Pulmonary hypertension and the potential of 'drug' repurposing: A case for African medicinal plants.

Abstract: Pulmonary hypertension (PH) is a haemodynamic disorder in which elevated blood pressure in the pulmonary circulation is caused by abnormal vascular tone. Despite advances in treatment, PH mortality remains high, and drug repurposing has been proposed as a mitigating approach. This article reviews the studies that have investigated drug repurposing as a viable option for PH. We provide an overview of PH and highlight pharmaceutical drugs with repurposing potential, based on limited evidence of their mechanisms of action. Moreover, studies have demonstrated the benefits of medicinal plants in PH, most of which are of Indian or Asian origin. Africa is a rich source of many medicinal plants that have been scientifically proven to counteract myriad pathologies. When perusing these studies, one will notice that some African medicinal plants can counteract the molecular pathways (e.g. proliferation, vasoconstriction, inflammation, oxidative stress and mitochondrial dysfunction) that are also involved in the pathogenesis of PH. We review the actions of these plants with actions applicable to PH and highlight that they could be repurposed as adjunct PH therapies. However, these plants have either never been tested in PH, or there is little evidence of their actions against PH. We therefore encourage caution, as more research is needed to study these plants further in experimental models of PH while acknowledging that the outcomes of such proof of-concept studies may not always yield promising findings. Regardless, this article aims to stimulate future research that could make timely contributions to the field. Study synopsis: What the study adds. Pulmonary hypertension (PH) remains a fatal disease, and 80% of the patients live in developing countries where resources are scarce and specialised therapies are often unavailable. Drug repurposing is a viable option to try to improve treatment outcomes.Implications of the findings. We propose that another form of 'drug' repurposing is the use of medicinal plants, many of which have demonstrated benefits against pathological processes that are also key in PH, e.g. apoptosis, tumour-like growth of cells, proliferation, oxidative stress and mitochondrial dysfunction.

Pulmonary hypertension in developing countries: Limiting factors in time to diagnosis, specialised medications and contextualised recommendations.

Pulmonary hypertension (PH) is a fatal disease with no cure. Combination therapy that includes several specialised medications can improve survival and quality of life. However, there are many challenges, and these include a lack of effective screening tools, misdiagnosis and late diagnosis, a lack of awareness among clinicians and patients, expensive PH medication and the unavailability of these medications in many developing countries. Based on the literature, this paper provides helpful approaches and 'out of the box' ideas to try to surmount these challenges. We make the following recommendations: develop better (contextually fitting) screening tools, investigate novel therapeutics or novel drug targets, implement incentivised and accredited training for clinicians and implement awareness campaigns (by using traditional and social media and promoting awareness at healthcare or educational institutions). Other recommendations include greater advocacy that engages public and private funders, combine scarce skills and networks of social sciences and implementation sciences and invite non-profit organisations to the fight against PH in conjunction with researchers. Furthermore, the implementation of breathlessness clinics in rural areas can be helpful, as well as the investigation of the biomarker potential of genetic mutations or unique gene signatures of patients during research. We hope that healthcare professionals, researchers, scientists and regulatory authorities or research bodies, can use our recommendations in a practical setting, especially in developing countries where resources are limited and the healthcare burden is high.

Improving retention of community-recruited participants in HIV prevention research through Saturday household visits; findings from the HPTN 071 (PopART) study in South Africa.

