| 1. |
Yuka Takao, Chiho Tsunoda, Maki Kimura, Koji Todaka, Safety information management in investigator-initiated trials in Japan, Japanese Journal of Clinical Pharmacology and Therapeutics, 10.3999/JSCPT.52.13, 52, 1, 13-19, 2021.01, Timely reporting and appropriate response to safety information related to ongoing clinical trials is crucial for conducting trials appropriately and safely. However, it is difficult to understand exactly what, when, and to whom information should be reported because there are different types of clinical trials in Japan, governed by different laws and regulations. For example, principal investigators need to report serious, unrelated adverse events in ＂Chiken＂clinical trials, but not in clinical trials specified under the Clinical Trials Act 2017. This paper clarifies the principal investigator's responsibility for reporting under the three laws related to clinical trials: the Pharmaceuticals and Medical Devices Act, the Clinical Trials Act, and the Act on the Safety of Regenerative Medicine. Report items were explained and summarized in a table. The paper also separately covers trials under other frameworks, such as the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The paper will therefore help principal investigators to better understand their responsibilities and manage safety information in clinical trials under various frameworks in Japan. The paper also discusses some current issues that still need resolving.. |
| 2. |
Takuya Nagata, Tomomi Ide, Takeshi Tohyama, Hidetaka Kaku, Nobuyuki Enzan, Shouji Matsushima, Masataka Ikeda, Koji Todaka, Hiroyuki Tsutsui, Long-Term Outcomes of Heart Failure Patients With Preserved, Mildly Reduced, and Reduced Ejection Fraction, JACC: Asia, 10.1016/j.jacasi.2022.11.013, 2023.03. |
| 3. |
A. Suyama, K. Sunagawa, K. Hayashida, M. Sugimachi, K. Todaka, Y. Nose, M. Nakamura, Random exercise stress test in diagnosing effort angina, Circulation, 10.1161/01.CIR.78.4.825, 78, 4 I, 825-830, 1988.10, 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, strenous-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 |
| 4. |
M. Sugimachi, K. Todaka, K. Sunagawa, M. Nakamura, Optimal afterload for the heart vs. optimal heart for the afterload., Frontiers of medical and biological engineering : the international journal of the Japan Society of Medical Electronics and Biological Engineering, 2, 3, 217-221, 1990.03. |
| 5. |
M. Sugimachi, T. Imaizumi, K. Sunagawa, Y. Hirooka, K. Todaka, A. Takeshita, M. Nakamura, A new method to identify dynamic transduction properties of aortic baroreceptors, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1990.258.3.h887, 258, 3 27-3, 1990.03, We identified, in 17 α-chloralose-anesthetized rabbits, the dynamic transduction characteristics of the aortic arch baroreceptors using a 'white-noise technique'. We recorded aortic pressure and aortic depressor nerve activity while perturbing pressure by rapid, intermittent ventricular pacing (400 beats/min). Dividing the cross-power spectrum between nerve activity and pressure by the power spectrum of pressure yielded the transfer function. The gain of the transfer function increased threefold as the frequency increased from 0.005 to 5 Hz, suggesting that the baroreceptors responded primarily to dynamic rather than to static changes in pressure. To quantify the nonlinear properties of baroreceptor transduction, we compared measured instantaneous nerve activity with that linearly predicted. We demonstrated that the major nonlinearity was attributable to 'threshold'. The overall baroreceptor transduction properties could be represented by a cascade connection of a linear subsystem followed by a nonlinear subsystem with threshold. The white-noise technique made it possible to identify the unbiased linear properties in a nonlinear system, and thus was very useful in identifying complex biological systems.. |
| 6. |
T. Kubota, R. Itaya, K. Todaka, M. Sugimachi, K. Sunagawa, A. Takeshita, Effects of the new cardiotonic phosphodiesterase inhibitor 1,2-dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridine-car bonitrile hydrochloride monohydrate on aortic input impedance, Arzneimittel-Forschung/Drug Research, 41, 12, 1211-1215, 1991.12, Beneficial effects of cardiotonic phosphodiesterase inhibitors on congestive heart failure are possibly mediated in part by a reduction of afterload. 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridine-car bonitrile hydrochloride monohydrate (E-1020, CAS 119615-63-3), a new cardiotonic phosphodiesterase inhibitor was evaluated for its effect on aortic input impedance in eight anesthetized open-chest dogs. First instantaneous aortic pressure and flow under random ventricular pacing before and after E-1020 infusions (10, 30, and 100 μg/kg i.v.) were measured. Then aortic input impedance over the frequency range of 0.024 to 20 Hz was estimated using a multichannel autoregressive model. With the infusion of E-1020, aortic input impedance was decreased in the low frequency range (below 0.1 Hz) and shifted leftward in the transitional frequency range (from 0.1 to 2 Hz), while it remained unchanged in the high frequency range (above 2 Hz). Parameterization of the aortic input impedance using a three-element Windkessel model indicated that E-1020 (at a dose of 100 μg/kg i.v.) decreased arterial resistance by 35% (p |
| 7. |
T. Kubota, R. Itaya, J. Alexander, K. Todaka, M. Sugimachi, K. Sunagawa, Autoregressive analysis of aortic input impedance: Comparison with Fourier transform, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1991.260.3.h998, 260, 3 29-3, 1991.03, We evaluated the advantages of the autoregressive (AR) model over the conventional Fourier transform in estimating aortic input impedance. In 10 anesthetized open-chest dogs, we digitized aortic pressure and flow at 200 Hz for 51.20 s under random ventricular pacing and subdivided them into five segments. We obtained aortic input impedance over the frequency range of 0.1-20 Hz both by AR model and by Fourier transform for various lengths of data, i.e., from one to four consecutive segments. For any given data length, the impedance spectrum estimated by the AR model was smoother than that obtained by the Fourier transform. To evaluate the accuracy of the estimated impedance, we predicted instantaneous aortic pressure of the fifth segment by convolving corresponding aortic flow with the impulse response of aortic input impedance. The prediction error was less with the AR model than that resulting from Fourier transform as long as the number of the segments was less than four. We conclude that the AR model provides a more accurate estimate of aortic input impedance than does the Fourier transform when data length is limited.. |
| 8. |
T. Kubota, J. Alexander, R. Itaya, K. Todaka, M. Sugimachi, K. Sunagawa, Y. Nose, A. Takeshita, Dynamic effects of carotid sinus baroreflex on ventriculoarterial coupling studied in anesthetized dogs, Circulation Research, 10.1161/01.RES.70.5.1044, 70, 5, 1044-1053, 1992.05, 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 (E(es)) and effective arterial elastance (E(a)) on a beat-to-beat basis, we determined transfer functions from the carotid sinus pressure to E(es) (H(Ees)) and from the carotid sinus pressure to E(a) (H(Ea)) over the frequency range spanning 0.002-0.25 Hz. Both H(Ees) and H(Ea) exhibited characteristics of a second- order low-pass filter. The gains of H(Ees) and H(Ea) 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 E(es) and E(a) to the same extent in the process of stabilizing arterial pressure. Because the arterial system extracts maximal external work from a given heart when E(a) equals E(es), 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.. |
| 9. |
