24-h Infusion Research Articles

A supplemental intravenous amino acid infusion sustains a positive protein balance for 24\xa0hours in critically ill patients

BackgroundProviding supplemental amino acids to ICU patients during a 3-h period results in improved whole-body net protein balance, without an increase in amino acid oxidation. The primary objective was to investigate if a 24-h intravenous amino acid infusion in critically ill patients has a sustained effect on whole-body protein balance as was seen after 3 h. Secondary objectives were monitoring of amino acid oxidation rate, urea and free amino acid plasma concentrations.MethodsAn infusion of [1-13C]-phenylalanine was added to ongoing enteral nutrition to quantify the enteral uptake of amino acids. Primed intravenous infusions of [ring-2H5]-phenylalanine and [3,3-2H2]-tyrosine were used to assess whole-body protein synthesis and breakdown, to calculate net protein balance and to assess amino acid oxidation at baseline and at 3 and 24 hours. An intravenous amino acid infusion was added to nutrition at a rate of 1 g/kg/day and continued for 24 h.ResultsEight patients were studied. The amino acid infusion resulted in improved net protein balance over time, from -1.6 ± 7.9 μmol phe/kg/h at 0 h to 6.0 ± 8.8 at 3 h and 7.5 ± 5.1 at 24 h (p = 0.0016). The sum of free amino acids in plasma increased from 3.1 ± 0.6 mmol/L at 0 h to 3.2 ± 0.3 at 3 h and 3.6 ± 0.5 at 24 h (p = 0.038). Amino acid oxidation and plasma urea were not altered significantly.ConclusionWe demonstrated that the improvement in whole-body net protein balance from a supplemental intravenous amino acid infusion seen after 3 h was sustained after 24 h in critically ill patients.Trial registrationThis trial was prospectively registered at Australian New Zealand Clinical Trials Registry. ACTRN, 12615001314516. Registered on 1 December 2015.

Monitorización terapéutica de metotrexato en pacientes leucémicos mediante cromatografía líquida de alta resolución. Desarrollo, validación y aplicación clínica del método analítico

IntroductionTherapeutic drug monitoring of methotrexate (MTX) is a practice used during acute lymphoblastic leukaemias treatments in order to adjust the leucovorin rescue dose and avoid toxicity. The aim of this work was to evaluate the performance of a bioanalytical method based on liquid chromatography in the control of paediatric acute lymphoblastic leukaemia treatments. Materials and methodsMTX plasma concentrations were evaluated in a total of 61 patients, divided in 2 groups according to the treatment: 24h infusion and 36h infusion. The method used 250μL aliquots of pre-processed plasma, using a validated analytical method, in an Agilent 1260 chromatograph with a 5μm Zorbax Eclipse XDB-C18 column (4.6×150mm) and a mobile phase composed of acetonitrile and 0.05mol/L of a sodium acetate buffer solution at pH 3.5. The detection was performed at 305nm. ResultsThe method did not show interferences by metabolites or other drugs. The lower limit of quantitation was 0.05μmol/L. Inter- and intra-assay precision and accuracy were acceptable in the working range (0.05-5.0μmol/L), and linear behaviour was observed. Toxic plasma levels of MTX were observed in 29.4% and 60% of the patients from 24h infusion and 36h infusion, respectively. Therefore, leucovorin rescue treatment was either applied earlier or reinforced. ConclusionsThe chromatography method was efficient and accessible for the therapeutic drug monitoring of MTX in paediatric patients, allowing appropriate medical decision making within a short time of analysis.

Validation of whole room indirect calorimeters: refinement of current methodologies.

