Stability of extemporaneously prepared hydroxyurea solutions.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To evaluate the stability of a new, more convenient (<30 minutes for preparation), extemporaneously prepared hydroxyurea solution over 78 days. METHODS: A high-performance liquid chromatography (HPLC) method using a hydrophilic interaction chromatography (HILIC) column was developed and validated to accurately measure the concentration of hydroxyurea directly from solution without the need for chemical derivatization. Hydroxyurea was dissolved in sterile water in less than 5 minutes to yield a 100-mg/mL solution, which was then diluted by an equal volume of ORA-sweet vehicle to yield a 50-mg/mL extemporaneously prepared solution of hydroxyurea. The solution samples were kept at refrigeration (4 °C), room temperature (26 °C), and elevated temperature (40 °C) for 78 days. RESULTS: The 50-mg/mL solutions of hydroxyurea in a 1:1 mixture of water and ORA-sweet kept at 4 °C and 26 °C showed no significant loss of potency (<2%) after 78 days. The solutions kept at 40 °C showed greater than 10% loss of potency after 28 days. CONCLUSION: Extemporaneously compounded hydroxyurea 50-mg/mL solutions prepared in a 1:1 mixture of water and ORA-Sweet and stored in amber polypropylene plastic bottles were stable for at least 78 days at room temperature and under refrigeration.

The Magnetic Resonance Imaging Appearance of Endoscopic Endonasal Skull Base Defect Reconstruction Using Free Mucosal Graft.

OBJECTIVE: At our institution, skull base reconstruction using a free mucosal graft from the nasal cavity floor has been the standardized technique after pituitary adenoma resection via transsellar approach. In this study, the expected appearance of the reconstruction on postoperative magnetic resonance imaging (MRI) scans is described and its integrity and impact on the sinonasal cavity are assessed. METHODS: Fifty patients were selected, and their electronic medical records were reviewed for postoperative course, Sino-Nasal Outcome Test-22 (SNOT-22) scores, and nasal endoscopy reports. A total of 116 postoperative MRI scans were available to evaluate 1) the appearance and thickness of the graft, 2) the enhancement of the graft, and 3) the T2 signal in sphenoid sinus as a potential indication for inflammatory disease. RESULTS: There was no significant change in the thickness of the graft over time. Except for the 7 scans that were obtained without intravenous contrast, all scans showed enhancement of the graft. About half of the patients showed persistent T2 hyperintense signal at 12 and 24 months. However, this finding was not clinically significant, because postoperative SNOT-22 scores showed minimal sinonasal impact. CONCLUSIONS: Postoperative MRI surveillance scans showed a stable appearance of the graft that mimics the native mucosa, with enhancement through time, reflecting its robust vascularization and integration to the skull base. Although persistent T2 hyperintense signal was detected in the sphenoid sinus, clinical evidence based on nasal endoscopy reports and SNOT-22 scores indicated minimal sinonasal morbidity.

Influence of Sterilization Technologies on Electrospun Poly(ester urea)s for Soft Tissue Repair.

Degradable poly(ester urea)s (PEU)s were electrospun into nanofiber sheets and assessed for their potential to be used in soft tissue repair. The level of residual solvent was measured and the effects of ethylene oxide and electron beam sterilization techniques on molecular mass, mass distribution, and morphology were quantified. Two PEU compositions that formed stable nanofiber sheets were advanced into a pilot study in vitro and in vivo as candidate materials for hernia repair. Cell viability, spreading, proliferation, and migration were examined in vitro. Nanofiber sheets were implanted subcutaneously into mice and analyzed via microangiography and histology for tissue incorporation. Nanofiber sheets performed similarly to decellularized extracellular matrix (ECM) in vitro, but the lack of sufficient pore structure inhibited cellular infiltration after 14 days of culture. The lack of microporous features in nanofiber sheets also contributed to low levels of cellular infiltration, angiogenesis, and matrix deposition in vivo. A preliminary study to increase pore size in nanofibers was performed using coaxial electrospinning resulting in significant improvement in tissue infiltration in vivo.

Headband sign on magnetic resonance imaging: An unusual finding of scurvy in a 5-year-old child described first time.

Scurvy usually presents with tender and painful limbs, swelling of joints, gum bleeding, poor wound healing, and muscle weakness. Here, we report a case of 5-year-old child with global developmental delay who presented with soft swelling of the head over scalp and protrusion of the left eye with extremely irritability. Neuroimaging was suggestive of diffuse extensive soft-tissue swelling involving the entire scalp with large necrotic collections with mild proptosis of the left orbit. It is not mentioned elsewhere, so we are giving name to this magnetic resonance imaging finding as "headband" sign or "turban" sign.

