[Idiosyncratic drug toxicity].
Explore the source record for details and available documents.
Adverse Drug Reaction Reporting Systems↗
Biomedical subjects
Jun-ichi Yamaguchi
Publications and source records attributed to Jun-ichi Yamaguchi.
A large-scale prospective cohort study on the current status of therapeutic modalities for acute myocardial infarction in Japan: rationale and initial results of the HIJAMI Registry.
BACKGROUND: In Western countries, several multicenter collaborative studies on acute myocardial infarction (AMI) have provided much information about this disease. In Japan, on the other hand, there have been few cohort studies in which a sufficient number of Japanese patients with AMI were registered during a short period. This fact explains the absence of a database from which strategies for treating Japanese patients with AMI could be established. The purpose of this study was to build a comprehensive database on Japanese patients with AMI to elucidate their characteristics. METHODS: Between January 1999 and June 2001, we consecutively registered all patients with AMI who were admitted to 17 participating medical institutions, including The Heart Institute of Japan, Cardiology (HIJC), Tokyo Women's Medical University. A standardized case report form was used to register all the patients. RESULTS: A total of 3,021 consecutive patients was registered (2,136 men, 70.7%; 885 women, 29.3%) with a median age of 69 years [59, 77]. Among the patients, there were 851 elderly individuals (28.2%) > or = 76 years and 1102 patients with diabetes (36.5%). On index electrocardiogram, ST-elevation myocardial infarction was observed in 2,392 patients (79.2%). Within 24 hours after the onset of AMI, coronary angiography was conducted for 2,177 patients (72.1%). Primary percutaneous coronary intervention and coronary thrombolysis were conducted for 1,755 (58.1%) and 491 patients (16.3%), respectively, and percutaneous coronary intervention or coronary artery bypass grafting was additionally carried out in 303 patients. By the time of discharge, coronary angiography and coronary artery bypass grafting were performed in 2,659 (88.0%) and 137 patients (4.5%), respectively. During initial hospitalization, 285 patients died and the overall inhospital mortality rate was 9.4%. During hospitalization, cardiogenic shock and cardiac rupture were observed in 6.1% and 2.8% of the patients, respectively. The inhospital mortality rate is still high in patients with AMI with such mechanical complications and in elderly patients. CONCLUSION: In our prospective cohort, we showed that Japanese patients with AMI could be characterized as (1) having a disease severity comparable with values observed in Western populations and (2) receiving early reperfusion therapy by PCI, which was used widely and safely, but nevertheless (3) exhibiting a high inhospital mortality rate. Our data indicate that further improvements in therapy for AMI in elderly patients and for AMI with mechanical complications are essential in Japan.
Aged↗
ATC0175: an orally active melanin-concentrating hormone receptor 1 antagonist for the potential treatment of depression and anxiety.
Melanin-concentrating hormone (MCH) has been implicated in a variety of physiological events. Recent studies clearly suggest that MCH plays an important role in the regulation of stress and emotion. To date, two receptor subtypes of MCH (MCH1R and MCH2R) have been identified. MCH1R has been suggested to mediate most of the physiological functions of MCH. Recently, we synthesized an orally active, nonpeptidic antagonist of MCH1R, N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride (ATC0175). This compound is a potent antagonist with a high affinity for MCH1R and additional affinities for 5-HT1A and 5-HT2B receptors. The receptor binding and the functional assay (MCH-induced increase in [Ca2+]i) indicated that ATC0175 is a noncompetitive antagonist at MCH1Rs. ATC0175 exhibited anxiolytic effects in numerous animal models of anxiety including the elevated plus-maze test, social interaction test, stress-induced hyperthermia and maternal separation-induced vocalization. Like with other stress-related peptide receptor antagonists, such as antagonists of corticotropin-releasing factor or vasopressin V1b receptor antagonists, anxiolytic effects of ATC0175 were more pronounced in models containing a stress component. ATC0175 also exhibited antidepressant effects in the forced swimming test. ATC0175 increased swimming performance without altering climbing behavior, as observed with selective serotonin reuptake inhibitors. ATC0175 has adequate ADME profile (reasonable oral bioavailability and brain penetration) and potent oral activity in animal models. In contrast, ATC0175 did not affect spontaneous locomotor activity, hexobarbital-induced sleeping time and did not impair rotarod performance. Thus, ATC0175 may be devoid of unwanted central nervous system side effects, which are sometimes observed with current medications. In addition, ATC0175 was well tolerated in rat repeated toxicity study, and had no genotoxic liability. Therefore, ATC0175 has the potential to be effective in the treatment of patients with depression and/or anxiety disorders.
Animals↗
Prognostic significance of serum creatinine concentration for in-hospital mortality in patients with acute myocardial infarction who underwent successful primary percutaneous coronary intervention (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] Registry).
This study evaluated the impact of serum creatinine levels on in-hospital mortality in 1,359 consecutive patients with acute myocardial infarction (from a Japanese prospective multicenter registry) who underwent successful primary percutaneous coronary intervention (PCI). Even in the patients who underwent successful primary PCI, the in-hospital mortality of patients with mild (1.2 </= creatinine < 2.0 mg/dl) and severe (creatinine >/=2.0 mg/dl) renal dysfunction was greater (17.1% and 34.5%, respectively) than that of patients without renal dysfunction (3.9%) (relative risk [RR] 1.72, 95% confidence interval [CI] 0.94 to 3.14, p = 0.080; and RR 4.26, 95% CI 1.48 to 12.27, p <0.0001, respectively).
