Polypharmacy among anabolic-androgenic steroid users: A descriptive metasynthesis

Background: As far as we are aware, no previous systematic review and synthesis of the qualitative/descriptive literature on polypharmacy in anabolic-androgenic steroid(s) (AAS) users has been published. Method: We systematically reviewed and synthesized qualitative/descriptive literature gathered from searches in electronic databases and by inspecting reference lists of relevant literature to investigate AAS users' polypharmacy. We adhered to the recommendations of the UK Economic and Social Research Council's qualitative research synthesis manual and the PRISMA guidelines. Results: A total of 50 studies published between 1985 and 2014 were included in the analysis. Studies originated from 10 countries although most originated from United States (n = 22), followed by Sweden (n = 7), England only (n = 5), and the United Kingdom (n = 4). It was evident that prior to their debut, AAS users often used other licit and illicit substances. The main ancillary/supplementary substances used were alcohol, and cannabis/cannabinoids followed by cocaine, growth hormone, and human chorionic gonadotropin (hCG), amphetamine/meth, clenbuterol, ephedra/ephedrine, insulin, and thyroxine. Other popular substance classes were analgesics/opioids, dietary/nutritional supplements, and diuretics. Our classification of the various substances used by AAS users resulted in 13 main groups. These non-AAS substances were used mainly to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. Conclusions: Our findings corroborate previous suggestions of associations between AAS use and the use of other licit and illicit substances. Efforts must be intensified to combat the debilitating effects of AAS-associated polypharmacy

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Development of Microsponges for Topical Delivery of Mupirocin

The goal of the present study was to develop and evaluate microsponge-based topical delivery system of mupirocin for sustained release and enhanced drug deposition in the skin. Microsponges containing mupirocin were prepared by an emulsion solvent diffusion method. The effect of formulation and process variables such as internal phase volume and stirring speed on the physical characteristics of microsponges were examined on optimized drug/polymer ratio by 32 factorial design. The optimized microsponges were incorporated into an emulgel base. In vitro drug release, ex vivo drug deposition, and in vivo antibacterial activity of mupirocin-loaded formulations were studied. Developed microsponges were spherical and porous, and there was no interaction between drug and polymer molecules. Emulgels containing microsponges showed desired physical properties. Drug release through cellulose dialysis membrane showed diffusion-controlled release pattern and drug deposition studies using rat abdominal skin exhibited significant retention of active in skin from microsponge-based formulations by 24 h. The optimized formulations were stable and nonirritant to skin as demonstrated by Draize patch test. Microsponges-based emulgel formulations showed prolonged efficacy in mouse surgical wound model infected with S. aureus. Mupirocin was stable in topical emulgel formulations and showed enhanced retention in the skin indicating better potential of the delivery system for treatment of primary and secondary skin infections, such as impetigo, eczema, and atopic dermatitis

A requiem for hybridity? The problem with Frankensteins, purées, and mules

Hybridity as an interpretive construct in the archaeology of colonialism has encountered many pitfalls, due largely to the way it has been set adrift from clear theoretical anchors and has been applied inconsistently to things, practices, processes, and even people. One of the telltale signs of its problematic nature is the ease with which archaeologists claim to identify the origin and existence of hybridity but the difficulty faced if asked when and how such hybridity actually ends, if it does. In that context, this paper offers a potential requiem for hybridity. If we need not go that far, archaeologists at least need to rein in the “Frankenstein” version of hybridity that permeates archaeology and occludes its variable and problematic origins, acknowledge the dangers of accentuating or even celebrating “purées,” and beware of the creation of cultural “mules” in analytical classifications and interpretations