The prolyl hydroxylase inhibitor GSK1120360A reduces early brain injury, but protection is not maintained in a neonatal rat model of hypoxic ischaemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) in newborns is associated with high morbidity and mortality, with many babies suffering long-term neurological deficits. Currently, treatment options are limited to therapeutic hypothermia, which is not appropriate for use in all babies. Previous studies have shown protective effects of increasing the transcription factor-hypoxia-inducible factor-1 (HIF-1) in animal models, by using mild hypoxia or compounds that act as prolyl hydroxylase inhibitors (PHIs). Here, we aimed to examine the neuroprotective actions of an orally active, small molecule PHI, GSK1120360A in a neonatal rat model of hypoxia-ischemia (HI) compared to another PHI, desferrioxamine (DFX). Sprague-Dawley rats underwent HI surgery on postnatal day 7 (P7), where unilateral carotid artery occlusion was performed followed by hypoxia (8% oxygen, 3 h). Initial testing showed that GSK1120360A and erythropoietin levels were detectable in plasma at 6 h following oral exposure to GSK1120360A. For the short-term neuroprotection study, pups were assigned to receive either saline (s.c), desferrioxamine (DFX-200 mg/kg, s.c), methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. Histological analysis showed that GSK1120360A in this setting reduced brain injury size 7 days after HI, compared to the methylcellulose vehicle control group. DFX had no significant effect on injury size compared to saline group at the same 7 day timepoint. In the long-term neuroprotection study, pups were randomly assigned to be administered methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. On P42, rats underwent behavioural testing using the forelimb grip strength, grid walking and novel object recognition tasks, and brains were collected for histological analysis. Long-term behavioural deficits were observed in grid walking, grip strength and novel object recognition tests after HI which were not improved in the GSK1120360A treatment group compared to the methylcellulose group. Similarly, there was no improvement in injury size on P42 in the GSK1120360A study group compared to the methylcellulose group. Here, we have shown that GSK1120360A can reduce brain injury at 7 days but that this neuroprotective benefit is not maintained when examined at 5 weeks after HI.

Increasing access to essential medicines through partnership: experience in developing and delivering chlorhexidine gel for newborn cord care.

Sustainable access to essential medicines in low-income and middle-income countries requires innovative cross-sectoral collaboration throughout the lifecycle of a medicine. Partnerships are essential to address the systemic challenges of global health and health inequity. Pharmaceutical companies, funders, governments, international non-governmental organisations (I-NGOs) and other key stakeholders can leverage, through effective partnership working, their unique expertise to help drive innovation and share learnings and risks. Here, we reflect on one approach taken in the development and supply of chlorhexidine digluconate 7.1% w/w gel (equivalent to 4% w/w chlorhexidine) for neonatal cord care. We describe and analyse the steps taken by GSK to increase access to chlorhexidine gel, including partnering with the I-NGO Save the Children in Western Kenya. Learning points gained along the journey are shared, together with subsequent steps taken to increase access, with the aim of making recommendations that may be applicable to similar enterprises in the future.

Cost and consequences of using 7.1 % chlorhexidine gel for newborn umbilical cord care in Kenya.

BACKGROUND: Omphalitis is an important contributor to neonatal mortality in Kenya. Chlorhexidine digluconate 7.1 % w/w (CHX; equivalent to 4 % w/w chlorhexidine) was identified as a life-saving commodity for newborn cord care by the United Nations and is included on World Health Organization and Kenyan Essential Medicines Lists. This pilot study assessed the potential resource savings and breakeven price of implementing CHX for neonatal umbilical cord care versus dry cord care (DCC) in Kenya. METHODS: We employed a cost-consequence model in a Kenyan birth cohort. Firstly, the number of omphalitis cases and cases avoided by healthcare sector were estimated. Incidence rates and treatment effect inputs were calculated from a Cochrane meta-analysis of randomised clinical trials (RCTs) (base case) and 2 other RCTs. Economic outcomes associated with omphalitis cases avoided were determined, including direct, indirect and total cost of care associated with omphalitis, resource use (outpatient visits and bed days) and societal impact (caregiver workdays lost). Costs and other inputs were sourced from literature and supplemented by expert clinical opinion/informed inputs, making necessary assumptions. RESULTS: The model estimated that, over 1 year, ~ 23,000 omphalitis cases per 500,000 births could be avoided through CHX application versus DCC, circumventing ~ 13,000 outpatient visits, ~ 43,000 bed days and preserving ~ 114,000 workdays. CHX was associated with annual direct cost savings of ~ 590,000 US dollars (USD) versus DCC (not including drug-acquisition cost), increasing to ~ 2.5 million USD after including indirect costs (productivity, notional salary loss). The most-influential model parameter was relative risk of omphalitis with CHX versus DCC. Breakeven analysis identified a budget-neutral price for CHX use of 1.18 USD/course when accounting for direct cost savings only, and 5.43 USD/course when including indirect cost savings. The estimated breakeven price was robust to parameter input changes. DCC does not necessarily represent standard of care in Kenya; other, potentially harmful, approaches may be used, meaning cost savings may be understated. CONCLUSIONS: Estimated healthcare cost savings and potential health benefits provide compelling evidence to implement CHX for umbilical cord care in Kenya. We encourage comprehensive data collection to make future models and estimates of impacts of upscaling CHX use more robust.

Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.