Future glucose-lowering drugs for type 2 diabetes

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.

Solubilisation of drugs within liposomal bilayers:alternatives to cholesterol as a membrane stabilising agent

Objectives The aim of this work was to investigate the effect of cholesterol on the bilayer loading of drugs and their subsequent release and to investigate fatty alcohols as an alternative bilayer stabiliser to cholesterol. Methods The loading and release rates of four low solubility drugs (diazepam, ibuprofen, midazolam and propofol) incorporated within the bilayer of multilamellar liposomes which contained a range of cholesterol (0–33 mol/mol%) or a fatty alcohol (tetradecanol, hexadecanol and octadecanol) were investigated. The molecular packing of these various systems was also investigated in Langmuir monolayer studies. Key findings Loading and release of drugs within the liposome bilayer was shown to be influenced by their cholesterol content: increasing cholesterol content was shown to reduce drug incorporation and inclusion of cholesterol in the bilayer changed the release profile of propofol from zero-order, for phosphatidyl choline only liposomes, to a first-order model when 11 to 33 total molar % of cholesterol was present in the formulation. At higher bilayer concentrations substitution of cholesterol with tetradecanol was shown to have less of a detrimental impact on bilayer drug loading. However, the presence of cholesterol within the liposome bilayer was shown to reduce drug release compared with fatty alcohols. Monolayer studies undertaken showed that effective mean area per molecule for a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) : cholesterol mixture deviated by 9% from the predicted area compared with 5% with a similar DSPC : tetradecanol mixture. This evidence, combined with cholesterol being a much more bulky structure, indicated that the condensing influence of tetradecanol was less compared with cholesterol, thus supporting the reduced impact of tetradecanol on drug loading and drug retention. Conclusions Liposomes can be effectively formulated using fatty alcohols as an alternative bilayer stabiliser to cholesterol. The general similarities in the characteristics of liposomes containing fatty alcohols or cholesterol suggest a common behavioural influence for both compounds within the bilayer.

Contraception and heterosex: an intimate relationship

Whilst the importance of contraception within heterosex has long been accepted, particularly in relation to the prevention of HIV/AIDS, the way in which the use, or non-use, of contraception re/constructs heterosexual encounters themselves has had far less attention. The embodied nature of both the risk of pregnancy, and most contraceptive technologies leads women to assert a right to bodily autonomy. Yet this assertion conflicts with their expectation of equitable coupledom within heterosexuality and their routine consideration of men’s preferences. This article will argue that the use of contraception is an intricate part of heterosexual practices, and shows how normative ideas about heterosexuality leave men as appearing as an absent presence within women’s contraceptive decisions.

Every child a wanted child: mid-life women's experiences of contraception

This paper is based on qualitative research which found that the contraceptive pill had achieved a "hegemonic status" among some British women in their thirties. In addition, despite the risk of sexually transmitted diseases, the idea of using condoms was very unpopular, and the research suggests that this is linked to a reluctance to rely on male cooperation over contraception. This paper will further argue that the women generally chose methods that they felt would be in their own best interests, and were often exercising considerable agency within the constraints of their relationships. Moreover, by accepting the responsibility for contraception, the women not only gained sole control over their fertility, but contraception may be an area within heterosexuality where women can exercise power.

Embodied expertise: women's perceptions of the contraception consultation

This research, based on qualitative interviews and non-participant observation, emerges from a larger study investigating what factors influence the ‘contraceptive careers’ of British women in their 30s. The women informants recognized that contraceptive products often impacted on their health, but viewed them as distinct from ‘medical matters’. Rather than doctors being seen as having expertise, it was women health professionals, be they nurses, midwives, health visitors or doctors, who were perceived as the ones who ‘know’ about contraception, through an assumption that they are contraception users.This embodied knowledge is valued by the women above their formal medical training. I will also show how general practice surgeries and family planning clinics were viewed as gendered spaces, which altered the expectations and experiences of the women during contraceptive consultations. This study found that as ‘real’ expertise over contraception stems from embodied rather than textual knowledge, the women’s choices were grounded by a gendered sense of trust.

I got pregnant, I was so like ... crying inside...: experiences of women of Pakistani ancestry seeking contraception in the UK

South Asian women in Britain are less likely to use contraception than women in other ethnic groups. Previous studies have identified a lack of knowledge combined with low levels of English language and/or literacy as barriers to using contraception, but have not examined in detail women's experiences of accessing services. This qualitative study focused on the experiences of 19 Muslim women of Pakistani ancestry and the views of six health and community workers. The findings detail considerable institutional barriers to accessing contraceptive services, such as a lack of information and the paternalistic attitudes of some health professionals. The study suggests that, although all the women were motivated to access and use contraception, their ability to make informed choices was often limited. It was only when the women encountered advocates, who might be professionals or from their social networks, that they could begin to take control of their fertility. This study is consistent with earlier research and shows that lack of access to contraceptive services can have high personal and social costs for South Asian women.

Strategies and therapeutic opportunities for the delivery of drugs to the esophagus

Targeting of drugs and therapies locally to the esophagus is an important objective in the development of new and more effective dosage forms. Therapies that are retained within the oral cavity for both local and systemic action have been utilized for many years, although delivery to the esophagus has been far less reported. Esophageal disease states, including infections, motility disorders, gastric reflux, and cancers, would all benefit from localized drug delivery. Therefore, research in this area provides significant opportunities. The key limitation to effective drug delivery within the esophagus is sufficient retention at this site coupled with activity profiles to correspond with these retention times; therefore, a suitable formulation needs to provide the drug in a ready-to-work form at the site of action during the rapid transit through this organ. A successfully designed esophageal-targeted system can overcome these obstacles. This review presents a range of dosage form approaches for targeting the esophagus, including bioadhesive liquids and orally retained lozenges, chewing gums, gels, and films, as well as endoscopically delivered therapeutics. The techniques used to measure efficacy both in vitro and in vivo are also discussed. Drug delivery is a growing driver within the pharmaceutical industry and offers benefits both in terms of clinical efficacy, as well as in market positioning, as a means of extending a drug's exclusivity and profitability. Emerging systems that can be used to target the esophagus are reported within this review, as well as the potential of alternative formulations that offer benefits in this exciting area.