Is the use of performance and image enhancing drugs (PIEDs) in women an issue of concern? The findings from a stakeholder consultation.

OBJECTIVES: There is limited research into the use of performance and image enhancing drugs among women who participate in sport, despite evidence that women do use these substances and experience related harms. The aim of this project is to capture stakeholder perspectives on the current research, policy, and practice landscape in Australia regarding women's performance and image enhancing drug use in regulated and unregulated sport settings. DESIGN: Qualitative interviews. METHODS: Thirty-two semi-structured interviews were conducted online with stakeholders from Australia between September and December 2021. Interviews ranged between 15 and 90 min in duration. Data were imported into the NVivo (Version 12) platform and analysed using thematic analysis. RESULTS: Thirty-two participants (20 females and 12 males) who held a variety of roles (e.g., coach/strength coaches, gym owners, anti-doping agents, athletes) were interviewed. Fourteen participants reported performance and image enhancing drug use. There were four overarching themes generated from the data: 'participation in untested sports'; 'environmental factors driving use'; 'individual rationalisation'; and, 'the dark side of performance and image enhancing drug use'. CONCLUSIONS: Performance and image enhancing drug use was identified as an issue of concern for women competing in non-elite strength and power-based sports. Of particular concern is the influence of unqualified advice from third parties (i.e., coaches and partners) regarding performance and image enhancing drug use. The environments in which performance and image enhancing drug use occurs can impact individual decisions of women and eventuate in significant and long-lasting physical and psychological harms.

α4-Containing GABAA Receptors on DRD2 Neurons of the Nucleus Accumbens Mediate Instrumental Responding for Conditioned Reinforcers and Its Potentiation by Cocaine.

Extrasynaptic GABAA receptors (GABAARs) composed of α4, ß, and δ subunits mediate GABAergic tonic inhibition and are potential molecular targets in the modulation of behavioral responses to natural and drug rewards. These GABAARs are highly expressed within the nucleus accumbens (NAc), where they influence the excitability of the medium spiny neurons. Here, we explore their role in modulating behavioral responses to food-conditioned cues and the behavior-potentiating effects of cocaine. α4-Subunit constitutive knock-out mice (α4-/-) showed higher rates of instrumental responding for reward-paired stimuli in a test of conditioned reinforcement (CRf). A similar effect was seen following viral knockdown of GABAAR α4 subunits within the NAc. Local infusion of the α4ßδ-GABAAR-preferring agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; Gaboxadol) into the NAc had no effect on responding when given alone but reduced cocaine potentiation of responding for conditioned reinforcers in wild-type, but not α4-/- mice. Finally, specific deletion of α4-subunits from dopamine D2, but not D1, receptor-expressing neurons (DRD2 and DRD1 neurons), mimicked the phenotype of the constitutive knockout, potentiating CRf responding, and blocking intra-accumbal THIP attenuation of cocaine-potentiated CRf responding. These data demonstrate that α4-GABAAR-mediated inhibition of DRD2 neurons reduces instrumental responding for a conditioned reinforcer and its potentiation by cocaine and emphasize the importance of GABAergic signaling within the NAc in mediating the effects of cocaine.

Gendered perspectives on women's anabolic-androgenic steroid (AAS) usage practices.

BACKGROUND: The masculinizing effects from anabolic-androgenic steroid (AAS) appear to be different between men and women, leading to calls for more gender-specific information regarding women and AAS use. This study sought to gather perspectives from both men and women on the unique challenges surrounding women's use of AAS, irrespective of their personal use. Secondly, the study interrogated how women's AAS practices differ from those of men specifically. METHODS: The data presented in this paper come from a subsample of participants who participated in a larger study investigating women and performance and image enhancing drug (PIED) use in Australia. Participants were included in the current analysis if they were: (i) males or females who competed with or coached female strength athletes using AAS and (ii) female and male strength athletes who used AAS. The final sample comprised 21 participants of which there was a proportion of males (n = 7) and females (n = 7) using AAS. RESULTS: Women's choices in AAS selection were predominantly around oral compounds (e.g. Oxandrolone) as well as other PIEDs (e.g. Clenbuterol). Some women report the use of injectable AAS represents a change in the profile of the typical female user as it reportedly comes alongside drastic physical and psychological changes. CONCLUSIONS: The unique challenges facing women who use AAS are largely isolation and stigma, with little evidence-based practice or education being available to them online or through peer-groups. Future work may consider piloting harm reduction strategies that may be co-designed with this group.

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor.

