Biomedical subjects

Manabu Itoh

Publications and source records attributed to Manabu Itoh.

12 recordsLinked to original sources

PubMed2006

Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats.

M58373, 4-[2-(4-hydroxy-4-{[N-(4-isopropoxyphenyl)-N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1-10 microM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3-10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1-10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10-100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.

Analgesics↗

PubMed2006

Aortic dissection late after aortic valve replacement.

We experienced 3 cases of an aortic dissection occurring late after an aortic valve replacement, and successfully treated by an aortic root replacement. An aortic dissection involving the ascending aorta can develop late after an aortic valve replacement, and such an occurrence is associated with a high mortality and morbidity. The development of effective surgical strategies at the initial aortic valve surgery, strict control of blood pressure after aortic valve replacement, serial evaluations of aortic size, and the prophylactic replacement of the ascending aorta for patients with aortic dilatation after aortic valve replacement, all play clinically important roles in preventing an aortic dissection after aortic valve replacement. When an aortic dissection occurs in patients with a previous aortic valve replacement, an aortic root replacement should be performed in order to avoid leaving the fragile diseased aortic wall including the sinus of Valsalva.

Adult↗

PubMed2006

Perioperative coronary artery spasm in off-pump coronary artery bypass grafting and its possible relation with perioperative hypomagnesemia.

PURPOSE: We experienced 3 cases of serious perioperative coronary artery spasm in off-pump coronary artery bypass grafting (OPCAB). In consideration of the causes, we directed our attention to hypomagnesemia, one of the triggers of coronary artery spasm. This study was performed to confirm the tendency to hypomagnesemia in OPCAB. METHODS: First, we report 3 patients having severe coronary artery spasm immediately after OPCAB with consideration of the causes. Second, serial magnesium (Mg) value (xylidyl blue method, normal 1.9-3.1 mg/dl) was measured in 45 consecutive patients with OPCAB between April and October 2002, 1) before starting the operation, and 2) after the patient's entrance into the intensive care unit. RESULTS: Preoperative and postoperative values of Mg (mg/dl) were 2.1+/-0.3, 1.7+/-0.3, respectively (p < 0.01). Postoperative incidence of hypomagnesemia was as high as 89% of the patients (40 out of 45 patients). In this study and thereafter, we corrected hypomagnesemia with magnesium sulfate during and after OPCAB, and no perioperative coronary artery spasm occurred. CONCLUSION: Hypomagnesemia, one of the triggers of coronary artery spasm, is very common in OPCAB. We strongly recommend the correction of hypomagnesemia during and after OPCAB for the prevention of perioperative coronary artery spasm.

Adult↗

PubMed2005

Three-dimensional recovery time dispersion map by 64-channel magnetocardiography may demonstrate the location of a myocardial injury and heterogeneity of repolarization.

BACKGROUND: QT dispersion reveals heterogeneities in the repolarization time in the three-dimensional (3D) structure of the ventricular myocardium. In this study, we report on a 3D function map of recovery time (RT) dispersions as measured by 64-channel magnetocardiography (MCG). METHODS: MCG were simultaneously recorded in 29 controls and 21 patients with previous myocardial infarction (MI). The 3D current density was calculated from 64-channel MCG data in the Bz component using a space filter. The heart outline, reconstructed from the integrated the current density, revealed both the atrium and ventricle. The RT for the intervals between QRS onset and the time of the maximum dT/dt of T wave, and the peak to the end of the T wave (T(peak)-negative dT/dt) were automatically measured by means of a computer from 3D MCG data. The corrected RT (RTc) and corrected T(peak)-negative dT/dt were then calculated using Bazett's formula. The 3D RTc and the corrected T(peak)-negative dT/dt dispersion map were superimposed on the heart outline generated by MCG. RESULTS: The RTc was significantly longer for the MI group than in the control group (67+/-25 ms1/2 vs. 16+/-6 ms1/2) (p<0.0001). The corrected T(peak)-negative dT/dt dispersions in each patient was also significantly longer for the MI group than in the control group (35+/-27 ms1/2 vs. 10+/-5 ms1/2) (p<0.0001). Furthermore, the 3D RTc and T(peak)-negative dT/dt dispersion maps corresponded with the space location of MI, as defined by Tc-99m tetrofosmin myocardial imaging CONCLUSIONS: 3D RTc and T(peak)-negative dT/dt dispersion maps in the ST segment, obtained by 64-channel MCG may be used demonstrate the location of a myocardial injury and heterogeneities of repolarization.

