How to save a life: Public awareness of a national mass media take home naloxone campaign, and effects of exposure to campaign components on overdose knowledge and responses.

BACKGROUND: Take home naloxone (THN) programmes are effective at reducing opioid related mortality, but require high levels of distribution, including to the general public. Mass media campaigns can be effective in improving public understanding of a topic and encouraging behavior change. Whilst mass media campaigns focusing on naloxone have been developed internationally, there is a lack of research on their potential impact. We investigated the effects of components of a recent national mass media campaign (Scotland, UK) designed to improve public awareness of drug related deaths, and readiness to intervene. METHODS: We undertook a cross-sectional online experimental study with a randomized design, conducted with a nationally representative sample. Participants (N = 1551; 52.6% female; age 46.1±16.5 years) were assessed on overdose knowledge and readiness to intervene after presentation of eight combinations of campaign components. RESULTS: Compared to a basic campaign description, exposure to all types of campaign component were associated with higher overdose knowledge (p < .001), but not knowledge of what to do in response to an overdose (p = .374), or readiness to intervene (p= .286). The greatest effects were associated with a media rich audio-visual resource (animated video with a popular song on the soundtrack, and narrated by a well-known actor). CONCLUSION: Our data suggest that harm reduction is an appropriate topic for large-scale mass media campaigns. However, effects may be limited to knowledge and awareness raising in the general public, and may be related to the types of media used. Audience segmentation is important and more general messaging about drug related deaths may be more appropriate for the majority of audiences.

'Pretty in Pink' and 'Girl Power': An analysis of the targeting and representation of women in alcohol brand marketing on Facebook and Instagram.

BACKGROUND: Alcohol marketing helps shape how gender roles and relations are understood, and the gendered nature of drinking learned. In recent years, changes in how women are presented and addressed in marketing, including alcohol marketing, have been observed. This reflects the shifting social, political and regulatory context, in which increased attention has been given to gender inequality and the damaging impact of gender stereotypes. Research is yet to explore the gendered nature of alcohol marketing within this contemporary context. METHODS: A quantitative content and qualitative thematic analysis of alcohol marketing posts (N = 2600) by 20 alcohol brands on Facebook and Instagram pages over an 18 month period (1st January 2019-30th June 2020) was conducted. Marketing strategies were identified, and the way in which posts targeted, represented and engaged women analysed. FINDINGS: New (e.g. 'influencer' collaborations) and established (e.g. competitions) strategies were being used to target both women and men. Drinking was presented as a feminine practice and as an important component of 'doing' a combination of traditional, post-feminist and feminist femininities. Women were assigned a range of gender roles that acknowledged their individual pleasures and achievements, and traditional gender roles and stereotypes were both reinforced and rejected to promote alcohol use. An important move away from sexualising and demeaning women to the appropriation of feminist and equality messages was observed, which may appeal to a wider range of women, including those embracing feminist identities. CONCLUSION: Alcohol brand marketing encourages alcohol use to women through both perpetuating and challenging gender stereotypes. Claims by brands of a commitment to equality are at odds with the harms related to alcohol consumption that contribute to the widening of health and social inequalities. It is important that future work on women's drinking and alcohol marketing is situated within the shifting social-political climate in which traditional, post-feminist and new fourth wave feminist rhetoric and femininities co-exist.

Performance and image enhancing drug interventions aimed at increasing knowledge among healthcare professionals (HCP): reflections on the implementation of the Dopinglinkki e-module in Europe and Australia in the HCP workforce.

BACKGROUND: Healthcare professionals (HCPs) provide an important point of contact through which people who use performance and image enhancing drugs (PIEDs) could access reliable information, advice, and interventions on a range of PIEDs, their use and related harms. However, HCPs often report difficulties engaging and building rapport with people who use PIEDs, and research suggests that they often lack specialist knowledge on these substances. Providing credible evidence-based resources to support HCPs is thus important. However, educational materials in this area are generally absent and the ones that exist have not been assessed for their utility in the HCP workforce. This paper examines the acceptability and usability of a PIED e-learning module (the Dopinglinkki e-module) targeted at HCPs in three EU Member States and Australia. METHODS: A standardised two stage, mixed methodology was implemented. Stage 1 involved HCPs completing the e-module and completing an online survey (N = 77). Stage 2 involved conducting individual structured interviews with a subset of survey respondents (N = 37). Normalisation Process Theory and the Theoretical Framework of Acceptability were used as conceptual lenses. FINDINGS: The e-module provided information that was perceived as useful for HCPs' current and future practice. However, several individual, organisational and societal level barriers were reported as preventing the e-module becoming an accepted and normalised aspect of the HCP workforce, including the need for up to date evidence, the time-consuming nature of completing the e-module, lack of organisational support, the use of over-complex language, and the module's potential to reinforce the stigmatisation of PIEDs. CONCLUSION: Providing credible evidence-based resources to support HCPs' knowledge development is important. Evidence-based and theory informed interventions are needed to equip HCPs with knowledge that can aid culturally sensitive interactions and effective engagement with people who use PIEDs. Reflecting on our study findings, it is important that the development of interventions should include the voices of both HCP and those using PIEDs, and that careful consideration is given to the various factors that may act as a barrier to effective implementation.

