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An efficient loading technique has been developed for flammable, toxic, or explosive gases which can be condensed at liquid nitrogen temperature and ambient pressure in membrane diamond anvil cells (DACs). This cryogenic technique consists in a deposition of small quantities of the desired gas directly into the sample chamber. The deposition is performed using a capillary that reaches the space between the diamond anvils. The DAC is kept under inert gas overpressure during the whole process, in order to avoid contamination from atmospheric O 2 , CO 2 , and H 2 O. This technique provides significant advantages over standard cryo-loading and gas-loading when the condensation of dangerous samples at liquid nitrogen temperature raises safety concerns because it allows dealing with minimum quantities of condensed gases. The whole procedure is particularly fast and efficient. The "spray-loading" has been successfully used in our laboratory to load several samples including acetylene, ammonia, ethylene, and carbon dioxide/water or red phosphorus/NH 3 mixtures.

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927., (© 2015 by The American Society of Hematology.)

Background: Istradefylline (KW-6002) is a selective adenosine A(2A) receptor antagonist investigated as adjunctive therapy to levodopa in PD patients with motor response complications. In Phase 2b/3 studies, Istradefylline reduced OFF time without worsening troublesome dyskinesia and was well tolerated., Methods: A randomized, 12-week, double-blind, placebo-controlled parallel-group study evaluated the efficacy of 10, 20, and 40 mg/day of Istradefylline in patients on levodopa therapy with motor response complications. The primary outcome measure was change from baseline to endpoint in the percentage of awake time/day spent in the OFF state as determined by patient diary., Results: Six hundred and ten patients were randomized. Five hundred and eighty four patients were included in the Intent-to-treat (ITT) group-146 placebo patients and 149 in the 10 mg, 144 in the 20, and 145 patients in the 40 mg Istradefylline groups. Baseline demographics were similar between groups. Treatment cohorts had been diagnosed an average of 9 years diagnosis and 3.6 years from the onset of motor fluctuations; at baseline they had an average of 6.7 h of OFF time and an average UPDRS motor score of 22 when ON. At endpoint, the amount and percentage of OFF time did not differ between Istradefylline and placebo, however a dose-ordering response was observed. Changes from baseline in the UPDRS motor score in the on state for the 40 mg were modest but significant compared to placebo (2.9 vs. 0.8; p < 0.05)., Conclusions: Although Istradefylline did not impact OFF time duration, it significantly improved motor score at 40 mg/day., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.

Glyburide is a poorly water-soluble oral hypoglycemic agent, with problems of variable bioavailability and bio-inequivalence related to its poor water-solubility. This work investigated the possibility of developing glyburide tablets, allowing fast, reproducible, and complete drug dissolution, by using drug solid dispersion in polyethylene glycol. Phase-solubility studies were performed to investigate the drug-carrier interactions in solution, whereas differential scanning calorimetry, X-ray powder diffraction, and infrared spectroscopy were used to characterize the solid state of solid dispersions. The effects of several variables related to both solid dispersion preparation (cofusion or coevaporation technique, drug-to-carrier ratio, polyethylene glycol molecular weight) and tablet production (direct compression or previous wet-granulation, tablet hardness, drug, and solid dispersion particle size) on drug dissolution behavior were investigated. Tablets obtained by direct compression, with a hardness of 7-9 Kp, and containing larger sized solid dispersions (20-35 mesh, i.e., 850-500 microm) of micronized glyburide in polyethylene glycol 6000 prepared by the cofusion method gave the best results, with a 135% increase in drug dissolution efficiency at 60 min in comparison with a reference tablet formulation containing the pure micronized drug. Moreover, the glyburide dissolution profile from the newly developed tablets was clearly better than those from various commercial tablets at the same drug dosage.

Rationale and Objectives: The purpose of this study was to measure and to clarify the diagnostic contributions of image-based features in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions., Materials and Methods: Six experienced abdominal radiologists each read images from 146 cases (including a contrast material-enhanced computed tomographic [CT] scan and contrast-enhanced and unenhanced magnetic resonance [MR] images) following a checklist-questionnaire requiring them to rate quantitatively each of as many as 131 image features and then reported on each of the two differentiations. The diagnostic value of each feature was assessed, and linear discriminant analysis was used to develop statistical prediction rules (SPRs) for merging feature data into computerized "second opinions." For the two differentiations, accuracy (area under the receiver operating characteristic curve [Az]) was then determined for the radiologists' readings by themselves and for each of three SPRs., Results: Thirty-seven candidate features had diagnostic value for each of the two differentiations (a slightly different feature set for each). Radiologists' performance at both differentiations was excellent (Az = 0.929 [benign vs malignant] and 0.926 [hepatocyte-containing vs non-hepatocyte-containing]). Performance of the SPR that operated on the features from all modalities together was better than that of radiologists (Az = 0.936 [benign vs malignant] and 0.951 [hepatocyte-containing vs non-hepatocyte-containing]), but this difference was of marginal statistical significance (P = .11). Contrast-enhanced MR imaging and contrast-enhanced CT each made significant adjunctive contributions to accuracy compared with unenhanced MR imaging alone., Conclusion: Many CT- and MR imaging-based features have diagnostic value in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. Radiologists could also benefit from the fully informed SPR's "second opinions."