K. Sunagawa, M. Sugimachi, K. Todaka, T. Kobota, K. Hayashida, R. Itaya, A. Chishaki, A. Takeshita, Optimal coupling of the left ventricle with the arterial system, Basic Research in Cardiology, 88, SUPPL. 2, 75-90, 1993.06, In the human the heart contracts more than 2.0 billion times during the lifetime. The total amount of energy required in this period is equivalent to lift a huge tanker (more than 200 thousand tons) above your head. Thus there is no question that the heart requires a huge amount of energy. Since minimization of energy requirements would be one of the major design goals of the cardiovascular system, we investigated energy efficiency of ventriculo-arterial coupling under various conditions. In normal conscious dogs, the arterial system extracted maximal work from the left ventricle during exercise as well as at rest. At the same time,the energy consumption of the left ventricle to support the peripheral demand was minimum. This optimal coupling condition was well maintained despite changes in blood volume. The baroreflex system appeared to play a crucial role in this optimization. In the presence of left ventricular dysfunction, however, this optimality was no longer maintained. We conclude that the efficiency of cardiac contraction is fairly well maintained under various stresses as long as left ventricular function is normal.. |
| 10. |
Marc L. Dickstein, Koji Todaka, Daniel Burkhoff, Left-to-right systolic and diastolic ventricular interactions are dependent on right ventricular volume, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1997.272.6.h2869, 272, 6 41-6, 1997.06, Three-compartment elastance modeling predicts that the magnitude of gain is solely dependent on the ratio of free wall and septal elastances. However, when nonlinearities in pressure-volume relationships are considered, the same model predicts that gain is load dependent. We therefore studied left-to- right ventricular interactions in the isolated cross-perfused canine heart preparation to determine whether, in fact, right ventricular volume modulates left-to-right ventricular interaction. We found that left-to-right systolic gain increased from 0.035 ± 0.022 to 0.073 ± 0.017 (P = 0.003) and left- to-right diastolic gain increased from 0.067 ± 0.050 to 0.186 ± 0.097 (P = 0.03) in response to increased right ventricular volume. This degree of volume dependency of gain is predicted by the three-compartment model when measured nonlinearities in time-varying elastance are taken into account. Future studies will need to account for changes in loading conditions when interpreting changes in systolic and diastolic interactions.. |
| 11. |
Koji Todaka, J. I.E. Wang, Mathias Knecht, Richard Stennett, Milton Packer, Daniel Burkhoff, Impact of exercise training on ventricular properties in a canine model of congestive heart failure, American Journal of Physiology - Heart and Circulatory Physiology, 41, 3, 1997.03, Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHFEX, 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2, 540 ±440 vs. 1, 720 ±300 mmHg/s, P |
| 12. |
Koji Todaka, David Leibowitz, Shunichi Homma, Peter E. Fisher, Carolyn Derosa, Richard Stennett, Milton Packer, Daniel Burkhoff, Characterizing ventricular mechanics and energetics following repeated coronary microembolization, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1997.272.1.h186, 272, 1 41-1, 1997.01, Myocardial mechanics and energetics were investigated in an animal model of moderate chronic heart failure (CHF) created by repeated coronary microembolizations in six dogs. The final fractional area change was 34 ± 4%. Hearts of these animals were isolated and cross-perfused, and balloons were placed in the left ventricle (LV). Chamber contractile state was markedly depressed in embolized hearts as assessed by the slope (E(es): 2.74 ± 0.49 vs. 4.00 ± 1.18 mmHg/ml, P |
| 13. |
Y. Mukai, H. Tsutsui, K. Todaka, M. Mohri, N. Hirai, H. Arai, A. Takeshita, Total occlusion of inferior vena cava in a patient with antiphospholipid antibody syndrome associated with Behçet's disease, Japanese Circulation Journal, 10.1253/jcj.65.837, 65, 9, 837-838, 2001.09, Behçet's disease frequently involves the venous system, usually affecting small vessels, but sometimes large vessels such as the vena cava. Antiphospholipid antibody syndrome is associated with an increased incidence of arterial and venous thrombosis. A 29-year-old male with Behçet's disease developed bilateral leg edema secondary to thrombotic occlusion of the inferior vena cava. Laboratory tests revealed positive antiphospholipid antibodies and lupus anticoagulant. Treatment with steroid and warfarin subsequent to intravenous administration of uro-kinase resulted in improvement of symptoms. The association of antiphospholipid antibody syndrome and Behçet's disease may have caused the total thrombotic occlusion of the vena cava in this case.. |
| 14. |
Juichiro Shimizu, Koji Todaka, Daniel Burkhoff, Load dependence of ventricular performance explained by model of calcium-myofilament interactions, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.00498.2001, 282, 3 51-3, 2002.03, Although a simple concept of load-independent behavior of the intact heart evolved from early studies of isolated, intact blood-perfused hearts, more recent studies showed that, as in isolated muscle, the mode of contraction (isovolumic vs. ejection) impacts on end-systolic elastance. The purpose of the present study was to test whether a four-state model of myofilament interactions with length-dependent rate constants could explain the complex contractile behavior of the intact, ejecting heart. Studies were performed in isolated, blood-perfused canine hearts with intracellular calcium transients measured by macroinjected aequorin. Measured calcium transients were used as the driving function for the model, and length-dependent rate constants yielding the highest concordance between measured and model-predicted midwall stress at different isovolumic volumes were determined. These length-dependent rate constants successfully predicted contractile behavior on ejecting contractions. This, along with additional model analysis, suggests that length-dependent changes in calcium binding affinity may not be an important factor contributing to load-dependent contractile performance in the intact heart under physiological conditions.. |
| 15. |
Takahiro Uchida, Fumiaki Ikeno, Koji Ikeda, Yuka Suzuki, Koji Todaka, Hiroyoshi Yokoi, Gary Thompson, Mitchel Krucoff, Shigeru Saito, Global cardiovascular device innovation: Japan-USA synergies - Harmonization by doing (HBD) program, a consortium of regulatory agencies, medical device industry, and academic institutions, Circulation Journal, 10.1253/circj.CJ-12-1431, 77, 7, 1714-1718, 2013.07, Background: Global medical devices have become more popular, but investment money for medical device development is not easily available in the market. Worldwide health-care budget constraints mean that efficient medical device development has become essential. To achieve efficient development, globalization is a key to success. Spending large amounts of money in different regions for medical device development is no longer feasible. Methods and Results: In order to streamline processes of global medical device development, an academic, governmental, and industrial consortium, called the Harmonization by Doing program, has been set up. The program has been operating between Japan and the USA since 2003. The program has 4 working groups: (1) Global Cardiovascular Device Trials; (2) Study on Post-Market Registry; (3) Clinical Trials; and (4) Infrastructure and Methodology Regulatory Convergence and Communication. Each working group has as its goals the achievement of speedy and efficient medical device development in Japan and the USA. The program has held multiple international meetings to deal with obstacles against efficient medical device development. Conclusions: This kind of program is very important to deliver novel medical devices. Involvement of physicians in this type of activity is also very helpful to achieve these goals.. |