Adult↗

PubMed2005

Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of alpha-ketoglutarate decarboxylase.

Mycobacterium tuberculosis (Mtb) has adapted its metabolism for persistence in the human macrophage. The adaptations are likely to involve Mtb's core intermediary metabolism, whose enzymes have been little studied. The tricarboxylic acid cycle is expected to yield precursors for energy, lipids, amino acids, and heme. The genome sequence of Mtb H37Rv predicts the presence of a complete tricarboxylic acid cycle, but we recently found that alpha-ketoglutarate dehydrogenase (KDH) activity is lacking in Mtb lysates. Here we showed that citrate synthase, aconitase, isocitrate dehydrogenase, fumarase, malate dehydrogenase, and succinate dehydrogenase, but not KDH, are present, raising the possibility of separate oxidative and reductive half-cycles. As a potential link between the half-cycles, we found that Rv1248c, annotated as encoding SucA, the putative E1 component of KDH, instead encodes alpha-ketoglutarate decarboxylase (Kgd) and produces succinic semialdehyde. Succinic semialdehyde dehydrogenase activity was detected in Mtb lysates and recapitulated with recombinant proteins GabD1 (encoded by Rv0234c) and GabD2 (encoded by Rv1731). Kgd and GabD1 or GabD2 form an alternative pathway from alpha-ketoglutarate to succinate. Rv1248c, which is essential or required for normal growth of Mtb [Sassetti, C., Boyd, D. H. & Rubin, E. J. (2003) Mol. Microbiol 48, 77-84] is the first gene shown to encode a Kgd. Kgd is lacking in humans and may represent a potential target for chemotherapy of tuberculosis.

Bacterial Proteins↗

PubMed2005

Construction of a three-dimensional outline of the heart and conduction pathway by means of a 64-channel magnetocardiogram in patients with atrial flutter and fibrillation.

BACKGROUND: Magnetocardiography (MCG) has the potential for collecting three-dimensional (3D) intracardiac electric information, because the magnetic field is unaffected by the shape of the lungs and torso. In the present study, we report on the generation of a 3D heart outline and conduction pathway by means of a current density map using a 64-channel SQUID system, and an evaluation of its significance in patients with atrial flutter (AFL) and atrial fibrillation (AFIB). METHODS: The subjects consisted of 20 healthy volunteers, and 3 patients with AFL and 4 patients with AFIB. A 64-channel MCG was recorded after digitization at 500 Hz, and a 3D current density was reconstructed from the magnetic fields using a space filter in conjunction with the minimum normalization method of Tikhonov. A 3D heart outline was generated from the integrated current density by the space filter. The conduction pathway was superimposed on a heart outline generated by a magnetic field. The heart outline was verified by the silhouette on the magnetic resonance (MR) images. An MCG was recorded pre- and post interventional therapy, and therapeutic efficacy was evaluated. RESULTS: The 3D heart outline of the atrium and ventricle corresponded to the silhouette of the right atrium and left ventricle, respectively, on an MR image. The serial conduction pathway of the QRS segment superimposed on the 3D heart outline map demonstrated the conduction pattern generated within the heart. The MCG revealed a counter-clockwise rotation in patients with AFL, and random micro-reentry in the case of AFIB. After interventional therapy, restoration of the sinus rhythm was verified in patients with both AFL and AFIB. CONCLUSIONS: A 64-channel MCG was used to evaluate the 3D heart outline and conduction pathway in patients with AFL and AFIB without the need for MR images. Condensed Abstract A 64-channel MCG was used to evaluate the 3D heart out line and conduction pathway in patients with AFL and AFIB.

