Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population.

BACKGROUND: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. METHODS: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. RESULTS: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. CONCLUSIONS: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.

Two cases of Alzheimer's disease showing deterioration of behavioral and psychological symptoms of dementia induced by switching from rivastigmine to donepezil.

Rivastigmine, galantamine, and memantine, in addition to donepezil, which has been on the market over 10 years, have been available for the treatment of Alzheimer's disease (AD) since 2011 in Japan, leading a new stage in the medical treatment of AD. We studied two AD patients showing sudden deterioration of behavioral and psychological symptoms of dementia (BPSD) associated with switching from rivastigmine to donepezil after the clinical trial of rivastigmine. In the patients, rivastigmine seemed to be more beneficial than donepezil for the control of BPSD. Although It was not obvious whether their different responses to the two cholinesterase inhibitors were due to the different pharmacological profiles, ie, the presence of inhibition of butyrylcholinesterase in rivastigmine, a particular cholinesterase inhibitor might be more effective in particular AD cases. Further investigations are needed to confirm the difference, and to identify the measures for selecting the most appropriate medication for each AD patient.

Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

AIM: The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies. METHODS: We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test. RESULTS: Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data. CONCLUSION: Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

Pilot study of pharmacological treatment for frontotemporal dementia: effect of Yokukansan on behavioral symptoms.

The aim of the present study was to investigate the efficacy of Yokukansan in improving behavioral symptoms of frontotemporal dementia. This study was a prospective, open-label trial of daily Yokukansan for 4 weeks in 20 frontotemporal dementia patients. Yokukansan treatment was found to significantly improve scores for the Neuropsychiatric Inventory and the Stereotypy Rating Inventory. No adverse effects or significant changes in physical findings and laboratory data occurred except for hypokalemia in two cases. The results indicate that Yokukansan can alleviate the behavioral symptoms of frontotemporal dementia. (The clinical trial registration number is UMIN000002704).

Identification of an aging-related spherical inclusion in the human brain.

Inclusions, such as corpora amylacea, axonal spheroids and ubiquitin-positive granular structures, are present in aged brains. We found a phosphorylated tau-positive inclusion in brain tissues obtained from 13 non-demented subjects and five patients with Alzheimer's disease. This inclusion was spherical and 3-20 microm in size. It was most frequently detected in the hippocampal CA1 region and in the prosubiculum but was not present in the white matter. The density of this inclusion increased significantly with aging and decreased after the occurrence of neurofibrillary tangles. The presence of the inclusion was confirmed using immunoelectron microscopy. These findings show a possibility that the inclusion is a novel aging-related structure in the human brain.

Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain.

Previous studies from our laboratory demonstrated that N(epsilon)-(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age-dependent manner. This suggests a potential link between AGE-accumulation and the aging process in neurons. The purpose of the present study was to examine whether this notion could be extended to other AGE structures, such as imidazolone and pentosidine. This was done using 19 human brains that were not affected by dementia. The immunohistochemical survey on distribution in brain tissues of imidazolone and pentosidine was carried out with monoclonal antibodies specific for imidazolone and pentosidine. A parallel control experiment was carried out with anti-CML antibody. The results showed that pentosidine and imidazolone were localized in neurons in different areas of human brain tissue, especially in neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine and imidazolone is very similar to that of CML. Furthermore, when the accumulation of these AGE structures was compared with the age of individual brains it was found that accumulation of imidazolone, pentosidine and CML in the CA4 region increased with age. These findings taken together support the notion that the accumulation of AGE structures in the CA4 region might be closely related to the aging process in neurons.