Randomized clinical trial evaluating transdermal Ibuprofen for moderate to severe knee osteoarthritis.

BACKGROUND: Osteoarthritis is a common condition, typically treated with orally administered analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Chronic administration of NSAIDs, serotonin-norepinephrine reuptake inhibitors (SNRIs, i.e., duloxetine), and opioid medications (i.e., tramadol) is regularly associated with multiple, serious side effects, in part due to the route of administration. Transdermal delivery of NSAIDs, such as ibuprofen, represents a potentially alternative treatment for this inflammatory pain condition with a better therapeutic profile. OBJECTIVE: Investigate the safety and efficacy of a novel transdermal ibuprofen formulation (VALE®-ibuprofen) containing 10% ibuprofen, compared to a placebo in a randomized, double-blinded clinical trial, for clinical improvement in patients with moderate to severe painful osteoarthritis of the knee. STUDY DESIGN: A randomized, placebo-controlled, double blind, multi-center Phase 2 clinical trial. SETTING: An academic medical center, and private rheumatology and interventional pain management practices. METHODS: The Phase 2 clinical study included patients with primary osteoarthritis in a single knee joint with a progression level of moderate to severe based in part on a grade II or III designation according to the Kellgren and Lawrence classification system. Patients received the corresponding, randomly assigned study formulation (VALE-ibuprofen or placebo) for application to the target knee at a dose of 2.0 grams of drug product (200 mg ibuprofen) twice daily for 14 days. The evaluation of the efficacy of the treatments utilized the widely accepted methods of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and the Visual Analog Scale (VAS) scores for the patients. RESULTS: The results indicate that the transdermal VALE-ibuprofen formulation was very well tolerated from a safety perspective during the 2-week trial and also produced significant, positive clinical improvements superior to the placebo in all clinical endpoints tested. In particular, the WOMACTotal and WOMACPhysical Functioning, for the VALE-ibuprofen, were superior compared to the placebo (P = 0.0283 and P = 0.0201, respectively). Other clinical endpoints including the WOMACPain, WOMACStiffness, and VASResting scores were superior to those obtained from the placebo group, trending towards statistical significance compared to placebo (P = 0.0811, 0.1103, and 0.0785, respectively). Based on the Patient and Physician Global Impression of Change survey, patient satisfaction slightly improved across both groups; however, no statistical significance was detectable as compared to the baseline. LIMITATIONS: The sample size of 64 subjects in the final data analysis and the lack of including an orally administered drug group are limitations of this study. CONCLUSIONS: The use of transdermal VALE-ibuprofen has beneficial clinical effects on the pain levels experienced in some patients with moderate to severe osteoarthritis of the knee as measured by the WOMAC Osteoarthritis Indices for stiffness, pain, physical function, and total. Visual Analog Scales (VAS) tests, VASMotion and VASWeight-bearing, again while appeared superior to placebo, were not statistically different from placebo. CLINICAL TRIAL REGISTRATION: NCT01496326.

Nanopatterns with biological functions.

Both curiosity and a desire for efficiency have advanced our ability to manipulate materials with great precision on the micrometer and, more recently, on the nanometer scale. Certainly, the semiconductor and integrated circuit industry has put the pressure on scientist and engineers to develop better and faster nanofabrication techniques. Furthermore, our curiosity as to how life works, and how it can be improved from a medical perspective, stands to gain a great deal from advances in nanotechnology. Novel nanofabrication techniques are opening up the possibilities for mimicking the inherently nano-world of the cell, i.e., the nanotopographies of the extracellular matrix (ECM) and the nanochemistry presented on both the cell membrane and the ECM. In addition, biosensing applications that rely on fabrication of high-density, precision arrays, e.g., DNA or gene chips and protein arrays, will gain significantly in efficiency and, thus, in usefulness once it becomes possible to fabricate heterogeneous nanoarrays. Clearly, continued advances in nanotechnology are desired and required for advances in biotechnology. In this review, we describe the leading techniques for generating nanopatterns with biological function including parallel techniques such as extreme ultraviolet interference lithography (EUV-IL), soft-lithographic techniques (e.g., replica molding (RM) and microcontact printing (muCP)), nanoimprint lithography (NIL), nanosphere lithography (NSL) (e.g., colloid lithography or colloidal block-copolymer micelle lithography) and the nanostencil technique, in addition to direct-writing techniques including e-beam lithography (EBL), focused ion-beam lithography (FIBL) and dip-pen nanolithography (DPN). Details on how the patterns are generated, how biological function is imparted to the nanopatterns, and examples of how these surfaces can and are being used for biological applications will be presented. This review further illustrates the rapid pace by which advances are being made in the field of nanobiotechnology, owing to an increasing number of research endeavors, for an ever increasing number of applications.

High salt stability and protein resistance of poly(L-lysine)-g-poly(ethylene glycol) copolymers covalently immobilized via aldehyde plasma polymer interlayers on inorganic and polymeric substrates.

