Post‐marketing survey of donepezil hydrochloride in Japanese patients with Alzheimer's disease with behavioral and psychological symptoms of dementia (BPSD)

Background: To investigate the efficacy and safety of donepezil hydrochloride (Aricept^®; Eisai Co., Ltd, Tokyo, Japan), we conducted a post‐marketing survey in Japanese patients with Alzheimer's disease (AD) who also had behavioral and psychological symptoms of dementia (BPSD), such as hallucinations/delusions, wandering, and aggression, which cause the greatest burden on caregivers. Methods: A prospective, centrally registered investigation was conducted through regular clinical settings with patients diagnosed as mild to moderate AD presenting with hallucinations/delusions, wandering, and/or aggression. The treatment period was 12 weeks and no restrictions were placed on concomitant medications. Results: The BPSD improvement rates at last‐observation‐carried‐forward (LOCF) were 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For all symptoms, improvement rates increased with the duration of the treatment period. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Assessment of cognitive function with both the revised Hasegawa Dementia Scale (HDS‐R) and Mini‐Mental State Examination (MMSE) indicated significant improvements after treatment. There were significant differences in the changes in HDS‐R scores between patients whose hallucinations/delusions or wandering were improved and patients whose symptoms were not improved. Moreover, the data suggested a possible correlation between changes in hallucinations/delusions and HDS‐R scores, changes in hallucinations/delusions and MMSE scores, and changes in wandering and MMSE scores. Patients in whom BPSD improved also demonstrated a greater improvement in cognitive function compared with patients in whom no improvement in BPSD was noted. Nursing burden on caregivers at LOCF showed 3.6% for ‘No burden’, 54.1% for ‘Burden decreased’, and 4.5% for ‘Burden increased.’ There was an increase in the combined ratio of ‘No burden’ and ‘Burden decreased’ in proportion with prolonged treatment period. Patients with improved BPSD had a significantly greater ratio (88.5–94.4%) of ‘No burden’ plus ‘Burden decreased’ than those patients in whom no improvement in BPSD was noted. Conclusions: These results suggest that donepezil not only improves the cognitive dysfunction of AD patients, but may also relieve BPSD in these patients. Treatment with donepezil was also found to alleviate the burden of caregivers for approximately 60% of patients. Moreover, the results indicate that donepezil is unlikely to trigger potential risks of excessive deterioration of BPSD, which would result in a heavier burden of nursing care.     

Vestibular testing by electrical stimulation in patients with unilateral vestibular deafferentation: galvanic evoked myogenic responses testing versus galvanic body sway testing.

OBJECTIVE: To investigate the agreement of a lesion site as indicated by two different vestibular tests with electrical stimulation, galvanic body sway testing (GBST) and galvanic evoked myogenic responses (galvanic vestibular evoked myogenic potential; galvanic VEMP) testing, in patients with unilateral vestibular deafferentation. METHODS: Nineteen patients with unilateral vestibular deafferentation were studied, and the criteria for patient selection were as follows: (1) absence of a caloric response to ice water on the affected side in a supine position, and (2) absence of VEMP to 95 dBnHL clicks on the affected side. We assessed the postural response of the subjects to long duration galvanic stimulation (1 mA, 5 s) by measuring the lateral displacement at the center of foot pressure with a cathode electrode on the forehead, and an anode electrode on the mastoid (GBST). We also recorded the electromyographic (EMG) activities of the sternocleidomastoid muscle (SCM) to short duration galvanic stimulation (3 mA, 1 ms) (galvanic VEMP) with a cathode electrode on the mastoid, and an anode electrode on the forehead. RESULTS: In 18 of the 19 patients, the lesion site indicated by GBST was identical to that indicated by galvanic VEMP. Fourteen patients had abnormal results in both tests while 4 patients had normal results in both tests. One patient with acoustic neuroma had normal results in GBST but abnormal results in galvanic VEMP. CONCLUSIONS: These results suggest that electrical stimulation in these two tests stimulates the same area of the peripheral vestibular afferent system, although the duration of stimulation was different, and that the estimate of the lesion site indicated by these tests in patients with complete or nearly complete unilateral vestibular damages is reliable. SIGNIFICANCE: These results suggest that short-duration galvanic stimulation as well as long-duration galvanic stimulation stimulates the vestibular system at the same level.     

