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NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated. [ABSTRACT FROM AUTHOR]

Background: NXY-059 is a novel free-radical trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke (AIS). In an initial Phase III study (SAINT I) NXY-059 has shown efficacy in AIS by reducing functional disability. NXY-059 is eliminated by renal excretion, primarily through glomerular filtration but with 30% estimated as active tubular secretion. This study was designed to further characterize the active renal excretion of NXY-059. Probenecid and cimetidine, substrates for renal systems that transport organic acids and bases, were chosen as model inhibitors.Methods: This was a single-center, randomized, open-label, parallel group study. 55 healthy subjects received a 12-h iv infusion of NXY-059 (target plasma concentrations 25-30 μmol/L) with one of these treatments given at 6h:Group A: Oral 1.5g probenecidGroup B: Oral 800mg cimetidineGroup C: ControlRenal clearance (CLR) of NXY-059 was estimated before and after administration of the inhibitor.Results: The CLR of NXY-059 in the probenecid group decreased by 30%, from an average of 108 mL/min (before 6h) to 75.5 mL/min (after 6h)[p<0.001]. There was no statistically significant difference in the mean CLR of NXY-059 before and after 6h for either the cimetidine or control group.Conclusions: The active tubular secretion of NXY-059 occurs through an organic acid transporter, not an organic base transporter. This active secretion contributes approximately 30% of the renal elimination.Clinical Pharmacology & Therapeutics (2005) 79, P72–P72; doi: 10.1016/j.clpt.2005.12.260 [ABSTRACT FROM AUTHOR]

This article provides a multilevel intersectional analysis of the prevalence and frequency of gender-based violence within universities and other research organizations in Europe. Results show not only the high prevalence of gender-based violence in this context, but also that in contrast to the prevailing discourse, that gender-based violence is not solely a "women's problem", but also a structural issue impacting diverse identities. Data on frequency show that physical and sexual violence usually occurs as isolated incidents, whereas psychological violence and harassment are often repeated., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Drawing from a nationally representative survey ( n  = 6,611), this article analyses the prevalence of men's economic abuse toward women in Sweden. Economic abuse is still a relatively marginalized area of research but is increasingly recognized as a distinct type of intimate partner violence. A few Swedish studies have specifically focused on economic abuse, yet none of which with a quantitative approach. A main finding is that motherhood significantly increases the risk of exposure. Furthermore, women report economic abuse from expartners (25%) to a much greater extent than from current partners (8%)., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The aim of the article is to discuss how thinking about gender-based violence intersectionally and in context can not only enrich our understanding but also lead to transformative change in organizations. The article argues that to better understand gender-based violence in universities and research institutions, analyses need to be intersectional and contextual. Such approaches go beyond binary understandings of gender and narrow legalistic definitions of gender-based violence. The article reflects on how to operationalize this to derive starting points for intersectional categories to consider and contextual factors to measure at micro-, meso-, and macro-levels. It concludes that a multilevel intersectional analysis leads to more nuanced knowledge on experiences of gender-based violence and is, therefore, better equipped to inform the development of measures to eradicate the problem in an inclusive way., Competing Interests: Declaration of Conflicting InterestsThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from the European Union H2020, project UniSAFE (Grant No. 101006261).

With the emergence and global proliferation of "sugar dating" websites, the phenomenon of sugar dating is gaining increased attention. Sugar dating is described by these websites as arrangements based on an exchange of financial or other forms of support for intimacy and companionship. The framing of sugar dating as something in between a business transaction and mutually enjoyable dating serves as the point of departure of this article, which draws on semi-structured interviews and a survey questionnaire with "sugar daddies" engaged in heterosexual sugar dating in Sweden. We examined how the tension between economic instrumentality and the ideal of mutual enjoyment is played out in "sugar daddies'" accounts of their sugar dating experiences. We demonstrate that the participants desire encounters with "sugar babies" to be based on both sexual and relational mutuality, i.e., they want the women to enjoy being with them beyond the economic rewards. We show that the men's use of economic incentives to gain access to "sugar babies" stands in a relationship of tension with their desire for interactions to be based on mutuality. However, through various mechanisms they still manage to reap the fruits of the experience of mutuality offered in sugar dating encounters.

