Short-term Infusion Research Articles

Angiotensin-(1-7) induces beige fat thermogenesis through the Mas receptor

ObjectiveAngiotensin-(1-7) [Ang-(1-7)], a component of the renin angiotensin system, is a vasodilator that exerts its effects primarily through the Mas receptor. The discovery of the Mas receptor in white adipose tissue (WAT) suggests an additional role for this peptide. The aim of the present study was to assess whether Ang-(1-7) can induce the expression of thermogenic genes in white adipose tissue and increase mitochondrial respiration in adipocytes. Materials/methodsStromal Vascular fraction (SVF)-derived from mice adipose tissue was stimulated for one week with Ang-(1-7), then expression of beige markers and mitochondrial respiration were assessed. Mas+/+ and Mas−/− mice fed a control diet or a high fat-sucrose diet (HFSD) were exposed to a short or long term infusion of Ang-(1-7) and body weight, body fat, energy expenditure, cold resistance and expression of beige markers were assessed. Also, transgenic rats overexpressing Ang-(1-7) were fed with a control diet or a high fat-sucrose diet and the same parameters were assessed. Ang-(1-7) circulating levels from human subjects with different body mass index (BMI) or age were measured. ResultsIncubation of adipocytes derived from SVF with Ang-(1-7) increased the expression of beige markers. Infusion of Ang-(1-7) into lean and obese Mas+/+mice also induced the expression of Ucp1 and some beige markers, an effect not observed in Mas−/− mice. Mas−/− mice had increased body weight gain and decreased cold resistance, whereas rats overexpressing Ang-(1-7) showed the opposite effects. Overexpressing rats exposed to cold developed new thermogenic WAT in the anterior interscapular area. Finally, in human subjects the higher the BMI, low circulating concentration of Ang-(1-7) levels were detected. Similarly, the circulating levels of Ang-(1-7) peptide were reduced with age. ConclusionThese data indicate that Ang-(1-7) stimulates beige markers and thermogenesis via the Mas receptor, and this evidence suggests a potential therapeutic use to induce thermogenesis of WAT, particularly in obese subjects that have reduced circulating concentration of Ang-(1-7).

Perioperative intravenous low-dose ketamine for neuropathic pain after major lower back surgery: A randomized, placebo-controlled study.

Chronic pain after major lower back surgery is frequent. We investigated in adults the effect of perioperative low-dose ketamine on neuropathic lower back pain, assessed by the DN4 questionnaire, 6 and 12months after major lower back surgery. In this single-centre randomized trial, 80 patients received intravenous ketamine 0.25mg/kg preoperatively, followed by 0.25mgkg-1 hr-1 intraoperatively, and 0.1mgkg-1 hr-1 from 1hr before the end of surgery until the end of recovery room stay; 80 controls received placebo. Preoperatively, 47.4% of patients in the ketamine group and 46.3% in the placebo group had neuropathic pain; 10% and 3.8%, respectively, were using strong opioids. At the end of the infusion, the median cumulative dose of ketamine was 84.8mg (IQR 67.4-106.7) and the median plasma level was 97ng/ml (IQR 77.9-128.0). At 6months, 28.8% of patients in the ketamine group and 23.5% in the placebo group had neuropathic pain (absolute difference, 5.2%; 95% CI -10.7 to 21.1; p=.607). At 12months, 26.4% of patients in the ketamine group and 17.9% in the placebo group had neuropathic pain (absolute difference 8.5%; 95% CI -6.7 to 23.6; p=.319). In this patient population with a high prevalence of neuropathic lower back pain undergoing major lower back surgery, a perioperative intravenous low-dose ketamine infusion did not have an effect on the prevalence of neuropathic lower back pain at 6 or 12months postoperatively. We were unable to show any analgesic benefit of a short-term perioperative ketamine infusion as an adjuvant to multimodal analgesia in patients with a high prevalence of neuropathic lower back pain undergoing major back surgery. Based on these data, the widespread opinion that ketamine is universally analgesic across different pain conditions must be challenged. Abstract presentation at the annual congress of the Swiss Society of Anaesthesiology, 2016, Basel, Switzerland. Registered by Dr Christoph Czarnetzki as principal investigator on February 20, 2008 at clinicaltrials.gov (NCT00618423).

