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Drug repositioning (DR) is the process of identifying new indications for existing drugs. DR usually focuses on drugs that have cleared phase-I safety trials but has yet to show efficacy for the intended indication. Therefore, DR can probably skip the preclinical and phase-I study, which can reduce the cost throughout drug development. However, the expensive phase-II/III trials are required to establish efficacy. The obstacles to DR include identification of new indications with a high success rate in clinical studies, obtaining funding for clinical studies, patent protection, and approval systems. To tackle these obstacles, various approaches have been applied to DR worldwide. In this perspective, we provide representative examples of DR and discuss the ongoing efforts to overcome obstacles to DR in Japan.

Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients.Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research.Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001).Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM.

IntroductionKCNQ1 and KCNE1 form slowly activating delayed rectifier potassium currents (IKs). Loss-of-function of IKs by KCNQ1 variants causes type-1 long QT syndrome (LQTS). Also, some KCNQ1 variants are reported to cause epilepsy. Segment 4 (S4) of voltage-gated potassium channels has several positively-charged amino acids that are periodically aligned, and acts as a voltage-sensor. Intriguingly, KCNQ1 has a neutral-charge glutamine at the third position (Q3) in the S4 (Q234 position in KCNQ1), which suggests that the Q3 (Q234) may play an important role in the gating properties of IKs. We identified a novel KCNQ1 Q234K (substituted for a positively-charged lysine) variant in patients (a girl and her mother) with LQTS and epileptiform activity on electroencephalogram. The mother had been diagnosed with epilepsy. Therefore, we sought to elucidate the effects of the KCNQ1 Q234K on gating properties of IKs.MethodsWild-type (WT)-KCNQ1 and/or Q234K-KCNQ1 were transiently expressed in tsA201-cells with KCNE1 (E1) (WT + E1-channels, Q234K + E1-channels, and WT + Q234K + E1-channels), and membrane currents were recorded using whole-cell patch-clamp techniques.ResultsAt 8-s depolarization, current density (CD) of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly larger than the WT + E1-channels (WT + E1: 701 ± 59 pA/pF; Q234K + E1: 912 ± 50 pA/pF, p < 0.01; WT + Q234K + E1: 867 ± 48 pA/pF, p < 0.05). Voltage dependence of activation (VDA) of the Q234K + E1-channels or WT + Q234K + E1-channels was slightly but significantly shifted to depolarizing potentials in comparison to the WT + E1-channels ([V1/2] WT + E1: 25.6 ± 2.6 mV; Q234K + E1: 31.8 ± 1.7 mV, p < 0.05; WT + Q234K + E1: 32.3 ± 1.9 mV, p < 0.05). Activation rate of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly delayed in comparison to the WT + E1-channels ([half activation time] WT + E1: 664 ± 37 ms; Q234K + E1: 1,417 ± 60 ms, p < 0.01; WT + Q234K + E1: 1,177 ± 71 ms, p < 0.01). At 400-ms depolarization, CD of the Q234K + E1-channels or WT + Q234K + E1-channels was significantly decreased in comparison to the WT + E1-channels (WT + E1: 392 ± 42 pA/pF; Q234K + E1: 143 ± 12 pA/pF, p < 0.01; WT + Q234K + E1: 209 ± 24 pA/pF, p < 0.01) due to delayed activation rate and depolarizing shift of VDA.ConclusionThe KCNQ1 Q234K induced IKs gain-of-function during long (8-s)-depolarization, while loss of-function during short (400-ms)-depolarization, which indicates that the variant causes LQTS, and raises a possibility that the variant may also cause epilepsy. Our data provide novel insights into the functional consequences of charge addition on the Q3 in the S4 of KCNQ1.