| 16. |
Koji Todaka, Jie Wang, Geng Hua Yi, Richard Stennett, Mathias Knecht, Milton Packer, Daniel Burkhoff, Effects of levosimendan on myocardial contractility and oxygen consumption, Journal of Pharmacology and Experimental Therapeutics, 279, 1, 120-127, 1996.10, Levosimendan is hypothesized to be primarily a calcium sensitizer in vitro. Therefore, its inotropic action may be similar in both the normal and the congestive heart failure (CHF) state, and it may be associated with a decreased energetic cost of inotropism in vivo. To test these hypotheses, we gave levosimendan to cross-circulated isolated hearts from normal (n = 11) and CHF (n = 7, 4-week rapid pacing) dogs. Peak isovolumic left ventricular pressure at an end-diastolic pressure of 5 mm Hg (P(max,5)) measured by an intraventricular balloon was 120 ± 15 mm Hg in normal dogs, and it was increased by ~40% in response to ~0.63 μM levosimendan. In CHF dogs, base- line P(max,5)) was only 60 ± 12 mm Hg (P |
| 17. |
K. Todaka, T. Jiang, J. T. Chapman, A. Gu, S. M. Zhu, E. Herzog, J. S. Hochman, S. F. Steinberg, D. Burkhoff, Functional consequences of acute collagen degradation studied in crystalloid perfused rat hearts, Basic Research in Cardiology, 10.1007/BF00788632, 92, 3, 147-158, 1997.06, Objectives: The impact of acute collagen disruption by the disulfide donor, 5,5'-dithio-2-nitrobenzoic acid (DTNB) on ventricular properties was tested in rat hearts. Methods: Collagen was degraded acutely in 13 isolated, isovolumically contracting rat hearts by perfusion with 1 mM DTNB added to Krebs Henseleit solution for 1 hour followed by 2-hour perfusion with normal solution. Another 13 hearts were perfused with normal solution for 3 hours (Control). Results: Collagen content was 3.5 ± 0.5% of ventricular dry weight in control group compared with 2.1 ± 0.4% in DTNB group (decrease by 40%, p |
| 18. |
Koji Todaka, Kazuhide Ogino, Anguo Gu, Daniel Burkhoff, Effect of ventricular stretch on contractile strength, calcium transient, and cAMP in intact canine hearts, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1998.274.3.h990, 274, 3 43-3, 1998.03, Isovolumic contractions were imposed by intraventricular balloon in 39 isolated, blood-perfused canine hearts to investigate the effects of myocardial stretch on contractile force. After stabilization at 37°C, left ventricular volume was increased so that end-diastolic pressure increased from 0 to 5 mmHg. After the immediate increase in developed pressure [DP; from 37 ± 14 to 82 ± 22 mmHg (means ± SD)], there was a slow secondary rise in DP (97 ± 27 mmHg) that peaked at 3 min. However, DP subsequently decreased over the next 7 min back to the initial value (84 ± 25 mmHg). Light emission from macroinjected aequorin (n = 10 hearts) showed that changes in intracellular calcium [3 min: 124 ± 15% (P |
| 19. |
Koji Todaka, Jie Wang, Geng Hua Yi, Anguo Gu, Shu Ming Zhu, Hui Zhang, Daniel Burkhoff, Effect of BAY y 5959 on myocardial function and metabolism in normal and failing hearts, American Journal of Physiology - Heart and Circulatory Physiology, 10.1152/ajpheart.1998.274.5.h1560, 274, 5 43-5, 1998.05, BAY y 5959 is a dihydropyridine derivative with positive inotropic actions mediated by a direct increase in intracellular calcium. We characterized the direct myocardial actions of this new agent in hearts isolated from seven normal dogs and from five dogs with repeated coronary microembolization-induced heart failure. Inotropic actions of BAY y 5959 were accompanied by little effect on duration of contraction and by prolongation of the monophasic action potential (MAP); in contrast, isoproterenol decreased contraction and MAP durations. Whereas inotropic responsiveness to isoproterenol was blunted in embolized hearts, these actions of BAY y 5959 were relatively preserved in the heart failure state. Isoproterenol increased heart rate, whereas BAY y 5959 had little effect. Changes in coronary vascular resistance also decreased similarly for isoproterenol and BAY y 5959. Finally, for comparable inotropy, increases in myocardial oxygen consumption were similar for isoproterenol and for BAY y 5959. In summary, preserved inotropic responsiveness and lack of positive chronotropic actions are two clinically favorable features of this type of inotropic agents compared with a typical β-adrenergic agonist.. |
| 20. |
Masayoshi Yoshida, Akiko Chishaki, Yoshinori Murayama, Satoshi Kimura, Makoto Ando, Toshirou Saito, Touru Shiino, Keiichiro Shiba, Koji Todaka, Kenji Sunagawa, Transcutaneous Bionic Baroreflex System Is Widely Applicable For Preventing Severe Orthostatic Hypotension In Patients With Cervical Cord Injury, CIRCULATION, 118, 18, S548-S548, 2008.10. |
| 21. |
Takahiro Inoue, Tomomi Ide, Henna Tyynismaa, Masayoshi Yoshida, Makoto Ando, Atsushi Tanaka, Koji Todaka, Dongchon Kang, Anu Suomalainen, Kenji Sunagawa, Overexpression of Mitochondria DNA Helicase, Twinkle, Ameliorates Cardiac Remodeling and Failure in Mice, CIRCULATION, 118, 18, S314-S315, 2008.10. |
| 22. |
Hiroshi Enaida, Akito Hirakata, Masahito Ohji, Kohji Nishida, Toshiaki Kubota, Nahoko Ogata, Koh Hei Sonoda, Makiko Uchiyama, Junji Kishimoto, Koji Todaka, Yoichi Nakanishi, Tatsuro Ishibashi, Efficacy and Safety of A0001 (Brilliant Blue G250) for Internal Limiting Membrane Staining and Peeling: Phase III Investigator-initiated Multicenter Clinical Trial, Nippon Ganka Gakkai zasshi, 120, 6, 439-448, 2016.06, PURPOSE: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy.. |
| 23. |
Takuya Nishikawa, Keita Saku, Koji Todaka, Yukimitsu Kuwabara, Shinobu Arai, Takuya Kishi, Tomomi Ide, Hiroyuki Tsutsui, Kenji Sunagawa, The challenge of magnetic vagal nerve stimulation for myocardial infarction -preliminary clinical trial, Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 10.1109/EMBC.2017.8037812, 2017, 4321-4324, 2017.09, Numerous studies have shown in animal models that vagal nerve stimulation (VNS) strikingly reduces infarct size of acute myocardial infarction (AMI) and prevents heart failure. However, the lack of techniques to noninvasively stimulate the vagal nerve hinders VNS from clinical applications. Transcranial magnetic stimulation is noninvasive and capable of stimulating central neurons in patients. In this study, we examined whether the magnetic stimulation could noninvasively activate the cervical vagal nerve in healthy human. Sixteen healthy males and 4 females were enrolled in this study. We used Magstim Rapid2 with a 70-mm double coil in the right neck. We randomly assigned the subjects to 5 Hz or 20 Hz stimulation. We defined the maximum intensity of stimulation (MAX) which is the intensity just below the threshold of adverse effects. We defined HALF as a half of MAX. Protocols comprised 2 sets of MAX and 2 sets of HALF. Each stimulation continued for 3 minutes. We monitored heart rate (HR) and assessed the bradycardic response as an index of successful VNS. Nineteen subjects completed all protocols. They had no problematic adverse events during and/or after magnetic VNS. The magnetic VNS induced transient bradycardic responses in some subjects, whereas failed to induce sustained bradycardia in pooled data in any settings. Arterial pressure did not change either. Successful magnetic stimulation requires technical improvements including narrowing the magnetic focus and optimization of stimulation site. These improvements may enable us to apply magnetic VNS in the management of AMI.. |
| 24. |