Whole room indirect calorimeter (WRIC) validation techniques consist of propane combustion (PC) or infusion of mixed carbon dioxide (CO 2) and nitrogen (N2) by a precision blender (PB). To determine the best method, PC of 6, 10, 22‐h and PB infusions of 6, 10, and 14‐h, were conducted. The 14‐h infusion consisted of two metabolic settings. Energy expenditure (EE; kJ), ventilation (V; liters/min) of oxygen (VO 2), VCO 2, and respiratory quotient (VCO 2/VO 2) obtained from the WRIC were extrapolated to the respective test durations and compared to similarly calculated values. Moreover, accurate equations (AE) were derived to correct infusions for additional N2. As a final evaluation of a PC validated WRIC, weight maintenance (WM), energy balance (EB), respiratory quotient (RQ), and food quotients (FQ) were determined in 22 subjects who had repeat 24‐h EE measurements. Statistical analyses (P < 0.05) were conducted (SPSS, version 23). Significant differences in RQ existed between PC and stoichiometry after 6‐h. Errors for the rest of the PC tests ranged from −1.5 ± 2.4 (VCO 2) to 2.8 ± 4.6% (EE). When compared with the WRIC, all uncorrected metabolic parameters for six and 10‐h PB infusions were significantly different with errors from −12.8 ± 1.6 (VO 2) to 6.0 ± 2.8% (RQ). The AE reduced the magnitude of errors to −12.4 ± 1.5 (RQ) to 2.2 ± 3.0% (RQ). The PB infusion with two settings showed similar performance. No differences in WM, EB, RQ, or FQ existed in the subjects. In conclusion, 10‐h PC tests are sufficient for validating WRICs.

Analgesia with continuous wound infusion of local anesthetic versus saline: Double-blind randomized, controlled trial in hepatectomy

BackgroundSurgical wound is source of pain in hepatectomy with laparotomy. Continuous wound infusion of ropivacaine may provide effective analgesia. MethodsThis prospective, randomized trial, patients scheduled for hepatectomy received a 48-h preperitoneal continuous wound infusion of either 0.23% ropivacaine or 0.9% saline at 5 ml/h. Primary endpoint was 48 h morphine consumption. Results53 patients included in the ropivacaine group and 46 in the saline group. Morphine consumption was 24.63 mg in the ropivacaine group, and 26.78 mg (p = 0.669) in the saline group. Pain was comparable between groups and there were no differences in solid food intake, ambulation, or length of hospital stay. No local or systemic complications were recorded. ConclusionsContinuous wound infusion with ropivacaine is safe, but it neither reduced morphine consumption nor enhanced recovery in patients undergoing hepatectomy. Success of enhanced recovery in hepatectomy is not influenced by the analgesic regimen if pain is well controlled.

Short communication: Short-term intravenous amino acid infusions as a method to detect limiting amino acids in dairy cattle diets

We hypothesized that the addition of limiting AA increases dry matter intake (DMI) by reducing anaplerosis and hepatic oxidation. Accordingly, the objective of this work was to examine the effects of short-term intravenous infusions of Met, Lys, and His (which are considered the most limiting AA) on DMI as a method to detect whether specific AA are limiting in dairy cow diets. We conducted 4 experiments using Holstein cows in the immediate postpartum period to address this objective. The first experiment used 4 cows 6 to 10 d postpartum (PP) in a 4 × 4 Latin square design with 1-d periods including 12 h for infusions and 12 h for recovery. Treatments were continuous infusions of 5 (low), 10 (medium), or 15% (high) of the calculated requirement of metabolizable Met, Lys, and His or 0.9% saline (control, CONT). In the second and third experiments, 8 cows (4-12 d PP) were divided into 2 groups of 4 cows, and each group received a different diet formulated to either be low in Lys (experiment 2) or Met (experiment 3). Each experiment was a crossover design with two 1-d periods with 12-h infusions (continuous) and 12 h for recovery. Treatments were 15% of the calculated requirement of metabolizable Met, Lys, and His (high), or 0.9% saline (CONT). In the fourth experiment, 5 cows (4-14 d PP) were used in a 5 × 5 Latin square design. Periods were 2 d in which treatments were continuously infused for the first 46 h. Treatments were 0.9% saline (CONT), all (Lys, Met, and His), LM (Lys and Met), LH (Lys and His), and MH (Met and His); dosages were equal to the estimated shortage in each specific AA. In each experiment, feed intake was recorded by a computerized data acquisition system, milk yield was recorded, and milk composition was analyzed for fat, protein, lactose, and milk urea nitrogen (MUN) concentrations. Treatments did not affect DMI or yield of milk or milk components in the first experiment. In the second experiment, AA treatment increased protein percentage and reduced lactose percentage but had no effect on protein and lactose yields or DMI. In the third experiment, the AA treatment tended to increase yields of milk, lactose, and protein as well as MUN concentration but did not affect DMI. In the fourth experiment, no effects were detected for DMI and milk yield, whereas the all, LH, and LM treatments reduced milk lactose concentration compared with CONT, and MH increased MUN concentration compared with CONT and other treatments. These results failed to provide support for our hypothesis that short-term addition of these potentially limiting AA will increase DMI. This may be due to our hypothesis being inaccurate or to other factors; other limiting AA could have prevented the effects of Lys, Met, and His infusions or the infusion periods could have been too short to induce a response in DMI. Accordingly, short-term infusion of AA is probably not a sensitive method to detect limiting AA in dairy cow diets.

Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir.

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h (P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h (P < 0.0001) and nitric oxide (NO) at 24 and 48 h (P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP (P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality (P = 0.01), increased MAP (P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively (P ≤ 0.03), and plasma NO at both times (P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h (P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality.NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.

Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies

Background:Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity.Methods:In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography.Results:Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m−2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred.Conclusions:Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

DOSE-EXPOSURE SIMULATION FOR PIPERACILLIN-TAZOBACTAM DOSING STRATEGIES IN INFANTS AND YOUNG CHILDREN

Background: Extended piperacillin-tazobactam (TZP) infusions have been associated with favorable outcomes. There are currently no pediatric dosing recommendations.&#x0D; Objective: To determine appropriate TZP dosing strategies in children 2 months – 6 years according to age and different minimal inhibitory concentrations (MICs).&#x0D; Methods: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal.&#x0D; Results: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants &gt; 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children &gt; 6m. While none of the tested regimens were optimal at MICs &gt; 16 mg/L in children &gt; 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants &gt; 2 to 6m.&#x0D; Conclusion: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants &gt; 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children &gt; 6m-6y achieved PTAs ≥ 90%.

Effect of hormonal and energy-related factors on plasma adiponectin in transition dairy cows

In transition dairy cows, plasma levels of the insulin-sensitizing hormone adiponectin fall to a nadir at parturition and recover in early lactation. The transition period is also characterized by rapid changes in metabolic and hormonal factors implicated in other species as positive regulators of adiponectin production (i.e., negative energy balance, lipid mobilization) and others as negative regulators (i.e., reduced leptin and insulin and increased growth hormone and plasma fatty acids). To assess the role of onset of negative energy balance and lipid mobilization after parturition, dairy cows were either milked thrice daily (lactating) or never milked (nonlactating) for up to 4 wk after parturition. Plasma adiponectin was 21% higher across time in nonlactating than lactating cows. Moreover, nonlactating cows recovered plasma adiponectin at similar rates as lactating cows even though they failed to lose body condition. Next, we assessed the ability of individual hormones to alter plasma adiponectin in transition dairy cows. In the first experiment, dairy cows received a constant 96-h intravenous infusion of either saline or recombinant human leptin starting on d 8 of lactation. In the second experiment, dairy cows were studied in late pregnancy (LP, starting on prepartum d -31) and again in early lactation (EL, starting on d 7 postpartum) during a 66-h period of basal sampling followed by 48 h of hyperinsulinemic-euglycemia. In the third experiment, cows were studied either in LP (starting on d -40 prepartum) or EL (starting on d 7 postpartum) during a 3-h period of basal sampling followed by 5 d of bovine somatotropin treatment. Plasma adiponectin was reduced by an average of 21% in EL relative to LP in these experiments, but neither leptin, insulin, or growth hormone treatment affected adiponectin in LP or EL. Finally, the possibility that plasma fatty acids repress plasma adiponectin was evaluated by intravenous infusion of a lipid emulsion in nonpregnant, nonlactating cows in the absence or presence of glucagon for 16 consecutive hours. The intralipid infusion increased plasma fatty acid concentration from 102 to over 570 µM within 3 h but had no effect on plasma adiponectin irrespective of presence or absence of glucagon. Overall, these data suggest that energy balance around parturition may regulate plasma adiponectin but do not support roles for lipid mobilization or sustained changes in the plasma concentration of leptin, insulin, growth hormone, or fatty acids.

Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children.

Extended piperacillin-tazobactam (TZP) infusions have been associated with favourable outcomes. There are currently no pediatric dosing recommendations. To determine appropriate TZP dosing strategies in children 2 months - 6 years according to age and different minimal inhibitory concentrations (MICs). Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal. PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.

Impact of renal replacement modalities on the clearance of piperacillin-tazobactam administered via continuous infusion in critically ill patients

This prospective pharmacokinetic study aimed to compare the clearance of piperacillin-tazobactam administered as a 24-h continuous infusion between continuous venovenous haemodiafiltration (CVVHDF) and continuous venovenous haemofiltration (CVVH) applied at equal dose in critically ill patients.A loading dose of 4.5 g of piperacillin-tazobactam followed by a continuous infusion (500 mg/h) was administered to patients randomized to receive CVVHDF or CVVH. Serial pre- and postfilter blood samples were drawn during an 8-h sampling interval. Piperacillin plasma concentrations were measured using a validated chromatography method. Piperacillin pharmacokinetics were calculated using a non-compartmental approach.In total, 212 piperacillin plasma concentrations were determined. Median [interquartile range (IQR)] total piperacillin clearance was 7.5 (5.9–11.2) L/h in the CVVHDF group and 4.7 (4.5–9.6) L/h in the CVVH group (P = 0.21). Median (IQR) piperacillin clearance related to continuous renal replacement therapy (CRRT) was 3.0 (2.7–3.2) L/h in the CVVHDF group and 2.6 (1.9–3.0) L/h in the CVVH group (P = 0.29). Mean (standard deviation) steady state concentrations were 68.4 (25.8) mg/L in the CVVHDF group and 89.1 (35.6) mg/L in the CVVH group (P = 0.16). The estimated unbound concentrations resulting from piperacillin continuous infusion were above the target susceptibility breakpoint (16 mg/L) for the entire dosing interval (100% fT>MIC) in all study patients.In the present study, higher (but not significantly) piperacillin clearance and lower piperacillin exposure were observed in patients receiving CVVHDF compared with CVVH. In patients receiving CRRT, the use of piperacillin continuous infusion should be considered to ensure optimal exposure for less susceptible pathogens.

The Role of Concomitant Radiation Boost in Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer.

This study analyzed the impact of concomitant boost on long-term clinical outcomes in locally advanced rectal cancer. A total of 141 patients (median age=61 years) were treated with neoadjuvant chemoradiotherapy. Median total dose was 50.4 Gy. Forty-three patients received a concomitant boost. Concurrent chemotherapy consisted of 5-fluorouracil (5-FU), given as a 24-h continuous infusion. Mean follow-up was 83.7 months. The 3, 5-, and 10-year overall survival (OS) rates were 91.9%, 84.6%, and 52.9%, respectively. Recurrence-free survival (RFS) rates at 3, 5, and 10 years were 91.4%, 88.9%, and 79.3%, respectively. Metastasis-free survival (MFS) rates at 3, 5, and 10 years were 84.6%, 75.4%, and 49.9%, respectively. Overall, 9.9% of all patients achieved pathological complete response. Down-staging of T- or N-stage was achieved in 55.1% and 41.5% of patients. Multivariate analysis revealed that female sex (p=0.011), concomitant boost-radiotherapy (p=0.014), and the presence of fewer than five positive lymph nodes (p<0.001) were positive predictors of OS. Fewer than five positive lymph nodes was also a positive predictor for RFS (p=0.019). Female gender (p=0.018) and fewer than five positive lymph nodes (p<0.001) were significant predictors for MFS. Our data support the efficacy of preoperative treatment for rectal cancer in terms of local outcomes. Intensified radiotherapy using a concomitant boost has a positive effect on OS.

