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41.
42.
In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease 总被引:1,自引:1,他引:0
Okamura N Funaki Y Tashiro M Kato M Ishikawa Y Maruyama M Ishikawa H Meguro K Iwata R Yanai K 《British journal of clinical pharmacology》2008,65(4):472-479
Aims
The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil.Methods
[5-11C-methoxy]-donepezil ([11C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [11C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months.Results
[11C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18–20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24–30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day−1) induced 61.6–63.3% reduction of donepezil binding in AD brains. The distribution volume of [11C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.Conclusions
[11C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.What is already known about this subject
- Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer''s disease (AD).
- Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD.
- The biodistribution of donepezil in the brain after administration is not precisely understood in vivo.
- There is no method to measure the amount of binding of orally administered donepezil to AChE.
What this study adds
- This study clearly visualizes the distribution of donepezil in human brain using [11C]-donepezil and positron emission tomography.
- This study demonstrates prominent reduction of the donepezil binding site in the AD brain.
- This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.
43.
Tashiro M Duan X Kato M Miyake M Watanuki S Ishikawa Y Funaki Y Iwata R Itoh M Yanai K 《British journal of clinical pharmacology》2008,65(6):811-821
AIMS
Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H1 receptor occupancy (H1RO) in the brain using positron emission tomography (PET). The aim was to measure H1RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine.METHODS
Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with 11C-doxepin in a crossover study design. Binding potential ratio and H1ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H1RO was examined.RESULTS
H1RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H1ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H1ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001).CONCLUSION
Oral bepotastine (10 mg), with its relatively low H1RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- ‘Bepotastine besilate’ is a novel second-generation antihistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies.
- However, only a few clinical studies regarding its sedative property are available.
- In addition, histamine H1 receptor occupancy (H1RO) of this new antihistamine has never been measured by positron emission tomography (PET).
WHAT THIS STUDY ADDS
- This paper provides the first measurement result of cerebral H1RO of bepotastine besilate (approximately 15%) as determined by PET.
- This result is in accordance with the clinical classification of bepotastine as a second-generation antihistamine.
- In addition, the relationship between subjective sleepiness and cerebral H1RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design.
44.
M Tofukuji N Matsuda C Dessy K G Morgan F W Sellke 《The Journal of thoracic and cardiovascular surgery》1999,118(1):163-172
OBJECTIVE: The effects of magnesium- and potassium-based crystalloid and blood-containing cardioplegic solutions on coronary smooth muscle intracellular free calcium ([Ca2+]i) accumulation and microvascular contractile function were examined. METHODS: Isolated ferret hearts were subjected to hyperkalemic (25 mmol/L K+) blood cardioplegic infusion, hypermagnesemic (25 mmol/L Mg2+, K+-free) crystalloid cardioplegic infusion, or hyperkalemic crystalloid cardioplegic infusion for 1 hour. Coronary arterioles were isolated, cannulated, and loaded with fura 2. Reactivity and [Ca2+]i were assessed with videomicroscopy. [Ca2+]i was measured at baseline and after application of 50 mmol/L KCl. In addition, [Ca2+]i and vascular contraction were measured during exposure to Mg2+ and K+ cardioplegic solution at both 4 degrees C and 37 degrees C. RESULTS: From a baseline [Ca2+]i of 177 +/- 52 nmol/L, K+ cardioplegic infusion (302 +/- 80 nmol/L potassium) markedly increased [Ca2+]i, whereas blood cardioplegic infusion (214 +/- 53 nmol/L) and Mg2+ cardioplegic infusion (180 +/- 42 nmol/L) did not alter [Ca2+]i. Although a difference between groups in percentage contraction after application of 50 mmol/L KCl was not observed, [Ca2+]i increased significantly more in vessels in the control group (764 +/- 327 nmol/L) and the K+ crystalloid cardioplegic infusion group (698 +/- 215 nmol/L) than in vessels in the blood cardioplegic infusion group (402 +/- 45 nmol/L) and the Mg2+ cardioplegic infusion group (389 +/- 80 nmol/L). Mg2+ cardioplegic solution induced no microvascular contraction at either 4 degrees C or 37 degrees C, nor was an increase in [Ca2+]i observed. K+ cardioplegic solution induced microvascular contraction at 37 degrees C but not at 4 degrees C; it increased [Ca2+]i at both 4 degrees C and 37 degrees C. CONCLUSION: An Mg2+-based cardioplegic solution, or appropriate Mg2+ or blood supplementation of a K+ crystalloid cardioplegic solution, may decrease the accumulation of [Ca2+]i in the vascular smooth muscle during ischemic arrest. 相似文献
45.
Motoko Seto Miki Ohta Tsuneo Ikenoue Takafumi Sugimoto Yoshinari Asaoka Motohisa Tada Dai Mohri Yotaro Kudo Hideaki Ijichi Keisuke Tateishi Motoyuki Otsuka Yoshihiro Hirata Shin Maeda Kazuhiko Koike Masao Omata 《International journal of cancer. Journal international du cancer》2011,128(6):1293-1302
RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like‐1 (RASAL1), a member of the RAS‐GTPase‐activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen‐activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re‐emphasize the importance of RAS signaling in gastric cancer development. 相似文献
46.