Kiminori Kimura, Akemi Ikoma, Maki Shibakawa, Shinji Shimoda, Kenichi Harada, Masanao Saio, Jun Imamura, Yosuke Osawa, Masamichi Kimura, Koji Nishikawa, Takuji Okusaka, Satoshi Morita, Kazuaki Inoue, Tatsuya Kanto, Koji Todaka, Yoichi Nakanishi, Michinori Kohara, Masashi Mizokami, Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial, EBioMedicine, 10.1016/j.ebiom.2017.08.016, 23, 79-87, 2017.09, Background There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. Methods In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160 mg/m2/day for six cycles of 1 week on and 1 week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). Findings Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160 mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10 mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40 mg/m2/day cohort, and improved in one patient by 3 points in the 160 mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10 mg/m2/day cohort, and improved in one patient in the 40 mg/m2/day cohort. Interpretation This study showed that administration of 10 or 40 mg/m2/day intravenous PRI-724 over 12 weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160 mg/m2/day cohort. Funding Source AMED.. |
| 25. |
Katsuya Kajimoto, Yuichiro Minami, Shigeru Otsubo, Naoki Sato, Naoki Sato, Kuniya Asai, Ryo Munakata, Toshiyuki Aokage, Asuka Yoshida, Yuichiro Minami, Dai Yumino, Masayuki Mizuno, Erisa Kawada, Kentaro Yoshida, Yuri Ozaki, Tomohito Kogure, Shintaro Haruki, Masayuki Mizuno, Katsuya Kajimoto, Koichi Nakao, Tadashi Sawamura, Toshiaki Nuki, Ryoji Ishiki, Shigeki Yokota, Hiroyuki Fujinaga, Takashi Yamamoto, Kenji Harada, Akihiro Saito, Norihito Kageyama, Takanobu Okumura, Noritake Hata, Koji Murai, Ayaka Nozaki, Hidekazu Kawanaka, Jun Tanabe, Yukihito Sato, Katsuhisa Ishii, Hitoshi Oiwa, Tomoaki Matsumoto, Daisuke Yoshida, Nobuo Kato, Hiroshi Suzuki, Nobuyuki Shimizu, Takehiko Keida, Masaki Fujita, Kentaro Nakamura, Toshiya Chinen, Kentaro Meguro, Tatsuro Kikuchi, Toshiyuki Nishikido, Marohito Nakata, Tatsuya Yamashita, Masaya Nakata, Akitoshi Hirono, Kazuaki Mitsudo, Kazushige Kadota, Noriko Makita, Nagisa Watanabe, Masaaki Kawabata, Kenichi Fujii, Shinichi Okuda, Shigeki Kobayashi, Ikuo Moriuchi, Kiyo o. Mizuno, Kazuo Osato, Tatsuaki Murakami, Yoshifumi Shimada, Katsushi Misawa, Hiromasa Kokado, Takashi Fujita, Yoshitomo Fukuoka, Syu Takabatake, Yoshifumi Takata, Manabu Miyagi, Nobuhiro Tanaka, Akira Yamashina, Shinji Sudo, Koichi Shimamura, Michitaka Nagashima, Tomoya Kaneda, Kosei Ueda, Hiromasa Kato, Toshinori Higashikata, Kanichi Fujimori, Hiroshi Kobayashi, Shinya Fujii, Masahiro Yagi, Yuri Ozaki, Jyunko Takaki, Eiji Yamashita, Takuji Toyama, Tetsuo Hirata, Kazuho Kamisihima, Toshiaki Oka, Ryushi Komatsu, Akira Itoh, Takahiko Naruko, Yukio Abe, Eiichirou Nakagawa, Atsuko Furukawa, Ischemic or Nonischemic Functional Mitral Regurgitation and Outcomes in Patients With Acute Decompensated Heart Failure With Preserved or Reduced Ejection Fraction, American Journal of Cardiology, 10.1016/j.amjcard.2017.05.051, 120, 5, 809-816, 2017.09, The aim of this study was to evaluate the association of functional mitral regurgitation (FMR), preserved or reduced ejection fraction (EF), and ischemic or nonischemic origin with outcomes in patients discharged alive after hospitalization for acute decompensated heart failure (HF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 3,357 patients were evaluated to assess the association of FMR, preserved or reduced EF, and ischemic or nonischemic origin with the primary end point (all-cause death and readmission for HF after discharge). At the time of discharge, FMR was assessed semiquantitatively (classified as none, mild, or moderate to severe) by color Doppler analysis of the regurgitant jet area. According to multivariable analysis, in the ischemic group, either mild or moderate to severe FMR in patients with a preserved EF had a significantly higher risk of the primary end point than patients without FMR (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.12 to 2.29; p = 0.010 and HR 1.98; 95% CI 1.30 to 3.01; p = 0.001, respectively). In patients with reduced EF with an ischemic origin, only moderate to severe FMR was associated with a significantly higher risk of the primary end point (HR 1.67; 95% CI 1.11 to 2.50; p = 0.014). In the nonischemic group, there was no significant association between FMR and the primary end point in patients with either a preserved or reduced EF. In conclusion, among patients with acute decompensated HF with a preserved or reduced EF, the association of FMR with adverse outcomes may differ between patients who had an ischemic or nonischemic origin of HF.. |
| 26. |
Susumu Takase, Tetsuya Matoba, Soichi Nakashiro, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Shunsuke Katsuki, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Mitsutaka Yamamoto, Makoto Usui, Kenji Sadamatsu, Shinji Satoh, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Kensuke Egashira, Kenji Sunagawa, Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting, Arteriosclerosis, Thrombosis, and Vascular Biology, 10.1161/atvbaha.116.308388, 37, 2, 350-358, 2017.02,
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.
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| 27. |
Kaku Nakano, Tetsuya Matoba, Jun-ichiro Koga, Yushi Kashihara, Masato Fukae, Ichiro Ieiri, Masanari Shiramoto, Shin Irie, Junji Kishimoto, Koji Todaka, Kensuke Egashira, Safety, Tolerability, and Pharmacokinetics of NK-104-NP, International Heart Journal, 10.1536/ihj.17-555, 59, 5, 1015-1025, 2018.09, Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.. |
| 28. |
Hiroyuki Kinoshita, Hiroshi Mannoji, Keita Saku, Jumpei Mano, Tadayoshi Miyamoto, Koji Todaka, Takuya Kishi, Shigehiko Kanaya, Kenji Sunagawa, Power Spectral Analysis of Short-Term Blood Pressure Recordings for Assessing Daily Variations of Blood Pressure in Human, Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 10.1109/EMBC.2018.8513040, 2018-July, 3626-3629, 2018.10, Although daily variations of blood pressure (BP) predict cardiovascular event risk, their assessment requires ambulatory BP monitoring which hinders the clinical application of this approach. Since the baroreflex is a major determinant of BP variations, especially in the frequency range of 0.01-0.1 Hz (baro-frequency), we hypothesized that the power spectral density (PSD) of short-term BP recordings in the baro-frequency range may predict daily variations of BP. In nine-week-old Wister-Kyoto male rats (N =5) with or without baroreflex dysfunction, we telemetrically recorded continuous BP for 24 hours and estimated PSD using Welch's periodogram for the recordings during the 12-hour light period. We compared the reference PSD of 12-hour recording with the PSDs obtained from shorter data lengths ranging from 5 to 240 minutes. The 30-minute BP recordings reproduced PSD of 12-hour recordingswell, and PSD in the baro-frequency range paralleled the standard deviation of 12-hour BP. Thus, the PSD of 30-minute BP reflects the daily BP variability in rats. In human subjects, we estimated PSD from 30-minute noninvasive continuous BP recordings. The rat and human PSDs shared remarkably similar characteristics. Furthermore, comparison of PSD between elderly and young subjects suggested that the baro-frequency range in humans overlapped with that in rats. In conclusion, PSD derived from 30-minute BP recordings is capable of predicting daily BP variations. Our proposed method may serve as a simple, noninvasive and practical tool for predicting cardiovascular events in the clinical setting.. |
| 29. |
Mutsunori Murahashi, Hisanobu Ogata, Toshihiko Okazaki, Yasuki Hijikata, Kazunari Yamada, Toshihisa Tsuruta, Junji Kishimoto, Kouta Funakoshi, Koji Todaka, Yoichi Nakanishi, Kenzaburo Tani, Investigator initiated clinical trial of cancer vaccine OCV-C01 in advanced and recurrent biliary tract cancer, ANNALS OF ONCOLOGY, 29, 2018.10. |
| 30. |