Correlation between a new growth modulation index (GMI)-based Geistra score and efficacy outcomes in patients (PTS) with advanced soft tissue sarcomas (ASTS) treated with trabectedin (T): A Spanish group for research on sarcomas (GEIS-38 study).

11070 Background: The GMI is a marker of drug activity and represents an intra-patient comparison of successive time to progression (TTP), defined as the TTP ratio between the second (or later) line (TTPn) of therapy divided by the prior line (TTPn−1). Defining a clinical profile of pts with GMI &gt;1.33 could help to identify pts who can gain greater benefit from T. Methods: We retrospectively evaluated the concordance between the GMI and the efficacy outcomes and clinical profiles of 198 pts with ASTS treated with trabectedin 1.5 mg/m² (24-h infusion q3w) as a 2nd or further-line treatment from Jan 2007 to Jun 2016. Results: After a median follow-up of 58 months (m; range: 18-172) median overall survival from ASTS diagnosis (MOS) and from T (MT-OS) were 27.5 m (23-32.1) and 10.8 m (8.9-12.7), respectively, while median TTP from T (MT-TTP) and T-1 were 3.4 m (2.8-4) and 3.5 m (2.8-4.2). Overall, 106 pts (53%) had a GMI &lt;1; 22 (11%) a GMI=1-1.33 and 70 pts (35%) a GMI &gt;1.33. A high GMI (&lt;1.33 vs &gt;1.33) correlated with favorable efficacy outcomes: MT-OS: 23 vs 36 m (p&lt;0.001), MT-TTP 2.3 vs 8.2 m (p&lt;0.001) and clinical benefit (objective response + stable disease) 23% vs 68% (p=0.001). The multivariate analysis identified L-type sarcoma (Odds ratio: 1.99, 95% CI 1.06-3.71), metastatic free interval (MFI) from initial diagnosis &gt; 8.1 m (2.24, 95%CI 1.19-4.18) and Karnofsky &gt;80 (2.3, 95%CI 1.00-5.28) as factors independently associated to GMI&gt; 1.33. Based on these 3 variables we defined a new GEISTRA score assigning 1 point for each adversely affected variable: non L-Sarcoma, MFI&lt;8.1m or Karnofsky &lt;80. This score showed a strong correlation with MT-TTP (p&lt;0.001) and MT-OS (p&lt;0.001). Conclusions: Based on the high GMI we defined a new GEISTRA score, which is strongly associated with favorable efficacy outcomes in pts with ASTS treated with T. Thus, GEISTRA score could be a potentially useful predictable clinical tool for T benefit. [Table: see text]

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of BAL101553, a novel tumor checkpoint controller (TCC), administered as 48-hour infusion in adult patients with advanced solid tumors.

TPS2602 Background: BAL101553 (prodrug of BAL27862), is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 has shown potent antitumor activity in diverse preclinical tumor models, including models refractory to standard therapies. In a completed Phase 1 study using 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. JCO 34, 2016 suppl; 2525) dose-limiting vascular effects were observed and appeared Cmax related. The recommended Phase 2 dose for 2-h IV BAL101553 is 30 mg/m2. Vascular toxicity was not observed in an ongoing study with oral BAL101553 (NCT02490800, CDI-CS-002) at daily doses up to 30 mg (QD). Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. BAL27862 has a half-life of ~15 h. Based on PK-modeling, extending the infusion from 2 h to 48 h was expected to result in ~4-fold higher AUC at a given Cmaxlevel and thereby improve the therapeutic window. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study (NCT02895360, CDI-CS-003/SAKK67/15) using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of 48-h infusions of BAL101553 in consecutive 28-day cycles at a starting dose of 30 mg/m2 administered on Day 1, 8 and 15 (q28d). The dose escalation scheme foresees up to ~ 50% dose increments depending on observed toxicities. During cycle 2, patients receive 7 days oral (QD) BAL101553 (Day 15–21) instead of the weekly IV infusion to assess absolute oral bioavailability. Patients with histologically-confirmed advanced or recurrent solid tumors are eligible for enrollment. Adverse events are assessed using CTCAEv4; tumor response by RECIST 1.1 (every 2 cycles). PD assessments include optional tumor biopsies and circulating tumor cells. PK profiles are assessed during the first 2 cycles. Two dose cohorts (30 and 45 mg/m2) have completed without DLTs or signs of vascular toxicity. Clinical trial information: NCT02895360.

