Characterization of Manganese-Induced Neurodegenration in C. elegans Treated with Winterberry Leaf Extract

Neurodegeneration is a condition present in Alzheimer’s disease (AD) and Parkinson’s disease (PD) in which the cells of the nervous system experience loss of function and death. Around the world, each year PD and AD affect 6.2 million and 29.8 million people, respectively, with the exact causes remaining unknown. Manganese (Mn) is a transition metal which is essential for human survival in trace concentrations. However, overexposure to Mn can induce neurodegeneration through the accumulation of reactive oxygen species and the eventual onset of oxidative stress. An extract produced from winterberry leaves (Ilex verticillata) exhibits antioxidant properties as it has been shown to protect against Mn-induced oxidative stress in the nematode worm, Caenorhabditis elegans. Due to this observed response in C. elegans, it was hypothesized that the winterberry leaf extract (WLE) could offer protection against neurodegeneration of dopaminergic neurons. To evaluate dopaminergic integrity and its effect on nematode behavior, a wild-type C. elegans strain was treated with several concentrations of WLE and manganese chloride (MnCl2). A motility assay with the wild-type N2 worm strain was anticipated to produce a dose-dependent increase in movement upon treatment with WLE. Mn-exposed worms pre-treated with WLE were expected to also have an increase in movement. In a 1-nonanol dopamine-dependent repulsion assay, worms pre-treated with WLE were predicted to repulse faster from 1-nonanol exposure compared to Mn-treated worms. The expected results of a progeny assay would show that pre-treatment of worms with WLE would increase the percentage of hatched progeny compared to the Mn control. Overall, our hypothesis is that pre-treatment with WLE may offer C. elegans protection against Mn-induced dopaminergic neurodegeneration and merits further exploration as a potential alternative medicine which could be used to treat people affected by neurodegenerative disorders

Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy

Objective: Few clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). Methods: This randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. Results: Most subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. Conclusions: Most subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated