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Biomedical subjects

W Tanaka

Publications and source records attributed to W Tanaka.

At least 19 recordsLinked to original sources
PubMed2000

Optimal route of administration of mixed endothelin receptor antagonist (TAK-044) in liver transplantation.

It is well known that endothelin-1(ET-1) is a factor involved in the pathogenesis of ischemia-reperfusion injury. This study was undertaken to investigate the optimal route (intravenous vs intraportal) for administering mixed endothelin receptor antagonist (TAK-044) in a liver transplantation. First, in a rat isolated liver cold-perfusion model, the pharmacodynamics of TAK-044 and endothelin-1 (ET) in the liver tissue and the systemic circulation after cold perfusion were compared in the different administration routes. Next, in a rat orthotopic transplantation model, we compared the hepatoprotective effect of TAK-044 among different administration routes. In each model, there were three groups: IV group, intravenous injection of TAK-044 (10mg/kg) immediately before cold perfusion or anhepatic phase; IP group, intraportal administration with cold perfusion solution or with reflush solution for the graft; control group, no treatment. In the cold perfusion model, liver tissue ET level increased to a similar extent after reperfusion in the three groups, and the plasma and liver tissue TAK-044 concentrations after reperfusion were highest in the IV group. However, the increase in plasma ET was also greatest, and therefore, the ratio of liver tissue to plasma TAK-044 was lower in the IV group compared with the IP group. In the transplantation model, elevation of plasma ET was significantly higher in the IV group. Leakage of serum alanine aminotransferase (ALT), sinusoidal narrowing, and cell swelling after grafting were significantly suppressed in the IP group. We conclude that intraportal administration before reperfusion offers more efficient accumulation of TAK-044 in the liver tissue, without harmful systemic elevation of ET, and achieves a hepatoprotective effect on the graft compared with intravenous administration.

Alanine Transaminase↗
PubMed2000

[A case of Down's syndrome associated with testicular seminoma].

Down's syndrome is an inherited disorder caused by trisomy of chromosome 21. In patients with Down's syndrome, an increased risk of leukemia has been observed. Recently, the coincidence of testicular cancer with this syndrome has been also emphasized. We present a case of Down's syndrome associated with testicular seminoma. This is the 19th case of Down's syndrome associated with testicular tumor in Japan.

Adult↗
PubMed1999

Dynamics of portal and peripheral endothelin-1 in hepatic resection and its implication.

BACKGROUND: The liver and portal circulation contribute to production and clearance of endothelin-1 (ET-1). This study was undertaken to investigate what variables relate to the dynamics of ET-1 in hepatic resection and its clinical implication. PATIENTS AND METHODS: On 20 patients with (n = 8) or without (n = 12) chronic liver disease who underwent hepatic resection, peripheral arterial and portal venous ET-1 were serially measured to determine a correlation with pre-, intra-, and postoperative variables. RESULTS: The preoperative factors with which the portal ET-1 showed a positive correlation were the indocyanine green retention rate at 15 min (ICG R15) and portal venous pressure. The ET-1 clearance, as calculated from the difference between the portal and the peripheral ET-1 concentrations, was also correlated with the ICG R15. The peripheral ET-1 elevated significantly in the patients with increasing intraoperative blood loss or hepatic inflow occlusion. An increase in the portal ET-1 was correlated with an elevation of portal venous pressure after hepatectomy. Postoperative increase in serum bilirubin was closely correlated with the peripheral ET-1 at closure. CONCLUSION: The peripheral and portal ET-1 are correlated with not only preoperative hepatic reserve and portal venous pressure but also invasiveness of hepatectomy and postoperative course.

Blood Loss, Surgical↗
PubMed1999

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia.

BACKGROUND: Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE: We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS: Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS: Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION: In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

5-alpha Reductase Inhibitors↗
PubMed1998

Idiopathic benign biliary stricture.