A first‐in‐human study of DS‐1040, an inhibitor of the activated form of thrombin‐activatable fibrinolysis inhibitor, in healthy subjects

Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45years) or elderly (65-75years) subjects (N=103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1mg to 40mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet aggregation were observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development.

Effects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome.

To investigate whether neuromuscular blocking agents (NMBA) exert beneficial effects in acute respiratory distress syndrome (ARDS) by reason of their action on respiratory mechanics, particularly transpulmonary pressures (P L). A prospective randomised controlled study in patients with moderate to severe ARDS within 48h of the onset of ARDS. All patients were monitored by means of an oesophageal catheter and followed up for 48h. Moderate ARDS patients were randomised into two groups according to whether they were given a 48-h continuous infusion of cisatracurium besylate or not (control group). Severe ARDS patients did not undergo randomisation and all received cisatracurium besylate per protocol. The changes during the 48-h study period in oxygenation and in respiratory mechanics, including inspiratory and expiratory P L and driving pressure, were assessed and compared. Delta P L (∆P L) was defined as inspiratory P L minus expiratory P L. Thirty patients were included, 24 with moderate ARDS and 6 with severe ARDS. NMBA infusion was associated with an improvement in oxygenation in both moderate and severe ARDS, accompanied by a decrease in both plateau pressure and total positive end-expiratory pressure. The mean inspiratory and expiratory P L were higher in the moderate ARDS group receiving NMBA than in the control group. In contrast, there was no change in either driving pressure or ∆P L related to NMBA administration. NMBA could exert beneficial effects in patients with moderate ARDS, at least in part, by limiting expiratory efforts.

A retrospective study of treatment and prophylaxis of ifosfamide-induced hemorrhagic cystitis in pediatric and adolescent and young adult (AYA) patients with solid tumors.

Ifosfamide (IFO) is considered an essential drug for the treatment of pediatric, adolescent and young adult patients with solid tumors. Hemorrhagic cystitis (HC) is one of the dose-limiting toxicity of IFO. However, there are insufficient evidence for risk factor and supportive care of IFO-induced HC. In this retrospective study, patients (<30-year-old) with malignant solid tumors who had been treated with IFO-based chemotherapy, were categorized according to the presence or absence of HC, and were analyzed possible risk factors for IFO-induced HC. In our institution, continuous hydration to increase urine output and intravenous 2-mercaptethane sulfonate (mesna) are used for prophylaxis of IFO-induced HC. Increased hydration and dosage of mesna are administered to patients who develop IFO-induced HC; they also receive 24-h continuous infusion of mesna in subsequent treatment cycles. Nine treatment regimens were used in the 70 study patients. The range of daily IFO dosage was 1.2-3.0 g/m(2). HC occurred in 14/425 IFO-based chemotherapy cycles (3.3%). The daily IFO dosages (mean±SD) in patients with or without HC were 2.23±0.58 g/m(2) and 1.85±0.50 g/m(2), respectively (P=0.006). Only one of the nine patients who developed IFO-induced HC had experienced this complication in a subsequent cycle of treatment. The incidence of IFO-induced HC may be associated with the dosage of IFO. When administering IFO higher than 2.0 g/m(2)/day, the volume of hydration, dosage of mesna and duration of mesna infusion should be increased to prevent HC.

Acute blood glucose fluctuation enhances rat aorta endothelial cell apoptosis, oxidative stress and pro-inflammatory cytokine expression in vivo.