Effects of messaging on public support for drug consumption rooms in scotland, UK.

BACKGROUND: There is evidence to suggest that medically supervised drug consumption rooms (DCRs) may form part of responses to reduce drug-related harm. Although DCRs have been established globally, they are perceived by some to be a controversial approach in the UK, and Government has repeatedly rejected proposals to establish one in Glasgow, Scotland. As public support is an important component of policy development and enactment, we sought to investigate the effects of different types of message framing on public support for DCR. METHODS: We undertook a cross-sectional online study with a randomised design, conducted with a nationally representative sample. Participants were randomised to one of six message conditions comprising combinations of four components. All conditions included i) a basic description of a DCR, and conditions included combinations of ii) factual information; iii) pre-emptive refutation of common public concerns about DCR; and/or iv) a sympathetic narrative describing a mother whose son died from a heroin overdose. After reading each message, participants completed a bespoke measure assessing support for DCR. Data were analysed using ANCOVA. RESULTS: Complete data were obtained from 1591 participants (50.3% Female; mean age 44.9 ± 16.1 years). Compared to reading a basic description of DCR alone, there was greater support for DCR in participants receiving the refutation (p < .001); sympathetic + factual (p < .05); and sympathetic + factual + refutation (p < .001) message conditions. Presenting factual or sympathetic messages alone were not associated with increased support. CONCLUSION: Our findings suggest that public support for DCRs is not improved through communication of factual statements outlining potential benefits of the intervention alone. Advocates seeking to foster public support, and thus influence policy making, should also consider communication campaigns that address common concerns that the public might have about DCRs, and present the intervention in relation to potential benefits that they hold for people indirectly affected by drug-related harm.

'We are still obsessed by this idea of abstinence': A critical analysis of UK news media representations of proposals to introduce drug consumption rooms in Glasgow, UK.

BACKGROUND: Drug consumptions rooms (DCRs) are a well-established and evidence-based harm reduction response to drug use. Recently, a consortium led by health services in Glasgow, United Kingdom (UK), proposed piloting a DCR. In this article, we examine how the proposals were represented in news media reporting, and the possible effects of such reporting. METHODS: A quantitative content and qualitative thematic analysis of UK news media (n = 174 articles) representations of the proposals to introduce DCRs in the city of Glasgow, UK, was conducted. Analysis was informed by Bacchi's (2009, 2012, 2017) approach to policy analysis, 'What's the problem represented to be?' FINDINGS: Competing representations of the 'problem' of injecting drug use (IDU) were contested by a range of actors with different political visions. The applicability of the 'evidence base', potential benefits of DCRs to both users and the public, and the associated economic costs, were presented in differing ways depending on the underlying assumptions and presumptions of the arguments constructed (e.g. harm reduction vs recovery). As a result, a number of conflicting subject positions were presented that may have implications for the way that people who inject drugs (PWID) see themselves, and how they are viewed and treated by society. Whilst proponents positioned DCRs within a discourse of public health, an underlying rhetoric of abstinence and recovery underpinned the arguments against DCRs. It was this latter discourse that underpinned the UK Government's rejection of the proposals, which the Scottish Government were prevented from overruling within the political constraints of their devolved powers, with the lived effect of people who use drugs (PWUD) being denied access to public health services that mitigate harm. CONCLUSION: We conclude that attempts to introduce and gain public and political support for harm reduction responses such as DCRs through the news media face challenges within the historical and political context of prohibitionist UK drugs policy.

Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes.

