ObjectivesBrain acetylcholine is decreased even in patients with cognitively preserved Parkinson’s disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients.MethodsA double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson’s Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping.ResultsKaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11–0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers.ConclusionsAlthough donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil.Trial registration numberUMIN000005403.

AimsApproximately 80% of uracil is excreted as b -alanine, ammonia and CO 2 via three sequential reactions. The activity of the first enzyme in this scheme, dihydropyrimidine dehydrogenase (DPD), is reported to be the key determinant of the cytotoxicity and side-effects of 5-fluorouracil. The aim of the present study was to re-evaluate the pharmacokinetics of uracil and its metabolites using a sensitive assay and based on a newly developed, physiologically based pharmacokinetic (PBPK) model. Methods [2-13 C]Uracil was orally administrated to 12 healthy males at escalating doses of 50, 100 and 200 mg, and the concentrations of [2-13 C]uracil, [2-13 C]5,6-dihydrouracil and b -ureidopropionic acid (ureido-13 C) in plasma and urine and 13 CO 2 in breath were measured by liquid chromatography-tandem mass spectrometry and gas chromatograph-isotope ratio mass spectrometry, respectively. Results The pharmacokinetics of [2-13 C]uracil were nonlinear. The elimination half-life of [2-13 C]5,6-dihydrouracil was 0.9-1.4 h, whereas that of [2-13 C]uracil was 0.2-0.3 h. The AUC of [2-13 C]5,6-dihydrouracil was 1.9-3.1 times greater than that of [2-13 C]uracil, whereas that of ureido-13 C was 0.13-0.23 times smaller. The pharamacokinetics of 13 CO 2 in expired air were linear and the recovery of 13 CO 2 was approximately 80% of the dose. The renal clearance of [2-13 C]uracil was negligible. ConclusionA PBPK model to describe 13 CO 2 exhalation after orally administered [2-13 C]uracil was successfully developed. Using [2-13 C]uracil as a probe, this model could be useful in identifying DPD-deficient patients at risk of 5-fuorouracil toxicity.

No abstract

BackgroundAs the toxicity associated with the α-GalCer-pulsed dendritic cell (DC) therapy could be considered to be negligible, its addition to postoperative adjuvant chemotherapy would be expected to greatly improve the therapeutic effect, and could result in prolonged survival.The aim of the present study is to compare the therapeutic efficacy of alpha-galactosylceramide-pulsed DC therapy in patients who have undergone a complete resection of stage II–IIIA non-small-cell lung cancer (NSCLC) followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to that in patients who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only).MethodsSubsequent to the complete resection of NSCLC, followed by the administration of cisplatin plus vinorelbine dual-agent combination adjuvant chemotherapy, patients who satisfy the inclusion criteria will be randomly allocated to either the α-GalCer-pulsed DC immune therapy group, or the standard treatment group.In total, 56 patients will be included in the study. The primary endpoint is recurrence-free survival, and the secondary endpoints are natural killer T-cell-specific immune response, the frequency of toxic effects and safety, and overall survival.DiscussionIn order to determine the efficacy of α-GalCer-pulsed DC therapy, the present study compares patients with stage II–III NSCLC who underwent complete surgical resection followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to those who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only).Trial registrationUMIN000010386 (R000012145). Registered on 1 April 2013.UMIN-CTR is officially recognized as a registration site which satisfies ICMJE criteria.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2103-4) contains supplementary material, which is available to authorized users.

No abstract