Aged↗

PubMed2004

Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists.

Novel group II metabotropic glutamate receptor (mGluR) antagonists, 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, were discovered by the incorporation of a hydroxy or alkoxyl group onto the C-3 portion of selective and potent group II mGluR agonist 5, (1R,2S,5R,6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Among these compounds, (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (-)-11be (MGS0039) was a highly selective and potent group II mGluR antagonist with the best pharmacokinetic profile. Compound (-)-11be exhibited high affinities for mGlu 2 (Ki = 2.38 +/- 0.40 nM) and mGlu 3 (4.46 +/- 0.31 nM) but low affinity for mGluR 7 (Ki = 664 +/- 106 nM), and potent antagonist activities for mGlu 2 (IC50 = 20.0 +/- 3.67 nM) and mGluR 3 (IC50 = 24.0 +/- 3.54 nM) but much less potent antagonist activities for mGlu 4 (IC50 = 1740 +/- 1080 nM), mGlu 6 (IC50 = 2060 +/- 1270 nM), mGlu 1 (IC50 = 93300 +/- 14600 nM), and mGluR 5 (IC(50) = 117000 +/- 38600 nM). No significant agonist activities of (-)-11be were found for mGluRs 2, 3, 4, 6, 1, and 5 (EC50 > 100,000 nM). Furthermore, (-)-11be exhibited dose-dependent oral absorption (plasma C(max): 214 +/- 56.7, 932 +/- 235, and 2960 +/- 1150 ng/mL for 3 mg/kg, 10 mg/kg, and 30 mg/kg, po, respectively) and acceptable blood-brain barrier penetration (brain C(max): 13.2 ng/mL for 10 mg/kg, p.o. 6 h). In this paper, we report the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives 11 and 12, and pharmacokinetic profiles of several typical compounds.

Administration, Oral↗

PubMed2004

New application method of fibrin glue for more effective hemostasis in cardiovascular surgery: rub-and-spray method.

OBJECTIVE: This study was performed to determine the most effective application method of fibrin glue as a hemostatic sealant in cardiovascular surgery. METHODS: The effectiveness of fibrin glue as a hemostatic sealant was compared between 4 methods of application; dripping, spray, spray-and-rub, and rub-and-spray methods. I. In vitro 'burst pressure' was measured in fibrin glue-sealed needle holes of polytetrafluoroethylene (PTFE) graft in each method. II. Fibrin glue-sealed needle holes of PTFE grafts implanted between an abdominal aorta and iliac arteries of a pig was microscopically examined to determine the effectiveness of fibrin glue sealing in each method. RESULTS: I. Burst pressures were 24.1 +/- 7.9 mmHg in dripping, 98.1 +/- 35.4 mmHg in spray, 140.8 +/- 34.8 mmHg in spray-and-rub and 206.7 +/- 26.1 mmHg in rub-and-spray method (statistically significant, p<0.01, between each method). II. Microscopically, no fibrin glue remained on the external surface of the PTFE graft in the dripping method. Fibrin glue plugged 1/3 or 2/3 of the depth of the needle hole in the spray method and spray-and-rub methods respectively. In the rub-and-spray method, fibrin glue covered the needle hole over the external surface of the graft, completely plugged the needle hole to its whole depth, leaving no spaces where blood came into the needle hole. CONCLUSION: The rub-and-spray method of fibrin glue application revealed the strongest sealing and hemostatic effects, and can be safely and effectively used for hemostasis in cardiovascular surgery that requires systemic heparinization or prolonged extracorporeal circulation.

Administration, Topical↗

PubMed2003

Off-pump coronary artery bypass grafting in octogenarians.

