Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study.

BACKGROUND: Chronic constipation is a common digestive complication of Parkinson's disease (PD). OBJECTIVES: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD. METHODS: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed. RESULTS: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported. CONCLUSIONS: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation. TRIAL REGISTRATION INFORMATION: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Investigating the efficacy and safety of elobixibat, an ileal bile acid transporter inhibitor, in patients with Parkinson's disease with chronic constipation: a multicentre, placebo-controlled, randomised, double-blind, parallel-group stud (CONST-PD).

INTRODUCTION: Chronic constipation worsens the quality of life (QOL) of patients with Parkinson's disease (PD). Elobixibat, an ileal bile acid transporter inhibitor, is a useful laxative, but its effect on chronic constipation in patients with PD remains unclear. Therefore, we designed a placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of elobixibat in patients with PD with chronic constipation. METHODS AND ANALYSIS: The study will consist of 2-week observation and 4-week treatment periods. Patients with clinically established PD will record the status of spontaneous bowel movements and use of rescue medications/concomitant medications in a Bowel Movement Diary from the start of the observation period at visit 1 (week -2). At visit 2 (week 0), patients will be assessed for final registration based on the diary records and physical examinations, and allocated to either the elobixibat or placebo group. Daily intake of the investigational drug will be recorded in the diary. Patients will undergo laboratory tests and answer constipation-related, PD-related and QOL-related questionnaires at visits 2 and 4 (week 4). Subjective symptoms and objective findings will be collected at visits 2, 3 (week 2) and 4. Since patients' motor function might be improved by treatment of constipation, the use of dopamine preparations will also be monitored. Bowel movement data and other parameters will be compared between groups.Safety information will be collected as adverse events, specifically focusing on those occurring in association with study conduct. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the Helsinki Declaration, the Clinical Trials Act of the Japan Ministry of Health, Labour and Welfare, and related laws and regulations. The study was approved by the Juntendo University Certified Review Board. The results will be disseminated through an online study registry (Japan Registry of Clinical Trials), presented at scientific conferences, and published in medical journals. TRIAL REGISTRATION NUMBER: JPRN-jRCTs031200172; Pre-results.

Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations.

Parkin (encoded by PRKN) is a ubiquitin ligase that plays an important role in cellular mitochondrial quality control. Mutations in PRKN cause selective dopaminergic cell loss in the substantia nigra and are presumed to induce a decrease in mitochondrial function caused by the defective clearance of mitochondria. Several studies have demonstrated that parkin dysfunction causes mitochondrial injury and astrocytic dysfunction. Using immunohistochemical methods, we analyzed astrocytic changes in human brains from individuals with PRKN mutations. Few glial fibrillary acidic protein- and vimentin-positive astrocytes were observed in the substantia nigra in PRKN-mutated subjects compared with subjects with idiopathic Parkinson's disease. We also differentiated patient-specific induced pluripotent stem cells into midbrain organoids and confirmed decreased numbers of glial fibrillary acidic protein-positive astrocytes in PRKN-mutated organoids compared with age- and sex-matched controls. Our study reveals PRKN-mutation-induced astrocytic alteration and suggests the possibility of an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons in brains of PRKN-mutated patients.

Diffusional kurtosis imaging of cingulate fibers in Parkinson disease: comparison with conventional diffusion tensor imaging.

OBJECTIVE: The pathological changes in Parkinson disease begin in the brainstem; reach the limbic system and ultimately spread to the cerebral cortex. In Parkinson disease (PD) patients, we evaluated the alteration of cingulate fibers, which comprise part of the limbic system, by using diffusional kurtosis imaging (DKI). METHODS: Seventeen patients with PD and 15 age-matched healthy controls underwent DKI with a 3-T MR imager. Diffusion tensor tractography images of the anterior and posterior cingulum were generated. The mean kurtosis (MK) and conventional diffusion tensor parameters measured along the images in the anterior and posterior cingulum were compared between the groups. Receiver operating characteristic (ROC) analysis was also performed to compare the diagnostic abilities of the MK and conventional diffusion tensor parameters. RESULTS: The MK and fractional anisotropy (FA) in the anterior cingulum were significantly lower in PD patients than in healthy controls. The area under the ROC curve was 0.912 for MK and 0.747 for FA in the anterior cingulum. MK in the anterior cingulum had the best diagnostic performance (mean cutoff, 0.967; sensitivity, 0.87; specificity, 0.94). CONCLUSIONS: DKI can detect alterations of the anterior cingulum in PD patients more sensitively than can conventional diffusion tensor imaging. Use of DKI can be expected to improve the ability to diagnose PD.