Inappropriate Antidiuretic Hormone Secretion and Cerebral Salt-Wasting Syndromes in Neurological Patients.

The differential diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) in patients with neurological disorders has been a perplexing clinical controversy. The purpose of this review is to summarize the characteristics and risk factors of patients with different types of neurological disorders complicated by hyponatremia (HN) and review various methods to distinguish SIADH from CSWS. Common neurological disorders with high rates of HN include subarachnoid hemorrhage (SAH), traumatic brain injuries, stroke, cerebral tumors, central nervous system (CNS) infections, and Guillain-Barré syndrome (GBS), which have their own characteristics. Extracellular volume (ECV) status of patients is a key point to differentiate SIADH and CSWS, and a comprehensive assessment of relevant ECV indicators may be useful in differentiating these two syndromes. Besides, instead of monitoring the urinary sodium excretion, more attention should be paid to the total mass balance, including Na+, K+, Cl−, and extracellular fluid. Furthermore, the dynamic detection of fractional excretions (FE) of urate before and after correction of HN and a short-term infusion of isotonic saline solution may be useful in identifying the etiology of HN. As for brain natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP), more prospective studies and strong evidence are needed to determine whether there is a pertinent and clear difference between SIADH and CSWS.

1062-P: Insulin Requirement Profiles of Short-Term Continuous Subcutaneous Insulin Infusion Therapy in Chinese Patients with Type 2 Diabetic Nephropathy

Our study aims to explore the insulin requirement profiles of short-term intensive continuous subcutaneous insulin infusion (CSII) in Chinese patients with type 2 diabetic nephropathy. CSII was applied in 68 patients with diagnosed type 2 diabetic nephropathy (using Paradigm 712, Medtronic). Daily insulin doses were titrated and recorded to achieve and maintain target glucose levels (FPG<7.0mmol/L and 2hPBG<10mmol/L) for 8-12 days. The patients were 60.0±13.1 years in age, 45.6% female (n=31), mean duration 11.3±7.2 years, BMI 25.0±3.3 kg/m2, mean HbA1c of 9.4±2.5%, median urinary microalbumin/creatine 78.2 mg/g (inter-quartile range 36.0-274.6 mg/g), and median creatine 72.0umol/l (inter-quartile range 53.5-110.8 umol/l). At the first day after the glycemic targets were achieved (Day1), total daily insulin dose (TDD), total basal and premeal dose were 44.3±17.5 IU (0.67±0.27 IU/kg), 19.6±9.2 IU (0.30±0.14 IU/kg) and 24.7±10.3 IU (0.37±0.15 IU/kg), respectively. At the end of CSII therapy, TDD was 43.7±18.1 IU (0.66±0.28 IU/kg). Total basal dose and total pre-meal dose were 19.2±9.0 IU (0.29±0.14 IU/kg, P>0.05 compared with Day1) and 24.5±11.2 (0.37±0.17 IU/kg, P > 0.05 compared with Day1), respectively. The ratio of basal insulin dose to TDD were 44%±11% at Day1 and 44%±12% at the end, respectively. The ratio of basal insulin dose to TDD at day 1 were 45%±11% and 40%±9% in subjects with eGFR >60ml/min (n=48) or eGFR <60ml/min (n=20), respectively (P=0.11). The ratio of basal insulin dose to TDD at day 1 were 49%±18% and 39%±12% in subjects with eGFR 60-90 ml/min or eGFR <30ml/min, respectively (P=0.041). The TDD at Day1 were 45.8±12.4 IU in subjects with 40.9±26.1 IU in subjects with eGFR >60ml/min or eGFR <60ml/min, respectively (P>0.05). These results suggested the ratio of basal insulin dose to TDD might be decreased while eGFR declined in patients with type 2 diabetic nephropathy. Disclosure S. Lin: None. K. Zhang: None. P. Li: None. K. Fang: None. L. Zeng: None. Funding Science and Technology Planning Project of Guangdong Province (2017A020215026); Medical Scientific Research Foundation of Guangdong Province (A2017314)

1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p<0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p<0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production. Disclosure X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.

