Title: Increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with Lewy bodies Manabe Y, Ino T, Yamanaka K, Kosaka K Ref: Psychogeriatrics, 16:202, 2016 : PubMed
BACKGROUND: As with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dose-dependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose. METHODS: The present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy. RESULTS: The Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. High-dose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms. CONCLUSIONS: We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.
Title: Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial Ikeda M, Mori E, Matsuo K, Nakagawa M, Kosaka K Ref: Alzheimers Res Ther, 7:4, 2015 : PubMed
INTRODUCTION: The efficacy of a cholinesterase inhibitor, donepezil, in patients with dementia with Lewy bodies (DLB) was investigated to confirm the superiority over placebo in the 12-week, double-blind phase of this phase III study. METHODS: Patients with probable DLB (n = 142) were randomly assigned to placebo or to 5 mg or 10 mg of donepezil administered once daily for 12 weeks. The co-primary endpoints were changes in cognitive function assessed using the Mini-Mental State Examination (MMSE) and behavioral and neuropsychiatric symptoms using the Neuropsychiatric Inventory (NPI-2: hallucinations and fluctuations). The superiority of each active group over placebo was determined with simultaneous statistical significance in both endpoints. Safety evaluations included adverse events (AEs) and the unified Parkinson's disease rating scale (UPDRS) part III. RESULTS: The predefined superiority of donepezil to the placebo was not confirmed in either active group in the primary analysis. MMSE score significantly improved compared to placebo in the 10 mg group (10 mg: 2.2 +/- 0.4, placebo: 0.6 +/- 0.5 (mean +/- standard error); P = 0.016). The change in MMSE score in the 5 mg group was not significant (1.4 +/- 0.5 (mean +/- standard error); P = 0.232). Although NPI-2 improved compared to baseline in the active groups, the differences from placebo were not significant. Most AEs were mild or moderate. Although the incidence of parkinsonism was slightly higher in the 10 mg group, the change in the UPDRS score was minimal and without a significant difference from the placebo group. CONCLUSIONS: The co-primary endpoints were not achieved in this trial. However, significant improvement in MMSE score was demonstrated with 10 mg, but not 5 mg, of donepezil. The evaluation of psychiatric symptoms might be affected by advanced education and instructions given to caregivers. Overall, donepezil was well tolerated in patients with DLB. With careful attention on gastrointestinal or parkinsonian symptoms, patients with DLB can safely benefit from treatment with donepezil. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011).
Title: Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial Mori E, Ikeda M, Kosaka K Ref: Annals of Neurology, 72:41, 2012 : PubMed
OBJECTIVE: Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial. METHODS: One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III. RESULTS: Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p < 0.001 for each); 3 mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10 mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups. INTERPRETATION: Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated.
Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the gamma-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl carbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
OBJECTIVES: Dementia associated with Lewy bodies in cortical and subcortical areas is classified as dementia of the non-Alzheimer type and termed diffuse Lewy body disease (DLBD). The generic term "dementia with Lewy bodies (DLB)" was proposed in the international workshop on Lewy body dementia to include the similar disorders presenting Lewy bodies. In DLB, a lower level of choline acetyltransferase (ChAT) activity in the neocortex was found compared with that in Alzheimer's disease. The purpose of the present study was to determine the total amount of muscarinic acetylcholine receptors (mAChRs) and relative proportion of each subtype (m1-m4) of mAChRs in the frontal and temporal cortex of seven DLBD and 11 Alzheimer's disease necropsied brains. METHODS: A [(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation assay using subtype-specific antibodies were performed. Each antibody was raised against fusion proteins containing peptides corresponding to the third intracellular (i3) loops of the respective mAChR subtype. RESULTS: The total amounts of mAChRs were significantly lower in the preparations of temporal cortices from DLBD and Alzheimer's disease than in those from dead controls (seven cases). In both diseases, the proportion of the m3 receptor in the frontal cortex was significantly increased and that of the m4 receptor in the temporal cortex was significantly decreased compared with the control specimens. The proportions of the m1 and m2 subtypes were significantly different in the temporal cortex. The proportion of the m1 receptor was significantly greater in the DLBD brains, whereas that of the m2 receptor was significantly greater in the Alzheimer's disease brains than in the controls. CONCLUSIONS: The m1 receptor is the major subtype in the cerebral cortex, and m2 is known to be present at presynaptic terminals. The higher proportions of m1 in DLBD and m2 in Alzheimer's disease suggest that the manner of degeneration in the cholinergic system is different between the diseases. It is hypothesised that a severe depletion of presynaptic cholinergic projective neurons causes the upregulation of m1 receptor in the temporal cortex in DLBD.
A 43-year-old woman and her 47-year-old brother were studied because of corneal opacity. They showed a marked decrease in plasma high density lipoproteins (HDL) and a decrease in the ester ratio of plasma total cholesterol. Discoidal particles were found in the HDL2 fraction (d 1.063-1.125). A marked heterogeneity of low density lipoproteins was disclosed in both patients by electron microscopy. Apoprotein analysis revealed an increase in apo E and a decrease in apo A-I and A-II in both patients. These abnormalities were similar to the data reported in other cases with hereditary lecithin : cholesterol acyltransferase (LCAT) deficiency. However, several interesting dissimilarities have been disclosed as compared with the previously reported cases. Neither patient had proteinuria, and their kidney functions were within the normal limits. The ester ratios of plasma cholesterol of both patients were the highest among the cases reported thus far. Their plasma LCAT activities were 14.4 and 15% of the normal mean values determined by Glomset-Wright's common-substrate method. The enzyme activities determined by Stokke-Norum's self-substrate method were 40.2 and 29% respectively. These results may indicate that this inherited disorder is not characterized by absence of plasma LCAT or presence of inhibitory factors in plasma, but by the presence of partially inactive LCAT in patients' plasma.