Identification and biochemical characterization of human plasma neutrophil inhibitor in vitro

In this study, assessment by a flow cytometric method using dichlorohydroxy fluorescin diacetate (DCFADH) in vitro revealed that human peripheral blood inhibits the production of active oxygen species by human peripheral neutrophis. It was also revealed that among the blood components, the plasma fraction inhibits active oxygen production most strongly. This plasma inhibitory activity was dose-dependent. Human serum also exerted an inhibitory activity; however, its activity was only one-third that of plasma. Moreover, when HL-60 human promyelocytic leukemic cells, with or without differentiation into the neutrophils by culturing with dimethyl sulfoxide (DMSO), active oxygen, which was also inhibited by plasma, was produced. Heat inactivation of the plasma did not alter the inhibitory activity, and gel filtration analysis showed that the peak activity was associated with a molecular mass of 70,000. The results of this study indicate that human plasma contains one or more substances that inhibit the active oxygen production of neutrophils, which may play an important role in inhibiting unneeded neutrophil activation in the bloodstream.     

Contribution of cerebral nitric oxide to bladder overactivity after cerebral infarction in rats.

PURPOSE: We investigated the contribution of cerebral nitric oxide to neurogenic voiding dysfunction after cerebral infarction. MATERIALS AND METHODS: The left mid cerebral artery in female Sprague-Dawley rats was occluded with 4-zero monofilament nylon thread. Bladder activity was monitored during infusion cystometrography. Time or dose dependent effects of intracerebral ventricular administration of the nonselective nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), were investigated in conscious, sham operated and cerebral infarcted rats. The selective neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl) imidazole was also administered to determine the participation of nitric oxide synthase subtypes. Cross-sectional infarct area was measured and infarct volume was calculated 12 hours after mid cerebral artery occlusion. RESULTS: Bladder capacity was reduced by 54% 30 minutes after mid cerebral artery occlusion. L-NAME significantly increased bladder capacity in a dose and time dependent manner in cerebral infarcted rats but had no effect on sham operated rats. L-NAME (50 microg./kg.) administered 3 or 5 hours after occlusion significantly increased bladder capacity. This effect of L-NAME was reversed by injecting 250 microg. L-arginine per rat, which alone did not produce any significant change in bladder capacity in cerebral infarcted rats. Administration of 1-(2-trifluoromethylphenyl) imidazole also significantly increased bladder capacity in these rats. On the other hand, 5 microg. of the nitric oxide donor FK-409 per rat reduced bladder capacity for 10 to 15 minutes. None of the drugs affected infarct volume. CONCLUSIONS: These results indicate that supraspinal nitric oxide has an important role in bladder overactivity after cerebral infarction but it does not affect normal micturition in rats. This finding suggests a central mechanism sensitive to nitric oxide for bladder overactivity after cerebral infarction.     

Pharmacokinetics of salazosulfapyridine in a hemodialysis patient]

The patient was a 62-year-old female. Total gastrectomy was performed due to gastric ulcer in 1969. She was diagnosed as rheumatoid arthritis (RA) in 1985 and was developed to amyloidosis in 1991. She was started on hemodialysis (HD) for chronic renal failure in 1996. In 1998, her arthralgia was aggravated, and 100 mg/day of bucillamine was administered on the day of HD. Her arthralgia persisted, and switching to salazosulfapyridine (SASP) was considered. As there were no standards and no reports for the use of SASP in HD patients, we examined the pharmacokinetics of SASP and its metabolites, and compared our patient with the results of phase one study in normal subjects in Japan. In this case, the blood concentration of SASP was similar to that in healthy controls after single administration of 500 mg of SASP on the day of non-HD, while the concentration of sulfapyridine (SP) was higher than that in healthy donors. However, the blood concentrations of SASP, SP, and N4-acetyl-SP (AcSP) at 24 hours after administration were similar to those obtained in healthy men. SASP was not dialyzed, while about half of SP and AcSP, were dialyzed. In a five-day consecutive administration study also, the blood concentrations of these compounds on Day 5 were similar to those of phase one study, suggesting no accumulation. No adverse drug reaction was observed. As this case had the past history of total gastrectomy and amyloidosis, it is possible that this result is influenced by the factors. Therefore it is necessary to examine pharmacokinetics of SASP and its metabolites beforehand when administering this agent to other HD/RA patients.     

