Search

Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.

[Objective]Patients with coronary artery disease (CAD) often have prior stroke or concomitant extra-cardiac vascular disease (EVD) such as cerebral, aortic, or peripheral vascular disease. However, clinical outcomes after coronary revascularization in patients with polyvascular disease have not been fully elucidated. [Methods]Among 15, 263 patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto registry Cohort-2 from January 2005 to December 2007, there were 1443 patients with prior stroke (stroke + CAD group), 974 patients with EVD (EVD + CAD group), 253 patients with both prior stroke and EVD (stroke/EVD/CAD group) and 12, 593 patients with neither prior stroke nor EVD (CAD alone group [reference]). [Results]The cumulative incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) through 3 years was significantly higher in patients with polyvascular disease compared with reference patients (19.9% in the stroke + CAD group, 18.5% in the EVD + CAD group, 20.1% in the stroke/EVD/CAD group, and 11.2% in the CAD alone group, P < 0.0001). After adjusting confounders, the presence of EVD and/or stroke was independently associated with higher risk for MACE compared with the reference group (adjusted HR [95%CI]: 1.34 [1.17–1.54], P < 0.0001 in the stroke + CAD group, 1.56 [1.32–1.84], P < 0.0001 in the EVD + CAD group, and 1.66 [1.24–2.23], P = 0.0007 in the stroke/EVD/CAD group). However, the presence of EVD and/or stroke was not associated with higher risk for myocardial infarction. [Conclusions]Clinical outcome after coronary revascularization was worse in patients with prior stroke and/or EVD, which was mainly driven by the increased risk for non-coronary cardiovascular events.

We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.

乳頭筋断裂は稀ではあるが重篤な急性心筋梗塞後の合併症である．今回われわれは急性心筋梗塞後の後乳頭筋部分断裂に対し僧帽弁形成術，冠動脈バイパス術を施行し良好な成績を得たので報告する．症例は85歳の男性で，急性心筋梗塞によるショックの診断で緊急入院した．緊急心臓カテーテル検査の結果，冠動脈3枝病変であり，責任病変の左回旋枝に経皮的冠動脈形成術を施行し再灌流を果たした．入院11日後に突然肺動脈圧が60台に上昇し収縮期雑音を聴取した．経食道心エコー検査にて僧帽弁前尖のA2からA3の逸脱と重度僧帽弁逆流を認めた．弁下に筋肉と思われる可動性のmassを認め後乳頭筋のanterior headの断裂と診断した．大動脈内バルーンパンピング（IABP）を挿入し血行動態は安定し，4日後（入院15日後）に手術を施行した．後乳頭筋anterior headが断裂しており，健常なposterior headに再縫着しCarpentier Edwards classical ring M28人工弁輪で弁輪形成し逆流を制御した．また左内胸動脈にて左前下行枝にバイパスした．術後の心エコー検査にて僧帽弁逆流を認めず，術後43日目に独歩退院した．

Background Adjunctive thrombus aspiration ( TA ) during primary percutaneous coronary intervention ( PCI ) was reported to promote better coronary and myocardial reperfusion. However, long‐term mortality benefit of TA remains controversial. The objective of this study is to investigate the clinical impact of TA on long‐term clinical outcomes in patients with ST ‐segment elevation myocardial infarction (STEMI) undergoing primary PCI . Methods and Results The CREDO ‐Kyoto AMI Registry is a large‐scale cohort study of acute myocardial infarction patients undergoing coronary revascularization in 2005–2007 at 26 hospitals in Japan. Among 5429 patients enrolled in the registry, the current study population consisted of 3536 patients who arrived at the hospital within 12 hours after the symptom onset and underwent primary PCI . Clinical outcomes were compared between the 2 patient groups with or without TA . During primary PCI procedures, 2239 out of 3536 (63%) patients underwent TA ( TA group). The cumulative 5‐year incidence of all‐cause death was significantly lower in the TA group than in the non‐ TA group (18.5% versus 23.9%, log‐rank P TA group was not significantly lower than that in the non‐ TA group (hazard ratio: 0.90, 95% CI : 0.76 to 1.06, P =0.21). The adjusted risks for cardiac death, myocardial infarction, stroke, and target‐lesion revascularization were also not significantly different between the 2 groups. Conclusions Adjunctive TA during primary PCI was not associated with better 5‐year mortality in STEMI patients.

