Towards Praxes of the Region: Agential Constructivist Approaches to Regionalisms.

While both formal and informal regionalisms examine the political ramifications of economic flows of capital, goods, and people, there is a blurring of such conceptual dichotomies in practice. Hence, in order to offer a more accurate account of the distinctions and overlap between the formal and informal - and to rectify the tendency to overlook the agency of African state actors and non-state actors - this article offers an agential constructivist approach that seeks to advance a praxis - or praxes - of the region. To that end, the article advances the concept of bifurcated interregionalisms as a means of analyzing cases of regional dynamics and regionalisms in Southern Africa and East Africa. The article concludes by offering some reflections on the future of regionalisms in an emerging global order in flux whereby illiberal and xenophobic variants of regionalisms compete with the liberal and cosmopolitan versions.

PMFF: Development of a Physics-Based Molecular Force Field for Protein Simulation and Ligand Docking.

The physics-based molecular force field (PMFF) was developed by integrating a set of potential energy functions in which each term in an intermolecular potential energy function is derived based on experimental values, such as the dipole moments, lattice energy, proton transfer energy, and X-ray crystal structures. The term "physics-based" is used to emphasize the idea that the experimental observables that are considered to be the most relevant to each term are used for the parameterization rather than parameterizing all observables together against the target value. PMFF uses MM3 intramolecular potential energy terms to describe intramolecular interactions and includes an implicit solvation model specifically developed for the PMFF. We evaluated the PMFF in three ways. We concluded that the PMFF provides reliable information based on the structure in a biological system and interprets the biological phenomena accurately by providing more accurate evidence of the biological phenomena.

Interleukin-4/interleukin-13 versus interleukin-5: a comparison of molecular targets in biologic therapy for the treatment of severe asthma.

PURPOSE OF REVIEW: Asthma is a chronic, inflammatory disorder of the airways caused by a complex interplay of various biologic mechanisms. Several monoclonal antibody therapies targeting interleukin (IL)-4/IL-13 and IL-5 cytokine pathways have been developed for the treatment of severe eosinophilic asthma. As individuals can display biomarkers and clinical features characteristic of several asthma phenotypes, selection of anoptimal biologic can be difficult. RECENT FINDINGS: Dupilumab, a monoclonal antibody that binds to the α subunit of the IL-4 receptor (IL-4Rα) and has been approved for the treatment of adults with severe atopic dermatitis, has been shown in recent phase 3 trials to also have significant clinical benefits in the asthmatic population irrespective of baseline eosinophil counts. SUMMARY: As monoclonal antibodies targeting either IL-4 or IL-13 cytokines individually have failed to demonstrate significant clinical benefits, biologics that target cytokine receptors may be more efficacious compared to those that target cytokines. Furthermore, inhibition of the IL-4/IL-13 signaling cascades may disrupt a broader Th2 inflammatory response compared to a more selective impairment of eosinophil proliferation and activity via blockage of the IL-5 pathway. Future research with independently funded, head-to-head trials of approved biologics is needed to elucidate a favorable therapeutic option.

Role of epigenetics and DNA-damage in asthma.

PURPOSE OF REVIEW: Although asthma is a common disease worldwide, its pathogenesis remains to be fully elucidated. There is increasing evidence of the interaction between epigenetics, DNA-damage, and environmental allergens in the development of asthma. In this review, we will focus on the role of epigenetics and DNA-damage in asthma. RECENT FINDINGS: There is growing evidence of environmental allergens, particularly house dust mite, stimulating oxidative DNA damage in airway epithelial cells. The repair of this DNA damage has been implicated in the secretion of Th2 cytokines and the induction of allergic inflammation. SUMMARY: Studies of the role of epigenetics, DNA-damage, and environmental allergens have begun to reveal the their complex interactions and their roles in the development of asthma. Further study in these areas may lead to novel prevention and treatment approaches.

Omalizumab as a desensitizing agent and treatment in mastocytosis: a review of the literature and case report.

Patients with all forms of mastocytosis can experience urticaria, abdominal cramps, nausea, diarrhea, or hypotension due to release of mediators by mast cells. Patients with mastocytosis and Hymenoptera venom allergy can develop severe adverse reactions to Hymenoptera stings. In addition, patients with mastocytosis and on venom immunotherapy are at high risk for incomplete protection and fatal reactions. Recent literature has reported the use of omalizumab as an adjunctive treatment in patients with mastocytosis, used for both symptom improvement and to dampen adverse effects caused by venom immunotherapy. This article reviews the literature regarding omalizumab use in the treatment of mastocytosis and for protection against the adverse effects during venom immunotherapy. In addition, we report the case of a patient at high risk and with cutaneous mastocytosis, whose symptoms improved with concomitant administration of omalizumab and venom immunotherapy.

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds.

Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.

Modular, gold-catalyzed approach to the synthesis of lead-like piperazine scaffolds.

Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines. Manipulation of the tetrahydropyrazines, by reduction or using multicomponent reactions, yielded piperazine scaffolds in which substitution of the carbon atoms was varied. Such scaffolds may have value in the synthesis of novel screening compounds with lead-like molecular properties.

Hereditary angioedema: epidemiology, management, and role of icatibant.

Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert®, Cinryze®, and Cetor®) and recombinant (Rhucin® and Ruconest™) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor®), and bradykinin B2 receptor antagonist-icatibant (Firazyr®). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr®), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients' quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient's quality of life.

Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic acid.

Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin. However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties. In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA. Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders. Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA.

Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial.

CONTEXT: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. OBJECTIVE: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma. DESIGN, SETTING, AND PARTICIPANTS: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. INTERVENTIONS: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. MAIN OUTCOME MEASURE: The primary outcome was time to treatment failure. RESULTS: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). CONCLUSION: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00495157.

Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks.

Patients with hereditary angioedema (HAE) may have attacks triggered by dental, medical, or surgical procedures. This analysis evaluated the efficacy and safety of preprocedural administration of nanofiltered C1 esterase inhibitor (C1 INH-nf; human) for the prevention of HAE attacks during and after dental, medical, or surgical procedures. Data were reviewed retrospectively from two acute treatment trials in which at least 1000 U of C1 INH-nf was administered i.v. within 24 hours before an emergency or noncosmetic medical, surgical, or dental procedure. Dosing data, HAE attacks reported within 72 hours, and adverse events (AEs) reported within 7 days after a preprocedural dose of C1 INH-nf were analyzed to assess efficacy and safety. Forty-one unique subjects (8 children and 33 adults) received C1 INH-nf for 91 procedures (40 in children and 51 in adults). The majority of procedures (56%) involved dental work and 44% involved a variety of surgical or medical procedures. A single 1000-U dose of C1 INH-nf was administered for 96% of procedures. An HAE attack did not occur within 72 hours after C1 INH-nf dosing for 98% (89/91) of procedures. Two HAE attacks were reported after the procedure, and both were treated with C1 INH-nf and achieved relief. None of the reported AEs were judged to be related to C1 INH-nf or were associated with an HAE attack. This analysis supports the efficacy and safety of preprocedural administration of C1 INH-nf for the prevention of HAE attacks.

Life with hereditary angioedema: then and now.

Originally identified in 1882, hereditary angioedema (HAE) is a debilitating and potentially fatal disorder. Although a number of therapies have been identified, many are relatively ineffective or are associated with significant side effect concerns that limit their efficacy. Fortunately, the 2008 approval of plasma-derived C1 esterase inhibitor concentrate for disease prophylaxis provides clinicians with a novel and effective treatment unencumbered with severe side effect concerns for those with this debilitating disorder. However, despite advances in modern medicine, HAE remains a condition marked by a myriad of symptoms that mimic a range of other disorders, from allergic angioedema to acute abdomen, and accurate diagnosis remains a concern. Using articles from the medical literature from the late nineteenth and early twentieth centuries documenting families with HAE, we will review its history and pathophysiology as well as describe current trends in its diagnosis and treatment. Additionally, we will emphasize the humanistic impact of the disorder by describing the real-life experiences of a contemporary family who has documented their experience with HAE across 7 generations.

Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening. METHODS: We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control. RESULTS: In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling. CONCLUSIONS: In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.)

SAMPL2 and continuum modeling.

An account is given of our contributions to the SAMPL2 challenge for vacuum-water transfer energies. These contributions include different charge sets and radii used with Poisson-Boltzmann continuum theory applied to a single low-energy conformation. A rationale for this approach is given, including a summary of what we have learnt over previous SAMPL events. The results strongly suggest the need for new and repeated experimental measurements, both to clarify what appears to be experimental discrepancies in older measurements and to advance the field in a statistically sound manner.