A rare case of idiopathic benign biliary stricture is reported. A 50-year-old man with liver dysfunction underwent ultrasonography, which revealed dilation of the intrahepatic bile ducts, and endoscopic retrograde cholangiopancreatography, which revealed a short, ring-like stenosis at the junction of the left and right hepatic ducts. Although a benign stricture was suspected, radiologic tests alone were insufficient to make a firm diagnosis. Therefore, a cholecystectomy and resection of the extrahepatic biliary tract were performed. Microscopic examination of the resected specimen demonstrated no evidence of malignancy. The final diagnosis was mild, localized, chronic cholangitis. The patient had not had previous biliary tract surgery, choledocholithiasis, nor did he have a congenital abnormality of the biliary tract, bile duct carcinoma, or pancreatic disease. Since there was no evidence of primary sclerosing cholangitis, the stricture was considered to be idiopathic.

Anastomosis, Surgical↗
PubMed1997

Hepatoprotective effect of a nonselective endothelin receptor antagonist (TAK-044) in the transplanted liver.

This study was designed to investigate whether or not a novel nonselective endothelin A/B (ETA/ETB) receptor antagonist (TAK-044) provides hepatoprotection during porcine liver transplantation. The grafts were stored in chilled Euro-Collins solution and recirculated following reflush with lactated Ringer's with (TAK group) or without (control group) TAK-044 (10 mg/kg). Intracellular (cytoplasma, mitochondria, and nucleus) calcium (Ca) concentrations were measured in the hepatic biopsy materials obtained serially at varying time point from donor laparotomy to recipient closure using an electron probe X-ray microanalyzer. Liver function tests also were determined. The cold and warm ischemia times of the grafts were comparable between the two groups. The peak endothelin-1 T-1) concentration after recirculation was significantly higher in the TAK group than in the control group (129 +/- 30 pg/ml vs 26 +/- 6.5 pg/ml). However, release of liver enzymes, increases in total bile acid, and deterioration of indocyanine green retention rate were significantly suppressed in the TAK group. In the control group, the intracellular Ca concentrations, especially in the mitochondrial fraction, were elevated markedly following recirculation of the hepatic arterial flow. In the TAK group, this effect was suppressed. Thus, the supplementary use of the nonselective ETA/ETB receptor antagonist TAK-044 via a rinse route may alleviate an early postreperfusion microcirculatory disturbance of the liver grafts without adverse effects by the increased ET-1 on the systemic circulation.

Animals↗
PubMed1997

Correlation of hepatitis virus serologic status with clinicopathologic features in patients undergoing hepatectomy for hepatocellular carcinoma.

BACKGROUND: This study investigated the relationship between clinicopathologic features and various viral serologies in patients who underwent hepatectomy in the treatment of hepatocellular carcinoma (HCC). METHODS: Two hundred two patients were allocated to four groups, according to their positivity or negativity for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb): Group I (HBsAg[-], HCVAb[+], n = 151), Group II (HBsAg[+], HCVAb[-], n = 27), Group III (HBsAg[-], HCVAb[-], n = 20), or Group IV (HBsAg[+], HCVAb[-], n = 4). The mean age of the HBsAg positive patients (Groups II and IV) was 10 years younger than that of the HBsAg negative patients (Groups I and III). RESULTS: The male-to-female ratio was higher in HCVAb negative groups (II and III). The HCVAb positive groups (I and IV) had a significantly poorer hepatic reserve and smaller resections than the HCVAb negative groups. Because the tumors were more advanced (as determined by TNM staging) in Group II, the 3-year crude and disease free survival rates were lower in Group II than in Group I. However, HCVAb negative groups (II and III), when compared at 5 years with the limited subsets of patients who had tumors at earlier stages or a curative resection, had significantly better crude and disease free 5-year survival rates than the HCVAb positive group (I). CONCLUSIONS: Clinicopathologic features differ from one another in accordance with the viral seromarkers in HCC patients. Significantly better crude and disease free survival after complete resection were promising results for patients with non-HCV-related HCC. By comparison, for patients with HCV-related HCC, the risk of intrahepatic recurrences never subsided even in later years after complete resection. Therefore, posthepatectomy follow-up management should be individualized depending on the viral serologic status of HCC patients.

Alanine Transaminase↗
PubMed1997

Immunohistochemical studies of proliferating cell nuclear antigen and cathepsin D in transitional cell carcinoma of the urinary bladder.

Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and cathepsin D was performed on 60 transitional cell carcinoma (TCC) specimens from 60 patients with bladder cancer. The percentage of PCNA-positive cells (PCNA-labelling index) was determined by counting 500 or 1,000 cells, and cathepsin D expression was graded according to the extent of immunoreactivity to anti-cathepsin D antibody. The PCNA-labelling index was significantly higher in high-grade and high-stage tumors compared to that in low-grade and low-stage tumors. Cathepsin D was highly positive in grade-1 tumors. In contrast, 82% of grade-3 tumors and 76% of advanced tumors showed negative or low reactivity to anti-cathepsin D. Groups of high PCNA-labelling index and negative cathepsin D had significantly poorer prognoses compared to those of the low PCNA group and cathepsin D highly positive group, respectively, in univariate analyses. However, neither of these two factors were independent prognostic factors in multivariate analyses. These results suggest that the PCNA-labelling index and cathepsin D expression may indicate the malignant potential of TCC and may be able to provide additional information for predicting survival when stratifying for grade of bladder cancer.

Adult↗
PubMed1997

Topical cooling-assisted hepatic segmentectomy for cirrhotic liver with hepatocellular carcinoma.

BACKGROUND: A safe limit for normothermic consecutive portal triad occlusion in hepatectomy for the cirrhotic liver was believed to be around 30 minutes. Possibly, the occlusion time can be prolonged by cooling the ischemic liver in vivo. We describe the technique of segmentectomy assisted by topical cooling and its usefulness in prolonging the hepatic inflow occlusion time for cirrhotic livers without causing further ischemic injury. STUDY DESIGN: Fifty patients with hepatocellular carcinoma and chronic hepatic disease who underwent right-sided segmentectomy under hemihepatic inflow occlusion were divided into two groups: normothermic (n = 27), and hypothermic with hemihepatic topical cooling using ice slush (n = 23). Segmentectomies were carried out in the same way in both groups, guided by initial enbloc ligation of the corresponding portal pedicles. RESULTS: The mean right hepatic inflow occlusion time was significantly longer in the hypothermic group than in the normothermic group (53 +/- 22 minutes compared with 17 +/- 9.3 minutes). Despite the significant difference in occlusion time, no differences were found in the recovery of hepatic functions and the incidence of postoperative complications between the groups. Intraoperative blood loss was significantly less in the hypothermic group. CONCLUSIONS: The hepatic right-sided partial inflow occlusion time can safely be prolonged to 60 to 90 minutes in the presence of cirrhosis without causing another injury from ischemia and intermittent reperfusion.

Aged↗
PubMed1996

Microwave coagulonecrotic therapy for hepatocellular carcinoma.

The present study reports on the usefulness of microwave coagulonecrotic therapy (MCT) as a treatment option for hepatocellular carcinoma (HCC) with poor hepatic reserve. From June 1992 to March 1995, MCT using a microwave electrode was employed on 8 patients using laparoscopic control and 19 with the open method, and wedge resection (Hx) was applied to the 23 patients. All patients had HCC with poor hepatic reserve. Radiation output was 100 watts with a mean radiation duration of about 30 minutes. The severity of liver dysfunction and the regional characteristics of the tumor (tumor size, multiplicity, portal invasion, tumor depth) were comparable between the MCT and Hx groups. The operative time was significantly shorter for the MCT group than the Hx group. The mean blood loss was 1570 ml in the Hx group but negligible in the MCT group. There was no operative mortality in the MCT group in contrast to 4.3% (1 of 23) in the Hx group. Complications were observed in 11.1% (3 of 27) and 34.8% (8 of 23), respectively, for the MCT and Hx groups. The postoperative total bilirubin had lower values and the start of diet was earlier in the MCT group than the Hx group. The 3-year crude and disease-free survival rates were 86% and 44%, respectively, for patients who underwent MCT, which were comparable to 75% and 14% for those with Hx. MCT can achieve long-term results equivalent to those obtained by wedge resections, but it is less invasive and technically easier. Therefore it can be an alternative option in place of limited resection for HCC with poor hepatic reserve.

Angiography↗
PubMed1995

Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma.