We report a case of a 42-year-old male with chronic thromboembolic pulmonary hypertension. His preoperative examination revealed severe hypoxemia (PaO2 48 mmHg, PaCO2 34 mmHg in room air), a mass in the right ventricle and severe pulmonary hypertension (pulmonary arterial pressure 70/33 mmHg). We successfully performed right ventricular thrombectomy to prevent further embolization from the right ventricular thrombus. Using inhaled low dose nitric oxide (NO) during perioperative period, weaning from cardiopulmonary bypass and ventilator were easily done. In this case, inhaled NO was successfully administered for the perioperative management of chronic pulmonary hypertension.

Aneurysm of the innominate artery is uncommon compared with other peripheral aneurysms, and holds the potential for rupture, embolization, or thrombosis as well as various complications caused by compression to the adjacent structures. The most effective treatment for this condition is surgical resection, but the earlier reports described high mortality rates. We report the case of an 83-year-old asymptomatic woman with an aneurysm in the innominate artery, which was successfully resected and repaired with the use of modern surgical techniques of hypothermic circulatory arrest and selective cerebral perfusion. Aggressive surgical intervention should be employed despite the fact that a patients is asymptomatic.

症例は54歳男性で夜間や軽い運動時の胸痛があるために本院を受診, エコーで右房内の腫瘤を発見された. 冠動脈造影検査にて異常は認められなかった. 腫瘤が大きいため, 体外循環下, 心停止下に摘出術を施行し, 三尖弁前尖に短茎を有する20×15×13mmの黄色, 球型の腫瘍を摘出した. 術後は合併症もなく退院し順調に経過している. 腫瘍は病理組織学的に乳頭状線維弾性腫と診断された. 同腫瘍は心臓弁に好発する腫瘍としてよく知られ, もともと剖検心において偶然発見されることが多かったが臨床例の報告も増加している. しかし同腫瘍の臨床報告例のほとんどは左心系発生例であり, 腫瘍の大小にかかわらず脳梗塞や心筋梗塞といった重大な合併症をきたしうるために手術適応は明確であるが, 右心系に関しては報告例もごく少なく手術適応も明らかではない. 本例と検索しえた内外の右心系発生の報告例合わせて18例を基に手術適応に関して検討を加えたので報告する.

A 7-month-old female infant with aortic stenosis, preductal coarctation, and pulmonary hypertension underwent operation. Intraoperative lung biopsy revealed marked medial hypertrophy of the pulmonary arterioles. This histopathology is compatible with persistent pulmonary hypertension in the newborn. She is alive about 5 years after the operation, but pulmonary hypertension remains. The pathogenesis is discussed.

先天性孤立性大動脈四尖弁は非常に希な先天性半月弁異常とされており,本邦での手術例の報告も少ない.症例は47歳,男性.発熱,呼吸困難のために当院入院後,症状が増悪し,挿管となり,人工呼吸管理が開始となった.血液培養にてStreptococcus agalactiaeが検出され,経食道心エコーでは,大動脈弁は四尖弁で,IV度の逆流と,弁尖に疣贅の付着を認め,感染性心内膜炎と診断された.抗生剤を投与したが,炎症反応は完全には改善せず,心不全も軽快しないため,挿管から26日目に,大動脈弁置換術を施行した.大動脈弁は四尖よりなり,2弁尖が大きく,ほかの2弁尖は小さい形態をしており,各弁尖間には完全な形の交連が存在していた.さらに,弁輪部には膿瘍の形成を認めた.膿瘍部は自己心膜を用いてパッチ閉鎖後,21mmのSJM弁を用いて置換した.術後4日目に抜管し,その後の経過はおおむね良好で,心電図上,ブロックも認めず,断層心エコー上も異常所見を認めず,術後46日目に退院となり,社会復帰した.

Hypofunction of brain N-methyl- d -aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co-agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4 H -1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC 50 = 92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for μ-opioid receptors (IC 50 = 1.83 μM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [ 3 H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3–3 mg/kg, p.o. and 0.3–1 mg/kg, p.o., respectively). ASP2535 (1–3 mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1–3 mg/kg, p.o. and 0.1 mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases.

症例は67歳女性, 胸部腫瘤影を指摘され来院.この腫瘤は, 造影 CTにて濃染し, また気管支動脈造影にて, いわゆる “メ導ンの皮の網目状の血管走行” を示した.これより肺硬化性血管腫を強く疑い, 腫瘍核出術を施行した.肺良性腫瘍は, 一般に術前診断をつけることは困難である.しかし, 肺硬化性血管腫は, 造影CTにて濃染することが多く, また気管支動脈造影にても特徴的な所見が得られる可能性が高いので, 肺良性腫瘍を疑った症例には, 施行すべき検査であると思われる.