BACKGROUND AND PURPOSE: The global heterozygous glucokinase (GK) knockout (gk(wt/del)) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model. EXPERIMENTAL APPROACH: We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gk(wt/del) mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. KEY RESULTS: A single dose of insulin (1 unit·kg(-1)), metformin (150, 300 mg·kg(-1)), glipizide (0.1, 0.3 mg·kg(-1)), exendin-4 (2, 20 µg·kg(-1)) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg·kg(-1)), metformin (300 mg·kg(-1)) and AZD6370 (30, 400 mg·kg(-1)) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg(-1)), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia. CONCLUSION AND IMPLICATIONS: Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gk(wt/del) mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model.

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes.

BACKGROUND AND PURPOSE: Pharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D. EXPERIMENTAL APPROACH: Two validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk(wt/del) mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined. KEY RESULTS: Treatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk(wt/del) mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose-stimulated insulin secretion. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans.

Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats.

BACKGROUND AND PURPOSE: Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in beta-cells. Here we examine whether the lowering of blood glucose levels in the rat by small molecule glucokinase activators (GKAs) can be predicted from in vitro enzyme potencies and plasma compound exposure. EXPERIMENTAL APPROACH: We developed an insulin resistant and hyperinsulinemic animal model, the high fat fed female Zucker (fa/fa) rat (HFFZ), and measured the acute in vivo glucose-lowering efficacy of a number of GKAs in an oral glucose tolerance test. KEY RESULTS: Four GKAs (at 1 to 30 mg kg(-1)), with different in vitro enzyme potencies, dose-dependently improved oral glucose tolerance in HFFZ rats (10-40% decrease glucose area under the curve (AUC) from vehicle control). The extent of glucose lowering, or the pharmacodynamic (PD) effect, of a GKA was directly related to the total compound concentration in the plasma; the pharmacokinetic (PK) measurement. This PK-PD relationship was extended across a series of GKAs by accounting for differences in protein binding and in the in vitro potency. CONCLUSIONS AND IMPLICATIONS: When the unbound GKA compound level is greater than the in vitro enzyme potency there was significant blood glucose lowering in vivo. This latter relationship was upheld in non-diabetic Wistar rats orally dosed with a GKA. The robust and predictive nature of the PK-PD relationship for GKAs may prove of value in testing these agents in early human clinical studies.

L-canavanine restores blood pressure in a rat model of endotoxic shock.

Administration of lipopolysaccharide to anaesthetised rats produced a reduction in mean arterial pressure, an increase in heart rate, and death at 4-6 h. Intravenous infusion of NG-nitro-L-arginine methyl ester (50 mg/kg), an inhibitor of constitutive and inducible nitric oxide (NO) synthase, 60 min after challenge with lipopolysaccharide, caused an immediate increase in blood pressure followed by a precipitous fall in pressure, and death. In contrast, intravenous infusion of L-canavanine (100 mg/kg), reported to be a selective inhibitor of inducible NO synthase in vitro, 60 min and 180 min after lipopolysaccharide challenge, produced an increase in mean arterial pressure and reversed the lipopolysaccharide induced hypotension. However, in lipopolysaccharide challenged animals protected from hypotension by administration of L-canavanine (60 min post challenge), intravenous infusion of NG-nitro-L-arginine methyl ester at 180 min post challenge caused an immediate rise in mean arterial pressure, followed by a rapid fall in blood pressure and heart rate, and sudden death. In contrast, a second dose of L-canavanine at 180 min post challenge maintained blood pressure for the duration of the experiment. These findings indicate that inhibition of both constitutive and inducible NO synthase during endotoxaemia is lethal. However, the use of a selective inhibitor of inducible NO synthase restores mean arterial pressure to baseline, and offers a therapeutic approach to managing hypotension in shock.

Inhibition of nitric oxide synthesis improves survival in a murine peritonitis model of sepsis that is not cured by antibiotics alone.

Inhibition of nitric oxide synthesis was investigated in a murine model of advanced sepsis in which antibiotic therapy alone did not improve survival. Seven hours after receiving a lethal intraperitoneal challenge with live Escherichia coli, mice were given either NG-monomethyl-L-arginine (L-NMMA) intravenously, imipenem-cilastatin subcutaneously or a combination of both. L-NMMA (3-300 mg/kg) or imipenem-cilastatin (10 or 50 mg/kg) given alone did not improve survival; co-administration of L-NMMA and either 10 or 50 mg imipenem-cilastatin/kg improved survival significantly. These findings suggest that nitric oxide contributes to the morbidity associated with advanced sepsis and that nitric oxide synthase inhibition may improve the efficacy of conventional antimicrobial treatment of severe infections.