A magneto-optic trap for micro-objects is described. Magnetic beads were trapped by optical tweezers while being rotated by a new integrated magnetic manipulator. Rotation was achieved with eight electromagnets with tip-pole geometry. The time orbital potential technique was used to achieve rotation of magnetic beads. Trapping in three dimensions and rotation of magnetic beads on three axes are demonstrated with forces up to 230 pN and force momenta of up to 10(-16)N m . A position-detection apparatus based on an interferometric scheme provides nanometer sensitivities in a few milliseconds.

The efficacy of contrast-enhanced magnetic resonance imaging (MRI) for detecting and characterizing, or excluding, hepatic masses was assessed in 404 patients, following the intravenous administration of mangafodipir trisodium (MnDPDP) injection, a hepatic MRI contrast agent. An initial contrast-enhanced computed tomography (CT) examination was followed by unenhanced MRI, injection of MnDPDP (5 micromol/kg IV), and enhanced MRI at 15 minutes post injection. Agreement of the radiologic diagnoses with the patients' final diagnoses was higher for enhanced MRI and for the combined unenhanced and enhanced MRI evaluations than for unenhanced MRI alone or enhanced CT using the clinical diagnosis as the gold standard. Mangafodipir-enhanced MRI uniquely provided additional diagnostic information in 48% of the patients, and patient management was consequently altered in 6% of the patients. MnDPDP-enhanced MRI was comparable or superior to unenhanced MRI and enhanced CT for the detection, classification, and diagnosis of focal liver lesions in patients with known or suspected focal liver disease.

A high-performance liquid chromatographic method is described for the determination of seven steroids in adrenocortical extracts showing a delta 4-3-ketonic conjugated system. The seven steroids (cortisol, cortisone, 11-dehydrocorticosterone, corticosterone, 11-deoxycortisol, aldosterone and 11-deoxycorticosterone) were separated with a chloroform-methanol gradient on a 5-micron silica column and with a water-acetonitrile gradient on a 10-micron RP-8 column. Effluents were monitored by UV absorption at 242 nm. Quantitative analysis was performed by comparing peak areas, which are proportional to the amounts of the individual substances (external standard method). The method is rapid, sensitive, easy to perform and reproducible.

A simple, fast, sensitive, and reliable method for the determination of 2-(3-benzoylphenyl)propionic acid in biological fluid is described. The method is based on a quantitative ether extraction of plasma samples followed by TLC separation, spot visualization and elution, and determination at 255 nm. The acid is detectable in amounts as low as 1 mug.

Concentrations of isoxicam in the plasma and synovial fluid of 7 patients were investigated by means of high-pressure liquid chromatography. The samples were collected after 7 days' treatment with a single 200 mg isoxicam capsule taken each morning. A highly significant correlation was found (r = 0.82; p less than 0.05) between isoxicam concentrations in the plasma and in the synovial fluid. The mean concentration (+/- s.d.) was 25.54 +/- 10.91 micrograms/ml in the plasma and 17.47 +/- 6.54 micrograms/ml in the synovial fluid; the ratio between isoxicam concentrations in the synovial fluid and in the plasma was 71.06% +/- 18.83.

A rapid, sensitive, and specific determination of ketoprofen in human and animal deproteinized body fluids by reversed-phase high-pressure liquid chromatography is presented. The acid is detectable in amounts as low as 0.1 microgram/ml. Limits of error are in the range of +/- 5.1% of the sample mean.

In this study the transcutaneous passage of ketoprofen (gel) topically administered and its distribution in the inner part of the knee-joint were evaluated in six patients. The ketoprofen concentrations detected were: 4.70 mcg/g +/- 3.87 in the intra-articular adipose tissue; 2.35 mcg/g +/- 2.41 in the capsular sample and 1.31 mcg/g +/- 0.89 in the synovial fluid. Plasma concentrations of the drug were also examined. In the samples studied, the ketoprofen levels amounted to about one hundred times higher than the plasma concentrations.