Isolated direct metastasis of uterine cervical carcinoma to the right ventricular endocardium is very rare. A 68-year-old woman was initially diagnosed as having stage IIIb squamous cell carcinoma of the uterine cervix, and was treated with radiation therapy. After 2 years, she developed heart failure and presented with a mass in the right ventricle. The results of further examinations were consistent with a tumor or a thrombus in the right ventricle. She underwent excision of the mass under cardiopulmonary bypass, and histopathologic examination of the resected tissue revealed metastatic squamous cell carcinoma of the uterine cervix. She was discharged 3 weeks after the operation, and underwent chemotherapy. However, she was readmitted with drug-induced interstitial pneumonia and died 5 months after the surgery. Patients with an intracardiac mass and a history of uterine cervical cancer should be suspected of having a myocardial metastasis until it is proven otherwise.

A 57-year-old man with dyspnea and dry cough exhibited pulmonary embolism. Pulmonary arteriography demonstrated absent perfusion of the left main and the right upper and middle lobe pulmonary arteries. A diagnosis of chronic pulmonary thromboembolism was assumed and surgical thromboendarterectomy was attempted under standard cardiopulmonary bypass. At operation, a tumor had invaded far into both the right and left pulmonary arteries and radical resection was impossible. The final pathological diagnosis was primary leiomyosarcoma of the pulmonary artery. The patient refused any adjuvant therapy and died 63 days after the surgery. The clinical presentation of this case was similar to that of pulmonary thromboembolism and its diagnosis and treatment were very difficult.

Adult T-cell leukemia-derived factor (ADF), identified in the supernatant of adult T-cell leukemia (ATL) cell culture, is a human homologue of thioredoxin and consists of 104 amino acids; it has two redox-active half-cysteine residues in an exposed active center. Human thioredoxin has many biological activities, including growth promotion, cell activation, and a catalase-like radical scavenging activity. We examined the protective effect of human thioredoxin (h-thioredoxin) against reperfusion-induced arrhythmias in an isolated rat heart model with 10-min regional ischemia followed by 30-min reperfusion. Male Wistar rats were assigned to six groups: a control, a superoxide dismutase (SOD 8 x 10(4) IU/L), and a catalase group (1 x 10(6) IU/L), and three groups treated with h-thioredoxin [approximately .01 microM (TRX-I group), approximately 0.1 microM (TRX-II group), and approximately 1 microM (TRX-III group)]. In the early reperfusion period, h-thioredoxin reduced the incidence of ventricular fibrillation (VF) to 8% in the TRX-II group (p < 0.01) from the control value of 75%. SOD and catalase reduced the incidence of VF to 43 and 33%, respectively (NS). During the entire reperfusion period, the incidence of VF in the SOD group was 79%, as compared to 83% in the control group. In the catalase and TRX-II groups, the incidence of VF was significantly reduced to 42 and 25%, respectively. These findings indicate that SOD failed to protect against the reperfusion-induced arrhythmias. h-Thioredoxin exerted a protective effect against these arrhythmias; a concentration of approximately 0.1 micro was the most effective.

The arterial ketone body ratio, which reflects the hepatic mitochondrial redox potential (NAD+/NADH), decreases markedly during cardiopulmonary bypass (CPB). One of the reasons for arterial ketone body ratio reduction may be hepatic hypoperfusion during CPB. To evaluate the hepatic circulation under nonpulsatile CPB, the authors used color Doppler ultrasonography to measure the portal venous flow (PVF) in 24 adult patients before, during (aortic clamping and rewarming period), and after CPB. Nonpulsatile hypothermic CPB was performed at a flow rate of 2.4 L/min/m2. PVF was calculated from the product of mean flow velocity and cross-sectional area of the portal vein. PVF was maintained during CPB at 0.44 +/- 0.13 and at 0.54 +/- 0.18 L/min/m2. PVF (%) in relation to systemic blood flow was obtained by calculating PVF/CI or PVF/PI, where CI is the cardiac index and PI is the perfusion index. PVF (%) before, during, and after CPB was 18.3 +/- 9.3, 18.5 +/- 5.5, and 17.4 +/- 6.7%, respectively. In conclusion, PVF was maintained during nonpulsatile CPB at a flow rate of 2.4 L/min/m2 and depended upon systemic blood flow.