Koji Todaka, Junji Kishimoto, Masayuki Ikeda, Koji Ikeda, Haruko Yamamoto, Impact of Risk-Benefit Perception and Trust on Medical Technology Acceptance in Relation to Drug and Device Lag: A Tripartite Cross-Sectional Survey, Therapeutic Innovation & Regulatory Science, 10.1177/2168479017739267, 52, 5, 629-640, 2018.09, BACKGROUND: New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets. METHODS: A tripartite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included. RESULTS: Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US ( P |
| 31. |
Akiomi Yoshihisa, Takamasa Sato, Katsuya Kajimoto, Naoki Sato, Yasuchika Takeishi, Kuniya Asai, Ryo Munakata, Toshiyuki Aokage, Asuka Yoshida, Yuichiro Minami, Dai Yumino, Masayuki Mizuno, Erisa Kawada, Kentaro Yoshida, Yuri Ozaki, Tomohito Kogure, Shintaro Haruki, Koichi Nakao, Tadashi Sawamura, Toshiaki Nuki, Ryoji Ishiki, Shigeki Yokota, Hiroyuki Fujinaga, Takashi Yamamoto, Kenji Harada, Akihiro Saito, Norihito Kageyama, Takanobu Okumura, Noritake Hata, Koji Murai, Ayaka Nozaki, Hidekazu Kawanaka, Jun Tanabe, Yukihito Sato, Katsuhisa Ishii, Hitoshi Oiwa, Tomoaki Matsumoto, Daisuke Yoshida, Nobuo Kato, Hitoshi Oiwa, Daisuke Yoshida, Nobuo Kato, Hiroshi Suzuki, Nobuyuki Shimizu, Takehiko Keida, Masaki Fujita, Kentaro Nakamura, Toshiya Chinen, Kentaro Meguro, Tatsuro Kikuchi, Toshiyuki Nishikido, Marohito Nakata, Tatsuya Yamashita, Masaya Nakata, Akitoshi Hirono, Kazuaki Mitsudo, Kazushige Kadota, Noriko Makita, Nagisa Watanabe, Masaaki Kawabata, Kenichi Fuji, Shinichi Okuda, Shigeki Kobayashi, Ikuo Moriuchi, Kiyo-O Mizuno, Kazuo Osato, Tatsuaki Murakami, Yoshifumi Shimada, Katsushi Misawa, Hiromasa Kokado, Takashi Fujita, Yoshitomo Fukuoka, Syu Takabatake, Yoshifumi Takata, Manabu Miyagi, Nobuhiro Tanaka, Akira Yamashina, Shinji Sudo, Koichi Shimamura, Michitaka Nagashima, Tomoya Kaneda, Kosei Ueda, Hiromasa Kato, Toshinori Higashikata, Kanichi Fujimori, Hiroshi Kobayashi, Shinya Fujii, Masahiro Yagi, Jyunko Takaki, Eiji Yamashita, Takuji Toyama, Etsuo Hirata, Kazuho Kamisihima, Toshiaki Oka, Ryushi Komatsu, Akira Itoh, Takahiko Naruko, Yukio Abe, Eiichirou Nakagawa, Atsuko Furukawa, Naoto Kinou, Shoko Uematsu, Isao Tabuchi, Taku Imai, Takafumi Sakamoto, Koji Todaka, Yuji Koide, Koji Maemura, Koichiro Yoshioka, Akiomi Yoshihisa, Takamasa Sato, Yasuchika Takeish, Toshiaki Ebina, Kazuo Kimura, Masaaki Konishi, Masahiko Kato, Yoshiharu Kinugasa, Katsunori Ishida, Shinobu Sugihara, Kiyotaka Yanagihara, Toshiharu Takeuchi, Motoi Okada, Naoyuki Hasebe, Tetsuo Sakai, Taku Asano, Yoshino Minoura, Tsutomu Toshida, Takatoshi Sato, Yuya Yokota, Seita Kondo, Yasushi Sakata, Issei Komuro, Kinya Otsu, Shizuya Yamashita, Yoshihiro Asano, Atsuya Kajimoto, Kazunori Kashiwase, Yasunori Ueda, Aizo Kondo, Katsuhiro Kawaguchi, Akinori Sawamura, Taro Saito, Tom Higa, Hiroo Noguchi, Yoko Yanagita, Keita Nakamura, Tomo Komaki, Oshihiro Muramatsu, Tomomi Koizumi, Yoshie Nakajima, Toshihiko Kikutani, Yoshifimi Ikeda, Tom Tamaki, Shuhei Funada, Harumi Ogawa, Koichiro Sakuragawa, Shun Kohsaka, Shin-ichi Ando, Toshiaki Kadokami, Eiko Ishida, Katsumi Ide, Yohei Sotomi, Yoshiharu Higuchi, Motoko Uehara, Toshihiko Goto, Nobuyuki Ohte, Masanobu Miura, Nobuyuki Shiba, Kotaro Nochioka, Hiroaki Shimokawa, Shiro Ishihara, Tokushi Koga, Shinichiro Fujishima, Shigeru Kaseda, Yoshie Haga, Keisuke Kida, Kazuho Kamisihima, Makiko Nakamura, Osahiko Sunagawa, Takafumi Miyara, Youji Taba, Takashi Touma, Osamu Shinjo, Oshioki Nishimura, Kazuomi Kario, Hayato Shimizu, Takahiro Uchida, Ken-ichi Amitani, Katsunori Shimada, Heterogeneous impact of body mass index on in-hospital mortality in acute heart failure syndromes: An analysis from the ATTEND Registry, EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE, 10.1177/2048872617703061, 8, 7, 589-598, 2019.10, Background: Although the obesity paradox may vary depending upon clinical background factors such as age, gender, aetiology of heart failure and comorbidities, the reasons underlying the heterogeneous impact of body mass index (BMI) on in-hospital cardiac mortality under various conditions in patients with acute heart failure syndromes (AHFSs) remain unclear. Methods: Among 4617 hospitalised patients with AHFSs enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, the patient characteristics and in-hospital cardiac mortality rates in those with low BMI (BMI 25 kg/m(2), n = 1354). Results: Compared to the high-BMI group, the low-BMI group was significantly older, less likely to be male and to have hypertensive or idiopathic dilated aetiologies and more likely to have valvular aetiologies and a history of prior hospitalisation for AHFS. The low-BMI group also had lower prevalence rates of diabetes, dyslipidaemia, hypertension and atrial fibrillation and higher prevalence rates of anaemia and chronic obstructive pulmonary disease. In addition, cardiac mortality was significantly higher in the low-BMI group than in the high-BMI group (5.5 vs. 1.5%, p |
| 32. |
Mamoru Ito, Hitomi Kawaji, Makoto Kubo, Eiji Oki, Eiji Iwama, Takahiro Maeda, Masanobu Ogawa, Masayuki Ochiai, Sawako Shikada, Hidetaka Yamamoto, Maya Suzuki, Koji Todaka, Naoki Nakashima, Minako Yoshihara, Mikita Suyama, Eishi Baba, Koichi Akashi, Yoichi Nakanishi, Current progress and issues of cancer genomic medicine in Kyushu University Hospital, ANNALS OF ONCOLOGY, 10.1093/annonc/mdz343.086, 30, 2019.10. |
| 33. |
Toshio Hisatomi, Hiroshi Enaida, Shigeo Yoshida, Akito Hirakata, Masahito Ohji, Kohji Nishida, Toshiaki Kubota, Nahoko Ogata, Takaaki Matsui, Kazuhiro Kimura, Koh-Hei Sonoda, Makiko Uchiyama, Junji Kishimoto, Koji Todaka, Yoichi Nakanishi, Tatsuro Ishibashi, Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial, Japanese Journal of Ophthalmology, 10.1007/s10384-020-00763-y, 64, 5, 455-461, 2020.09, Purpose: To evaluate the safety and efficacy of BBG (Brilliant Blue G250) for lens capsular staining during cataract surgery with continuous curvilinear capsulorhexis. Study design: Prospective clinical study. Methods: This clinical trial enrolled 30 eyes of 30 patients who underwent cataract surgery with BBG (0.25 mg/mL Brilliant Blue G250) for capsular staining. Visualization of the lens capsule and the ease of capsulorhexis with BBG staining were evaluated in five grades (grade 0 to 4) by the Independent Data Monitoring Committee and the surgeons. The safety of BBG was also evaluated in terms of ocular and systemic tolerance for 7 days after surgery. Results: The use of BBG improved visualization of the lens capsule and complete capsulorhexis was performed in all patients. The major endpoint (Independent Data Monitoring Committee evaluation) showed that use of BBG improved visualization of the lens capsule and the ease of capsulorhexis (grades 2 to 4); the committee’s grading results were similar to those of the surgeons. Frequent complications observed in more than two eyes were conjunctival injection, corneal edema and intraocular pressure elevation. No severe complications were observed in ocular and systemic evaluations. Conclusion: BBG staining contributed to improved visualization of the lens capsule and aided in the completion of capsulorhexis during cataract surgery. The use of BBG for capsular staining also exhibited favorable safety results.. |
| 34. |
Kenichi Nakamura, Hitoshi Ozawa, Taro Shibata, Nobuko Ushirozawa, Tomomi Hata, Natsuko Okita, Nozomu Fuse, Norihiro Sato, Koji Ikeda, Hideki Hanaoka, Tatsuya Maruyama, Michihiko Wada, Shinobu Shimizu, Hiroi Kasai, Yoichi Yamamoto, Jun Sakurai, Koji Todaka, Shimon Tashiro, Haruko Yamamoto, Survey Results and Recommendations from Japanese Stakeholders for Good Clinical Practice Renovation, Therapeutic Innovation & Regulatory Science, 10.1007/s43441-021-00350-4, 56, 2, 220-229, 2021.11, Abstract
Background
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders.