AIMS: Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. METHODS: Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. RESULTS: GSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen. CONCLUSIONS: GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.

Clinical efficacy and tolerability of a novel selective corticosteroid in atopic dermatitis--two randomised controlled trials.

Topical corticosteroids remain the first-line therapy for atopic dermatitis (AD). Hence, we investigated the efficacy and safety profile of a novel selective corticosteroid, GW870086. We performed 2 randomised, double-blind, controlled studies with 25 AD patients and 20 healthy subjects. The changes in the Three-Item Severity (TIS) score and the skin thickness were the primary end points, respectively. The adjusted TIS score (day 22) shows that the novel corticosteroid resulted in a non-significant, but dose-dependent reduction compared to placebo (GW870086 0.2% vs. placebo = -0.38, GW870086 2% vs. placebo = -0.89). Significant skin thinning was observed in the second study on days 14 and 21 when patients were treated with the comparator but not with the novel corticosteroid compared to placebo. The clinical efficacy of the new selective corticosteroid was not superior to placebo, although a dose-dependent improvement upon treatment was noticed without the onset of skin thinning.

Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia.

STUDY OBJECTIVES: Investigate the hypnotic effects of repeated doses of neurokinin-1 receptor antagonist, vestipitant, in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled 28-day parallel-group study. SETTING: Eleven sleep centers in Germany. PATIENTS: One hundred sixty-one patients with primary insomnia. INTERVENTIONS: Patients received vestipitant (15 mg) or placebo for 28 days; 2-night polysomnographic assessment occurred on nights 1/2 and 27/28. MEASUREMENTS AND RESULTS: Wake after sleep onset (WASO) was improved on nights 1/2 and 27/28 (ratio, vestipitant versus placebo [95% confidence interval]: 0.76 [0.65, 0.90], P = 0.001 and 0.79 [0.65, 0.96], P = 0.02, respectively), demonstrating maintenance of the effect following repeated dosing. Latency to persistent sleep was shorter with vestipitant on nights 1/2 (P = 0.0006 versus placebo), but not on nights 27/28. Total sleep time (TST) improved with vestipitant (nights 1/2: P < 0.0001, nights 27/28: P = 0.02 versus placebo). Next-day cognitive function tests demonstrated no residual effects of vestipitant (P > 0.05 versus placebo). Adverse events (AEs) occurred in 25% of vestipitant patients versus 22% for placebo. Headache was the most common AE (8% of vestipitant patients versus 9% for placebo). CONCLUSIONS: Vestipitant improved sleep maintenance in patients with primary insomnia, with no associated next-day cognitive impairment. The effects on wake after sleep onset and total sleep time were maintained following repeated dosing.

Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study.

BACKGROUND: The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy. METHODS: The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 µg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812). RESULTS: Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%. CONCLUSION: In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

Pharmacokinetics, Safety, and Tolerability Following the Administration of a Single Dose of a Combination Tablet Containing Sumatriptan and Naproxen Sodium in Adolescent Patients With Migraine and in Healthy Adult Volunteers.

OBJECTIVE: The objective was to compare the pharmacokinetics of sumatriptan and naproxen in adolescent migraineurs and healthy adults after administration of sumatriptan/naproxen sodium combination tablets. DESIGN: The design was an open-label, randomized, parallel group study. Adolescent migraineurs (12-17 years) and healthy adults received 1 dose of sumatriptan/naproxen: 10 mg/60 mg, 30 mg/180 mg, or 85 mg/500 mg. Pharmacokinetic and safety assessments were conducted. RESULTS: Sumatriptan achieved Cmax rapidly (median tmax : 0.8-1.5 hours for adolescents, 0.5-2.0 hours for adults); elimination was also rapid (geometric mean t½ : <2 hours for adolescents, 1.9-2.4 hours for adults). Compared with sumatriptan, naproxen was absorbed and eliminated more slowly (median tmax : 1.0-4.0 hours for adolescents, 1.0-3.0 hours for adults; geometric mean t½ : 13.4-16.3 hours for adolescents, 14.3-16.6 hours for adults). Sumatriptan Cmax and AUC were similar for adolescents and adults for the 85 mg/500 mg dose; exposure for the 2 lower doses showed slight differences (not significant). Naproxen Cmax and AUC were comparable between the 2 groups at all doses. Increases in sumatriptan Cmax and AUC were dose proportional; for naproxen, slightly less than proportional. The tablets were generally well tolerated. CONCLUSION: Sumatriptan and naproxen pharmacokinetics were not dissimilar between adolescent migraineurs and healthy adults.

Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.

Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p=0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.