Kentaro Sudo Takeshi Ishihara Nobuto Hirata Fumiaki Ozawa Tadashi Ohshima Ryosaku Azemoto Kenji Shimura Takeshi Nihei Takayoshi Nishino Akihiko Nakagawa Kazuyoshi Nakamura Taro Hara Motohisa Tada Rintaro Mikata Katsunobu Tawada Osamu Yokosuka So Nakaji Taketo Yamaguchi 《Cancer chemotherapy and pharmacology》2014,73(2):389-396
Purpose
The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer.Methods
Patients were randomly assigned to receive GS (oral S-1 60 mg/m2 daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m2 on days 8 and 15) or gemcitabine (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS).Results
One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.43–0.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.61–1.41; P = 0.714). Grade 3–4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm.Conclusions
GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer. 相似文献47.
Motohisa Kato Shigetoyo Saji Katsuyuki Kunieda Tatsuhiro Yasue Kimitoshi Nishio Mitsuri Adachi 《Surgery today》1997,27(8):766-768
We experienced a case of mediastinal lipoma, which is considered to be a relatively rare disease. A 3-year-old girl was referred
to Gifu University hospital because of fever and an abnormal shadow on her chest X-ray. The chest X-ray clearly showed a well-delineated
tumor shadow which seemed to oppress the diaphragm and the right atrium in the right lower lung area. A computed tomogram
(CT) of the chest showed a homogeneous mass localized on the right diaphragm and adjoining the right anterior chest wall and
heart. The mass showed a fat density measuring about-100 HU. Magnetic resonance imaging (MRI) showed a high-intensity mass
which was almost the same level as the subcutaneous fat on both the T1-weighted and T2-weighted images. Thoracotomy was performed and a fatty tumor was found. It arose from the right side of the pericardium and
adjoined the diaphragm, the anterior chest wall, and the thymus. There was no adhesion between the tumor and the surrounding
organs. It was resected easily and its contents were yellowish and homogeneous. The patient made an uneventful recovery and
was discharged 10 days after the operation. Light microscopy showed a lipoma consisting of mature adipose tissue and no malignancy
was found. 相似文献
48.
Masato Hanada Motohisa Takami Toshiaki Takada Masaharu Kimura 《Pathology international》1985,35(1):243-249
A case of histologically low-grade leiomyosarcoma of the rectum showing an unusually late appearance of hepatic metastasis is reported. This was found at autopsy 17 years after a curative resection of the primary rectal tumor that had been diagnosed initially as a leiomyoma. 相似文献
49.
Mikiko Ohara Hiroki Takahashi Chisako Suzuki Motohisa Yamamoto Yasuyoshi Naishiro Hiroyuki Yamamoto Kenji Saga Yasuhisa Shinomura Kohzoh Imai 《Nihon Rinshō Men'eki Gakkai kaishi》2007,30(1):48-54
A 52-year-old female visited the outpatient department of Sapporo Medical University hospital in 1984 due to a refractory rash on the skin of the trunk. Histological findings of a skin biopsy specimen indicated a diagnosis of lupus erythematosus profundus (LEP). The eruption remained quiescent with moderate doses of prednisolone. In October 2003, she was suddenly admitted to our hospital with abdominal pain, fever and bloody stool. Lupus enteritis was diagnosed based on an elevated level of anti-DNA antibody, low complementemia and diffuse edematous change of the intestinal walls on CT scans. Although high doses of corticosteroids resulted in transient improvement, melena developed again on the 24th hospital day. Colonoscopy revealed deep ulceration at the rectum and a gastrografin enema indicated perforation. Accordingly, the involved rectum was resected and an artificial anus was constructed on the 50th hospital day. Examination of the resected specimen by microscopy showed that the ulceration approached at the depth of the subserosal layer with intense infiltration of inflammatory cells around the vessels. The pathogenesis of the rectal lesion might have been due to vasculitis associated with systemic lupus erythematosus (SLE). The disease did not recur under the administration of 10 mg of prednisolone daily until November 2004. Colonic function made a remarkably untroubled recovery after the artificial anus was closed in February 2005. The LEP was generally accompanied by a mild form of SLE. This case seemed to be rare in that SLE was associated with severe lupus enteritis and a refractory rectal ulcer developed from LEP. Patients with SLE and intestinal involvement should be carefully monitored in cooperation with a surgeon. 相似文献
50.
BACKGROUND: The purpose of this study was to determine the influence of oxygenation of a hyperkalemic cardioplegic solution (K-CP) on endothelial modulation of vasomotor tone and to correlate these changes with the intracellular calcium concentration ([Ca++]i) in microvascular smooth muscle. METHODS: Rat coronary arterioles were studied in a pressurized, no-flow normothermic state. Simultaneous monitoring of luminal diameter and [Ca++]i (fura-2) was performed with use of microscopic image analysis. Vessels were subjected to 60 minutes of oxygenated or hypoxic K-CP (K+ = 25.0 mmol/L) and were then reperfused with oxygenated Krebs-physiologic saline solution for 60 minutes. RESULTS: In oxygenated K-CP, the K-CP-induced contraction and [Ca++]i accumulation were significantly increased in endothelium-denuded (ED) vessels compared with endothelium-intact vessels. The effect of ED in oxygenated K-CP was mimicked by administration of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Conversely, in hypoxic K-CP the contraction was significantly attenuated in ED vessels compared with endothelium-intact vessels, although there was no significant difference in [Ca++]i. Indomethacin did not affect the endothelium-dependent contraction during hypoxic K-CP. CONCLUSIONS: Endothelium-derived nitric oxide modulates the vascular tone during K-CP by regulating the vascular smooth muscle [Ca++]i, whereas endothelium-derived contracting factor(s), which is not predominantly a product of cyclo-oxygenase, may play a prominent role under hypoxic K-CP by increasing vascular smooth muscle Ca++ sensitivity. 相似文献