Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE: PF-04360365 is a humanized IgG(2)Δa anti-amyloid ß (Aß) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS: 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS: All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aß species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS: PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

Perceptions of specialized inpatient palliative care: a population-based survey in Japan.

This study aimed to clarify and compare the awareness and perceptions of the specialized inpatient palliative care service. A cross-sectional questionnaire survey was performed on the general population selected by stratified two-stage random sampling (n=2,548) and bereaved families who actually received specialized inpatient palliative care at 12 palliative care units (PCUs) in Japan (n=513). The respondents reported their awareness and perceptions of PCUs. Thirty-eight percent of the general population answered that they had "considerable" or "moderate" knowledge of PCUs, but 24% answered that they had "no" knowledge. Bereaved families who received PCU care (PCU-bereaved families) were likely to have better perceptions of PCUs than the general population: "alleviates pain" (68% of the general population and 87% of PCU-bereaved families agreed), "provides care for families" (67% and 86%, respectively), and "provides compassionate care" (67% and 87%, respectively). Both groups, however, expressed concerns about PCUs: "a place where people only wait to die" (30% and 40%, respectively) and "shortens the patient's life" (8% and 17%, respectively). These perceptions were associated with overall satisfaction with received care, and differed among the 12 PCUs. In conclusion, public awareness of PCUs was insufficient in Japan. Although PCU-bereaved families were generally likely to have better perceptions of PCUs than the general population, both groups shared concerns that a PCU was a place where people only wait to die. To facilitate appropriate use of specialized palliative care services, more efforts to inform the general population about the actual palliative care system are needed. In addition, the role of PCUs might be reconsidered in terms of the continuum of cancer care.

Knowledge and beliefs about end-of-life care and the effects of specialized palliative care: a population-based survey in Japan.

To clarify the knowledge and beliefs of the Japanese general population related to legal options, pain medications, communication with physicians, and hydration/nutrition in end-of-life care, and to explore the associations between end-of-life care they had experienced and these beliefs, a questionnaire survey was conducted on two target populations: 5000 general population subjects and 866 bereaved family members of cancer patents who died in 12 palliative care units in Japan. The respondents were requested to report the legal knowledge about end-of-life options, pain-related beliefs, communication-related beliefs, and hydration/nutrition-related beliefs, and their experiences with end-of-life care. A total of 3061 responses were analyzed (effective response rate, 54%). The respondents were classified into six groups: no bereavement experience (n = 949), those who had lost family members within the past 10 years from noncancer diseases at institutions (n = 673), those who lost family members from noncancer disease at home (n = 264), those who lost family members from cancer at institutions other than palliative care units (n = 525), those who lost family members from cancer at home (n = 86), and those who lost family members from cancer at palliative care units (n = 548). Across groups, 32-45% and 50-63% of the respondents stated that treatment withdrawal and double effect act were legal, respectively. Between 34% and 44% believed that cancer pain is not sufficiently relieved, 27-38% believed that opioids shorten life, and 24-33% believed that opioids cause addiction. Communication-related beliefs potentially resulting in barriers to satisfactory end-of-life discussion were identified in 31-40% ("physicians are generally poor at communicating bad news") and in 14-25% ("physicians are not comfortable discussing death"). The bereaved family members of the patients who died in palliative care units were significantly more likely than the other groups to believe that cancer pain is sufficiently relieved, and significantly less likely to believe that opioids shorten life, that opioids cause addiction, that physicians are generally poor at communicating bad news, and that physicians are uncomfortable discussing death. Between 33% and 50% of the respondents, including families from palliative care units, believed "artificial hydration should be continued as the minimum standard until death," while 15-31% agreed that "artificial hydration relieves patient symptoms." A significant proportion of the Japanese general population has beliefs about legal options, pain medications, and communication with physicians that potentially result in barriers to quality end-of-life care. As their experiences in specialized palliative care significantly influenced their belief, systematic efforts to spread quality palliative care activity are of value to lessen these barriers and achieve quality end-of-life care.

Low-density lipoprotein cholesterol levels and lipid-modifying therapy prescription patterns in the real world: An analysis of more than 33,000 high cardiovascular risk patients in Japan.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is a key modifiable risk factor in the development of cardiovascular (CV) disease. In 2012, the Japan Atherosclerosis Society (JAS) issued guidelines recommending statins as first-line pharmacotherapy for lowering LDL-C in patients at high risk for CV events. This study assessed achievement of recommended LDL-C goals and lipid-modifying therapy (LMT) use in a high CV risk population in Japan. METHODS: Patients from the Medical Data Vision (MDV) database, an electronic hospital-based claims database in Japan, who met the following inclusion criteria were included in this study: LDL-C measurement in 2013; ≥20 years of age; ≥2 years representation in the database; and a high CV risk condition (recent acute coronary syndrome (ACS), other coronary heart disease (CHD), ischemic stroke, peripheral arterial disease (PAD) or diabetes). LDL-C goal attainment was assessed based on LDL-C targets in the JAS guidelines. RESULTS: A total of 33,325 high CV risk patients met the inclusion criteria. Overall, 68% of the cohort achieved guideline recommended LDL-C targets, with only 42% receiving current treatment with statins. Attainment of LDL-C goals was 68% for ACS, 55% for CHD, and 80% each for ischemic stroke, PAD, and diabetes patients. Concomitant use of non-statin LMTs was low. CONCLUSIONS: In a high CV risk population in a routine care setting in Japan, guideline recommended LDL-C goal attainment and utilization of statins and other LMT was low. In addition, physicians appeared to be more likely to consider the initiation of statins in patients with higher baseline LDL-C levels.

