Search

Competing Interests: Disclosures Dr Hosokawa reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside the submitted work. Dr Taniguchi reports grants from Janssen Pharmaceutical and Nippon Shinyaku; and personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside the submitted work. Dr Ikeda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, and Bristol-Myers Squibb, outside the submitted work. Dr Inami reports personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Murohara reports a grant and personal fees from Daiichi Sankyo, outside the submitted work. Dr Hatano reports a grant from Japan Agency for Medical Research and Development and personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Tamura reports grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside the submitted work. Dr Yamashita reports a grant from Abbott Vascular Japan; and personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside the submitted work. Dr Tsujino reports personal fees from Janssen Pharmaceutical and Nippon Shinyaku; and affiliation with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside the submitted work. Dr Yaoita reports personal fees from Bayer Yakuhin and Konica Minolta, outside the submitted work. Dr Minatsuki reports a grant from Fukuda Foundation for Medical Technology, outside the submitted work. Dr Todaka reports a grant from Mochida Pharmaceutical; and personal fee from Bayer Yakuhin, outside the submitted work. Dr Fukuda reports grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside the submitted work. Dr Tsutsui reports grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, MEDINET, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; personal fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe Pharma, Pfizer Japan, Daiichi Sankyo, Novartis Pharma, Janssen Pharmaceutical, Pfizer Japan, Bayer Yakuhin, Otsuka Pharmaceutical, AstraZeneca, and Nippon Rinsho; and is Chairman of Japan Heart Failure Society, outside the submitted work. Dr Abe reports a grant from Konica Minolta and Daiichi Sankyo, outside the submitted work. Drs Watanabe, Yasuda, Kobayakawa, Adachi, and Tatsumi report no conflicts of interest.

Objectives: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting., Approach and Results: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels., Conclusions: The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels., (© 2016 American Heart Association, Inc.)

The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the adults. Binding parameters of PHT to serum proteins in our study were compared with in vivo or in vitro binding parameters of PHT to serum proteins reported by other investigators. Serum samples in the study were obtained from 36 adult patients (17 men, 19 women) receiving PHT monotherapy. A total of 43 steady-state concentrations were analyzed in the study. Patients' age ranged from 16 to 73 years (mean [SD], 42.9 [14.7] years). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. The association constant (K) was 0.014 L x micromol(-1), whereas the total concentration of binding sites (n(Pt)) was 754 micromol x L(-1). The number of binding sites per albumin molecule (n) was 1.16, whereas binding ability (n.K) was 0.016 L x micromol(-1). The fu was 0.087. The n.K is approximately 1.2 times higher in PHT monotherapy patients of Pospísil and Perlík (ie, 0.0191 L x micromol(-1)) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al (ie, 0.0186 L x micromol(-1)) than in our study, whereas n is similar between the two studies. The fu in our patients is similar to the unbound serum PHT fraction in patients receiving PHT therapy reported by Richens (ie, 0.1). Our results suggest that there may be small differences in the binding affinity of PHT to serum proteins between in vivo and in vitro studies. The unbound serum fraction of PHT in epileptic patients can be assumed to be relatively constant in the therapeutic concentration range of PHT.

The aim of the present study was to determine the gender-related binding characteristics of phenytoin (PHT) to serum proteins in adult patients with epilepsy. Serum samples examined in the study were obtained from 80 adult patients (40 men and 40 women) with epilepsy on PHT monotherapy. Their age ranged from 16 to 64 years (mean [SD], 36.0 [11.7] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C). The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. No significant differences were observed in age and serum concentrations of albumin between male and female patients (p > 0.05), but significant differences were observed in serum concentrations of total and unbound PHT between the two groups (p < 0.05). The mean association constant of PHT to serum proteins is the same value of 0.008 L micromol(-1) between male and female patients, whereas total concentration of binding sites seems to be similar between the two groups (1389 micromol L(-1) for men and 1345 micromol L(-1) for women). No significant differences were observed in binding characteristics of PHT to serum proteins between male and female patients (p > 0.05). Our results show that gender does not have a significant effect on the binding characteristics of PHT to serum proteins in adult patients receiving monotherapy under normal pathophysiologic conditions.