2325-PUB: Estimation Formula for the Long-Term Glycemic Remission in Patients with Newly Diagnosed Type 2 Diabetes Receiving Short-Term Intensive Insulin Therapy

Aims: Half of the patients with newly diagnosed type 2 diabetes who received short-term continuous subcutaneous insulin infusion (CSII) were able to achieve a long-term drug-free glycemic remission. It is meaningful to develop an estimation formula to predict the glycemic remission. Methods: We collected data from three prospective trials conducted from 2002 to 2015. A 2∼3 weeks of CSII was provided for the patients with newly diagnosed diabetes to achieve and maintain normal glucose. The one-year drug-free remission rate was observed. Differences between patients with remission and those without remission were evaluated. Estimation formula was developed by using the logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of the estimation formula at different score cutoffs. Results: Data of 244 patients were analyzed. After comparisons, age, gender, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), red cell distribution width (RDW), ratio of fasting plasma glucose to HbA1c (FPG/HbA1c) at baseline, FPG, postprandial plasma glucose (PPG) and the homeostasis model assessment of insulin resistance (HOMA-IR) after short-term CSII treatment were analyzed. We developed a formula as follows: R=11.936-1.626*HDL-1.56*FPG/HbA1c-0.14*RDW-0.496*FPG’ (FPG’ means FPG after short-term CSII). When R is greater than 0.5, it indicates a possible glycemic remission. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 82.8%, 62.2%, 73.7%, 73.3% and 74.2%, respectively. Conclusions: We provide a prediction formula for long-term glycemic remission. For those who is predicted glycemic non-remission, sequential treatment after CSII secession may be beneficial for the long-term glucose control. Disclosure L. Xu: None. L. Liu: None. X. Wan: None. Z. Huang: None. Y. Li: None.

Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.

10013 Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 < 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&scIL2. Patients with evaluable disease prior DB or DB&scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&4 toxicity was lower in the group with DB vs DB&scIL2 for fever (14%vs31%, p < 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate > 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.

Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.

Pharmacokinetic and pharmacodynamic modeling of gut hormone peptide YY(3–36) after pulmonary delivery

Peptide YY(3–36) (PYY(3–36)) is an endogenous appetite suppressing peptide. The present research was to perform pharmacokinetic/pharmacodynamic (PK/PD) analysis for predicting the concentration- and response-time profiles of PYY(3–36) after systemic and pulmonary delivery in mice, with the goal of suggesting a potential pulmonary dosing regimen in humans. A PK/PD model was developed to describe PYY(3–36) plasma concentration - and relative food intake rate ratio (as % of control) - time profiles after intraperitoneal and subcutaneous administration, and inhalation in mice. The absorption of inhaled PYY(3–36) from the lungs of mice could only be described with a combined slow (absorption rate of 0.147 L/h) and fast (absorption rate of 104.4 L/h) absorption process, presumably related to absorption from the central and peripheral regions of the lungs. The estimates for IC50 and Imax were 6.8 ng/mL and 63.5%, respectively, based on inhibitory Emax model. The PK parameters, such as clearance (CL), volume of distribution at steady state (Vdss), and the absorption rates (ka), were then scaled to human’s. The scaled human CL and Vdss for obese subjects were 24.8 L/h and 9.0 L, respectively. The model predicted human plasma PYY(3–36) concentrations agreed reasonably well with placebo-normalized plasma PYY(3–36) concentrations after short-term infusion and SC injection in literature. An inhalation dose of PYY(3–36) of about 100 µg was proposed for obese subjects based on simulations. This PK/PD analysis satisfactorily described PYY(3–36) concentration-time and relative food intake rate ratio- time profiles at all doses and routes. The developed model might facilitate the inhalation dose selection of PYY(3–36).

Cardiovasculaire, respiratoire, gastro-intestinale en gedragseffecten van intraveneuze lidocaïnetoediening bij gezonde paarden bij bewustzijn en evaluatie van de relatie met serumconcentraties van lidocaïne en mono-ethylglycinexylidide

Deze studie had als doel de relatie te bepalen tussen de serumconcentraties van lidocaïne/monoethylglycinexylidide (MEGX) en hun effect op de verschillende lichamelijke stelsels bij het paard. Vijf gezonde paarden bij bewustzijn kregen een twee uur durende placebo-intraveneuze infusie gevolgd door een twee uur durende lidocaïne-infusie (bolus van 1,3 mg/kg in tien minuten gevolgd door een constante infusie van 0,05 mg/kg/min). De lidocaïne- en MEGX-serumconcentraties werden om de tien à vijftien minuten gemeten. Het evenwichtsverlies, de spiertrillingen, het ademhalings-, spijsverterings- en cardiovasculaire stelsel werden beoordeeld met behulp van verschillende niet-invasieve methoden. Tijdens de toediening van de lidocaïne-infusie was de gemiddelde (± standaarddeviatie) lidocaïne- en MEGXconcentratie respectievelijk 768,88 ± 93,32 ng/ml en 163,08 ± 108,98 ng/ml. De toediening van een lidocaïne- infusie beïnvloedde significant de aanwezigheid van trillen. Ook veroorzaakte ze een statistisch maar niet-klinisch significante afname van de systolische en diastolische bloeddruk, die beide correleerden met de lidocaïne- en MEGX-serumconcentratie. Verder verhoogde ze eveneens de duodenale contractiefrequentie, die correleerde met de serumlidocaïne-concentratie. In de voorliggende studie werden milde hypotensieve en prokinetische kortetermijneffecten van een lidocaïne-infusie waargenomen.

Safety and Efficacy of Periprocedural Heparin Plus a Short-Term Infusion of Tirofiban Versus Bivalirudin Monotherapy in Patients Who Underwent Percutaneous Coronary Intervention (from the Intermountain Heart Institute STAIR Observational Registry)

Glycoprotein IIb/IIIa inhibitors, used as a standard intravenous bolus followed by a prolonged infusion for 12 to 18 hours, reduces ischemic complications during percutaneous coronary interventions (PCI) but often at a cost of increased bleeding. Today, when dual oral antiplatelet therapy is routine, heparin use plus short-term (bolus alone or with a <6 hours infusion) glycoprotein IIb/IIIa inhibitors, or bivalirudin monotherapy, have been proposed as potentially superior alternatives. This observational study evaluated the safety and efficacy of heparin plus short-term tirofiban versus bivalirudin monotherapy during PCI. Patients with successful PCI and no cardiogenic shock who were anticoagulated with either of the above regimens were followed for 30-day major bleeding and major adverse cardiovascular events (death, nonfatal myocardial infarction, and urgent target vessel revascularization) at 30 days, 1 year, and long term. A total of 727 patients receiving tirofiban (age = 63 ± 13 years, males = 76%, ACS presentation = 75%, radial access = 51%) and 459 patients receiving bivalirudin, (age = 65 ± 13 years, males = 71%, ACS presentation = 78%, radial access = 18%) were included. Thirty-day major bleeding was 0.7% and 4.1% for tirofiban and bivalirudin, respectively (adjusted odds ratio = 0.17 [0.06, 0.46], p = 0.001). During 30-day, 1-year, and long-term (1.7 ± 0.9 years) follow-up, major adverse cardiovascular events risk did not differ significantly between tirofiban and bivalirudin. However, long-term death was significantly lower in those receiving tirofiban (adjusted hazard ratio = 0.58 [0.34, 1.00], p = 0.05). In conclusion, in this observational study, PCI patients receiving heparin plus short-term tirofiban experienced significantly lower 30-day major bleeding, and improved long-term survival, than those receiving bivalirudin monotherapy.

Physiological and phased approach to newborns at-risk of hyperinsulinemic hypoglycemia: A neonatal perspective

