In order to determine the safety or otherwise of amlodipine, we evaluated lipid and lipoprotein indices as well as fibrinolytic parameters in Japanese hypertensive patients undergoing amlodipine treatment. Lipids, lipoproteins, tissue plasminogen activator (t-PA), total and free plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complexes were determined in twenty-seven patients with essential hypertension before and after 3 months of amlodipine treatment. Plasma renin and noradrenaline levels were also determined. The mean systolic and diastolic blood pressures and heart rate were reduced, while the plasma renin and noradrenaline levels remained unchanged after amlodipine therapy. Triglycerides, very low density lipoprotein-cholesterol (VLDLC), total and free PAI-1 levels were significantly reduced, while the levels of total cholesterol (TC), high density lipoprotein-cholesterol (HDLC), low density lipoprotein-cholesterol (LDLC), HDLC/TC ratio, t-PA and t-PA-PAI-1 complex did not change from their pretreatment values after amlodipine treatment. There was a significant positive correlation between HDLC and t-PA-PAI-1 complex levels after amlodipine treatment. The findings from the present study show that amlodipine is effective for the treatment of hypertension and dose not cause reflex tachycardia in Japanese patients. We also found that amlodipine treatment is a safe antihypertensive agent characterized by beneficial lipid changes and enhanced fibrinolysis in Japanese hypertensive patients. The direct relationship between lipid levels and fibrinolytic function seen in this study has added to our understanding and knowledge of the pathogenesis of atherosclerosis during antihypertensive pharmacotherapy.
Atrial fibrillation (AF) is an important cause of ischemic stroke that often remains undetected until stroke occurs. Awareness of the risk factors and symptoms is important so that AF can be diagnosed and thromboprophylaxis given. However, the extent of public awareness of AF is uncertain. We assessed public awareness of AF across six continents and compared it with that of other thrombotic and non-thrombotic disorders.In collaboration with Ipsos-Reid, we conducted an internet-based, cross-sectional survey between September and October of 2016 in 10 countries: Argentina, Australia, Canada, Germany, Japan, Thailand, the Netherlands, Uganda, United Kingdom, and United States. Participants were selected from survey panels in weighted, age-stratified categories (40-60, 61-74, and ≥75 years). The survey included 11 questions about demographics and assessed awareness about AF, as well as that of other thrombotic and non-thrombotic disorders. Proportions and 95% confidence intervals (CI) were calculated.Of a total of 6312 respondents, overall awareness of AF was 48% (95% CI, 46-50%), which was lower than awareness about other thrombotic and non-thrombotic disorders except for deep vein thrombosis (awareness 43%, 95% CI, 41-45%). Awareness about AF ranged from 25% to 69% across countries, while awareness of the risk factors for AF ranged from 8% to 52%, and awareness that AF leads to stroke ranged from 36% to 46%. Among those reporting awareness of AF, 82% correctly identified palpitations as an AF symptom.Global public awareness of AF is low. Improving awareness may empower patients to seek timelier stroke preventive care.
We successfully visualized the secretory dynamics of tissue-type plasminogen activator (tPA) tagged by green fluorescent protein (tPA-GFP) from cultured vascular endothelial cells (VECs) using total internal reflection fluorescence (TIRF) microscopy and demonstrated that tPA-GFP secreted from VECs was retained on cell surfaces in a heavy-chain-dependent manner. Progressive binding of Alexa568-labeled Glu-plasminogen was also observed on the surface of active tPA-GFP expressing cells via lysine binding sites (LBS), which was not observed on inactive mutant tPA-GFP expressing cells. These results suggest that retained tPA on VECs effectively activated plasminogen to plasmin, which then facilitated the binding of additional plasminogen on the cell surface by proteolytically cleaving surface-associated proteins and exposing their C-terminal lysine residues. Thus prolonged retention of tPA appeared to play an important role in initiating and amplifying plasmin generation on VECs. LBS-dependent binding of plasminogen was also observed as a narrow band at the lytic front of the fibrin mesh formed on active tPA-GFP expressing cells, which expanded outward as the lytic area increased. This binding was not observed on inactive mutant tPA-GFP expressing cells or in the presence of aprotinin. The binding of plasminogen to partially digested fibrin appears to be indispensable for spontaneous fibrinolysis.
