Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Synthesis of Small Peptide Nanogels Using Radiation Crosslinking as a Platform for Nano-Imaging Agents for Pancreatic Cancer Diagnosis.

Nanoparticle-based drug delivery systems (DDS) have been developed as effective diagnostic and low-dose imaging agents. Nano-imaging agents with particles greater than 100 nm are difficult to accumulate in pancreatic cancer cells, making high-intensity imaging of pancreatic cancer challenging. Peptides composed of histidine and glycine were designed and synthesized. Additionally, aqueous peptide solutions were irradiated with γ-rays to produce peptide nanogels with an average size of 25-53 nm. The mechanisms underlying radiation-mediated peptide crosslinking were investigated by simulating peptide particle formation based on rate constants. The rate constants for reactions between peptides and reactive species produced by water radiolysis were measured using pulse radiolysis. HGGGHGGGH (H9, H-histidine; G-glycine) particles exhibited a smaller size, as well as high formation yield, stability, and biodegradability. These particles were labeled with fluorescent dye to change their negative surface potential and enhance their accumulation in pancreatic cancer cells. Fluorescent-labeled H9 particles accumulated in PANC1 human pancreatic cancer cells, demonstrating that these particles are effective nano-imaging agents for intractable cancers.

Radiation Crosslinked Smart Peptide Nanoparticles: A New Platform for Tumor Imaging.

Nanoparticles have been employed to develop nanosensors and drug carriers that accumulate in tumors. Thus, it is necessary to control the particle size, surface potential, and biodegradability of these nanoparticles for effective tumor accumulation and safe medical application. In this study, to form a nanoparticle platform suitable for diagnostic and drug delivery system (DDS) applications, peptides composed of aromatic amino acid residues were designed and synthesized based on the radiation crosslinking mechanism of proteins. The peptide nanoparticles, which were produced by γ-ray irradiation, displayed a positive surface potential, maintained biodegradability, and were stable in water and phosphoric buffer solution during actual diagnosis. The surface potential of the peptide nanoparticles could be changed to negative by using a fluorescent labeling reagent, so that the fluorescent-labeled peptide nanoparticles were uptaken by HeLa cells. The radiation-crosslinked nanoparticles can be applied as a platform for tumor-targeting diagnostics and DDS therapy.

[Case of interstitial pneumonitis induced by a Chinese herbal medicine, bofu-tsusho-san].

The patient was a 64-year-old woman. She had complained of dyspnea during exercise, productive cough, and pyrexia for two months after treatment to reduce her body weight with a Chinese herbal medicine, bofu-tsusho-san. This symptom worsened gradually, and she was admitted to our hospital for the examination and therapy. Chest radiography and CT scanning on admission showed ground-glass-attenuation with partial consolidation. Replacement of the medicine with treatment with oxygen and few medications for two weeks, made her condition well. The result of DLST for the herbal medicine, Bofu-tsusho-san was negative, but we strongly think it induced pneumonitis. The Chinese herbs ogon and kanzo which are ingredients of bofu-tsusho-san, can cause drug-induced pneumonitis. In conclusion, care should be taken if side effects, hypersensitivity, lung disease, liver injury, or other morbid conditions arise during the use of herbal medicines, because these disorders may lead to serious illness.

Long-term effects of beraprost sodium on arteriosclerosis obliterans: a single-center retrospective study of Japanese patients.

INTRODUCTION: Arteriosclerosis obliterans (ASO) causes ischemic symptoms of the lower limbs, reducing quality of life (QOL), and has a poor prognosis. Early diagnosis and treatment are necessary. In this study, the effects of long-term administration of beraprost sodium (beraprost) to treat ASO were investigated. METHODS: One hundred and eighty eight patients treated with beraprost for ≥1 year were retrospectively identified. Outcomes were lower limb ischemic symptoms, carotid intima/media thickness (IMT), and cardiovascular events. Patients reported visual analog scale scores for major symptoms at baseline and after 3, 6, and 12 months of treatment. RESULTS: Overall, 188 patients (mean age 70.8 ± 10.15 years, Fontaine classification: grade I 14.4%, grade II 85.6%) treated with beraprost for 2.4-10.7 years (mean 6.5 years) were included in this study. Administration of beraprost significantly reduced patient-reported severity of lower limb ischemic symptoms in all patients at 12 months, including those with diabetes, hypertension, or dyslipidemia. IMT decreased from 1.09 ± 0.09 mm at baseline to 1.04 ± 0.11 mm at 12 months (P < 0.001). Decreases in IMT were similar in patients with diabetes, hypertension, or dyslipidemia. Overall, 26 (13.8%) events occurred during a mean follow-up of 6.5 years, including 23 cardiovascular events (unstable angina in three patients, myocardial infarction in six patients, cerebral infarction in eight patients, and transient cerebral ischemic attack in six patients) and non-cardiovascular death in three patients. Beraprost at 120 µg/day significantly reduced the risk of ischemic symptoms compared with <120 µg/day (adjusted hazard ratio: 0.17; 95% confidence interval: 0.06, 0.45; P < 0.001). No severe adverse events or adverse events requiring dose reductions/discontinuation occurred during long-term administration of beraprost. CONCLUSION: Beraprost reduced lower limb ischemic symptoms, IMT, and the incidence of cardiovascular events in patients with ASO.

