Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis and other atopic comorbidities.

Background: Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. Objective: This post hoc pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Methods: Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed via treatment-emergent adverse events (TEAEs). Results: This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Conclusion: Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), www.clinicaltrials.gov.

Efficacy and safety of nonsteroidal anti-inflammatory drugs in Asian patients with knee osteoarthritis: summary of a randomized, placebo-controlled study.

AIM: To compare the efficacy, tolerability and safety of celecoxib, naproxen and placebo in Asian patients with osteoarthritis (OA) of the knee. METHOD: Patients of Asian descent with knee OA, aged ≥ 45 years, in a flare state with a functional capacity classification of I-III, received celecoxib 200 mg once daily, naproxen 500 mg twice daily or placebo, for 6 weeks. The change in Patient's Assessment of Arthritis Pain (week 6 vs. baseline) was the primary endpoint. Secondary endpoints, including Patient's and Physician's Global Assessments of Arthritis, Western Ontario and McMaster Universities OA Index (WOMAC), use of complementary and alternative medicines, incidence of treatment-emergent adverse events (TEAEs) and measurements of upper gastrointestinal tolerability, were also assessed. RESULTS: Three hundred and sixty-seven patients were randomized: 145 to celecoxib, 144 to naproxen and 78 to placebo. Celecoxib was as effective as naproxen in reducing OA pain (least squares mean change from baseline in visual analogue scale score [standard error] -37.1 [2.0] for celecoxib and -37.5 [2.0] for naproxen). Patient's and Physician's Global Assessment of Arthritis, WOMAC scores, Pain Satisfaction Scale and Patient Health Questionnaire-9 showed statistically significant improvement in active treatment groups versus placebo, with the exception of naproxen WOMAC scores. Treatment-related TEAEs occurred in 19 (13%), 34 (24%) and six (8%) patients in the celecoxib, naproxen and placebo groups, respectively. CONCLUSION: Celecoxib and naproxen were comparable in their effects to reduce the signs and symptoms of knee OA in Asian patients. Celecoxib was shown to be safe and well tolerated in this patient population.

Electrochemical imaging of hydrogen peroxide generation at individual gold nanoparticles.

Localised hydrogen peroxide generation at individual catalytic gold nanoparticles within ensemble electrodes is mapped for the first time using combined scanning electrochemical-scanning ion conductance microscopy (SECM-SICM).

Mapping electroactivity at individual catalytic nanostructures using high-resolution scanning electrochemical-scanning ion conductance microcopy.

Combined scanning electrochemical-scanning ion conductance microcopy (SECM-SICM) has been used to map the electroactivity of surfaces decorated with individual features at the 100-150 nm scale. Dual channel capillary probes consisting of an open SICM barrel, and a solid carbon SECM electrode enabled correlation of surface activity with accurate topographical information. Measurements were validated by approach curve analysis and imaging of model systems in feedback and substrate generation-tip collection modes and then applied to the examination of two nanostructured test substrates. First, electronically isolated gold nanodisk arrays were imaged using a simple electrochemical redox mediator, in which a clear positive feedback signal was observed at the SECM electrode, and the topographical channel compared well with AFM imaging. Second, platinum nanosphere ensembles were mapped using platinum-modified carbon probes to detect oxygen consumption in a redox competition mode, demonstrating the means to study electrocatalytic processes at individual nanoparticles. This work demonstrates the value of high-resolution SECM-SICM for low-current amperometric imaging of nanosystems, and is a step toward quantitative measurement of electrokinetics at the single particle level.

Positionable vertical microfluidic cell based on electromigration in a theta pipet.

