Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models.

Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure.

BACKGROUND AND PURPOSE: Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure. EXPERIMENTAL APPROACH: LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain. KEY RESULTS: LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378. CONCLUSION AND IMPLICATIONS: LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials.

Effects of pharmacological inhibition of the sodium-dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models.

An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium-dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle-treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.

Who bears the cost of 'informal mhealth'? Health-workers' mobile phone practices and associated political-moral economies of care in Ghana and Malawi.

Africa's recent communications 'revolution' has generated optimism that using mobile phones for health (mhealth) can help bridge healthcare gaps, particularly for rural, hard-to-reach populations. However, while scale-up of mhealth pilots remains limited, health-workers across the continent possess mobile phones. This article draws on interviews from Ghana and Malawi to ask whether/how health-workers are using their phones informally and with what consequences. Health-workers were found to use personal mobile phones for a wide range of purposes: obtaining help in emergencies; communicating with patients/colleagues; facilitating community-based care, patient monitoring and medication adherence; obtaining clinical advice/information and managing logistics. However, the costs were being borne by the health-workers themselves, particularly by those at the lower echelons, in rural communities, often on minimal stipends/salaries, who are required to 'care' even at substantial personal cost. Although there is significant potential for 'informal mhealth' to improve (rural) healthcare, there is a risk that the associated moral and political economies of care will reinforce existing socioeconomic and geographic inequalities.

Informal m-health: How are young people using mobile phones to bridge healthcare gaps in Sub-Saharan Africa?

The African communications 'revolution' has generated optimism that mobile phones might help overcome infrastructural barriers to healthcare provision in resource-poor contexts. However, while formal m-health programmes remain limited in coverage and scope, young people are using mobile phones creatively and strategically in an attempt to secure effective healthcare. Drawing on qualitative and quantitative data collected in 2012-2014 from over 4500 young people (aged 8-25 y) in Ghana, Malawi and South Africa, this paper documents these practices and the new therapeutic opportunities they create, alongside the constraints, contingencies and risks. We argue that young people are endeavouring to lay claim to a digitally-mediated form of therapeutic citizenship, but that a lack of appropriate resources, social networks and skills ('digital capital'), combined with ongoing shortcomings in healthcare delivery, can compromise their ability to do this effectively. The paper concludes by offering tentative suggestions for remedying this situation.

CONTEXT MATTERS: FOSTERING, ORPHANHOOD AND SCHOOLING IN SUB-SAHARAN AFRICA.

A growing body of research suggests that orphanhood and fostering might be (independently) associated with educational disadvantage in sub-Saharan Africa. However, literature on the impacts of orphanhood and fostering on school enrolment, attendance and progress produces equivocal, and often conflicting, results. This paper reports on quantitative and qualitative data from sixteen field-sites in Ghana and Malawi, highlighting the importance of historical and social context in shaping schooling outcomes for fostered and orphaned children. In Malawi, which has been particularly badly affected by AIDS, orphans were less likely to be enrolled in and attending school than other children. By contrast, in Ghana, with its long tradition of 'kinship fostering', orphans were not significantly educationally disadvantaged; instead, non-orphaned, purposively fostered children had lower school enrolment and attendance than their peers. Understanding the context of orphanhood and fostering in relation to schooling is crucial in achieving 'Education for All'.

Health impacts of pedestrian head-loading: a review of the evidence with particular reference to women and children in sub-Saharan Africa.

Across sub-Saharan Africa, women and children play major roles as pedestrian load-transporters, in the widespread absence of basic sanitation services, electricity and affordable/reliable motorised transport. The majority of loads, including water and firewood for domestic purposes, are carried on the head. Load-carrying has implications not only for school attendance and performance, women's time budgets and gender relations, but arguably also for health and well-being. We report findings from a comprehensive review of relevant literature, undertaken June-September 2012, focussing particularly on biomechanics, maternal health, and the psycho-social impacts of load-carrying; we also draw from our own research. Key knowledge gaps and areas for future research are highlighted.

Out of the reach of children? Young people's health-seeking practices and agency in Africa's newly-emerging therapeutic landscapes.

Despite a dominant view within Western biomedicine that children and medicines should be kept apart, a growing literature suggests that children and adolescents often take active roles in health-seeking. Here, we consider young people's health-seeking practices in Ghana: a country with a rapidly-changing therapeutic landscape, characterised by the recent introduction of a National Health Insurance Scheme, mass advertising of medicines, and increased use of mobile phones. Qualitative and quantitative data are presented from eight field-sites in urban and rural Ghana, including 131 individual interviews, focus groups, plus a questionnaire survey of 1005 8-to-18-year-olds. The data show that many young people in Ghana play a major role in seeking healthcare for themselves and others. Young people's ability to secure effective healthcare is often constrained by their limited access to social, economic and cultural resources and information; however, many interviewees actively generated, developed and consolidated such resources in their quest for healthcare. Health insurance and the growth of telecommunications and advertising present new opportunities and challenges for young people's health-seeking practices. We argue that policy should take young people's medical realities as a starting point for interventions to facilitate safe and effective health-seeking.

Proposing love on the way to school: mobility, sexuality and youth transitions in South Africa.

Young people's daily mobility in sub-Saharan Africa remains largely invisible and under-researched. Drawing on qualitative and quantitative data from the Child Mobility Project in South Africa, we show how young people's daily journeys (to school and other places) shape, and are shaped by, the possibility of sexual encounters. Young women are seen to be at risk of sexual violence as they travel around their neighbourhoods and fears of sexual violence and transgressive relationships lead to controls over their mobility, with potentially negative consequences for education and social opportunities. However, mobility can also present opportunities for welcomed sexual encounters and experimentation, which are seen as part of growing up. We discuss the implications for young women's ability to negotiate safe routes to adulthood.

Children as research collaborators: issues and reflections from a mobility study in sub-Saharan Africa.

This paper reflects on issues raised by work with children in an ongoing child mobility study in three sub-Saharan African countries: Ghana, Malawi and South Africa. There are now 70 school pupils of varying ages involved in the project, but the paper is particularly concerned with the participation of those children 14 years and under. We examine the significant ethical issues associated with working with younger child researchers, and linked questions concerning the spaces open to them in African contexts where local cultural constructions of childhood and associated economic imperatives (which commonly drive family and household endeavour) help shape the attitudes of adults to children's rights and responsibilities and inter-generational power relations.