Aged↗
Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization.
BACKGROUND: Stromal cell-derived factor-1 (SDF-1) is a chemokine considered to play an important role in the trafficking of hematopoietic stem cells. Given the close relationship between hematopoietic stem cells and endothelial progenitor cells (EPCs), we investigated the effect of SDF-1 on EPC-mediated vasculogenesis. METHODS AND RESULTS: Flow cytometric analysis demonstrated expression of CXCR4, the receptor of SDF-1, by 66+/-3% of EPCs after 7 days in culture. In vitro modified Boyden chamber assay showed a dose-dependent EPC migration toward SDF-1 (control versus 10 ng/mL SDF-1 versus 100 ng/mL SDF-1, 24+/-2 versus 71+/-3 versus 140+/-6 cells/mm2; P<0.0001). SDF-1 attenuated EPC apoptosis (control versus SDF-1, 27+/-1 versus 7+/-1%; P<0.0001). To investigate the effect of SDF-1 in vivo, we locally injected SDF-1 into athymic ischemic hindlimb muscle of nude mice combined with human EPC transplantation to determine whether SDF-1 augmented EPC-induced vasculogenesis. Fluorescence microscopic examination disclosed increased local accumulation of fluorescence-labeled EPCs in ischemic muscle in the SDF-1 treatment group (control versus SDF-1=241+/-25 versus 445+/-24 cells/mm2, P<0.0001). At day 28 after treatment, ischemic tissue perfusion was improved in the SDF-1 group and capillary density was also increased. (control versus SDF-1, 355+/-26 versus 551+/-30 cells/mm2; P<0.0001). CONCLUSION: These findings indicate that locally delivered SDF-1 augments vasculogenesis and subsequently contributes to ischemic neovascularization in vivo by augmenting EPC recruitment in ischemic tissues.
Animals↗
Metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenyl-ethoxy)-phenyl]-ethyl-amine-monohydrochloride (NE-100), a novel sigma ligand: contribution of cytochrome P450 forms involved in the formation of individual metabolites in human liver and small intestine.
In the present study, human cytochrome P450 (CYP) forms involved in producing the primary metabolites of NE-100 were identified. Major metabolites of NE-100 in human liver microsomes (HLM) were N-depropylation of NE-100 (NE-098), p-hydroxylation of phenyl group of NE-100 (NE-152), m-hydroxylation of phenyl group of NE-100 (NE-163) and O-demethylation of NE-100 (NE-125). Judging from the correlation and inhibition studies, NE-125 and NE-152+163mix formations were predominantly mediated by CYP2D6 and NE-098 formation was mediated by multiple CYP forms at a low NE-100 concentration (0.1 microM) in the HLM. According to relative activity factor (RAF) approaches, all these reactions were predominantly catalyzed by CYP2D6 at a substrate concentration assuming a plasma level of NE-100 (K(m)>>S) in case of the human liver. Depending on the increase in NE-100 concentrations, the rate of contribution for NE-098 and NE-152+163mix formations increased in CYP3A4, although the predominant contribution of CYP2D6 for NE-125 formation did not change. In human intestinal microsomes (HIM), NE-100 was mainly metabolized to NE-098 and NE-152+163mix by CYP3A4. The intrinsic clearance for their formations in HIM was 3.2 and 14.9 times less than those in HLM, respectively, and no formation of NE-125 was observed in HIM. These results strongly suggest that CYP2D6 is the predominant form for NE-100 metabolism in the human liver in in vivo conditions (K(m)>>S) and the liver plays a more important role than does the small intestine in the first pass metabolism.
Journal Article↗
Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration.
BACKGROUND: Previous studies have established that bone marrow-derived endothelial progenitor cells (EPCs) are present in the systemic circulation. In the current study, we investigated the hypothesis that gene transfer can be used to achieve phenotypic modulation of EPCs. METHODS AND RESULTS: In vitro, ex vivo murine vascular endothelial growth factor (VEGF) 164 gene transfer augmented EPC proliferative activity and enhanced adhesion and incorporation of EPCs into quiescent as well as activated endothelial cell monolayers. To determine if such phenotypic modulation may facilitate therapeutic neovascularization, heterologous EPCs transduced with adenovirus encoding VEGF were administered to athymic nude mice with hindlimb ischemia; neovascularization and blood flow recovery were both improved, and limb necrosis/autoamputation were reduced by 63.7% in comparison with control animals. The dose of EPCs used for the in vivo experiments was 30 times less than that required in previous trials of EPC transplantation to improve ischemic limb salvage. Necropsy analysis of animals that received DiI-labeled VEGF-transduced EPCs confirmed that enhanced EPC incorporation demonstrated in vitro contributed to in vivo neovascularization as well. CONCLUSIONS: In vitro, VEGF EPC gene transfer enhances EPC proliferation, adhesion, and incorporation into endothelial cell monolayers. In vivo, gene-modified EPCs facilitate the strategy of cell transplantation to augment naturally impaired neovascularization in an animal model of experimentally induced limb ischemia.
Adenoviridae↗