From the therapeutic viewpoint the

From the therapeutic viewpoint, the best and quick way to address the hurdles of controlling parasitic nematodes lies in the solid understanding of the basic biology of the organism and drawing parallels to targets of approved drugs that already have established safety profiles. This approach of repurposing FDA approved drugs () greatly cuts down the huge lag-time in identifying lead-compound(s) for testing and is gaining momentum in the global efforts to control helminth infections. This study by Wang et al., hopefully will be a beneficial tool for narrowing down such targetable pan-nematoda or tissue-specific or species specific ‘spot spots’ that can possibly address potential problems of drug resistance as well. Conflict of Interest This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
In this issue of , Kishi et al. report on their intriguing finding that pre-treatment with meclizine prevents renal ischemia–reperfusion injury in male mice (). Furthermore, they provide a potential mode of action of this reno-protective intervention: intracellular accumulation of phosphoethanolamine, which in turn activates glycolysis and attenuates mitochondrial oxidative phosphorylation. These metabolic changes are associated with reduced ROS formation and reperfusion injury with secondary effects on IR-related inflammation and subsequent collateral damage. The authors must be congratulated for this timely contribution in this field, which stands in a long tradition from this group in their quest for new therapeutic options to prevent renal injury (). Ischemia–reperfusion injury is an important determinant of the clinical success of renal transplantation—it is likely involved in the pathogenesis of pde inhibitors nephropathy and plays an important role in renal injury due to shock as occurs in sepsis, or major (cardiovascular) surgery. Therefore, prevention of renal ischemia–reperfusion injury with a clinically safe and effective intervention is expected to have a significant impact on health care and survival (). In that regard, the translation of the reported therapeutic action of meclizine from mice to men seems (at least theoretically) rather straightforward since this drug is available as an over the counter drug both in Europe and the US as tablets of 12.5mg to prevent motion sickness. A typical dose in humans is 25mg in adults and in children this dose is reduced (12.5mg in children > 6 years and 6.25mg in children 3-6 years). However, this is not the first intervention in animals that claims to prevent ischemia–reperfusion injury in the kidney or other vital organs such as brain and heart. Other successful interventions in animal models include ischemic conditioning (protective effect of short bouts of non-injurious ischemia and reperfusion of target or remote organ ()), diannexin, metformin, dipyridamole, erythropoietin, adenosine, statins, cyclosporine and many others. This list includes drugs that are easily available by prescription or are not difficult to apply (remote ischemic conditioning). Nevertheless, evidence-based clinical management to prevent renal injury is still limited to optimization of organ perfusion and prevention of exposure to drugs that are toxic to the hypo-perfused kidney (i.e. aminoglycosides, NSAIDs and inhibitors of the renin-angiotensin-aldosterone system) because clinical trials exploring other strategies to prevent ischemia–reperfusion injury are not conclusive or negative (). Thus, the conclusion is justified that, at least up to now, strategies that prevent ischemia–reperfusion injury in pre-clinical models are stuck in translation to the clinic (). What is the reason for these disappointments in the clinical development of promising pre-clinical interventions to prevent ischemia–reperfusion injury? First, as reviewed recently, pre-clinical studies in the field of ischemia–reperfusion often have serious methodological flaws, resulting in potential serious bias of results (). In that regard, we should however compliment Kishi et al. for their accurate report of their methodology and findings: some important basic methodological essentials were addressed such as drop-outs, randomization and blinding. However, there is still some doubt: although most essential experimental conditions were well monitored, blood pressure and/or renal perfusion was not measured throughout the experiments. Differences in blood pressure (and therefore renal perfusion) between meclizine treated and control animals could theoretically have confounded the results, in particular when these differences occurred during reperfusion.