A microscale vertical fluidic cell system has been implemented, based on a simple theta pipet pulled to a sharp point (ca. 10-20 µm diameter for the studies herein) and positioned with a high degree of control on a surface. The dual channel arrangement allows an electric field to be generated between an electrode in each compartment of the pipet that can be used to control the electromigration of charged species between the two compartments, across a thin liquid meniscus in contact with the substrate of interest. By visualizing the interfacial region using laser scanning confocal microscopy, the adsorption of fluorescently-labeled materials on surfaces is monitored quantitatively in real time, exemplified through studies of the adsorption of anionic microparticles (1.1 µm diameter) on positively and negatively charged substrate surfaces of poly-L-lysine (PLL) and poly-L-glutamic acid (PGA), respectively, on glass. These studies highlight significant electrostatic effects on adsorption rates and also that the adsorption of these particles is dominated by the three phase meniscus/solid/air boundary. The technique is easily modified to the case of a submerged substrate, resulting in a much larger deposition area. Finite element method modeling is used to calculate local electric field strengths that are used to understand surface deposition patterns. To demonstrate the applicability of the technique to live biological substrates, the delivery of fluorescent particles directly to the surface of a single root hair cell of Zea mays is demonstrated. The mobile pipet allows deposition to be directed to specific regions of the cell, allowing discrete sites to be labeled with particles. Finally, the technique is used to study the uptake of fluorescent polymer molecules to single root hair cells, with quantitative analysis of the adsorption rates of vinyl-sulfonic acid copolymers, with varying rhodamine B content.

Efficacy and tolerability of celecoxib and naproxen versus placebo in Hispanic patients with knee osteoarthritis.

BACKGROUND: Celecoxib is an effective treatment for osteoarthritis (OA). However, information on its efficacy and safety profile in different racial/ethnic groups is limited. Noticeable differences among racial groups are found in other disease states, but a thorough investigation of OA is lacking. The objective of this study was to determine if celecoxib 200 mg once daily is as effective as naproxen 500 mg twice daily in the treatment of OA of the knee in Hispanic patients. METHODS: Hispanic patients aged ≥45 years with knee OA were randomized to receive celecoxib 200 mg once daily, naproxen 500 mg twice daily, or placebo for 6 weeks. The primary efficacy variable was the change in Patient's Assessment of Arthritis Pain at 6 weeks compared with baseline. Secondary variables were change in Patient's and Physician's Global Assessments of Arthritis from baseline to week 6/early termination, change in Western Ontario and McMaster Universities OA Index (WOMAC) from baseline to week 6/early termination, change in American Pain Society pain score, Pain Satisfaction Scale, Patient Health Questionnaire (PHQ-9), and measurements of upper gastrointestinal tolerability. RESULTS: In total, 239 patients completed the trial (96 celecoxib, 96 naproxen, 47 placebo). Celecoxib was as effective as naproxen in reducing OA pain (least squares mean change from baseline [standard error] -39.7 [2.7] for celecoxib and -36.9 [2.6] for naproxen). Patient's and Physician's Global Assessments of Arthritis, WOMAC scores, upper gastrointestinal tolerability, Pain Satisfaction Scale, and PHQ-9 showed no statistically significant differences between the celecoxib and naproxen groups. The incidence of adverse events and treatment-related adverse events were similar among the treatment groups. CONCLUSION: Celecoxib 200 mg once daily was as effective as naproxen 500 mg twice daily in the treatment of signs and symptoms of knee OA in Hispanic patients. Celecoxib was shown to be safe and well tolerated in this patient population.

Meniscus confined fabrication of multidimensional conducting polymer nanostructures with scanning electrochemical cell microscopy (SECCM).

Scanning electrochemical cell microscopy (SECCM) is demonstrated as a new approach for the construction of extended multi-dimensional conducting polymer (polyaniline) nanostructures, making use of a mobile dual-channel theta pipette cell to control and monitor the location, rate and extent of electropolymerisation.

A new view of electrochemistry at highly oriented pyrolytic graphite.

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)(6)(4-/3-) and Ru(NH(3))(6)(3+/2+). Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)(6)(4-/3-) and >100 for Ru(NH(3))(6)(3+/2+)), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)(6)(4-/3-) shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes.

Evanescent wave cavity ring-down spectroscopy (EW-CRDS) as a probe of macromolecule adsorption kinetics at functionalized interfaces.

