Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain

Lynn R Webster1, John F Peppin2, Frederick T Murphy3,4, Jeffrey K Tobias5, Geertrui F Vanhove51Lifetree Clinical Research and Pain Clinic, Lifetree Medical Inc, Salt Lake City, UT, USA; 2Clinical Research Division, The Pain Treatment Center of the Bluegrass, Lexington, KY, USA; 3Altoona Center for Clinical Research, Duncansville, PA, USA; 4University of Pennsylvania, School of Medicine, Philadelphia, PA, USA; 5NeurogesX Inc, San Mateo, CA, USABackground: The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain.Methods: This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4® [Ferndale Laboratories Inc, Ferndale, MI], Topicaine® Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL]) for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included “pain now” Numeric Pain Rating Scale (NPRS) scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs), clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for “average pain for the past 24 hours” from baseline to weeks 2 through 12.Results: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate, and could be adequately managed by local cooling or short-acting oral opioid analgesics. Although slightly more patients used medication for treatment-related discomfort following pretreatment with Topicaine compared with L.M.X.4 or Betacaine, there were no statistical differences between the topical anesthetics. Neuropathic pain reduction from baseline to weeks 2 through 12 was approximately 30% and was similar among the topical anesthetics; the proportion of responders ranged from 45% to 50%.Conclusion: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated; no significant differences in the parameters measured were noted between the pretreatment groups.Keywords: neuropathic pain, capsaicin patch, tolerability, topical anesthetic

Development of a High Latent Effectiveness Energy Recovery Ventilator with Integration into Rooftop Package Equipment

This Final Report covers the Cooperative Program carried out to design and optimize an enhanced flat-plate energy recovery ventilator and integrate it into a packaged unitary (rooftop) air conditioning unit. The project objective was to optimize the design of a flat plate energy recovery ventilator (ERV) core that compares favorably to flat plate air-to-air heat exchanger cores on the market and to cost wise to small enthalpy wheel devices. The benefits of an integrated unit incorporating an enhanced ERV core and a downsized heating/cooling unit were characterized and the design of an integrated unit considering performance and cost was optimized. Phase I was to develop and optimize the design of a membrane based heat exchanger core. Phase II was the creation and observation of a system integrated demonstrator unit consisting of the Enhanced Energy Recovery Ventilator (EERV) developed in Phase I coupled to a standard Carrier 50HJ rooftop packaged unitary air conditioning unit. Phase III was the optimization of the system prior to commercialization based on the knowledge gained in Phase II. To assure that the designs chosen have the possibility of meeting cost objectives, a preliminary manufacturability and production cost study was performed by the Center for Automation Technologies at RPI. Phase I also included a preliminary design for the integrated unit to be further developed in Phase II. This was to assure that the physical design of the heat exchanger designed in Phase I would be acceptable for use in Phase II. An extensive modeling program was performed by the Center for Building Performance & Diagnostics of CMU. Using EnergyPlus as the software, a typical office building with multiple system configurations in multiple climatic zones in the US was simulated. The performance of energy recovery technologies in packaged rooftop HVAC equipment was evaluated. The experimental program carried out in Phases II and III consisted of fabricating and testing a demonstrator unit using Carrier Comfort Network (CCN) based controls. Augmenting the control signals, CCN was also used to monitor and record additional performance data that supported modeling and conceptual understanding. The result of the testing showed that the EERV core developed in Phase I recovered energy in the demonstrator unit at the expected levels based on projections. In fact, at near-ARI conditions the core recovered about one ton of cooling enthalpy when operating with a three-ton rooftop packaged unit

