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Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3–5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50 = 5.5 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50 = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).

Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P(1)) and participates in many pathological conditions. We developed a novel type S1P(1)-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P(1) resulting in reduced signaling downstream of S1P(1), including GTPγS-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P(1)-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P(1) antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P(1) agonists on lymphocyte sequestration results from their functional antagonism.

Micro-molding of microneedle features was conducted using several injection-molding techniques. Injection compression molding and injection molding were performed with supercritical carbon dioxide fluid and with or without vacuum processing inside the mold cavity. Effects of process parameters on processability and surface replication of the molded parts were evaluated. The height replication ratio for microneedles was improved using injection compression molding. At a shorter compression stroke, the needle height was improved, and the influence of compression delay time was also small. Moreover, the effects of vacuum processing inside the mold cavity under the filling process were slight. The height replication ratio for microneedles showed the highest values using injection molding using supercritical carbon dioxide fluid with vacuum inside the mold cavity.

Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking through the type 1 sphingosine 1-phosphate receptor (S1P1) and participates in many pathological conditions, including autoimmune diseases. We developed a novel S1P1-selective antagonist, TASP0277308, which is structurally unrelated to S1P. This antagonist competitively inhibited S1P-induced cellular responses, such as chemotaxis and receptor internalization. Furthermore, differing from previously reported S1P1 antagonists, TASP0277308 demonstrated in vivo activities to induce lymphopenia, a block in T cell egress from the thymus, displacement of marginal zone B cells, and upregulation of CD69 expression on both T and B cells, all of which recapitulate phenotypes of S1P1-deficient lymphocytes. In a mouse collagen-induced arthritis model, TASP0277308 significantly suppressed the development of arthritis, even after the onset of disease. These findings provide the first chemical evidence to our knowledge that S1P1 antagonism is responsible for immunosuppression in the treatment of autoimmune diseases and also resolve the discrepancies between genetic and chemical studies on the functions of S1P1 in lymphocytes.

We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s10nM) for Lck kinase inhibition.

We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s

Background: The efficacy of rabeprazole sodium 20 mg/d for the treatment of reflux esophagitis has been demonstrated in several studies in Japan. However, studies of rabeprazole sodium 10 mg/d are lacking. Objective: This study was conducted to assess the efficacy and tolerability of rabeprazole 10 mg/d for the treatment of reflux esophagitis. Methods: Patients diagnosed with reflux esophagitis in routine clinical practice were enrolled in this single-center, open-label, practice-based, post-marketing surveillance investigation. Patients were to receive 10 mg of rabeprazole once daily for 8 weeks. The efficacy of rabeprazole was assessed on the basis of symptoms and endoscopic findings in accordance with the modified Los Angeles classification. Tolerability was assessed using subjective symptoms recorded before, during, and after treatment. Results: Of a total of 61 patients enrolled in this study, 47 (77%; 29 men, 18 women; mean age, 63 years) were included in the efficacy and tolerability analyses. Fourteen (23%) patients, including 5 (8.2%) patients who were treated with rabeprazole 20 mg/d, were excluded from the analyses. Endoscopic examinations were performed before and after treatment in 32 of 47 (68.1%) patients; mucosal lesions were healed in 20 of 32 (62.5%) patients after rabeprazole treatment. In patients with mild mucosal lesions prior to treatment, complete remission was achieved in 17 of 24 (70.8%) patients after treatment. Rates of improvement of symptoms were as follows: epigastralgia, 76%; heartburn, 76.7%; dull pain in the esophagus, 86.7%; and belching, 72.2%. Rabeprazole was well tolerated throughout the study; no serious symptomatic adverse events were reported. Although 1 case each of elevated alkaline phosphatase and gamma-glutamyltranspeptidase levels were reported, these changes were mild and improved after continuous treatment with rabeprazole. Conclusion: In this study, rabeprazole 10 mg/d was well tolerated and was shown to have satisfactory efficacy in the healing of esophagitis and the relief of the symptoms of esophagitis.

A multivariate analysis of CAMPAS-PX2 can increase its diagnostic accuracy in differential diagnosis of pancreatic cancer from benign pancreatic or extrapancreatic disease, when compared with CA19-9 alone. However, the improvement in diagnostic accuracy is still not satisfactory in spite of an elaborate combination of serum markers in diagnosis for pancreatic cancer. Optimal combination of a sensitive serum marker and another diagnostic modality, such as ultrasonography, can be a practical way to improve important diagnostic and cost-effectiveness in diagnosis for pancreatic cancer.No specific biological test has yet been developed for diagnosis of pancreatic cancer, although increasing numbers of tumor markers become available. For improvement in the diagnostic and cost effectiveness, it is important to select optimal combination of several serum markers relatively independent of each other.A new model of discriminant function, computer-aided multivariate and pattern analysis system for pancreatic cancer examination 2 (CAMPAS-PX2), was developed based on the data of the 23 serum tumor markers from the first prospective trial (1) to differentiate between pancreatic cancer and benign pancreatobiliary disease by logistic regression analysis using a stepwise selection method. In 243 patients suspected of having pancreatic pancreatic cancer by a multicenter prospective study, the diagnostic value of the multivariate analysis, CAMPAS-PX2, was compared with the 23 markers.Pancreatic cancer was subsequently identified in 27 patients. Positive in disease, negative in health, and area under receiver operating characteristic curve were significantly higher by CAMPAS-PX2 (89, 87, 91%) than by CA 19-9 (78, 82, 84%), the most sensitive marker among the 23 markers.