BackgroundComplications of diabetes mellitus (DM) are related not only to elevated plasma glucose, but also plasma glucose fluctuations. However, the specific mechanism underlying the role of plasma glucose fluctuation in the pathogenesis of DM complications remains poorly understood. In the present study, the influence of acute fluctuant hyperglycemia and persistent hyperglycemia on vascular endothelial cell apoptosis, function, oxidative stress and inflammation was examined in vivo.MethodsRats were assigned to three different groups (n = 10/group) that received 48-h infusions of saline (SAL group), continuous 50 % glucose (constant high glucose group [CHG]), or intermittent 50 % glucose (acute blood glucose fluctuation group [AFG]). Plasma 8-isoprostaglandin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) levels were quantified by using enzyme-linked immunosorbent assay (ELISA) commercial kits. Plasma insulin levels were measured by radioimmunoassays (RIAs) using kits. The aortic segment was collected. The levels of malondialdehyde (MDA) and activity of glutathione peroxidase (GSH-PX) were measured in endothelial homogenates prepared from endothelial cells harvested from the aorta using colorimetric kits. Apoptosis of vascular endothelial cells was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Endothelial dysfunction was assessed by isometric tension recording to evaluate the endothelial function. The expression of B cell lymphoma-2 (Bcl-2), Bcl-2 Associated X protein (Bax), pro caspase-3, caspase-3 p17, 3-nitrotyrosine (3-NT) and p47phox protein in rat aortic endothelial cells were tested with Western blot analysis. Endothelial cells reactive oxygen species (ROS) formation was determined using dihydroethidium-dependent fluorescence microtopography in aortic cryo-sections. Expression of IL-6, TNF-α and ICAM-1 mRNAs in vascular endothelial cells were determined by real-time quantitative PCR.ResultsEndothelial cells apoptosis and dysfunction were observed significantly in the aortas of the AFG group (P < 0.05). The AFG had reduced Bcl-2 and pro caspase-3 levels and enhanced Bax mitochondrial translocation and caspase-3 p17 protein levels in comparison with the CHG group (P < 0.05). Both AFG and CHG induced β-cell dysfunction and insulin resistance (P < 0.05). AFG increased MDA and 8-isoprostaglandin levels in plasma, oxidative stress in vascular endothelial cells, and inflammatory cytokines in plasma and vascular endothelial cells (P < 0.05).ConclusionAcute glucose fluctuation may cause significant oxidative stress and inflammation in endothelial cells, increase the adhesion of monocytes to endothelial cells, and elevate endothelial cell apoptosis, resulting in severe cardiovascular injury.

Metastatic extraskeletal Ewing's sarcoma treated with trabectedin: A case report.

The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin®) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment. Trabectedin is a novel treatment option for patients with ESFT. The present study reports the case of a Caucasian 69-year-old female patient who presented with a soft tissue mass on the chest wall that had developed 7 months earlier. A computed tomography scan revealed a 9×8×7-cm mass on the anterior chest wall above the pectoral muscle. Histopathological evaluations and molecular analysis indicated that it was consistent with a metastatic extraskeletal Ewing's sarcoma. The patient was treated with an alternating VAC/IE regimen; however, an inadequate response was observed. The patient received second-line treatment with a gemcitabine and dacarbazine combination regimen, but the disease progressed. Subsequently, treatment with trabectedin (1.5 mg/m2 as a 24-h continuous infusion every 3 weeks) was initiated. Trabectedin treatment resulted in long-lasting (18 months) progression-free survival. It is vital that novel drugs continue to being developed for patients with ESFT following progression subsequent to standard chemotherapy. The current report presents a case of a patient with metastatic, pre-treated Ewing's sarcoma achieving disease stabilization with trabectedin. Based on these results and the observed tolerability profile, trabectedin represents an alternative treatment for patients with ESFT. Further studies are required in order to determine the efficacy of trabectedin as monotherapy or in combination with other drugs. It is also important to identify which tumor subtypes, specific translocations and patient profiles will benefit the most from treatment with trabectedin.

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin’s lymphoma

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5g/m(2)/day and MESNA 5g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5g/m(2) over 12h (day 3), and mitoxantrone 20mg/m(2) (day 1) administered every 2weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96% of patients. Overall response rate was 74% (89% in relapsing and 45% in refractory patients) with 31% complete remissions. After a median follow-up of 54months, 5-year event-free survival was 56% (69% for relapsing and 35% for refractory patients), and 5-year overall survival was 67% (73% for relapsing and 55% for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options.