord of cisplatin-treated groups pretreated with either saline, NaHCO3 or resveratrol/cisplatin-treated groups. However, IL-6 and TNF-alpha were elevated in the kidneys in all cisplatin-treated groups. Our studies also demonstrate that 60 days after the last cisplatin treatment, body weight, body temperature, kidney functions and mRNA levels have returned to baseline although the neuropathic pain (mechanical and cold) is maintained. CONCLUSIONS: Studies employing cisplatin should include NaHCO3 or vitamin C pretreatment to improve animal health status and reduce nephrotoxicity (lower creatinine and kidney weight ratio) without affecting the development of chemotherapy-induced neuropathy or analgesic efficacy.