Reversible posterior leukoencephalopathy syndrome after carboplatin and paclitaxel regimen for lung cancer.

Reversible posterior leukoencephalopathy syndrome (RPLS) is uncommon neurological syndrome that is characterized by specific clinical and radiologic findings. Previous reported associations of RPLS include hypertension, eclampsia, renal impairment and drugs. Prompt diagnosis and therapy is critical to ensure resolution of the neurological disability. Some cases have been reported in association with the increased use of antineoplastic agents in cancer patients. We report the case of a 62-year-old man who was diagnosed with RPLS after receiving carboplatin and paclitaxel chemotherapy for lung cancer. This case appears to be the first recognized association of RPLS with this regimen.

Effects of irbesartan on 24-h blood pressure changes and urinary albumin levels in Japanese outpatients.

In Japan, ambulatory blood pressure monitoring (ABPM) became covered by health insurance in April 2008. In The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2009), the importance of 24-h blood pressure monitoring was also described in an additional section. Therefore, ABPM may be increasingly applied in hypertension treatment. However, in Japan, few studies have presented data on the effects of various anti-hypertensive agents on 24-h blood pressure changes. Irbesartan became commercially available in July 2008 as the sixth angiotensin II type 1 receptor blocker in Japan. In the present study, 24-h blood pressure control was examined using ABPM in Japanese patients with essential hypertension who were treated with irbesartan, and its efficacy was evaluated. This study was completed in 30 of the 32 subjects. This agent decreased both the nocturnal and daytime blood pressures and reduced the rate of change in the systolic blood pressure early in the morning, resulting in favorable blood pressure control. It also significantly decreased the urinary albumin level, suggesting that it exhibits renoprotective effects at doses approved in Japan.

Angiotensin receptor blockers and microalbuminuria in hypertensive patients with early (microalbuminuric) stage diabetic nephropathy.

Although protection of the kidneys by renin-angiotensin system (RAS) inhibitors is well known, differences in renal protection and the characteristics of RAS inhibitors have not been fully investigated. We randomly allocated 80 patients with hypertension complicated by type 2 diabetes and accompanied by microalbuminuria to 4 groups for treatment with the angiotensin receptor blockers (ARBs) telmisartan, losartan, candesartan and valsartan. Strict anti-hypertensive therapy was performed for 12 months (target blood pressure: lower than 130/80 mmHg), and renal function was compared. At study completion, all groups achieved the hypotensive target and no difference was noted in blood pressure levels. However, influences on renal function differed. In the telmisartan group in particular, the serum creatinine level was unchanged while the urinary albumin level and protein excretion were significantly decreased, displaying a strong renoprotective effect. These findings suggest that, although renal protection is a class effect of ARBs, the effect of telmisartan is particularly strong.

IgG-antiphospholipid antibodies in follicular fluid of IVF-ET patients are related to low fertilization rate of their oocytes.

PROBLEM: Patients undergoing in vitro fertilization and embryo transfer (IVF-ET) failures show an increased incidence of antiphospholipid antibodies (aPL) in their blood. The physiological manifestations of aPL in this patient group are nonetheless controversial. Pathological effects of aPL on embryos in vitro have been documented. We questioned whether aPL if found in follicular fluids (FFs) could result in embryonic damage. METHOD OF STUDY: Blood from 44 patients with three or more IVF-ET failures were tested by enzyme-linked immunosorbent assays (ELISA) for the presence of immunoglobulin (Ig)G, IgM and IgA aPL. Both the 29 aPL-positive and 15 aPL-negative patients gave permission for FF collection during their next IVF-ET attempt for additional aPL determinations. RESULTS: Patients with no aPL in their blood, had no aPL in their FFs. Patients with IgG and/or IgM aPL in their blood had IgG but not IgM in their respective FFs. CONCLUSIONS: The presence of IgG aPL in FFs and increased infertility length were significantly related to lower fertilization rates, independently. Follicular fluid IgG aPL appears as a risk factor in association with successful IVF-ET outcomes.