BACKGROUND: Identifying successful strategies to improve participant retention in longitudinal studies remains a challenge. In this study we evaluated whether non-traditional fieldworker shifts (after hours during the week and weekends) enhanced participant retention when compared to retention during traditional weekday shifts in the HPTN 071 (PopART) population cohort (PC). METHODS: HPTN 071 (PopART) PC participants were recruited and followed up in their homes on an annual basis by research fieldworkers over a 3-4 year period. The average number of successful follow-up visits, where a PC participant was found and retained in the study, was calculated for each of 3 visit schedules (early weekday shift, late weekday shift, and Saturday shift), and standardized to account for variation in fieldwork shift duration. We used one-way univariate analysis of variance (ANOVA) to describe differences in mean-successful visits and 95% confidence intervals between the shift types. RESULTS: Data on 16 651 successful visits were included. Successful visit rates were higher when conducting Saturday visits (14.0; 95% CI: 11.3-16.6) compared to both regular (4.5; 95% CI: 3.7-5.3) and late weekday shifts (5.3; 95% CI: 4.7-5.8) overall and in all subgroup analyses (P<0.001). The successful visit rate was higher amongst women than men were during all shift types (3.2 vs. 1.3, p<0.001). Successful visit rates by shift type did not differ significantly by age, over time, by PC round or by community triplet. CONCLUSION: The number of people living with HIV continues to increase annually. High quality evidence from longitudinal studies remains critical for evaluating HIV prevention and treatment strategies. This study showed a significant benefit on participant retention through introduction of Saturday shifts for home visits and these data can make an important contribution to the emerging body of evidence for improving retention in longitudinal research. TRIAL REGISTRATION: PopART was approved by the Stellenbosch University Health Research Ethics Committees (N12/11/074), London School of Hygiene and Tropical Medicine (6326) ethics committee and the Division of AIDS (DAIDS) (Protocol ID 11865). PopART was registered with ClinicalTrials.gov (registration number NCT01900977 ).

Myocardial susceptibility to ischaemia/reperfusion in obesity: a re-evaluation of the effects of age.

BACKGROUND: Reports on the effect of age and obesity on myocardial ischaemia/reperfusion (I/R) injury and ischaemic preconditioning are contradictory. The aim of this study was to re-evaluate the effects of age and diet-induced obesity (DIO) on myocardial I/R injury and preconditioning potential. METHODS: Four groups of Wistar male rats were used: age-matched controls (AMC) receiving standard rat chow for (i) 16 weeks and (ii) 16 months respectively; DIO rats receiving a sucrose-supplemented diet for (iii) 16 weeks and (iv) 16 months respectively. The ages of groups (i) and (iii) were 22 weeks ("young") and groups (ii) and (iv) 17 months ("middle-aged") at time of experimentation. Isolated perfused working hearts were subjected to 35 min regional ischaemia/1 h reperfusion. Endpoints were infarct size (tetrazolium staining) and functional recovery. Hearts were preconditioned by 3 × 5 min ischaemia/5 min reperfusion. Results were processed using GraphPad Prism statistical software. RESULTS: Age did not affect baseline heart function before induction of ischaemia and I/R damage as indicated by infarct size and similar values were obtained in hearts from both age groups. Age also had no effect on functional recovery of hearts during reperfusion after regional ischaemia in AMC rats, but cardiac output during reperfusion was better in hearts from middle-aged than young DIO rats. The diet reduced infarct size in hearts from young rats (% of area at risk: AMC: 32.4 ± 3.6; DIO: 20.7 ± 2.9, p < 0.05), with no differences in hearts from middle-aged rats (AMC: 24.6 ± 4.6; DIO: 28.3 ± 13.5, p = NS). Compared to their respective AMC, diet-induced obesity had no significant effect on functional recovery of hearts from both age groups after exposure to regional ischaemia. When exposed to the more severe stress of global ischaemia, the functional recovery potential of middle-aged DIO rats appeared to be impeded compared to hearts of young DIO rats, while age had no effect on the functional recovery of AMC hearts. Preconditioning reduced infarct size in hearts from young control rats and both middle-aged groups, but not from young DIO rats. Age had a significant effect on functional recovery in preconditioning: it was improved in hearts from young control and DIO rats, but depressed in both middle-aged groups. CONCLUSIONS: The data showed that middle-age and obesity had no effect on baseline myocardial function and did not increase susceptibility to I/R damage upon exposure to regional ischaemia. On the contrary, obesity reduced I/R damage in young rats. Preconditioned aging hearts showed a decreased infarct size, but a reduction in functional recovery.