Molecular shape and medicinal chemistry: a perspective.

The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for "decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward. Certainly, it is encouraging that as computation has enabled our intuition, molecular shape has consistently surprised us in its usefulness and adaptability. The first Aurelius question, "What is the essence of a thing?", seems well answered, however, the third, "What do molecules do?", only partly so. Are the topics covered here exhaustive, or is there more to come? To date, there has been little published on the use of the volumetric definition of shape described here as a QSAR variable, for instance, in the prediction or classification of activity, although other shape definitions have been successful applied, for instance, as embodied in the Compass program described above in "Shape from Surfaces". Crystal packing is a phenomenon much desired to be understood. Although powerful models have been applied to the problem, to what degree is this dominated purely by the shape of a molecule? The shape comparison described here is typically of a global nature, and yet some importance must surely be placed on partial shape matching, just as the substructure matching of chemical graphs has proved useful. The approach of using surfaces, as described here, offers some flavor of this, as does the use of metrics that penalize volume mismatch less than the Tanimoto, e.g., Tversky measures. As yet, there is little to go on as to how useful a paradigm this will be because there is less software and fewer concrete results.Finally, the distance between molecular shapes, or between any shapes defined as volumes or surfaces, is a metric property in the mathematical sense of the word. As yet, there has been little, if any, application of this observation. We cannot know what new application to the design and discovery of pharmaceuticals may yet arise from the simple concept of molecular shape, but it is fair to say that the progress so far is impressive.

Using electronic polarization from the internal continuum (EPIC) for intermolecular interactions.

Recently, the vacuum-phase molecular polarizability tensor of various molecules has been accurately modeled (Truchon et al., J Chem Theory Comput 2008, 4, 1480) with an intramolecular continuum dielectric model. This preliminary study showed that electronic polarization can be accurately modeled when combined with appropriate dielectric constants and atomic radii. In this article, using the parameters developed to reproduce ab initio quantum mechanical (QM) molecular polarizability tensors, we extend the application of the "electronic polarization from internal continuu" (EPIC) approach to intermolecular interactions. We first derive a dielectric-adapted least-square-fit procedure similar to RESP, called DRESP, to generate atomic partial charges based on a fit to a QM abinitio electrostatic potential (ESP). We also outline a procedure to adapt any existing charge model to EPIC. The ability of this to reproduce local polarization, as opposed to uniform polarization, is also examined leading to an induced ESP relative root mean square deviation of 1%, relative to ab initio, when averaged over 37 molecules including aromatics and alkanes. The advantage of using a continuum model as opposed to an atom-centered polarizable potential is illustrated with a symmetrically perturbed atom and benzene. We apply EPIC to a cation-pi binding system formed by an atomic cation and benzene and show that the EPIC approach can accurately account for the induction energy. Finally, this article shows that the ab initio electrostatic component in the difficult case of the H-bonded 4-pyridone dimer, a highly polar and polarized interaction, is well reproduced without adjusting the vacuum-phase parameters.

The SAMP1 solvation challenge: further lessons regarding the pitfalls of parametrization.

This paper describes an investigation into the performance of different charges and radii with the Poisson-Boltzmann method for the calculation of vacuum-water transfer energies. The test set consisted of 63 drug-like molecules used in a blind-test challenge. The results are consistent with earlier reports, namely, that more physical charges perform better and that radii parametrization can both improve and also dramatically worsen results, with the latter suggesting a failure to capture all of the basic physics of solvation.

Mediators of anaphylaxis.

Anaphylaxis is a life-threatening condition closely linked to IgE activation of mast cells with subsequent release of preformed mediators, including histamine, neutral proteases (tryptase and chymase), and proteoglycans (eg, heparin) from intracellular granules. These factors participate in the development of classic symptoms involving the skin, respiratory tract, circulation, and gastrointestinal system. Release of these granules is followed quickly by increased synthesis from membrane arachidonic acid of prostaglandins and leukotrienes that have an additional role in clinical symptoms. Thereafter, mast cells release numerous chemokines and cytokines that initiate recruitment and activation of additional inflammatory cells, including basophils, eosinophils, and Th2 cells.