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Unlike cytarabine, cellular entry of Elacytarabine, the elaidic acid ester derivative of cytarabine, is independent of the human equilibrative nucleoside transporter 1 (hENT1). This phase II study tested whether the hENT1 blast expression level can be used as a predictive marker for cytarabine response and if the efficacy of elacytarabine is independent of hENT1 expression. A total of 51 patients with acute myeloid leukemia (AML) induction failure were given elacytarabine-idarubicin as a second induction course. The hENT1 expression level was analyzed prior to first induction and/or prior to treatment with elacytarabine. The overall response rate (ORR) was 41% and the safety profile was manageable. There is a trend suggesting that hENT1 expression influences response to cytarabine, but not sufficient to support it as a biomarker for guiding treatment. Further, we conclude that the activity of elacytarabine is not significantly predicted by the hENT1 expression level.

Purpose: Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care., Patients and Methods: A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS)., Results: There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation., Conclusion: Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population., (© 2014 by American Society of Clinical Oncology.)

Elacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms. A non-clinically significant, elacytarabine exposure-dependent increase in cholesterol was caused by a cholesterol rich lipoprotein depleted of apolipoprotein B formed by infused phospholipids complexing cholesterol. Elacytarabine is clinically active in relapsed/refractory AML: overall response rate (CR + CRi) was 44% (16/36 with 7 non-evaluable patients) and adverse events were manageable. Clinical Trials.gov Identifier: NCT01258816., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Elacytarabine is a novel cytotoxic nucleoside analogue, independent of nucleoside transporters (e.g. human Equilibrative Nucleoside Transporter 1 [hENT1]) for cell uptake, and mechanisms of action similar to those of cytarabine. This Phase II study assessed the efficacy and safety of elacytarabine in patients with advanced stage acute myeloid leukaemia (AML). Patients received 2000 mg/m(2) per d continuously i.v. during days 1-5 every 3 weeks. Patients were matched by six risk factors with historical controls; remission rate (assessed after 1 or 2 cycles) and 6-month survival were compared. Sixty-one patients, median age 58 years, were enrolled; 52% had five or six risk factors. The remission rate was 18% (95% confidence interval: 9-30%) vs. 4% in controls (P < 0·0001), 6-month survival rate was 43%, median overall survival was 5·3 months (vs. 1·5 months); 10 patients (16%) were referred for stem cell transplantation after treatment. Side effects were predictable and manageable. The most common grade 3/4 non-haematological adverse events were febrile neutropenia, hypokalemia, fatigue, hyponatraemia, dyspnoea and pyrexia. Thirty-day all-cause mortality, after start of treatment, was 13% vs. 25% in controls. Elacytarabine has monotherapy activity in patients with advanced AML. This study provides proof-of-concept that lipid esterification of nucleoside analogues is clinically relevant., (© 2012 Blackwell Publishing Ltd.)

This study evaluated combination drug partners for CP-4055, the C18:1(Delta9,trans) unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition was assessed by ATP assay and drug interaction by the combination index and three dimensional methods. Synergy was observed in HL-60 cells for simultaneous combinations of CP-4055 with gemcitabine, irinotecan and topotecan, while combinations with cloretazine (VNP40101M) and idarubicin were additive. In U937 cells, synergy was observed with gemcitabine and additivity for the other drugs. In HL-60, the IC50 concentration of CP-4055 could be reduced 10-fold and that of gemcitabine 3-fold in combination versus the agents alone, an interaction that was independent of drug sequence, ratio and exposure time. In contrast, interactions of CP-4055 with the topoisomerase inhibitors became antagonistic when the drugs were administered 24 h prior to CP-4055 and at certain drug ratios, particularly in U937 cells. In summary, CP-4055 produced additive to synergistic anti proliferative activity when combined simultaneously with drugs from four mechanistic classes in cell culture models of human leukemia and lymphoma. The impact of drug sequence and ratio on the interactions argues for incorporation of these parameters into the design of combination chemotherapy regimens.