Abdominal aortic aneurysm (AAA) is a vascular disease that results in the gradual dilation of the abdominal aorta and has a high rupture-related mortality rate. However, the mechanism of AAA rupture remains unknown. In our previous study, we established a novel AAA animal model (hypoperfusion-induced AAA rat model) with spontaneous AAA rupture. Using the hypoperfusion-induced AAA rat model, we demonstrated that the abnormal appearance of adipocytes in the vascular wall is associated with AAA rupture. However, pathological analysis of the rupture area has not been performed because it is particularly difficult to identify the rupture point. In this study, we succeeded in obtaining samples from the rupture point and performed a histological analysis of the ruptured area in the vascular wall in the hypoperfusion-induced AAA rat model. Adipocytes were observed along the AAA-ruptured area of the vascular wall. In the areas around the adipocytes, macrophage infiltration and protein levels of matrix metalloproteinases 2 and 9 were significantly increased and collagen-positive areas were significantly decreased, as compared with areas without adipocytes. The AAA diameter was correlated with the number of adipocytes in the vascular wall of the hypoperfusion-induced AAA rat model. On the other hand, serum triglyceride levels and serum total cholesterol levels were not correlated with the number of adipocytes in the vascular wall. These results suggest that local adipocyte accumulation in the vascular wall, not serum lipids, has an important role in AAA rupture.
We have developed the highly efficient neutron detector system MANDALA for the inertial-confinement-fusion experiment. The MANDALA system consists of 842 elements plastic scintillation detectors and data acquisition electronics. The detection level is the yield of 1.2×105 for 2.5 MeV and 1×105 for 14.1 MeV neutrons (with 100 detected hits). We have calibrated the intrinsic detection efficiencies of the detector elements using a neutron generator facility. Timing calibration and integrity test of the system were also carried out with a Co60 γ ray source. MANDALA system was applied to the implosion experiments at the GEKKO XII laser facility. The integrity test was carried out by implosion experiments.
Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed classes of drugs throughout the world, because of their excellent cholesterol-lowering effect and overall safety profile except for rare but fatal rhabdomyolysis arising either directly or indirectly by pharmacokinetic interactions with certain other drugs. As package inserts in pharmaceuticals are the primary source of information for health care providers, we carried out a literature search to examine how crucial information was provided in package inserts of five statins approved in Japan (simvastatin, atorvastatin, fluvastatin, pravastatin and pitavastatin).A MEDLINE search from 1996 to June 2004 was carried out to identify studies on clinical pharmacokinetic drug interactions for the five statins. We mainly collected information on area under plasma concentration (AUC) following co-administration of statins with other drugs. The current package inserts used in Japan were obtained from the website of the Pharmaceutical and Medical Device Agency whereas USA package inserts were obtained from the Food and Drug Administration website.The majority of package inserts listed the drugs that interacted with statins with most describing the risk of rhabdomyolysis because of the possibility of increases in blood concentration. However, quantitative information such as change in AUC was provided in only a few cases. Instructions for dosage adjustment are seldom provided in the Japanese package inserts. USA package inserts list almost identical drug interactions as the Japanese package inserts, although they contain more quantitative data, especially for typical cytochrome P450 (CYP) inhibitors.All pharmacokinetic drug interactions including relevant quantitative data for potential effectors and details on mechanisms of interaction need to be given in package inserts as soon as the information becomes available, to ensure safe and proper use of the drugs concerned. Including such information in the package insert will be an extremely valuable aid for health care providers.