Methods
A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public.
Results
The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP’s scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data.
Conclusion
The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.
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| 35. |
Mitsuru Arima, Hirosuke Inoue, Shintaro Nakao, Akiko Misumi, Maya Suzuki, Itsuka Matsushita, Shunsuke Araki, Chiemi Yamashiro, Kazumasa Takahashi, Masayuki Ochiai, Noriko Yoshida, Masayuki Hirose, Junji Kishimoto, Koji Todaka, Shunji Hasegawa, Kazuhiro Kimura, Koichi Kusuhara, Hiroyuki Kondo, Shouichi Ohga, Koh-Hei Sonoda, Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity, BMJ Open, 10.1136/bmjopen-2020-047003, 11, 7, 2021.07, Introduction Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP. Methods and analysisThis is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints. Ethics and disseminationThis study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. Trial registration numbersNCT04621136 and jRCT2071200047. . |
| 36. |
Takeshi Tohyama, Tomomi Ide, Masataka Ikeda, Hidetaka Kaku, Nobuyuki Enzan, Shouji Matsushima, Kouta Funakoshi, Junji Kishimoto, Koji Todaka, Hiroyuki Tsutsui, Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure, ESC Heart Failure, 10.1002/ehf2.13556, 8, 5, 4077-4085, 2021.10, Aims: Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy-to-use prediction model with high accuracy using the top predictors identified by the ML algorithm. Methods and results: Machine learning-based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow-up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy-to-use prediction model was developed based on these predictors. The c-statistics and Brier scores of the developed ML-based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD-VC) achieved the highest c-statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non-loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART-HF) was established as an easy-to-use prediction model. Compared with the conventional models, SMART-HF achieved a higher c-statistic {ACD-VC: 0.777 [95% confidence interval (CI) 0.751–0.803], SMART-HF: 0.765 [95% CI 0.739–0.791], SHFM: 0.713 [95% CI 0.684–0.742], MAGGIC: 0.726 [95% CI 0.698–0.753]} and better Brier scores (ACD-VC: 0.121, SMART-HF: 0.124, SHFM: 0.139, MAGGIC: 0.130). Conclusions: The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART-HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART-HF model has the clear merit of easy operability even by non-healthcare providers with a user-friendly online interface (https://hfriskcalculator.herokuapp.com/). Risk models developed using SMART-HF may provide a novel modality for risk stratification of patients with HF.. |
| 37. |
Satoko Oda, Kenji Ashida, Makiko Uchiyama, Shohei Sakamoto, Nao Hasuzawa, Ayako Nagayama, Lixiang Wang, Hiromi Nagata, Ryuichi Sakamoto, Junji Kishimoto, Koji Todaka, Yoshihiro Ogawa, Yoichi Nakanishi, Masatoshi Nomura, An Open-label Phase I/IIa Clinical Trial of 11β-HSD1 Inhibitor for Cushing’s Syndrome and Autonomous Cortisol Secretion, The Journal of Clinical Endocrinology & Metabolism, 10.1210/clinem/dgab450, 106, 10, e3865-e3880, 2021.09, Abstract
Context
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing’s syndrome (CS) and autonomous cortisol secretion (ACS) patients.
Objective
To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients.
Design
A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database.
Setting
Kyushu University Hospital, Kurume University Hospital, and related facilities.
Patients
Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance.
Intervention
Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks.
Main Outcome Measures
The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks.
Results
S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by −7.1% [SD, 14.8 (90% CI −14.8 to −1.0), P = 0.033] and −2.7% [14.5 (−10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by −2.5% [1.7 (−3.3 to −1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001].
Conclusions
S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients.
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| 38. |
Kiminori Kimura, Tatsuya Kanto, Shinji Shimoda, Kenichi Harada, Masamichi Kimura, Koji Nishikawa, Jun Imamura, Eiichi Ogawa, Masanao Saio, Yoshihiro Ikura, Takuji Okusaka, Kazuaki Inoue, Tetsuya Ishikawa, Ichiro Ieiri, Junji Kishimoto, Koji Todaka, Terumi Kamisawa, Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study, eBioMedicine, 10.1016/j.ebiom.2022.104069, 80, 2022.06, Background: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/β-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. Methods: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child–Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT 03620474). Findings: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. Interpretation: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted. Funding: AMED, Ohara Pharmaceutical. |
| 39. |
Kazuya Hosokawa, Kohtaro Abe, Junji Kishimoto, Yuko Kobayakawa, Koji Todaka, Yuichi Tamura, Koichiro Tatsumi, Takumi Inami, Nobutaka Ikeda, Yu Taniguchi, Shun Minatsuki, Toyoaki Murohara, Satoshi Yasuda, Keiichi Fukuda, Hiroyuki Tsutsui, Efficacy and safety of edoxaban in patients with chronic thromboembolic pulmonary hypertension: protocol for a multicentre, randomised, warfarin-controlled, parallel group trial-KABUKI trial, BMJ Open, 10.1136/bmjopen-2022-061225, 12, 7, 2022.07, Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent recurrence of PE and secondary in situ thrombus formation. Warfarin, a vitamin K antagonist, is commonly used for anticoagulation in CTEPH based on historical experience and evidence. The anticoagulant activity of warfarin is affected by food and drug interactions, requiring regular monitoring of prothrombin time. The lability of anticoagulant effect often results in haemorrhagic and thromboembolic complications. Thus, lifelong warfarin is a handicap in terms of safety and convenience. Currently, the use of direct oral anticoagulants (DOACs) in CTEPH has increased with the advent of four DOACs. The safety of DOACs is superior to warfarin, with less intracranial bleeding in patients with non-valvular atrial fibrillation and venous thromboembolism. Edoxaban, the latest DOAC, also has proven efficacy and safety for those diseases in two large clinical trials; the ENGAGE-AF trial and HOKUSAI-VTE trial. The present trial seeks to evaluate whether edoxaban is non-inferior to warfarin in preventing worsening of CTEPH. Methods and analysis The KABUKI trial (is an investigator-initiated, multicentre, phase 3, randomised, single-blind, parallel-group, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban versus warfarin (vitamin K Antagonist) in subjects with chronic thromBoembolic pUlmonary hypertension taking warfarin (vitamin K antagonIst) at baseline) is designed to prove the non-inferiority of edoxaban to warfarin in terms of efficacy and safety in patients with CTEPH. Ethics and dissemination This study is approved by the Institutional Review Board of each participating institution. The findings will be published in a peer-reviewed journal, including positive, negative and inconclusive results. Trial registration number NCT04730037. Protocol version This paper was written per the study protocol V.4.0, dated 29 January 2021.. |