Purpose: The purpose of this article was to assess the impact of intravenous (IV) anticholinergic hyoscine butylbromide in abdominal magnetic resonance (MR) imaging with oral magnetic particles (OMP) [ABDOS-CAN, Ferristene (USAN), Nycomed Imaging AS, Oslo, Norway]., Materials and Methods: In 31 patients with abdominal tumors, T1-weighted spin-echo (SE) images (SE 600/ 15; 1.5 T) were obtained without and with IV hyoscine butylbromide (20 mg) before and after administration of 800 ml of OMP. Two blinded readers assessed motion artifacts, bowel-wall visualization, and lesion delineation on the four sets of T1-weighted images. The two-tailed Wilcoxon paired sample test was used for statistical analysis (p < .05)., Results: Hyoscine butylbromide reduced motion artifacts and improved bowel-wall visualization on precontrast and OMP-enhanced images at a statistically significant level (p = 0.0006-0.037). The lowest degree of artifacts was recorded on OMP images with hyoscine butylbromide. OMP with hyoscine butylbromide significantly improved lesion delineation compared to studies without antiperistaltic drug before (p = 0.019) and after OMP administration (p = 0.01)., Conclusions: The authors conclude that the use of IV hyoscine butylbromide is recommended for OMP-enhanced abdominal MR imaging with T1-weighted SE pulse sequences at 1.5 T.

Rationale and Objectives: In this phase III study, we evaluated the efficacy and safety of a negative contrast medium, ferristene (oral magnetic particles), among 277 patients undergoing magnetic resonance (MR) imaging of the abdomen., Methods: Enhanced (800 ml ferristene) MR images were compared with unenhanced MR images in an intraindividual-patient control design. Adverse events were recorded. The examinations were performed on 1.5-T MR systems (T1- and T2-weighted sequences)., Results: Ferristene increased the diagnostic information in 50.9% of the patients, particularly in those with abdominal masses, lymphoma, or pancreatic disease. Distribution of ferristene in the stomach, duodenum, jejunum, and ileum was complete or sufficient in 70.5-85% of the studies. In 64% of the patients, we were confident in the MR findings after the use of ferristene, and ferristene disclosed additional findings in 22% of the patients. The incidence of adverse events was 9.0%, but only 3.6% of all patients experienced ferristene-related adverse events (e.g., nausea, vomiting). Most events were mild or moderate in intensity., Conclusion: Ferristene was well tolerated, and for 50% of the patients it added useful diagnostic information.

Iodixanol (Visipaque, 320 mgI/ml) was compared with iopamidol (Solutrast, 370 mgI/ml) in a double-blind, randomized, parallel group, intravenous DSA phase-III trial for evaluation of safety and efficacy. A total of 117 patients received iodixanol (n = 60) or iopamidol (n = 57). Diagnostic efficacy was evaluated using categoric and visual analogue scales. Discomfort and adverse events were recorded. A total of 39 patients collected urine up to 72 h after the examination for analysis. Diagnostic efficacy and radiographic density were similar in both groups. Discomfort was milder with iodixanol. The difference between the frequency of adverse events between both groups (iodixanol = 7, iopamidol = 2) was without statistical significance. Creatinine clearance was slightly more affected by iodixanol, whereas the increase in renal excretion of N-acetyl-beta-glucosaminidase (NAG) in the first 24-h collection period after the examination was significantly higher (p < 0.01) with iopamidol. Iodixanol was of equal diagnostic efficacy compared with iopamidol despite its reduced iodine content. Both contrast media are well suited for IV DSA.

A phase III trial was conducted in 40 patients with known or suspected skull base tumors to evaluate the safety and efficacy of high-dose gadodiamide injection for use as a paramagnetic contrast medium in conventional and dynamic magnetic resonance (MR) imaging. Contrast material enhancement was assessed dynamically with use of a gradient-recalled sequence. The time-intensity curve of selected regions of interest showed a reproducible dropout effect in the form of a dip in the curve during the early enhancement of the sigmoid sinus and jugular bulb; the same phenomenon was observed in all glomus tumors of the skull base, regardless of size or location. In contrast, schwannomas, meningiomas, and a variety of other lesions showed a continuous increase in the time-intensity curve. The drop-out sign, which is probably a result of a paramagnetic phenomenon during the early phase of enhancement, seems to be specific for glomus tumors. High-dose gadodiamide injection may show a specific dynamic pattern for glomus tumors, allowing differentiation from other tumors of the middle and posterior skull base.

