Excretion of the Polymyxin Derivative NAB739 in Murine Urine.

Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine pyelonephritis at doses only one-tenth of that needed for polymyxin B.

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii.

The antibiotic crisis has reinstated polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective derivatives of polymyxins such as NAB739. Simultaneously, polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare.

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.

Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs on chips" - are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms.

Accuracy and precision of patient positioning for pelvic MR-only radiation therapy using digitally reconstructed radiographs.

Background And Purpose: Magnetic resonance imaging (MRI) has in recent years emerged as an imaging modality to drive precise contouring of targets and organs at risk in external beam radiation therapy. Moreover, recent advances in MRI enable treatment of cancer without computed tomography (CT) simulation. A commercially available MR-only solution, MRCAT, offers a single-modality approach that provides density information for dose calculation and generation of positioning reference images.

Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis.

Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree.

Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity.

Recent years have brought in an increased interest to develop improved polymyxins. The currently used polymyxins, i.e.

Antimicrobial activity of the novel polymyxin derivative NAB739 tested against Gram-negative pathogens.

Objectives: In spite of reported nephrotoxicity, polymyxins have been reinstated as the last-line therapy to treat infections caused by Gram-negative bacterial strains that are resistant to other agents. NAB739 has a cyclic portion identical to that of polymyxin B, but its linear peptide portion consists of threonyl-d-serinyl instead of diaminobutyryl-threonyl-diaminobutyryl. Therefore, NAB739 lacks both of the positive charges present in the linear part of polymyxin B.

Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells.

The emergence of very multiresistant Gram-negative bacterial strains has reinstated polymyxins (polymyxin B, colistin), pentacationic lipopeptides, in the therapy, in spite of their nephrotoxicity. Extensive tubular reabsorption concentrates polymyxin in proximal tubular cells. The novel polymyxin derivatives NAB739, NAB7061 and NAB741 have their cyclic part identical to that of polymyxin B, but their side chain consists of uncharged octanoyl-threonyl-d-serinyl, octanoyl-threonyl-aminobutyryl, and acetyl-threonyl-D-serinyl respectively.

Volumetric feedback ablation of uterine fibroids using magnetic resonance-guided high intensity focused ultrasound therapy.

Objective: The purpose of this prospective multicenter study was to assess the safety and technical feasibility of volumetric Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) ablation for treatment of patients with symptomatic uterine fibroids.

Methods: Thirty-three patients with 36 fibroids were treated with volumetric MR-HIFU ablation. Treatment capability and technical feasibility were assessed by comparison of the Non-Perfused Volumes (NPVs) with MR thermal dose predicted treatment volumes.

Structure-activity studies on novel polymyxin derivatives that carry only three positive charges.

Polymyxin B and colistin are pentacationic lipopeptides that possess a cyclic heptapeptide portion, a linear tripeptide portion, and a fatty acyl tail. They are used, in spite of nephrotoxicity, to treat infections caused by extremely multiresistant Gram-negative bacteria. We have recently developed novel derivatives, that carry three cationic charges only.

A novel polymyxin derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane.

Polymyxins are cationic lipopeptides (five cationic charges) and the last resort for the treatment of serious Gram-negative infections caused by multiresistant strains. NAB741 has a cyclic peptide portion identical to that of polymyxin B but carries in the linear peptide portion a threonyl-D-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (two cationic charges). At the N terminus of the peptide, NAB741 carries an acetyl group instead of a mixture of methyl octanoyl and methyl heptanoyl residues.

Novel polymyxin derivatives are effective in treating experimental Escherichia coli peritoneal infection in mice.

Objectives: Novel synthetic polymyxin derivatives including NAB737 and NAB739 are as effective as polymyxin B in vitro against the common opportunistic pathogen Escherichia coli. Another derivative, NAB7061, lacks direct antibacterial action but sensitizes E. coli to several other antibacterial agents including macrolides.

Susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin.

Objectives: To determine the susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin. NAB739 and NAB7061 are novel polymyxin derivatives that lack the cationic charges in the linear peptide portion of polymyxin B and have pharmacokinetic properties different from those of polymyxin B.

Methods: MIC determinations were performed by the agar dilution method using CLSI guidelines.

Pharmacokinetics of novel antimicrobial cationic peptides NAB 7061 and NAB 739 in rats following intravenous administration.

Objectives: To determine the disposition of novel antimicrobial cationic peptides NAB 7061 and NAB 739 following intravenous administration in rats.

Methods: Sprague-Dawley rats received a single intravenous bolus of 1.0 mg/kg NAB 7061 or NAB 739.

Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents.

The lack of novel antibiotics against gram-negative bacteria has reinstated polymyxins as the drugs of last resort to treat serious infections caused by extremely multiresistant gram-negative organisms. However, polymyxins are nephrotoxic, and this feature may complicate therapy or even require its discontinuation. Like that of aminoglycosides, the nephrotoxicity of polymyxins might be related to the highly cationic nature of the molecule.

Pulse repetition time and contrast enhancement: simulation study of Gd-BOPTA and conventional contrast agent at different field strengths.

Objectives: To investigate theoretically enhancement and optimal pulse repetition times for Gd-BOPTA and Gd-DTPA enhanced brain imaging at 0.23, 1.5, and 3.

MR-guided breast biopsy and hook wire marking using a low-field (0.23 T) scanner with optical instrument tracking.

The purpose of this study was to evaluate the technical feasibility of MR-guided percutaneous breast biopsy (LCNB) and breast hook wire marking in a low-field (0.23 T) MRI system with optical instrument tracking. MR-guided core biopsy and/or hook wire marking was performed on 13 lesions observable at MR imaging only.

Magnetic resonance imaging-guided diskography and diagnostic lumbar 0.23T MRI: an assessment study.

Purpose: To describe the in vivo appearance of magnetic resonance imaging (MRI) diskograms of normal and degenerated lumbar intervertebral disks, and to evaluate the differences in imaging findings between sequential diagnostic MRI and MRI diskography.

Material And Methods: Nine consecutive patients underwent MRI-guided diskography in order to determine possible pain provocation during puncture and contrast medium injection. All patients had preceding clinical suspicion of lumbar diskogenic pain and findings of lumbar disk degeneration in diagnostic (MRI, computed tomography (CT), plain radiography).

Dynamic MR imaging of brain tumors in low field using undersampled projection reconstruction.

A new application of the projection reconstruction method was developed, enabling dynamic T(1)-weighted contrast-enhanced magnetic resonance image (MRI) of brain tumors in a low-field imager. Two undersampled projection reconstruction spin echo sequences were implemented in an open low-field (0.23-T) MR imager, one with 64 and another with 42 projections in [0,pi], repetition time 150 ms, echotime 15 ms, and six slices were used in both sequences.

MR imaging-guided laser ablation of osteoid osteomas with use of optical instrument guidance at 0.23 T.

The purpose of this study was to determine the feasibility and features of low-field MR imaging in performing interstitial laser ablation of osteoid osteomas. Between September 2001 and April 2002, five consecutive patients with clinical and imaging findings suggesting osteoid osteoma and referred for removal of osteoid osteoma were treated with interstitial laser treatment. A low-field open-configuration MRI scanner (0.

Percutaneous MR-guided discography in a low-field system using optical instrument tracking: a feasibility study.

Purpose: To evaluate the feasibility of MRI-guided discography with optical tracking.

Material And Methods: 12 consecutive patients who had a clinical suspicion of lumbar discogenic pain and/or suggestive finding of disc degeneration in imaging studies (MRI, CT, plain radiography) underwent MRI-guided discography in order to determine possible pain provocation during puncture and contrast injection. An 0.

MRI-guided periradicular nerve root infiltration therapy in low-field (0.23-T) MRI system using optical instrument tracking.

The purpose of this study was to evaluate the feasibility of the MRI-guided periradicular nerve root infiltration therapy. Sixty-seven nerve root infiltrations under MRI guidance were done for 61 patients suffering from lumbosacral radicular pain. Informed consent was acquired from all patients.

MR temperature measurement in liver tissue at 0.23 T with a steady-state free precession sequence.

MRI can be used for monitoring temperature during a thermocoagulation treatment of tumors. The aim of this study was to demonstrate the suitability of a 3D steady-state free precession sequence (3D Fast Imaging with Steady-State Precession, 3D TrueFISP) for MR temperature measurement at 0.23 T, and to compare it to the spin-echo (SE) and spoiled 3D gradient-echo (3D GRE) sequences.

Dynamic contrast-enhanced MR imaging and MR-guided bone biopsy on a 0.23 T open imager.

Objective: To assess the feasibility of MR (magnetic resonance)-guided bone biopsies.

Design And Patients: Thirty-six consecutive patients with known or suspected benign or malignant bone lesions underwent comprehensive MR imaging. A dynamic contrast-enhanced sequence followed by stationary T1-weighted sequences were obtained and MR-guided bone biopsy of the tumor at the site with fastest enhancement was performed using an open 0.