Evanescent wave cavity ring-down spectroscopy (EW-CRDS) has been employed to study the interfacial adsorption kinetics of coumarin-tagged macromolecules onto a range of functionalized planar surfaces. Such studies are valuable in designing polymers for complex systems where the degree of interaction between the polymer and surface needs to be tailored. Three tagged synthetic polymers with different functionalities are examined: poly(acrylic acid) (PAA), poly(3-sulfopropyl methacrylate, potassium salt) (PSPMA), and a mannose-modified glycopolymer. Adsorption transients at the silica/water interface are found to be characteristic for each polymer, and kinetics are deduced from the initial rates. The chemistry of the adsorption interfaces has been varied by, first, manipulation of silica surface chemistry via the bulk pH, followed by surfaces modified by poly(L-glutamic acid) (PGA) and cellulose, giving five chemically different surfaces. Complementary atomic force microscopy (AFM) imaging has been used for additional surface characterization of adsorbed layers and functionalized interfaces to allow adsorption rates to be interpreted more fully. Adsorption rates for PSPMA and the glycopolymer are seen to be highly surface sensitive, with significantly higher rates on cellulose-modified surfaces, whereas PAA shows a much smaller rate dependence on the nature of the adsorption surface.

Evanescent wave cavity ringdown spectroscopy: a platform for the study of supported lipid bilayers.

Evanescent wave cavity ringdown spectroscopy (EW-CRDS) is advocated as an approach for monitoring the formation of supported lipid bilayers (SLBs) on quartz substrates in situ and for the quantitative study of fast molecular adsorption kinetics at the resulting modified biomimetic surface. This approach is illustrated using SLBs of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Complementary atomic force microscopy (AFM) and quartz crystal microbalance with dissipation (QCM-D) measurements confirm the formation of bilayers on quartz. The subsequent interaction of the porphyrin, 5,10,15,20-tetraphenyl-21H,23H-porphine-p,p',p'',p'''-tetrasulfonic acid tetrasodium hydrate (TPPS) with the cationic bilayer-modified silica surface has been studied using EW-CRDS combined with an impinging-jet to deliver analyte to the surface in a well-defined manner. The adsorption of TPPS to the bilayer was kinetically controlled and the adsorption rate constant was found to be 1.7 (±0.6) × 10(-4) cm s(-1) from finite element modeling of the jet hydrodynamics and associated convective-diffusion equation, coupled to a first-order surface process describing adsorption. These proof-of-concept studies provide a platform for the investigation of molecular processes at biomembranes using EW-CRDS for chemical species showing optical absorbance in the visible and ultraviolet range.

Scanning electrochemical cell microscopy: theory and experiment for quantitative high resolution spatially-resolved voltammetry and simultaneous ion-conductance measurements.

Scanning electrochemical cell microscopy (SECCM) is a high resolution electrochemical scanning probe technique that employs a dual-barrel theta pipet probe containing electrolyte solution and quasi-reference counter electrodes (QRCE) in each barrel. A thin layer of electrolyte protruding from the tip of the pipet ensures that a gentle meniscus contact is made with a substrate surface, which defines the active surface area of an electrochemical cell. The substrate can be an electrical conductor, semiconductor, or insulator. The main focus here is on the general case where the substrate is a working electrode, and both ion-conductance measurements between the QRCEs in the two barrels and voltammetric/amperometric measurements at the substrate can be made simultaneously. In usual practice, a small perpendicular oscillation of the probe with respect to the substrate is employed, so that an alternating conductance current (ac) develops, due to the change in the dimensions of the electrolyte contact (and hence resistance), as well as the direct conductance current (dc). It is shown that the dc current can be predicted for a fixed probe by solving the Nernst-Planck equation and that the ac response can also be derived from this response. Both responses are shown to agree well with experiment. It is found that the pipet geometry plays an important role in controlling the dc conductance current and that this is easily measured by microscopy. A key feature of SECCM is that mass transport to the substrate surface is by diffusion and, for charged analytes, ion migration which can be controlled and varied quantifiably via the bias between the two QRCEs. For a working electrode substrate this means that charged redox-active analytes can be transported to the electrode/solution interface in a well-defined and controllable manner and that relatively fast heterogeneous electron transfer kinetics can be studied. The factors controlling the voltammetric response are determined by both simulation and experiment. Experiments demonstrate the realization of simultaneous quantitative voltammetric and ion conductance measurements and also identify a general rule of thumb that the surface contacted by electrolyte is of the order of the pipet probe dimensions.