Parallax and Luminosity Measurements of an L Subdwarf

We present the first parallax and luminosity measurements for an L subdwarf, the sdL7 2MASS J05325346+8246465. Observations conducted over three years by the USNO infrared astrometry program yield an astrometric distance of 26.7+/-1.2 pc and a proper motion of 2.6241+/-0.0018"/yr. Combined with broadband spectral and photometric measurements, we determine a luminosity of log(Lbol/Lsun) = -4.24+/-0.06 and Teff = 1730+/-90 K (the latter assuming an age of 5-10 Gyr), comparable to mid-type L field dwarfs. Comparison of the luminosity of 2MASS J05325346+8246465 to theoretical evolutionary models indicates that its mass is just below the sustained hydrogen burning limit, and is therefore a brown dwarf. Its kinematics indicate a ~110 Myr, retrograde Galactic orbit which is both eccentric (3 <~ R <~ 8.5 kpc) and extends well away from the plane (Delta_Z = +/-2 kpc), consistent with membership in the inner halo population. The relatively bright J-band magnitude of 2MASS J05325346+8246465 implies significantly reduced opacity in the 1.2 micron region, consistent with inhibited condensate formation as previously proposed. Its as yet unknown subsolar metallicity remains the primary limitation in constraining its mass; determination of both parameters would provide a powerful test of interior and evolutionary models for low-mass stars and brown dwarfs.Comment: Accepted to ApJ 10 September 2007; 13 pages, 5 figures, 3 tables, formatted in emulateapj styl

Food Distribution and Consumption in Knoxville: Exploring Food-Related Local Planning Issues

Summary: City planners have traditionally made an effort to understand the interrelationships between urban activities and various support systems, such as transportation, water and sewer, waste management, communications and energy. Food is also an important urban support system with a complex system of supply, distribution, and consumption. An understanding of the nature of the food supply and distribution system seems important, but in the past has not been an area of concern for the planning profession. It was the intent of this project to develop a basis from which to seek an understanding of the Knoxville food support system and its implications for local planning policy in Knoxville. The thrust of the study was three-fold. First, food-related problems and issues were identified. Then, further work was undertaken in order to propose remedial measures or public programs that might be initiated by local units of government. Finally, the group considered the possibility of establishing some kind of public oversight of the local food supply and distribution function. The approach has been general and comprehensive. One assumption here is that before public action can be initiated, those with responsibility for maintaining the public interest must understand the system. Thus, an analysis which would describe the system comprehensively, while allowing an opportunity to detect interrelationships among system components, was utilized. Patterns of consumption, food services and programs, and marketing channels by food types were also explored. The development of information involves consultation with literature, academicians, public officials, and industry representatives

Human Cerebral Neuropathology of Type 2 Diabetes Mellitus

The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the ‘Pubmed Era’. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer\u27s disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer\u27s Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical–radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2

Definition of Germ Layer Cell Lineage Alternative Splicing Programs Reveals a Critical Role for Quaking in Specifying Cardiac Cell Fate

Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Mechanistically, we find that QKI represses inclusion of exon 7 in BIN1 pre-mRNA via an exonic ACUAA motif, and this is concomitant with intron removal and cleavage from chromatin. Collectively, our results uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

The structural basis of rubisco phase separation in the pyrenoid

Approximately one-third of global CO2 fixation occurs in a phase-separated algal organelle called the pyrenoid. The existing data suggest that the pyrenoid forms by the phase separation of the CO2-fixing enzyme Rubisco with a linker protein; however, the molecular interactions underlying this phase separation remain unknown. Here we present the structural basis of the interactions between Rubisco and its intrinsically disordered linker protein Essential Pyrenoid Component 1 (EPYC1) in the model alga Chlamydomonas reinhardtii. We find that EPYC1 consists of five evenly spaced Rubisco-binding regions that share sequence similarity. Single-particle cryo-electron microscopy of these regions in complex with Rubisco indicates that each Rubisco holoenzyme has eight binding sites for EPYC1, one on each Rubisco small subunit. Interface mutations disrupt binding, phase separation and pyrenoid formation. Cryo-electron tomography supports a model in which EPYC1 and Rubisco form a codependent multivalent network of specific low-affinity bonds, giving the matrix liquid-like properties. Our results advance the structural and functional understanding of the phase separation underlying the pyrenoid, an organelle that plays a fundamental role in the global carbon cycle