The electrostatic adsorption onto charged surfaces of comb copolymers comprising a polyelectrolyte backbone and pendent PEG side chains, such as poly(l-lysine)-g-poly(ethylene glycol) (PLL-g-PEG), has in previous studies provided protein-repellent thin coatings, particularly on metal oxide surfaces. A drawback of this approach is, however, the instability of such adsorbed layers under extreme pH values or high ionic strength. We have overcome this limitation in the present study by covalently immobilizing PLL-g-PEG copolymers onto aldehyde plasma-modified substrates. Silicon wafers, optical waveguide chips, and perfluorinated ethylene-co-propylene (FEP) polymer substrates were first coated with a thin plasma polymer layer using a propionaldehyde plasma, followed by covalent immobilization of PLL-g-PEG via reductive amination between amine groups of the PLL backbone with aldehyde groups on the plasma-deposited interlayer. The stability in high salt media and the protein resistance of different molecular architectures of immobilized PLL-g-PEG layers were quantitatively investigated by XPS, an optical waveguide technique (OWLS), and ToF-SIMS. The adsorption of bovine serum albumin was found to be below the detection limit (<2 ng/cm(2)), as for electrostatically adsorbed PLL-g-PEG layers. However, after 24 h of exposure of covalently immobilized layers of PLL-g-PEG to high ionic strength buffer (2400 mM NaCl), no significant change in the protein resistance was observed, whereas under the same conditions electrostatically adsorbed PLL-g-PEG coatings lost their protein resistance. Moreover, covalent immobilization via an aldehyde plasma interlayer enabled the application of PLL-g-PEG layers onto substrates such as FEP onto which electrostatic binding is not possible. These findings create a generic platform for the covalent immobilization of PLL-g-PEG onto a wide variety of substrates.

Serial EEG findings in sporadic and iatrogenic Creutzfeldt-Jakob disease.

OBJECTIVE: To study temporal and spatial development of EEG patterns in sporadic and iatrogenic Creutzfeldt-Jakob disease patients. METHODS: Temporal and spatial development of EEG patterns in 4 patients with sporadic Creutzfeldt-Jakob disease and 2 patients with iatrogenic Creutzfeldt-Jakob disease due to implantation of contaminated brain depth electrodes were investigated. A total of 56 EEGs were analyzed, over time spans ranging from 1272 to 3 days prior to death. RESULTS: Frontal intermittent rhythmical delta activity (FIRDA) was seen at early timepoints in 4/6 patients and might represent an early EEG pattern that is associated, with human prion diseases. EEG patterns associated with CJD are sensitive to midazolam. Initial EEG changes were seen at the site of prion exposure in iatrogenic Creutzfeldt-Jakob disease patients, before they could be observed at distant sites, suggesting that prion disease was initiated at the site of prion exposure. CONCLUSIONS: Serial EEG recordings are a valuable tool not only in the early diagnosis of sporadic CJD, but also in the determination of prion exposure in iatrogenic Creutzfeldt-Jakob disease. SIGNIFICANCE: FIRDA occur at an early stage of CJD and are progressively replaced by the classical PSWC. The EEG patterns of CJD are sensitive to midazolam. The initial EEG changes in iatrogenic CJD are seen at the site of prion exposure.

Implications of prion diseases for neurosurgery.

Prion diseases comprise a group of diseases characterised by transmissibility, spongiosis, gliosis, neuronal loss, and accumulation of an abnormally folded membrane protein, PrP(Sc). Infectivity resists almost all chemical and physical processes that inactivate conventional viruses, whereas protein extraction abolishes infectivity. This fact is of great importance to surgery, especially neurosurgery, since conventional cleaning of surgical instruments does not abolish infectivity. As a matter of consequence, few cases of putative neurosurgical transmission of Creutzfeldt-Jakob disease (CJD) have been reported. Putative transmission has also been reported through the use of lyophilised dura mater, corneal transplants, and cortical EEG electrodes. Moreover, many children have been infected with CJD by intramuscular or subcutaneous injection of cadaveric pituitary-derived human growth hormone. In recent years, the occurrence of bovine spongiform encephalopathy and consequently new variant Creutzfeldt-Jakob disease has increased concerns that prions also may contaminate the blood supply. Animal models of prion disease can help the understanding of how prions spread within an infected organism and the identification of which tissues may be contagious. Taking the right precautions against iatrogenic transmission requires knowledge about the nature of prion diseases - not only for the persons working out the directives but also for health care workers potentially involved with CJD patients or contaminated specimens.

Transmission of prion disease.

The transmission of bovine spongiform encephalopathy to humans as variant Creutzfeldt-Jakob disease (vCJD) has focused public attention on how prion diseases are transmitted and how prions reach the brain after exposure. Prion diseases are characterised by transmissibility and neuropathological features of gliosis, neuronal loss and microscopic vacuoles, termed spongiosis. The principal component of prions is the glycoprotein PrP(Sc), which is a conformational modified isoform of the normal membrane protein PrP(C). How are prions transmitted and how do prions find their way once they have been ingested? Prion models in mouse and hamster point to lymphoreticular cells which support an early replication phase of prions before reaching the central nervous system via peripheral nerves. Whilst some key players seem to have been identified so far, the mechanisms of prion propagation to the brain are still not fully understood. Seemingly contradictory results have led to some confusion and have provoked discussion.