The effects of temperature on binding characteristics of phenytoin (PHT) to serum proteins were determined in adult patients with epilepsy. Serum samples examined in the study were obtained from 47 adult patients (29 men, 18 women) with epilepsy on PHT monotherapy. Ages ranged from 18 to 64 years (mean [SD], 36.8 [12.1] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. Significant differences were observed in serum concentrations of unbound PHT between paired data (P <.05). The mean association constants (K) of PHT to serum proteins are 0.009 L micromol(-1) at 25 +/- 3 degrees C and 0.003 L micromol(-1) at 37 degrees C, whereas mean total concentrations of binding sites [n(Pt)] are 1215 micromol L(-1) for 25 +/- 3 degrees C and 2263 micromol L(-1) for 37 degrees C. Significant differences were observed in binding characteristics of PHT to serum proteins between the data determined in different conditions of ultrafiltration (P <.05). Our study confirms that binding affinity for PHT-serum protein interaction is approximately 67% lower at 37 degrees C than at 25 +/- 3 degrees C, and, consequently, binding potential [K.n(Pt)] is approximately 38% lower at 37 degrees C than at 25 +/- 3 degrees C.

We evaluated dynamic effects of the carotid sinus baroreflex on ventriculoarterial coupling. In seven anesthetized, vagotomized dogs, we bilaterally isolated carotid sinuses and randomly changed carotid sinus pressure while measuring aortic pressure, aortic flow, and left ventricular pressure. Estimating left ventricular end-systolic elastance (Ees) and effective arterial elastance (Ea) on a beat-to-beat basis, we determined transfer functions from the carotid sinus pressure to Ees (HEes) and from the carotid sinus pressure to Ea (HEa) over the frequency range spanning 0.002-0.25 Hz. Both HEes and HEa exhibited characteristics of a second-order low-pass filter. The gains of HEes and HEa were 0.085 +/- 0.065 (mean +/- SD) and 0.081 +/- 0.049 mm Hg/ml/mm Hg, respectively. There were no significant differences in natural frequencies (0.039 +/- 0.013 versus 0.039 +/- 0.007 Hz) or damping ratios (0.65 +/- 0.11 versus 0.64 +/- 0.24). The results indicated that the carotid sinus baroreflex dynamically altered Ees and Ea to the same extent in the process of stabilizing arterial pressure. Because the arterial system extracts maximal external work from a given heart when Ea equals Ees, the carotid sinus baroreflex appeared to be designed to regulate the ventricular and arterial properties to optimize the energy transmission from the left ventricle to the arterial system in anesthetized, vagotomized dogs.

To improve the performance of exercise stress testing in the diagnosis of effort angina while minimizing risks of serious complications, we evaluated an impulse response of ST changes, which is a transient ST response resulting from a hypothetical, strenuous-impulselike exercise, without actually imposing the strenuous load. To obtain the impulse response, subjects walked intermittently according to a computer-generated random binary sequence on a treadmill for 20 minutes (with a constant speed of 1.7 mph and a slope of 10%). We used Fourier transform for beat-to-beat changes in ST level and the binary sequence of exercise. We then determined the transfer function by taking the ratio of Fourier transformed ST level to exercise over the frequency range of 0.5 through 5.0 cycles/min. Converting the transfer function to the time domain yielded the impulse response of ST change. The subjects consisted of 49 patients (60 +/- 9 years) with effort angina, 13 patients with atypical chest pain (56 +/- 9 years), and 30 healthy, male volunteers (23 +/- 7 years). In 82 subjects (89%), the ST impulse response showed an initial depression followed by a smooth, gradual restoration toward the preexercise ST level (type I response). The average duration of the initial depression was 8 +/- 3 seconds in the healthy volunteers, whereas it was significantly prolonged to 23 +/- 14 seconds in effort angina (p less than 0.05). The depression in patients with atypical chest pain was not significantly different from that in the healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)