Are phylogenetic trees suitable for chemogenomics analyses of bioactivity data sets: the importance of shared active compounds and choosing a suitable data embedding method, as exemplified on Kinases.

BACKGROUND: 'Phylogenetic trees' are commonly used for the analysis of chemogenomics datasets and to relate protein targets to each other, based on the (shared) bioactivities of their ligands. However, no real assessment as to the suitability of this representation has been performed yet in this area. We aimed to address this shortcoming in the current work, as exemplified by a kinase data set, given the importance of kinases in many diseases as well as the availability of large-scale datasets for analysis. In this work, we analyzed a dataset comprising 157 compounds, which have been tested at concentrations of 1 µM and 10 µM against a panel of 225 human protein kinases in full-matrix experiments, aiming to explain kinase promiscuity and selectivity against inhibitors. Compounds were described by chemical features, which were used to represent kinases (i.e. each kinase had an active set of features and an inactive set). RESULTS: Using this representation, a bioactivity-based classification was made of the kinome, which partially resembles previous sequence-based classifications, where particularly kinases from the TK, CDK, CLK and AGC branches cluster together. However, we were also able to show that in approximately 57% of cases, on average 6 kinase inhibitors exhibit activity against kinases which are located at a large distance in the sequence-based classification (at a relative distance of 0.6 - 0.8 on a scale from 0 to 1), but are correctly located closer to each other in our bioactivity-based tree (distance 0 - 0.4). Despite this improvement on sequence-based classification, also the bioactivity-based classification needed further attention: for approximately 80% of all analyzed kinases, kinases classified as neighbors according to the bioactivity-based classification also show high SAR similarity (i.e. a high fraction of shared active compounds and therefore, interaction with similar inhibitors). However, in the remaining ~20% of cases a clear relationship between kinase bioactivity profile similarity and shared active compounds could not be established, which is in agreement with previously published atypical SAR (such as for LCK, FGFR1, AKT2, DAPK1, TGFR1, MK12 and AKT1). CONCLUSIONS: In this work we were hence able to show that (1) targets (here kinases) with few shared activities are difficult to establish neighborhood relationships for, and (2) phylogenetic tree representations make implicit assumptions (i.e. that neighboring kinases exhibit similar interaction profiles with inhibitors) that are not always suitable for analyses of bioactivity space. While both points have been implicitly alluded to before, this is to the information of the authors the first study that explores both points on a comprehensive basis. Excluding kinases with few shared activities improved the situation greatly (the percentage of kinases for which no neighborhood relationship could be established dropped from 20% to only 4%). We can conclude that all of the above findings need to be taken into account when performing chemogenomics analyses, also for other target classes.

A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.

Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.

The importance of being profiled: improving drug candidate safety and efficacy using ion channel profiling.

Profiling of putative lead compounds against a representative panel of relevant enzymes, receptors, ion channels, and transporters is a pragmatic approach to establish a preliminary view of potential issues that might later hamper development. An early idea of which off-target activities must be minimized can save valuable time and money during the preclinical lead optimization phase if pivotal questions are asked beyond the usual profiling at hERG. The best data for critical evaluation of activity at ion channels is obtained using functional assays, since binding assays cannot detect all interactions and do not provide information on whether the interaction is that of an agonist, antagonist, or allosteric modulator. For ion channels present in human cardiac muscle, depending on the required throughput, manual-, or automated-patch-clamp methodologies can be easily used to evaluate compounds individually to accurately reveal any potential liabilities. The issue of expanding screening capacity against a cardiac panel has recently been addressed by developing a series of robust, high-throughput, cell-based counter-screening assays employing fluorescence-based readouts. Similar assay development approaches can be used to configure panels of efficacy assays that can be used to assess selectivity within a family of related ion channels, such as Nav1.X channels. This overview discusses the benefits of in vitro assays, specific decision points where profiling can be of immediate benefit, and highlights the development and validation of patch-clamp and fluorescence-based profiling assays for ion channels (for examples of fluorescence-based assays, see Bhave et al., 2010; and for high-throughput patch-clamp assays see Mathes, 2006; Schrøder et al., 2008).

Pruritic rash and eosinophilia in a patient receiving peritoneal dialysis.