A prospective Phase III trial was performed to evaluate the efficacy in clinical practice of a new gastro-intestinal contrast agent, Oral Magnetic Particles (OMP), for use in abdominal and pelvic magnetic resonance imaging (MRI). This was an open study comprising 35 patients each given 800 ml of OMP at a concentration of 0.5 g/l. Distribution of the agent was most reliable in the small bowel. General contrast effect was satisfactory, and image quality and diagnostic confidence were enhanced. Administration of OMP increased diagnostic information in the magnetic resonance (MR) image in 50% of patients. No clinically significant adverse effects were observed. The results confirm in a clinical setting a potential role for this new contrast agent.

Oral magnetic particles (OMP) have been evaluated in a clinical phase II trial program comprising 216 patients in 7 European centers. Adult patients referred for MR imaging for various abdominal pathologies were examined. The patients received OMP at a concentration of 0.1 g/l (ultralow field) or 0.5 g/l (mid/high field) and OMP was diluted in water or in a more viscous liquid formulation. Depending on the area of interest, OMP was ingested in a volume of 300 to 800 ml. OMP was well tolerated with no serious adverse events and the patient acceptability was good. OMP had a good contrast effect on all applied pulse sequences. The viscous formulation of OMP was homogeneously distributed through the entire gastrointestinal tract without inducing disturbing susceptibility artifacts. The postcontrast diagnostic information was improved in 70% of the cases. Based on the encouraging results in phase II, OMP has been advanced to phase III clinical trials.

To determine the value of oral magnetic particles (OMP) as a superparamagnetic MR contrast agent for the gastrointestinal tract in lower abdominal and pelvic lesions, 30 patients underwent spin-echo imaging before and after ingestion of OMP at a dose of approximately 80 mg of iron in 800 ml water. The preparation was divided into four portions and taken by the patient over a 2-h period. Two readers independently reviewed the MR images. The contrast material was well tolerated and the distribution of the contrast material was good to excellent in the proximal and pelvic small bowel, but was not sufficient in the colon with the dose and timing used in the study. Postcontrast images showed a significantly better delineation of the lesions, the small bowel, and the paraaortic region, but no significant improvement in the delineation of the colon, the iliac vessels area, the bladder or genital tract. Compared with precontrast images, confidence in defining or excluding disease on postcontrast images was better, equal or worse in 40, 60 and 0% of cases, respectively (P less than 0.001) with a substantial agreement between readers (kappa = 0.71). OMP produced susceptibility artefacts of significant intensity in only one case. These results indicate that OMP may be useful in the delineation of lower abdominal and pelvic lesions at MR imaging. Marking of the colon by a contrast agent might improve the results.

The effect of Diamphidia toxin, isolated from pupae of Diamphidia nigro-ornata, was tested on two different cell lines (GH4C1 cells and HL-60 cells) and on human lymphocytes. The toxin raised intracellular Ca2+ concentration, as assessed with quin 2, in a dose-related manner in all three cell types. The effect was abolished when extracellular Ca2+ was chelated by EGTA. Low concentrations of the toxin evoked a delayed as well as a smaller response. The response time was also temperature-dependent, with a Q10 of about 2. Low, but effective concentrations of the toxin did not affect cell membrane integrity, as tested with Trypan blue, and induced a seemingly physiological release of prolactin from the GH4C1 cells. Diamphidia toxin's effect on the membrane permeability of GH4C1 cells was further investigated with patch-clamp techniques. The toxin appeared to increase the conductance for all small ions without affecting the normal ionic channels present in these cells. We conclude that Diamphidia toxin has a general effect on the plasma membrane of different cell types and thereby increases, probably non-specifically, the permeability for small ions.