Measuring violence against women raises methodological questions, as well as the wider question of how to understand violence and locate it in relation to a societal context. This is all the more relevant given that measurement of violence against women in the EU has made an interesting phenomenon apparent, the so-called 'Nordic Paradox', whereby prevalence is higher in more gender equal countries. This article examines this phenomenon by exploring a range of factors-methodological, demographic and societal-to contextualise disclosed levels of violence. The analysis makes use of a multilevel analytic approach to take into account how macro and micro levels contribute to the prevalence of violence. The intercepts are then used to illustrate how taking these into account might provide an alternative ranking of levels of violence against women in EU countries. The results show that the 'Nordic Paradox' disappears-and can be undone-when factors at individual and country levels are considered. We conclude that the 'Nordic Paradox' cannot be understood independently from a wider pattern of violence in society, and should be seen as connected and co-constituted in specific formations, domains or regimes of violence. Our results show that the use of multi-level models can provide new insights into the factors that may be related to disclosed prevalence of violence against women. This can generate a better understanding of how violence against women functions as a system, and in turn inform better policy responses., Competing Interests: The authors have declared that no competing interests exist.

This article explores minority migrant men's attitudes towards female genital mutilation (FGM), and how these attitudes can be used to develop strategies to engage men in the eradication of FGM. Based on interviews and focus group discussions, the article finds that men's attitudes can be enabling, disabling or neutral: the identification of and variations between these need to be taken into account when developing strategies to engage men in the eradication of FGM. There is currently a window of opportunity for involving minority migrant men in the prevention of FGM and in the challenging of a minority migrant gender regime.

During the course of urinary tract infection (UTI) nitric oxide (NO) is generated as part of the host response. This study investigates the significance of the NO-detoxifying enzyme flavohemoglobin (Hmp) in protection of uropathogenic Escherichia coli (UPEC) against nitrosative stress. An hmp (J96Deltahmp) knockout mutant of UPEC strain J96 was constructed using single-gene deletion. The viability of J96Deltahmp was significantly reduced (P<0.001) compared to the wild-type strain after exposure to the NO-donor DETA/NO. The NO consumption in J96Deltahmp was significantly (P<0.001) impaired compared to J96wt. Screening UPEC isolates from patients with UTI revealed increased hmp expression in all patients. In a competition-based mouse model of UTI, the hmp mutant strain was significantly (P<0.05) out-competed by the wild-type strain. This study demonstrates, for the first time, that Hmp contributes to the protection of UPEC against NO-mediated toxicity in vitro. In addition, hmp gene expression occurs in UPEC isolates from the infected human urinary tract and UPEC that were hmp-deficient had a reduced ability to colonize the mouse urinary tract. Taken together the results suggest that NO detoxification by Hmp may be a fitness advantage factor in UPEC, and a potentially interesting target for development of novel treatment concepts for UTI., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.

Objective: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment., Methods: Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 micro mol/l for subjects with mild (GFR 50-100 ml/min) and moderate (GFR 30-49 ml/min) renal impairment, and 30 micro mol/l for subjects with severe renal impairment (GFR <30 ml/min). GFR was measured as sinistrin clearance., Results: The data indicated no tolerability or safety concerns with NXY-059. The half-life, which normally is approximately 2-4 h, was in the order of 10-12 h in subjects with moderate and severe renal impairment. The distribution parameters steady-state volume of distribution (V(ss)) and unbound fraction in plasma at 13-15 l and 0.53-0.58, respectively, were virtually the same as previously observed in healthy subjects. Plasma clearance of NXY-059, which ranged from 9 ml/min to 76 ml/min, was directly proportional to kidney function (GFR) with no discernible contribution by non-renal clearance. The correlation coefficient squared (r(2)) was 0.93, both when the renal function parameter was GFR and when it was creatinine clearance estimated from serum creatinine, age, weight and sex., Conclusion: Non-renal elimination of NXY-059 appeared to be insignificant even in subjects with low renal capacity. Patients with renal impairment should have their dose of NXY-059 adjusted for renal function, conveniently assessed from serum creatinine.

