Enhancing the understanding of palatability assessment used in the development of paediatric medicines

Children are averse to unpalatable medicines. A medicine will only elicit its desired effect if it is taken by the patient, therefore unpalatable medicines threaten the effective treatment of paediatric indications. Regulators thus now require all new medicines to have associated plans for paediatric formulation development; key to which is palatability testing. Therefore, there is a real need to enhance our understanding of the nascent area of pharmaceutical palatability testing. Much of this research has focused on the rat brief access taste aversion (BATA) model, which uses water-deprived rats to evaluate aversiveness of a given sample by counting the number of rat licks relative to water and has the distinct advantage of being used preclinically due to the absence of human participants. The overall aims of this research were to: explore the methodological limitations of promising palatability assessment methodologies; expand the formulation repertoire and push the limits of the BATA model; and leverage the data from the BATA model to minimise animal use. Our understanding of pharmaceutical palatability testing has been enhanced. Key questions such as the number of participants necessary for a human pharmaceutical taste panel are now known. The limits of the BATA model have been explored, and we now know that it can provide information on mouthfeel as well as taste, enabling assessment of more complex liquid oral dosage forms such as suspensions. Furthermore, by leveraging the data from the BATA model, a methodology for assessing solid oral dosage forms and an in silico model for prediction of palatability were developed. This work has both answered and yielded questions and more work is need to improve pharmaceutical palatability assessment and thus children’s medicines. However, it is clear we are on a path towards more palatable children’s medicines and thus more effective treatment of paediatric diseases

Improving sepsis care in Africa: an opportunity for change?

Sepsis is common and represents a major public health burden with significant associated morbidity and mortality. However, despite substantial advances in sepsis recognition and management in well-resourced health systems, there remains a distinct lack of research into sepsis in Africa. The lack of evidence affects all levels of healthcare delivery from individual patient management to strategic planning at health-system level. This is particular pertinent as African countries experience some of the highest global burden of sepsis. The 2017 World Health Assembly resolution on sepsis and the creation of the Africa Sepsis Alliance provided an opportunity for change. However, progress so far has been frustratingly slow. The recurrent Ebola virus disease outbreaks and the COVID-19 pandemic on the African continent further reinforce the need for urgent healthcare system strengthening. We recommend that African countries develop national action plans for sepsis which should address the needs of all critically ill patients

Clostridium difficile: a healthcare associated infection of unknown significance in adults in sub-Saharan Africa

Background: Clostridium difficile infection (CDI) causes a high burden of disease in high-resource healthcare systems, with significant morbidity, mortality and financial implications. CDI is a healthcare-associated infection for which the primary risk factor is antibiotic usage and it is the leading cause of bacterial diarrhoea in HIV infected patients in USA. Little is known about the disease burden of CDI in sub-Saharan Africa, where HIV and healthcare associated infection have a higher prevalence and antibiotic usage is less restricted. Aim: To review published literature on CDI in sub-Saharan Africa, highlighting areas for future research. Methods: English language publications since 1995 were identified from online databases (PubMed, Medline, Google Scholar, SCOPUS) and personal collections of articles, using combinations of keywords to include C. difficile, Africa and HIV. Results: Ten relevant studies were identified. There is considerable variation in methodology to assess for carriage of toxigenic C. difficile and its associations. Eight studies report carriage of toxigenic C. difficile. Three (of four) studies found an association with antibiotic usage. One (of four) studies showed an association with HIV infection. One study showed no association with degree of immunosuppression in HIV. Two (of three) studies showed an association between carriage of toxigenic C. difficile and diarrhoeal illness. Conclusion: Whilst the carriage of toxigenic C. difficile is well described in sub-Saharan Africa, the impact of CDI in the Region remains poorly l understood and warrants high quality research

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies

Life-cycle assessment of hydrogen utilization in power generation: A systematic review of technological and methodological choices

Interest in reducing the greenhouse gas emissions from conventional power generation has increased the focus on the potential use of hydrogen to produce electricity. Numerous life-cycle assessment (LCA) studies of hydrogen-based power generation have been published. This study reviews the technological and methodological choices made in hydrogen-based power generation LCAs. A systematic review was chosen as the research method to achieve a comprehensive and minimally biased overview of hydrogen-based power generation LCAs. Relevant articles published between 2004 and 2021 were identified by searching the Scopus and Web of Science databases. Electrolysis from renewable energy resources was the most widely considered type of hydrogen production in the LCAs analyzed. Fuel cell technology was the most common conversion equipment used in hydrogen-based electricity LCAs. A significant number of scenarios examine the use of hydrogen for energy storage and co-generation purposes. Based on qualitative analysis, the methodological choices of LCAs vary between studies in terms of the functional units, allocations, system boundaries, and life-cycle impact assessment methods chosen. These discrepancies were likely to influence the value of the environmental impact results. The findings of the reviewed LCAs could provide an environmental profile of hydrogen-based electricity systems, identify hotspots, drive future research, define performance goals, and establish a baseline for their large-scale deployment