| 40. |
Yasuhiro Nakano, Mitsutaka Yamamoto, Tetsuya Matoba, Shunsuke Katsuki, Soichi Nakashiro, Susumu Takase, Yusuke Akiyama, Takuya Nagata, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Makoto Usui, Kenji Sadamatsu, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Hiroyuki Tsutsui, Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial., Journal of atherosclerosis and thrombosis, 10.5551/jat.63507, 2022.12, AIM: Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial. METHODS: The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up. RESULTS: After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S ＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression. CONCLUSIONS: Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.. |
| 41. |
Yuko Kobayakawa, Koji Todaka, Yu Hashimoto, Senri Ko, Wataru Shiraishi, Junji Kishimoto, Jun ichi Kira, Ryo Yamasaki, Noriko Isobe, A novel quantitative indicator for disease progression rate in amyotrophic lateral sclerosis, Journal of the Neurological Sciences, 10.1016/j.jns.2022.120389, 442, 2022.11, Objective: The current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS). Methods: We used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n = 92) was used for external validation. Results: We derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p |
| 42. |
Arima M, Inoue H, Nakao S, Misumi A, Suzuki M, Matsushita I, Araki S, Yamashiro C, Takahashi K, Ochiai M, Yoshida N, Hirose M, Kishimoto J, Todaka K, Hasegawa S, Kimura K, Kusuhara K, Kondo H, Ohga S, Sonoda K. , Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity. , BMJ Open. , 10.1136/bmjopen-2020-047003. , 11, 7, e047003, 2021.07. |
| 43. |
Satoko Oda, Kenji Ashida, Makiko Uchiyama, Shohei Sakamoto, Nao Hasuzawa, Ayako Nagayama, Lixiang Wang, Hiromi Nagata, Ryuichi Sakamoto, Junji Kishimoto, Koji Todaka, Yoshihiro Ogawa, Yoichi Nakanishi, Masatoshi Nomura,
, An open-label phase Ⅰ/Ⅱ a clinical trial of 11β-HSD1 inhibitor for Cushing's syndrome and autonomous cortisol secretion
, J Clin Endocrinol Metab. , 10.1210/clinem/dgab450., 2021.07. |
| 44. |
Nakamura K, Ozawa H, Shibata T, Ushirozawa N, Hata T, Okita N, Fuse N, Sato
N, Ikeda K, Hanaoka H, Maruyama T, Wada M, Shimizu S, Kasai H, Yamamoto Y,
Sakurai J, Todaka K, Tashiro S, Yamamoto H., Survey Results and Recommendations from Japanese Stakeholders for Good Clinical Practice Renovation, Ther Innov Regul Sci. , 10.1007/s43441-021-00350-4., 17, 1-10, 2021.11. |
| 45. |
Hisatomi T, Enaida H, Yoshida S, Hirakata A, Ohji M, Nishida K, Kubota T, Ogata N, Matsui T, Kimura K, Sonoda KH, Uchiyama M, Kishimoto J, Todaka K, Nakanishi Y, Ishibashi T, Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial., Jpn J Ophthalmol. , 64, 5, 455-461, 2020.05. |
| 46. |
高尾結佳，角田千穂，木村真紀，戸高浩司, 研究者主導臨床試験に望まれる安全性情報の取扱いについて, 臨床薬理, 52, 1, 13-20, 2021.01. |
| 47. |
Hiroyuki Kinoshita, Hiroshi Mannoji, Keita Saku, Jumpei Mano, Tadayoshi Miyamoto Koji Todaka, Takuya Kishi, Shigehiko Kanaya, and Kenji Sunagawa, Power Spectral Analysis of Short-Term Blood Pressure Recordings for Assessing Daily Variations of Blood Pressure in Human, Conf Proc IEEE Eng Med Biol Soc., 10.1109/EMBC.2018.8513040, 2018, 3626-3629, 2018.07, Although daily variations of blood pressure (BP) predict cardiovascular event risk, their assessment requires ambulatory BP monitoring which hinders the clinical application of this approach. Since the baroreflex is a major determinant of BP variations, especially in the frequency range of 0.01-0.1 Hz (baro-frequency), we hypothesized that the power spectral density (PSD) of short-term BP recordings in the baro-frequency range may predict daily variations of BP. In nine-week-old Wister-Kyoto male rats (N = 5) with or without baroreflex dysfunction, we telemetrically recorded continuous BP for 24 hours and estimated PSD using Welch's periodogram for the recordings during the 12-hour light period. We compared the reference PSD of 12-hour recording with the PSDs obtained from shorter data lengths ranging from 5 to 240 minutes. The 30-minute BP recordings reproduced PSD of 12-hour recordings well, and PSD in the baro-frequency range paralleled the standard deviation of 12-hour BP. Thus, the PSD of 30-minute BP reflects the daily BP variability in rats. In human subjects, we estimated PSD from 30-minute noninvasive continuous BP recordings. The rat and human PSDs shared remarkably similar characteristics. Furthermore, comparison of PSD between elderly and young subjects suggested that the baro-frequency range in humans overlapped with that in rats. In conclusion, PSD derived from 30-minute BP recordings is capable of predicting daily BP variations. Our proposed method may serve as a simple, noninvasive and practical tool for predicting cardiovascular events in the clinical setting.. |
| 48. |
Nakano K, Matoba T, Koga JI, Kashihara Y, Fukae M, Ieiri I,
Shiramoto M, Irie S, Kishimoto J, Todaka K, Egashira K., Safety, Tolerability, and Pharmacokinetics of NK-104-NP., Int Heart J, 10.1536/ihj.17-555, 59, 5, 1015-1025, 2018.09. |
| 49. |
戸高 浩司, Junji Kishimoto, Masayuki Ikeda, Koji Ikeda, Haruko Yamamoto, Impact of Risk-Benefit Perception and Trust on Medical Technology Acceptance in Relation to Drug and Device Lag: A Tripartite Cross-Sectional Survey, Therapeutic Innovation & Regulatory Science, 10.1177/2168479017739267, 52, 5, 629-640, First Published November 29, 2017, 2018.09, Background: New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets. Methods: A tri- partite cross-sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included. Results: Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US (P < .01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as “useful,” “acceptable,” and “trustworthy,” whereas Japan was clustered with intermediate to negative responses such as “neither” and “untrustworthy.” Conclusions: Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan.. |
| 50. |
木村 公則, 戸高 浩司, Nakanishi Y, Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/β-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial., EBioMedicine, 10.1016/j.ebiom.2017.08.016, 23, 79-87, 2017.09, BACKGROUND:
There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis.
METHODS:
In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440).
FINDINGS:
Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort.
INTERPRETATION:
This study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort.