BACKGROUND: The mode of tumor growth of intrahepatic cholangiocarcinoma (CC) varies considerably from patient to patient. This study describes the clinicopathologic variety of the extraductal mass-forming type of CC. METHODS: Patients with CC characterized by an extraductal mass (n = 26) who underwent hepatectomy from 1976 through 1992 were clinicopathologically classified into three types: Type I (n = 7), no biliary stricture; Type II (n = 13), biliary stricture without jaundice; and Type III (n = 6), biliary stricture with jaundice. RESULTS: Type I included three patients with microductular-trabecular arrangement and behavior reminiscent of hepatocellular carcinoma (high association with chronic liver disease, mild positivity for alpha-fetoprotein [AFP], no lymph node metastasis, but frequent intrahepatic metastasis), in contrast to the other typical cholangiocarcinoma. Hepatolithiasis was associated only with Type II CC: The serum positivity for AFP and carcinoembryonic antigen was much higher in Type I CC, whereas positivity of CA 19-9 was highest in Type III. Involvement of the portal vein, hepatic artery, or hepatic duct was most frequent in Type III CC, which necessitated resection of the extrahepatic bile duct and hepatectomy. CONCLUSION: The clinicopathologic behavior of intrahepatic CC differs considerably according to the presence or absence of stricture of the biliary tree. Thus, CC without biliary stricture behaves more like hepatocellular carcinoma, whereas CC with biliary stricture is more like hilar or extrahepatic bile duct carcinoma.

Adult↗
PubMed1995

Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK-0591, in healthy volunteers.

1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

5-Lipoxygenase-Activating Proteins↗
PubMed1993

High-performance liquid chromatographic determination of PZ-peptidase activity.

A rapid and sensitive assay method for the determination of PZ-peptidase activity is reported. This method is based on the monitoring of the absorption at 320 nm of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu (PZ-Pro-Leu), enzymatically formed from the substrate 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (PZ-peptide), after separation by high-performance liquid chromatography using a C18 reversed-phase column by isocratic elution. This method is sensitive enough to measure PZ-Pro-Leu at levels as low as 10 pmol, yields highly reproducible results and requires less than 5.5 min per sample for separation and determination. The optimum pH for PZ-peptidase activity was 7.5-8.0. The Km and Vmax values were 166.7 microM and 5.35 pmol/min.microgram protein, respectively, with the use of enzyme extract obtained from mouse whole brain. The approximate molecular mass of this enzyme was estimated to be 64,000 by gel filtration. PZ-peptidase activity was strongly inhibited by Zn2+, Cu2+ and p-chloromercuriphenylsulphonic acid. By using this method, PZ-peptidase activity could be readily detected in a single mouse pituitary gland. Among the tissues examined in various mouse brain regions, the highest specific activity of the enzyme was found in cerebral cortex. The sensitivity and selectivity of this method will aid in efforts to examine the physiological role of this peptidase.

Amino Acid Sequence↗
PubMed1993

Biochemical activity, pharmacokinetics, and tolerability of MK-886, a leukotriene biosynthesis inhibitor, in humans.

MK-886, a leukotriene biosynthesis inhibitor, was evaluated in double-blind, placebo-controlled, randomized single- and multiple-dose studies in 12 and 24 healthy male subjects, respectively. The effects of a single dose (250, 500, and 750 mg) and multiple doses (100 mg and 250 mg every 8 hours) of MK-886 on calcium ionophore stimulated leukotriene B4 synthesis ex vivo in whole blood were evaluated. Inhibition of leukotriene B4 biosynthesis ex vivo occurred in a dose-related manner up to a 500 mg single dose, and 250 mg every 8 hours. A single dose of 500 mg MK-886 significantly inhibited leukotriene B4 biosynthesis by a maximum of 60% at 2 hours after the dose (p < 0.05). Multiple doses of 250 mg significantly inhibited leukotriene B4 biosynthesis by a maximum of 52% at 2 hours after the dose (p < 0.05). The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-886 concentrations (r = 0.78). In conclusion, the single and multiple doses of MK-886 evaluated in this study were well tolerated overall and partially inhibited leukotriene B4 biosynthesis ex vivo in whole blood.

Administration, Oral↗
PubMed1993

Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98 +/- 37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n = 4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean +/- SD), compared with the placebo run-in day, first dose: -8.8 +/- 9.6/-6.8 +/- 5.0, last dose: -11.6 +/- 8.9/-7.0 +/- 4.8 mm Hg (p < 0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2 +/- 0.6 to 12.0 +/- 6.3 (first dose) and 9.6 +/- 4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3 +/- 1.7 to 72.4 +/- 33.3 and 45.7 +/- 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p < 0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide.

Adolescent↗