A neonatologist plays a critical role in the management of babies with hypoglycemia. Although neonatal hypoglycemia has been conventionally defined as glucose ≤2.5 mmol/L, levels ≤2.8 mmol/L among neonates raise concerns of neuroglycopenia, supporting the Pediatric Endocrine Societies' suggestion to target plasma glucose levels >2.8 mmol/L in at-risk infants 3.3 mmol/L for those aged >48 h. The neonatologist needs to identify at-risk babies and enroll them into a pathway that ensures safe, physiological transition to extrauterine life. Physiological transition constitutes early enteral feeding, navigating the glucose nadir while maintaining mother–child bonding. Smooth umbilical to enteral transition of glucose homeostasis following birth needs adequate glycogen stores and appropriate counter-regulatory hormone responses. When stores are inadequate and counter-regulatory responses fail, glucose regulation becomes more dependent on appropriate β-cell responses. However, β-cell dysregulation may cause inappropriate insulin secretion when hypoglycemic (hyperinsulinemic hypoglycemia [HH]) that can be transient, prolonged, or persistent. The majority comprise transient and prolonged forms of HH that recover in days to weeks with feeds or short-term parenteral glucose infusion or rarely with use of KATP channel agonist, diazoxide. The minority with persistent forms may have genetic mutations in at least 12 genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PGMM2) and need medical and/or surgical intervention, as well as long-term multidisciplinary specialist care. Although there is complexity to a management framework that begins in the first hours to days of life, a gentle, physiological, and phased approach can lead to better outcomes. This review article describes such an approach.

Brain Endothelial Cells are Exquisite Sensors of Age-Related Circulatory Cues

Brain endothelial cells (BECs) are key elements of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Because circulatory factors have prominent age-related effects on adult neurogenesis, microglia, neuronal activity, and learning and memory in mice the question arises how signals are relayed between the blood and brain. Using single cell RNA sequencing of hippocampal BECs we discovered that capillary BECs, compared with arterial and venous cells, exhibit the greatest transcriptional changes with aging, upregulating innate immunity, TGF-β signaling and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulated key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice had the opposite effect, essentially rejuvenating the BBB endothelial transcriptome. Interestingly, we find correlations between upregulated surface receptors on aging capillaries and the level of their ligands in aging mouse plasma. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.

Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans

1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet.2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics.3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders.4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC50 for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.

Disabling Resting Tremors Induced by the Short-term Infusion of Valproate: A Reversible Phenomenon

<strong>Background:</strong> Drug-induced tremors after long-term administration of anti-epileptics have been described in the literature. Such tremors are usually postural or action in nature with infrequent resting nature. <strong>Case Report:</strong> A 23-year-old female presented in status epilepticus. Past and family histories were negative for seizures. She was managed per protocol with valproate. Within hours, she developed resting tremors. The tremors subsided on changing the anti-epileptic. <strong>Discussion:</strong> Resting tremors have mostly been described in the literature as long-term side-effects of valproate. This case illustrates that even short-term infusion of valproate can cause resting tremors.

High doses of ANP and BNP exacerbate lipolysis in humans and the lipolytic effect of BNP is associated with cardiac triglyceride content in pigs

Drugs facilitating the cardioprotective effects of natriuretic peptides are introduced in heart failure treatment. ANP and BNP also stimulate lipolysis and increase circulating concentrations of free fatty acids (FFAs); an aspect, however, thought to be confined to primates. We examined the lipolytic effect of natriuretic peptide infusion in healthy young men and evaluated the effect in a porcine model of myocardial ischemia and reperfusion.Six young healthy normotensive men underwent infusion with ANP, BNP, or CNP for 20 min. Blood samples were collected before, during, and after infusion for measurement of FFAs. In a porcine model of myocardial ischemia and reperfusion, animals were infused for 3 h with either BNP (n = 7) or saline (n = 5). Blood samples were collected throughout the infusion period, and cardiac tissue was obtained after infusion for lipid analysis.In humans, ANP infusion dose-dependently increased the FFA concentration in plasma 2.5-10-fold (baseline vs. 0.05 μg/kg/min P < 0.002) and with BNP 1.6–3.5-fold (P = 0.001, baseline vs. 0.02 μg/kg/min) 30 min after initiation of infusion. Infusion of CNP did not affect plasma FFA. In pigs, BNP infusion induced a 3.5-fold increase in plasma FFA (P < 0.0001), which remained elevated throughout the infusion period. Triglyceride content in porcine right cardiac ventricle tissue increased ∼5.5 fold in animals infused with BNP (P = 0.02).Natriuretic peptide infusion has similar lipolytic activity in human and pig. Our data suggest that short-term infusion increases the cardiac lipid content, and that the pig is a suitable model for studies of long-term effects mediated by natriuretic peptides.

In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes.