A 28-year-old woman with end-stage renal disease maintained on peritoneal dialysis developed a hyperpigmented macular pruritic rash on multiple parts of her body associated with an eosinophilia of 22%. The consulting allergist suspected a silicone allergy from the peritoneal dialysis catheter. A patch test confirmed this diagnosis. Treatment with both topical and systemic steroids was ineffective. Following a living nonrelated renal transplant and removal of the catheter the rash and eosinophilia resolved.

Studying single nanocrystals under high pressure using an x-ray nanoprobe.

In this report, we demonstrate the feasibility of applying a 250-nm focused x-ray beam to study a single crystalline NbSe(3) nanobelt under high-pressure conditions in a diamond anvil cell. With such a small probe, we not only resolved the distribution and morphology of each individual nanobelt in the x-ray fluorescence maps but also obtained the diffraction patterns from individual crystalline nanobelts with thicknesses of less than 50 nm. Single crystalline diffraction measurements on NbSe(3) nanobelts were performed at pressures up to 20 GPa.

Newer therapies for osteoporosis.

The existing drugs for treatment of osteoporosis are limited in scope, tolerability, and efficacy. Newer osteoclast-targeted agents like inhibitors of receptor activator nuclear factor kappaB pathway, Cathepsin K, and integrins are under clinical development. Osteoblast-targeted therapies include the agents acting through the Wnt signaling pathway like sclerostin antagonists. The potential molecular targets and the emerging drugs for treatment of osteoporosis are discussed in this review.

Gout and hyperuricemia.

Hyperuricemia is an elevated uric acid level in blood. Gout is a common systemic metabolic disease characterized by deposition of monosodium urate monohydrate crystals with resultant acute intense inflammation of the involved joint. The clinical spectrum ranges from asymptomatic hyperuricemia to intermittent acute episodes of gouty arthritis to chronic tophaceous gout and chronic gouty arthropathy.

Automatic sensor algorithms expedite pacemaker follow-ups.

OBJECTIVE: Automatic algorithms can be used to optimize settings and reduce the duration of pacemaker (PM) clinical follow-up. METHODS: This study prospectively evaluated 87 patients (74.2 +/- 10.7 years old, 52% men) who received PM with the Autoslope algorithm. Patients randomized to the manual group (group M, n = 43) performed a walk test and used sensor-indicated rate histograms to adjust the sensor, while in the automatic group (group A, n = 44) the sensor was automatically adjusted by the Autoslope. The patients were followed for 6 months. Follow-up time required for device interrogation and optimal sensor set-up, and the number of sensor parameters reprogramming were recorded. Changes in the patients' activity level were also evaluated. RESULTS: Group A required significantly less follow-up time than group M (9.4 +/- 5.7 min vs 13.5 +/- 8.5 min, P = 0.0002). The average number of sensor parameters reprogrammed during visits was significantly lower in group A than M (0.6 +/- 0.9 vs 0.9 +/- 1.3, P = 0.048). Threshold was adjusted 34.4% of the time in the sensor evaluations in group M versus 12.9% in group A (P = 0.0004). Although more patients in group A reported being more active, the changes in patients' activity level did not lead to increasing sensor setup time or number of parameter reprogramming in either group. CONCLUSIONS: Auto sensor adjustment required less time during routine PM clinical follow-up by reducing steps needed for manual sensor threshold adjustment.

Is there a clinically significant gender bias in post-myocardial infarction pharmacological management in the older (>60) population of a primary care practice?

BACKGROUND: Differences in the management of coronary artery disease between men and women have been reported in the literature. There are few studies of potential inequalities of treatment that arise from a primary care context. This study investigated the existence of such inequalities in the medical management of post myocardial infarction in older patients. METHODS: A comprehensive chart audit was conducted of 142 men and 81 women in an academic primary care practice. Variables were extracted on demographic variables, cardiovascular risk factors, medical and non-medical management of myocardial infarction. RESULTS: Women were older than men. The groups were comparable in terms of cardiac risk factors. A statistically significant difference (14.6%: 95% CI 0.048-28.7 p = 0.047) was found between men and women for the prescription of lipid lowering medications. 25.3% (p = 0.0005, CI 11.45, 39.65) more men than women had undergone angiography, and 14.4 % (p = 0.029, CI 2.2, 26.6) more men than women had undergone coronary artery bypass graft surgery. CONCLUSION: Women are less likely than men to receive lipid-lowering medication which may indicate less aggressive secondary prevention in the primary care setting.