Distribution of Ankle-Brachial Index among Inpatients with Cardiovascular Disease: Analysis Using the Kumamoto University Hospital Medical Database.

OBJECTIVE: To describe the distribution of ankle-brachial index (ABI) among Japanese cardiovascular inpatients and to explore risk factors of peripheral arterial disease (PAD) associated with ABI ≤0.9. MATERIALS AND METHODS: This study was a retrospective analysis using clinical record databases of patients with cardiovascular disease admitted to the Department of Cardiovascular Medicine, Kumamoto University Hospital between 2007 and 2014. RESULTS: Of 3639 patients included in the analysis, male patients accounted for 62.1% and the mean age of patients was 66.1 years. Ischemic heart disease (IHD) was observed in 49.1%. ABI ≤0.9 was observed in 11.3% of all patients, 14.1% in the IHD group and 8.5% in the non-IHD group. Age of ≥65 years (odds ratio [OR]: 2.93, 95% confidence interval [CI]: 2.22-3.86), current smoking (OR: 2.28, 95%CI:1.71-3.04), diabetes (OR: 2.15, 95%CI:1.71-2.71), hypertension (OR: 1.42, 95%CI:1.12-1.81) and chronic kidney disease (OR: 2.52, 95%CI:1.82-3.48) were significantly associated factors with ABI ≤0.9. CONCLUSIONS: This study suggests that PAD is prevalent even in patients without IHD. Active management of risk factors, early detection of PAD based on ABI, and therapeutic intervention could be effective in preventing future cardiovascular events or death.

Opioid rotation from morphine to fentanyl in delirious cancer patients: an open-label trial.

Although recent studies suggest that opioid rotation could be an effective treatment strategy for morphine-induced delirium, there have been no prospective studies to investigate the treatment effects of opioid rotation using fentanyl. The primary aim of this study was to clarify the efficacy of opioid rotation from morphine to fentanyl in symptom palliation of morphine-induced delirium. Twenty-one consecutive cancer patients with morphine-induced delirium underwent opioid rotation to fentanyl. Physicians recorded the symptom severity of delirium (the Memorial Delirium Assessment Scale, MDAS), pain, and other symptoms (categorical verbal scale from 0: none to 3: severe) and the Schedule for Team Assessment Scale (STAS) (from 0: none to 4: extreme); and performance status at the time of study enrollment and three and seven days after. Of 21 patients recruited, one patient did not complete the study. In the remaining 20 patients, morphine was substituted with transdermal fentanyl in 9 patients and parenteral fentanyl in 11 patients. Total opioid dose increased from 64 mg oral morphine equivalent/day (Day 0) to 98 mg/day (Day 7), and the median increase in total opioid dose was 42%. Treatment success, defined as an MDAS score below 10 and pain score of 2 or less, was obtained in 13 patients on Day 3 and 18 patients on Day 7. The mean MDAS score significantly decreased from 14 (Day 0) to 6.4 and 3.6 (Days 3 and 7, respectively, P < 0.001). Pain scores significantly decreased from 2.2 (Day 0) to 1.3 and 1.1 on the categorical verbal scale (Days 3 and 7, respectively, P < 0.001); from 2.6 (Day 0) to 1.6 and 1.3 on the STAS (Days 3 and 7, respectively, P < 0.001). Symptom scores of dry mouth, nausea, and vomiting significantly decreased, and performance status significantly improved. Opioid rotation from morphine to fentanyl may be effective in alleviating delirium and pain in cancer patients with morphine-induced delirium.

Economic Burden of Venous Thromboembolism in Patients Undergoing Major Abdominal Surgery.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication that arises after major abdominal surgery. VTE poses risks of negative outcomes and health care burden. The literature on the cost of VTE in Japanese surgical patients, however, is scarce. OBJECTIVE: This study was conducted to investigate the economic consequences of VTE in Japanese patients with major abdominal surgery, using a hospital claims database. METHODS: This is a retrospective, matched cohort study. Patients who had a VTE event up to 90 days after their first major abdominal surgery and initiated warfarin or heparin within 1 day of VTE diagnosis with continued treatment for more than 4 weeks were matched with controls for surgery type, hospital, and date of surgery ± 6 months in a 1:2 scheme. The primary outcome was 90-day costs associated with major abdominal surgery. The secondary outcomes were 6-month total costs, average length of initial inpatient stay, and cost of initial inpatient stay. RESULTS: The 90-day cumulative incidence of VTE was 4.89%. The development of a VTE event in patients undergoing major abdominal surgery resulted in a 1.5-fold increase in the length of hospitalization and a 2.8-fold increase in total costs 90 days after the surgery. Total costs further increased to 3.4-fold at 6 months. Overall, costs incurred in patients with VTE are on average much higher than in patients without VTE throughout 6-month postsurgery. CONCLUSIONS: The preventive care for VTE using more effective prophylactic treatment is recommended to reduce the economic burden associated with major abdominal surgery.

Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders.

Recent post-mortem and imaging studies provide evidence for a glial reduction in different brain areas in mood disorders. This study was aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor (TGF)-beta superfamily, in blood levels was associated with mood disorders. We measured GDNF and TGF-beta levels in whole blood in remitted patients with mood disorders [n=56; major depressive disorders (MDD) 39, bipolar disorders (BD) 17] and control subjects (n=56). GDNF and TGF-beta were assayed with the sandwich ELISA method. Total GDNF levels were significantly lower in MDD and in BD than in control subjects (MDD, p=0.0003; BD, p=0.018), while no significant difference in total TGF-beta1 or total TGF-beta2 levels was found in these groups. Our study suggests that lower GDNF levels might be involved in the pathophysiology of mood disorders, although this preliminary study has several limitations.