FUNDING SOURCE:
AMED.. |
| 51. |
西川 拓也, 朔 啓太, 戸高 浩司, Hiroyuki Tsutsui, Sunagawa K, The challenge of magnetic vagal nerve stimulation for myocardial infarction -preliminary clinical trial., Conf Proc IEEE Eng Med Biol Soc., 10.1109/EMBC.2017.8037812, 2017, 4321-4324, 2017.07, Numerous studies have shown in animal models that vagal nerve stimulation (VNS) strikingly reduces infarct size of acute myocardial infarction (AMI) and prevents heart failure. However, the lack of techniques to noninvasively stimulate the vagal nerve hinders VNS from clinical applications. Transcranial magnetic stimulation is noninvasive and capable of stimulating central neurons in patients. In this study, we examined whether the magnetic stimulation could noninvasively activate the cervical vagal nerve in healthy human. Sixteen healthy males and 4 females were enrolled in this study. We used Magstim Rapid2 with a 70-mm double coil in the right neck. We randomly assigned the subjects to 5 Hz or 20 Hz stimulation. We defined the maximum intensity of stimulation (MAX) which is the intensity just below the threshold of adverse effects. We defined HALF as a half of MAX. Protocols comprised 2 sets of MAX and 2 sets of HALF. Each stimulation continued for 3 minutes. We monitored heart rate (HR) and assessed the bradycardic response as an index of successful VNS. Nineteen subjects completed all protocols. They had no problematic adverse events during and/or after magnetic VNS. The magnetic VNS induced transient bradycardic responses in some subjects, whereas failed to induce sustained bradycardia in pooled data in any settings. Arterial pressure did not change either. Successful magnetic stimulation requires technical improvements including narrowing the magnetic focus and optimization of stimulation site. These improvements may enable us to apply magnetic VNS in the management of AMI.. |
| 52. |
Takase S, Tetsuya Matoba, Nakashiro S, Yasushi Mukai, Inoue S, Keiji Oi, Taiki Higo, Katsuki S, Takemoto M, Suematsu N, Eshima K, Miyata K, Yamamoto M, Usui M, Sadamatsu K, Satoh S, Kadokami T, Hironaga K, 戸高 浩司, Ezetimibe in Combination with Statins Ameliorates Endothelial Dysfunction in Coronary Arteries after Stenting: The CuVIC Trial, a Multicenter Randomized Controlled Trial, Arterioscler Thromb Vasc Biol., ３７, 2, 350-358, 2017.02. |
| 53. |
清水公治, 伊藤達也, 岩江荘介, 大守伊織, 倉田真由美, 住谷昌彦, 戸高 浩司, 村山敏典, 山本晴子, 川上浩司, 医療機器を用いた臨床研究実施に関するアンケート調査結果, 医療機器学, ８６, 5, 482-488, 2016.05. |
| 54. |
江内田 寛, 平形 明人, 大路 正人, 西田 幸二, 久保田 敏昭, 緒方 奈保子, 園田 康平, 内山 麻希子, 岸本 淳司, 戸高 浩司, 中西 洋一, 石橋 達朗, A0001（ブリリアントブルーG250）の内境界膜染色と剝離に対する有効性と安全性の検討―多施設共同第III相医師主導治験, 日眼会誌, 120, 6, 439-448, 2016.05. |
| 55. |
戸高 浩司, 臨床研究と開発：Academic Research Organizationの役割, 日本外科学会雑誌, 117, 3, 233-235, 2016.05. |
| 56. |
荻原 俊男, 戸高 浩司, 恋田 直子, イルベサルタン/トリクロルメチアジド配合錠(S-474474)の有効性と安全性の検討― 本態性高血圧症患者を対象とした多施設共同長期投与試験, 血圧, 20, 8, 101-115, 2013.08. |
| 57. |
Uchida T, Ikeno F, Ikeda K, Suzuki Y, 戸高 浩司, Yokoi H, Thompson G, Krucoff M, Saito S, Global Cardiovascular Device Innovation: Japan-USA Synergies., Circ J, 77, 1714-1718, 2013.07, Background: Global medical devices have become more popular, but investment money for medical device development is not easily available in the market. Worldwide health-care budget constraints mean that efficient medical device development has become essential. To achieve efficient development, globalization is a key to success. Spending large amounts of money in different regions for medical device development is no longer feasible. Methods and Results: In order to streamline processes of global medical device development, an academic, governmental, and industrial consortium, called the Harmonization by Doing program, has been set up. The program has been operating between Japan and the USA since 2003. The program has 4 working groups: (1) Global Cardiovascular Device Trials; (2) Study on Post-Market Registry; (3) Clinical Trials; and (4) Infrastructure and Methodology Regulatory Convergence and Communication. Each working group has as its goals the achievement of speedy and efficient medical device development in Japan and the USA. The program has held multiple international meetings to deal with obstacles against efficient medical device development. Conclusions: This kind of program is very important to deliver novel medical devices. Involvement of physicians in this type of activity is also very helpful to achieve these goals.. |
| 58. |
荻原 俊男, 戸高 浩司, 恋田 直子, イルベサルタン/トリクロルメチアジド配合錠(S-474474)の有効性と安全性の検討― イルベサルタン 200 mg 配合剤の優越性検証試験, 血圧, 20, 6, 101-114, 2013.06. |
| 59. |
川上浩司, 中里適, 北川雄光, 清水公治, 田上和夫, 戸高 浩司, 松田公志, 山本晴子, 「未承認医療機器を用いた臨床研究実施の手引き」抜粋版, 薬理と治療, 40, (suppl-1), ５０４８-５０５２, 2012.03. |
| 60. |
戸高浩司, 日本の新薬開発は特殊なのか？, Jpn J Clin Pharmacol Ther (臨床薬理), 37(4): 69S-70S, 2006.01. |
| 61. |
Koji Todaka, Do we need combination products?, J Clin Therap Med（臨床医薬）, 22: 661-668, 2006.01. |
| 62. |
佐瀬一洋、米本直裕、戸高浩司, 予測予防対応型の医薬品安全監視計画, Jpn Pharmacol Ther（薬理と治療）, 33(9): 883-891, 2005.01. |
| 63. |
戸高浩司, GRP：日本における薬剤開発のインフラとしての医師の役割, 臨床評価, 31(3):567-571, 2004.01. |
| 64. |
戸高浩司, Review of Bridging Programs, Regulatory Successes, 臨床評価, 31(supp XX):55-66, 2004.01. |
| 65. |
Shimizu J, Todaka K, Burkhoff D, Load dependence of ventricular performance explained by model of calcium-myofilament interactions, American Journal of Physiology, 2002 Mar;282(3):H1081-91, 2002.03. |
| 66. |
Todaka K, Wang J, Yi GH, Gu A, Zhu SM, Zhang H, Burkhoff D, Effect of BAY y 5959 on myocardial function and metabolism in normal and failing hearts., American Journal of Physiology, 274(5 Pt 2):H1560-8, 1998.05. |
| 67. |
Todaka K, Ogino K, Gu A, Burkhoff D, Effect of ventricular stretch on contractile strength, calcium transient, and cAMP in intact canine hearts, American Journal of Physiology, 274, 3, H990-H1000, 274(3 Pt 2):H990-1000, 1998.03. |
| 68. |
Todaka K, Wang J, Yi GH, Knecht M, Stennett R, Packer M, Burkhoff D, Impact of exercise training on ventricular properties in a canine model of congestive heart failure., American Journal of Physiology, 272(3 Pt 2):H1382-90, 1997.03. |
| 69. |
Dickstein ML, Todaka K, Burkhoff D, Left-to-right systolic and diastolic ventricular interactions are dependent on right ventricular volume., American Journal of Physiology, 272(6 Pt 2):H2869-74, 1997.06. |
| 70. |
Todaka K, Leibowitz D, Homma S, Fisher PE, DeRosa C, Stennett R, Packer M, Burkhoff D, Characterizing ventricular mechanics and energetics following repeated coronary microembolization., American Journal of Physiology, 272(1 Pt 2):H186-94, 1997.01. |
| 71. |
Todaka K, Jiang T, Chapman JT, Gu A, Zhu SM, Herzog E, Hochman JS, Steinberg SF, Burkhoff D, Functional consequences of acute collagen degradation studied in crystalloid perfused rat hearts., Basic Research in Cardiology, 92(3):147-58, 1997.06. |
| 72. |
Todaka K, Wang J, Yi GH, Stennett R, Knecht M, Packer M, Burkhoff D, Effects of levosimendan on myocardial contractility and oxygen consumption., Journal of Pharmacology & Experimental Therapeutics, 279(1):120-7, 1996.10. |