The quasispecies nature of hepatitis C virus (HCV) in patients with mixed HCV subtype infection was compared with that in patients with single HCV subtype infection. The number of HCV quasispecies was compared between 35 patients with mixed HCV subtype infection and 83 patients with single subtype infection. Subtype was determined by primers deduced from the core region and by line probe assay respectively. The number of quasispecies was evaluated by polymerase chain reaction amplification of hypervariable region 1 and by fluorescence single-strand conformation polymorphism analysis. There was no difference in clinical background between patients with mixed subtype infection and patients with single subtype infection. The number of quasispecies in patients with multiple subtype HCV infection was larger than in patients with single subtype HCV infection. The immunologic environments which allow the coexistence of more HCV quasispecies in patients with multiple HCV subtype infection differs from that in patients with single HCV subtype infection.

胆管内発育型胆管細胞癌の報告は非常にまれであり, その1切除例を経験したので報告する. 症例は65歳女性. 閉塞性黄疸にて来院し, 経皮経肝胆道ドレナージ術を施行した.胆管像では乳頭状の陰影欠損によって肝門部胆管は閉塞し, 腹部CTでは右尾状葉から右葉後区域にかけて径30mmの腫瘍を認めた. 経皮経肝胆道鏡検査では右肝管から総肝管まで伸びる乳頭状腫瘍を認め, 生検にて腺癌の診断を得た. 経皮経肝門脈造影では門脈右枝は左右分岐部直後で閉塞していた. 術前の癌進展度診断により, 右尾状葉から発生した胆管内発育型胆管細胞癌と診断し, 肝右葉切除, 尾状葉全切除, 胆管切除, 下大静脈合併切除を施行した.本疾患の鑑別診断には経皮経肝胆道鏡検査による胆管内腫瘍の診断が有用であった. また, 手術術式決定の上では胆管内腫瘍と主腫瘍の存在, 部位, 進展範囲, 進展様式の診断が重要であった.

The subjects of this study were 151 patients (69 males and 82 females) who underwent examination and liver biopsy owing to liver dysfunction in an epidemic area with hepatitis C. Second generation hepatitis C virus antibody (HCV Ab) was positive in 116 (76.8%) of 151 cases. HCV-RNA was detected in 120 (79.5%) by polymerase chain reaction (PCR). In 7 (4.6%) cases, HCV Ab could not be found, but HCV-RNA was detected. Three (2.0%) cases were positive for HCV Ab but negative for HCV-RNA. On the basis of variation in nucleotide sequence within a restricted region in the putative core gene of HCV, HCV genotypes were classed into four types of I, II, III and IV by PCR. The genotypes were identified in 120 cases. Ninety-eight (81.7%) cases carried one of the four types. Type II was found in 76 (63.3%) cases and type III in 22 (18.3%). The other 22 (18.3%) carried simultaneously two different genotypes (mixed type): 21 (17.5%) cases with type II + III and one (0.8%) case with type II + IV. In comparison with the incidence of HCV mixed types in cases with hepatitits C in a non-epidemic area, carriers of mixed types were found at a significantly higher rate in the epidemic area. Liver biopsy of 120 cases with identified HCV genotypes in the epidemic area showed 93 cases of chronic active hepatitis, nine of chronic lobular hepatitis, 10 of chronic persistent hepatitis and eight of liver cirrhosis. No significant correlation could be detected between liver histology and HCV genotypes. Of the 120 cases, 63 (52.5%), 54 (45.0%) and 12 (10.0%) cases had past histories of folk remedies accompanying bleeding, operation and transfusion, respectively. The repetition of these medications may have caused a high ratio of carriers of the mixed genotypes of HCV.

A 50-year-old asymptomatic woman was detected having an abdominal tumor at a medical checkup. abdominal ultrasonography revealed a 3cm-sized circular and internally heterogenous hypoechoic picture at the retropancreatic region and in the right front of the aorta. Abdominal CT visualized a circular, homogenous, and well-defined low density area adjacent to the retropancreatic region and the liver, excepting a part of the center of the area. Angiography showed a stenosis in the left gastric artery and displacement at the root of SMA. ERCP revealed no abnormalities in the bile and pancreatic ducts. The patient was diagnosed as having a retroperitoneal tumor and was operated on. The tumor adhered to the common hepatic artery and celiac artery, where both the tumor and celiac artery existed in a condition enclosed in the plexus. With exposure of the arterial wall the tumor was freed from the artery and excised. The excised tumor was 25×23×20mm in size, elastic soft, encapsulated and well-defined. The section was yellowish brown with hemorrhage in the center. Histopathologically it was Antoni type A neurinoma. No malignancy was detected. Based on intraoperative findings, the tumor appeared to be arised in the celiac plexus.