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Short-term intra-arterial infusion chemotherapy for head and neck cancer patients maintaining quality of life

PurposeHead and neck cancer treatment achieves good locoregional tumor control rates while causing severe side effects. Therapy with chemotherapeutic drugs administered intravenously is limited because either the concentrations at the tumor site are too low or the total dosages are too high. The evaluation of a technique for short-term intra-arterial infusion chemotherapy is described herein.MethodsIn a retrospective study, we reviewed the medical records of 97 patients with head and neck cancers who received short-term intra-arterial infusion chemotherapy (62 patients previously untreated, 35 patients with prior radiotherapy). All patients refused further radiotherapy. Response rates, overall survival and adverse effects were the study endpoints. The blood supply of the tumors was controlled with indigocarmine blue infusion and staining of the tumor region.ResultsComplete or partial response was found in 67%, 52% and 63% of previously untreated patients and in 25%, 30% and 29%, respectively, of previously irradiated patients for staging groups I–III, IVA and IVB/C. Patients with T3/T4 tumors who were previously irradiated showed a median overall survival of 9 months, and those without pretreatment showed a median overall survival of 22.5 months. None of the patients required tube feeding. No new case of dysphagia, xerostomia, or functional speech and hearing loss was reported. Pain and clinical symptoms were reduced for all patient groups. Indigocarmine staining showed reduced tumor blood supply in previously irradiated regions but good blood supply in untreated regions.ConclusionsShort-term intra-arterial infusion chemotherapy achieves promising response rates and lacks severe adverse effects.

Efficacy of treprostinil in the SU5416-hypoxia model of severe pulmonary arterial hypertension: haemodynamic benefits are not associated with improvements in arterial remodelling.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH. Male Sprague Dawley rats were injected with SU (20mg·kg-1 , s.c.) followed by 3weeks of Hx (10% O2 ) to induce severe PAH. Four weeks post-SU injection, baseline right ventricular (RV) systolic pressure (RVSP) was measured, and the rats were randomized to receive vehicle or treprostinil treatment (Trep-100: 100ng·kg-1 ·min-1 or Trep-810: 810ng·kg-1 ·min-1 ). Following 3weeks of treatment, haemodynamic and echocardiographic assessments were performed, and tissue samples were collected for protein expression and histological analysis. At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs. Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.

Pharmacodynamic model for β-lactam regimens used in surgical prophylaxis: model-based evaluation of standard dosing regimens.

Background Continual evolution of resistance among bacteria against methods of surgical prophylaxis may make currently used beta-lactam regimens inadequate. Objective To re-evaluate beta-lactamregimensin surgical prophylaxis. Setting A pharmacodynamic Monte Carlo simulation (MCS) modelbased on a number of patients in China. Methods Pharmacodynamic profiling using Monte Carlo simulation up to 4hours postinfusion was conducted for standard-dose, short-term (0.5h) and prolonged (2 to 4h) infusions of ampicillin, cefazolin, cefotaxime, cefoxitin, cefuroxime, ertapenem, and piperacillin/tazobactam in adult patients with normal renal function. Microbiological data were incorporated. Cumulative fraction of response (CFR) was determined for each regimen against populations of S. aureus, coagulase-negative staphylococci and E. coli. The optimal CFR was defined as ≥ 90% response. Main Outcome Measure Cumulative fractions of responseof pharmacodynamic target attainment. Results During the first 2hours postinfusion, piperacillin/tazobactam 3.375g exhibited consistently optimal cumulative fractions against S. aureus, CoNS and E. coli. Ampicillin 2g (2h) also displayed optimal CFRs for S. aureus and E. coli but not for coagulase-negative staphylococci. Cefoxitin 2g didnot achieve any optimal CFRs, even via 2-h prolonged infusion (maximum 72.8% CFR for S. aureus and 64.5% CFR for E. coli). Cefazolin 2g (4h) and cefuroxime 1.5g (4h) provided desired CFRs across 4h postinfusion for S. aureus but provided poor CFRs for coagulase-negative staphylococci and E. coli. Only ertapenem 1g for E. coli and S. aureus and cefotaxime 1g for E. coli consistently yielded ≥ 90% CFRs for 4hour postinfusion. Conclusions Certain dosing regimens may warrant adjustment for improved prevention efficiency and enhanced empirical antibiotic regimens for surgical prophylaxis.