In Vivo Investigation of (2-Hydroxypropyl)-β-cyclodextrin-Based Formulation of Spironolactone in Aqueous Solution for Paediatric Use

Spironolactone (SPL), a potent anti-aldosterone steroidal drug used to treat several diseases in paediatric patients (e.g., hypertension, primary aldosteronism, Bartter’s syndrome, and congestive heart failure), is not available in child-friendly dosage forms, and spironolactone liquids have been reported to be unpalatable. Aiming to enhance SPL solubility in aqueous solution and overcome palatability, herein, the effects of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) were thoroughly investigated on solubilisation in water and on masking the unpleasant taste of SPL in vivo. Although the complexation of SPL with HP-β-CyD was demonstrated through phase solubility studies, Job’s plot, NMR and computational docking studies, our in vivo tests did not show significant effects on taste aversion. Our findings, on the one hand, suggest that the formation of an inclusion complex of SPL with HP-β-CyD itself is not necessarily a good indicator for an acceptable degree of palatability, whereas, on the other hand, they constitute the basis for investigating other cyclodextrin-based formulations of the poorly water-soluble steroidal drug, including solid dosage forms, such as spray-dried powders and orodispersible tablets

Willingness to Buy and/or Pay Disparity: Evidence from Fully Autonomous Vehicles

We seek to understand whether environmental concerns, fears of potential accidents, and merits regarding fully autonomous vehicles (FAVs) are motivators of willingness to buy (WTB) and willingness to pay (WTP) of FAVs. To do so, a large-scale survey on FAVs of more than 180,000 respondents was collected in Japan, and structural equation modeling (SEM) validated our findings. Interestingly, this study implicates a form of WTB-WTP disparity: those interested in natural environment conservation would purchase FAVs because they show high interest in overall social problems, and new technologies such as FAVs can resolve such problems, according to previous works. However, our result implies that they would not show high WTP because adopting FAVs does not `directly' contribute to natural environment conservation. Additionally, our results indicate that those who appreciate potential merits would have higher WTB and WTP, while those who fear FAV technology would not purchase FAVs and would have lower WTP. The results bear crucial policy implications for planners by showing the complexity between the factors of FAV WTB and WTP

Are renewables as friendly to humans as to the environment?: A social life cycle assessment of renewable electricity

The adoption of renewable energy technologies in developing nations is recognized to have positive environmental impacts; however, what are their effects on the electricity supply chain workers? This article provides a quantitative analysis on this question through a relatively new framework called social life cycle assessment, taking Malaysia as a case example. Impact assessments by the authors show that electricity from renewables has greater adverse impacts on supply chain workers than the conventional electricity mix: Electricity production with biomass requires 127% longer labor hours per unit-electricity under the risk of human rights violations, while the solar photovoltaic requires 95% longer labor hours per unit-electricity. However, our assessment also indicates that renewables have less impacts per dollar-spent. In fact, the impact of solar photovoltaic would be 60% less than the conventional mix when it attains grid parity. The answer of “are renewables as friendly to humans as to the environment?” is “not-yet, but eventually.

Rats can predict aversiveness of Active Pharmaceutical Ingredients.

Taste is crucial for patient acceptability and compliance with prescribed medicines, in particular with pediatric patients. Evaluating the taste of new active pharmaceutical ingredients (APIs) is therefore essential to put in place adequate taste-masking techniques, if needed, which will lead to acceptable palatable formulations. Thus, there is an urgent need to develop and optimize taste assessment methods that could be used at different stages of the drug development process. The aim of this study was to investigate the suitability of the rat brief-access taste aversion (BATA) model as a screening tool for assessment of APIs aversiveness that could predict human taste responses. Presently, the taste intensity of nine marketed APIs known to have different levels of bitter intensity (quinine hydrochloride dihydrate, 6-n-propylthiouracil, sildenafil citrate, diclofenac sodium, ranitidine hydrochloride, caffeine citrate, isoniazid, telbivudine and paracetamol) was investigated at different overlapping concentrations with two in vivo taste assessment methods: the rat BATA model and human taste panels with the intention of determining the drugs' concentrations to produce half of the maximal rating. Overall there was a strong correlation (R2?=?0.896) between rats IC50 and humans EC50 values. This correlation verifies the BATA model as a rapid and reliable tool for quantitative assessment of API aversiveness. A comparable ranking order was obtained mainly for high and medium aversive compounds, whereas it was less aligned for weakly aversive compounds. It was nonetheless possible to propose a classification of poor taste intensity determined in rats that would predict human taste tolerability