The tolerability, safety, and pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent under development for the treatment of acute ischemic stroke, were investigated in 2 double-blind, placebo-controlled dose-escalation studies in healthy subjects. In the first study in 6 panels of young male subjects (n = 48, 22-45 years), constant rate infusions lasted 8 hours and ranged from 0.16 to 5.25 micromol/kg/h (0.06 to 2.0 mg/kg/h). In the second study, elderly male and female subjects (n = 24, 57-72 years) were infused over 24 hours or 72 hours to reach target plasma levels of 30 micromol/L or 60 micromol/L, respectively, using doses in the range 1.4-4.0 micromol/kg/h. With a 1-hour loading infusion set at 3 times the maintenance infusion rate, the target plasma level was reached in 1 hour. Adverse events were mild or moderate, and no clinically relevant changes in vital signs, ECG recordings, or laboratory values were noted. Steady-state levels in both studies increased proportionally to the infusion rate, indicating linear kinetics. Renal elimination was predominant, the recovery of unchanged drug in urine being 80% to 90% irrespective of age. The average plasma clearance in young and elderly subjects was 7.0 L/h and 4.1 L/h, respectively. It was estimated that glomerular filtration and active tubular secretion of NXY-059 accounted for approximately two-thirds and one-third of its renal clearance, respectively. In the elderly, clearance of NXY-059 was significantly correlated to creatinine clearance. The renal clearance was insensitive to variations in urine pH and urine flow rate. It appears that NXY-059 is well tolerated and has a highly predictable pharmacokinetic profile.

A double-blind randomized crossover analgesic trial was carried out on 70 patients undergoing surgical removal of one lower third molar at each visit. The analgesic efficacy of a two-dose regimen of the combination ibuprofen-codeine, 400 to 60 mg, was compared with ibuprofen, 400 mg. Each of the two doses was taken when the patient needed pain relief and the pain intensity was measured on a visual analog scale during the 10-hour period after the first medication. Because of carryover effects between periods 1 and 2, the analysis was carried out only for period 1 according to a parallel group design. Of the 60 patients who were evaluated for analgesic effect, the mean pain reduction of dose 1 was 63% for the 29 patients given ibuprofen-codeine and 50% for the 31 patients given ibuprofen; the mean duration of effect was 7.5 and 6.3 hours, respectively. The difference in pain reduction index (pain reduction X duration of effect) between the two treatments was significant in favor of the combination, whereas the separate variables of pain reduction and duration of effect were not significantly different. The mean pain reduction was 67% after doses 1 and 2 for patients on ibuprofen-codeine and 52% for those on ibuprofen; the mean duration of effect was 9.4 and 9.2 hours, respectively. For doses 1 and 2, the difference in pain reduction index per dose between the two treatments was significant but not the difference for the separate variables, pain reduction, and duration of effect.(ABSTRACT TRUNCATED AT 250 WORDS)

In a double blind randomised multicentre study the effect of intravenous clodronate plus hydration was compared with placebo plus hydration in the treatment of hypercalcaemia in breast cancer patients with bone metastases. The patients were treated either with hydration plus clodronate 300 mg/day or hydration plus placebo, up to 7 days or until serum ionised calcium was below 1.4 mmol/l. 25 patients received clodronate and 19 placebo. A significant difference in favour of clodronate was observed in the time to reach normocalcaemia (P = 0.004) and in the number of patients achieving normocalcaemia (P = 0.0003). 17 patients of 21 evaluable patients on clodronate achieved normocalcaemia compared with 4 of 19 patients on placebo. The only adverse event clearly associated with clodronate was symptomatic hypocalcaemia in 1 patient. Thus, clodronate seems to be a safe and highly efficacious drug for the treatment of hypercalcaemia in breast cancer patients.

Foscarnet is shown to inhibit influenza A virus replication by inhibiting viral RNA synthesis in infected cells. Viral RNA synthesis by isolated nuclei from infected cells was as sensitive to foscarnet as viral RNA synthesis by enzymes from isolated virions or viral cores. It is, therefore, unlikely that the mere association of the polymerase in a replication complex, as in isolated nuclei and infected cells, is the reason for the fact that foscarnet is 10-20 times less active in inhibiting virus replication than cell-free RNA synthesis. We, therefore, tested 44 esters of foscarnet for improved antiviral effect. Of these only a few phenyl esters were more potent than foscarnet itself. These esters did not inhibit the viral RNA polymerase activity and may be hydrolyzed intracellularly to foscarnet. The increased antiviral potency of the phenyl esters was, however, accompanied by increased cellular toxicity, and these compounds, therefore, were less selective antiviral agents than foscarnet. The results suggest that it is not possible to increase the anti-influenza activity of foscarnet by converting it to an ester.