OBJECTIVES: Off-pump coronary artery bypass grafting (CABG) has become accepted for myocardial revascularization because it reduces perioperative morbidity. We assessed the safety and efficacy of bypass surgery on the beating heart in elderly patients. METHODS: Off-pump CABG was done in 25 patients aged 80 years or older between February 1996 and February 2001. We retrospectively compared clinical results for these patients to those of 18 consecutive age-matched patients undergoing on-pump CABG during the same period. RESULTS: Mean patient age in both groups was similar--82.2 +/- 2.3 years in the off-pump group vs 81.9 +/- 2.0 years in the on-pump group (p = 0.66). Preoperative risk was similar in both groups, but significantly more patients in the on-pump group had triple-vessel disease. Distal anastomoses were significantly fewer in the off-pump group than in the on-pump group at 2.0 +/- 1.0 vs 2.8 +/- 0.5 (p < 0.01). The off-pump group had a shorter postoperative ventilation--13.4 +/- 17.2 hours vs 45.2 +/- 52.8 hours (p < 0.05)--, and less blood transfused--16% vs 89% (p < 0.01)--than the on-pump group. Mean postoperative hospitalization and intensive care unit stay were 18.6 days and 3.2 days in the off-pump group, versus 37.1 days and 9.4 days in the on-pump group (p < 0.05). No difference was seen in the incidence of major postoperative complications between groups. No hospital deaths occurred in the off-pump group. CONCLUSION: Off-pump CABG is thus a safe and effective for myocardial revascularization in the elderly.

Aged↗

PubMed2003

[A clinical study of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for liver metastases].

We followed patients who underwent hepatic arterial infusion chemotherapy (HAI) with 5-FU and Leucovorin for liver metastases. Since CR (complete response) and PR (partial response) were achieved, this therapy seems to be effective. 5-FU metabolized on its first pass through the liver, and the hepatic extraction with rapid HAI is lower than that with slow HAI. It is suggested that control of extrahepatic lesions thought rapid HAI is useful for life prolongation.

Aged↗

PubMed2002

Assessment of ascending aorta using epiaortic ultrasonography during off-pump coronary artery bypass grafting.

BACKGROUND: Use of an aortic partial clamp for proximal anastomosis during off-pump coronary artery bypass is known to increase the risk of fatal complications. The purpose of this study was to assess the management of the ascending aorta evaluated with epiaortic ultrasonography during off-pump coronary artery bypass. METHODS: Intraoperative ultrasonography of the ascending aorta with a 10-MHz probe was performed consecutively in 155 patients undergoing off-pump coronary artery bypass between August 1999 and July 2001. The findings from ultrasonography, surgical modifications, and operative results were analyzed. RESULTS: In 54 patients (34.8%), epiaortic ultrasonography showed atherosclerotic findings in the anterior side of the ascending aorta (group A). The remaining 101 patients had either normal findings or atherosclerotic findings in only the posterior side (group NA). A proximal anastomosis to the aorta was preoperatively planned in 117 patients (group A, 42; group NA, 75). In group A, a graft modification without clamping was implemented in 29 patients (24.8% of 117 patients), whereas the clamp site was modified to a different segment in 13 patients (11.1% of 117 patients). In all 75 patients in group NA, partial clamping was used in the standard fashion. There were no cerebral infarctions or operative deaths related to partial clamping. However, aortic dissection occurred in 1 patient in group NA. CONCLUSIONS: In 35% of patients undergoing off-pump coronary artery bypass, epiaortic ultrasonography identified atherosclerotic findings in the anterior wall of the ascending aorta. This study suggests that revascularization without aortic manipulation during off-pump coronary artery bypass is indicated in as many as 25% of patients.

Adult↗

PubMed2002

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities.

Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. We have investigated substituents in the central part of a lead compound (3: M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC(50)=0.006 microM), with high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful than the lead compound.

Arylsulfonates↗