We studied 349 patients with chronic infection due to hepatitis C virus (HCV), including 83 with coagulopathy, 122 with community-acquired infection, 20 with chronic posttransfusion hepatitis C, and 124 for whom the transmission mode was unknown. The prevalence of mixed-subtype HCV infection was investigated in each group of patients. The serum HCV RNA concentration and the response to interferon (IFN) therapy were evaluated. HCV infection with mixed subtypes was more frequent in patients who had been at high risk for exposure to HCV, such as those with coagulopathy or community-acquired infection. HCV RNA concentrations were lower in patients infected with mixed subtypes, except for those with subtypes 1a and 1b. Ten of 11 patients with mixed subtypes (not including those with 1a and 1b) achieved complete clearance of HCV RNA with IFN therapy.

Summary In 403 patients suspected of having pancreatic cancer, we prospectively studied a combination assay of various serum tumor markers: CA19-9, DUPAN2, tissue polypeptide antigen, elastase 1, γ-glutamyltranspepti-dase, lactate dehydrogenase, lipase, amylase, and alkaline phosphatase. The diagnostic value of each marker was compared with a multivariate analysis (computer-aided multivariate and pattern analysis system for pancreatic cancer examine-1: CAMPAS-PX1). Pancreatic cancer was subsequently identified in 47 patients. CAM-PAS-PX1 had higher negative in health and positive predictability than those of each marker used alone in the diagnosis of pancreatic cancer. CAMPAS-PX1 proved the most effective marker for diagnosing pancreatic cancer, but in terms of its codbenefit ration CAMPAS-PX1 was not superior to CA19-9 used alone. In this prospective trial, we experienced poor generalizability in the statistical models (CAMPAS-PX1). We believe that selection bias was present in samples used for model building. Based on this study a new model has been designed.

In a 42 year old female, a fistula developed between the splenic vein and the pancreatic duct through the cavity of a pseudocyst in the tail of the pancreas and resulted in an extrahepatic portal hypertension. The fistula was visualized by endoscopic retrograde cholangiopancreatography and percutaneous transhepatic portography, then was successfully resected by surgery. The possible etiology of extended obstruction of both splenic and portal veins in chronic pancreatitis with pseudocyst was discussed.

肝疾患診断におけるcomputed tomography(以下CTと略す)の意義と限界を明らかにする目的で,瀰漫性肝疾患90例と腫瘤性肝疾患37例を対象として第3世後半のCT装置(GECT/T 8800)を用いて各疾患のCT像を比較検討した.肝硬変症ではRIスキャンで認められる右葉萎縮や左葉肥大などの所見は明らかで無く,脾臓前後径の増大,肝表面の凹凸,腹水の存在が特異的な所見であった.脂肪肝は全例で肝臓のCT値が低値を示し,肝臓と脾臓のCT値の比が0.9以下という基準は脂肪肝のスクリーニングとして有用と言えた.急性肝炎では肝内胆管拡張を認めない点が肝外閉塞性黄疸との鑑別に役立つと考えられた.SOLの存在診断能はRIスキャンより優れており,嚢胞に関しては質的診断も可能であった.現段階ではCTにより高度の脂肪,鉄沈着や広汎な壊死以外の肝組織学的変化を知ることは不可能であり,また固形腫瘤の質的診断も困難な場合が多い.

組織学的に確定診断された肝瀰漫性脂肪化56例,慢性肝炎41例,肝硬変39例のCT像を対比して,CTによる脂肪化の診断能と診断基準を検討した.軽度脂肪化は診断困難であったが,高度脂肪化(脂肪肝)に関しては肝CT値/脾CT値比が0.85未満という診断基準の設定が可能であった.上腹部CT 6,800件中,197件(2.9%),実数169例(瀰漫性141例,限局性28例)がこれに該当した.成因としては瀰漫性,限局牲いずれも肥満,糖尿病,多飲酒の順に多かった.血液生化学検査正常例が肝生検にもとづく従来の報告よりも高率にみられた.反復施行37例の検討では,肝CT値の推移は各成因の改善度をよく反映し,CTは治療効果判定にも有用であった.瀰漫性,限局性脂肪肝は相互に移行がみられたので,限局性脂肪肝は脂肪肝の進展や改善途中で生ずる一過性の病態と考えられる.

The pancreatic excretion test with a weak acid of 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) was performed concomitantly with the pancreozymin-secretin test in 28 patients with pancreatolithiasis, 14 patients with pancreatic carcinoma, and 67 healthy subjects. The DMO concentration and total output of duodenal content after secretin stimulation, when corrected to the simultaneously determined plasma DMO concentration, were significantly reduced in the patients. While the pancreozymin-secretin test was abnormal in 96% of patients with pancreatolithiasis and in 86% of those with pancreatic carcinoma, the pancreatic DMO excretion test gave abnormal results in 100% of the patients. This suggests that the new test may well become effective in detecting early stages of pancreatic disease including carcinoma and chronic pancreatitis. (Arch Intern Med137:754-760, 1977)