A malignant proliferating trichilemmal tumor simulating a squamous cell carcinoma

An 84-year-old man with a 3x3 cm tumor of the nasal dorsum is described. The tumor was surgically removed, reconstruction was with a forehead flap. Histologically the tumor was a malignant proliferating trichilemmal tumor (MPTT). There has been no recurrence or distant spread two years after surgery. MPTT is a rare tumor occurring mainly on the scalp and face in elderly men. It can be difficult to differentiate from a squamous cell carcinoma (SCC), both clinically and histologically. It has a tendency to metastasize and recur more frequently than SCC. When a malignant tumor occurs on the scalp or face, the diagnosis of MPTT should be considered by both surgeon and pathologist.     

维生素A对牙周致病菌免疫小鼠免疫应答调节的作用

目的:探讨维生素A缺乏对特异性牙周致病菌-伴放线放线杆菌(A.actinomycetetemcomitans,Aa)引起的小鼠免疫应答作用的影响.方法:整个实验过程采用无维生素A饮食(vitamine A-depleted diet,VAD)或常规维生素A饮食(vitamine A-sufficient regular diet,RD)喂养BALB/c鼠.2周后,免疫Aa建立免疫动物模型,6周后处死小鼠,ELISA法测定血清中的抗Aa特异性抗体总IgG、IgM及IgG亚类抗体滴度及细胞上清中细胞因子的浓度,3H-Tdr掺入法测定T细胞增殖反应.实验结果采用SPSS 11.5软件包进行统计学分析.结果:Aa免疫的总IgG和IgM抗体水平明显升高,非免疫组则不能产生抗体.Aa免疫+VAD组与Aa免疫+RD组相比,总IgG水平显著升高(P<0.05);IgG2a的抗体水平明显增加,而IgG1亚型的抗体水平却明显降低,差异显著(P<0.05).Aa免疫组可诱导机体产生较强的特异性T细胞免疫反应,而Aa免疫+VAD组T细胞增殖反应明显高于Aa免疫+RD组,具有统计学差异(P<0.05);细胞上清中RANKL、IFN-γ及TNF-α的表达增加,IL-10的表达降低(P<0.05).结论:饮食中维生素A缺乏,可增加Aa免疫鼠引起的免疫炎症反应,提示充足的维生素A是维持机体健康的重要因素.     

Pain relief of oral ulcer by dibucaine-film

A water-soluble three-layered oral mucosa-adhesive film made from hydroxypropyl cellulose containing dibucaine (0.25 mg of drug/cm(2)) was designed for alleviation of severe pain due to oral ulcers, caused by chemotherapy and/or radiotherapy. We report two patients with constant severe pain ulcers treated with the dibucaine film. Patients were asked to record the time that pain was relieved while chewing following first application of the film. Pain relief lasted for 2-5 h after application of the dibucaine film.     

Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist

1. The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4β-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat.
2. CP-101,606 30 mg kg⁻¹, s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat.
3. CP-101,606 also inhibited capsaicin- and PMA-induced nociceptive responses (licking behaviour) with ED₅₀ values of 7.5 and 5.7 mg kg⁻¹, s.c., respectively.
4. These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists.

     

Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog

The differentiation of mesenchymal cells into chondrocytes and chondrocyte proliferation and maturation are fundamental steps in skeletal development. Runx2 is essential for osteoblast differentiation and is involved in chondrocyte maturation. Although chondrocyte maturation is delayed in Runx2-deficient (Runx2(-/-)) mice, terminal differentiation of chondrocytes does occur, indicating that additional factors are involved in chondrocyte maturation. We investigated the involvement of Runx3 in chondrocyte differentiation by generating Runx2-and-Runx3-deficient (Runx2(-/-)3(-/-)) mice. We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2(-/-)3(-/-) mice showed a complete absence of chondrocyte maturation. Further, the length of the limbs was reduced depending on the dosages of Runx2 and Runx3, due to reduced and disorganized chondrocyte proliferation and reduced cell size in the diaphyses. Runx2(-/-)3(-/-) mice did not express Ihh, which regulates chondrocyte proliferation and maturation. Adenoviral introduction of Runx2 in Runx2(-/-) chondrocyte cultures strongly induced Ihh expression. Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter. These findings demonstrate that Runx2 and Runx3 are essential for chondrocyte maturation and that Runx2 regulates limb growth by organizing chondrocyte maturation and proliferation through the induction of Ihh expression.