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1.
J Clin Pharm Ther ; 43(5): 675-681, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29679392

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: For analysis of blood concentrations of everolimus, many hospital laboratories use either latex agglutination turbidimetric immunoassay (LTIA) or electrochemiluminescence immunoassay (ECLIA). However, no studies have compared both immunoassay methods under the same conditions. Accordingly, in this study, we compared everolimus blood concentrations obtained by LTIA and ECLIA in renal transplant patients. METHODS: Blood samples (n = 230) from 60 renal transplant patients (19 female and 41 male) were evaluated using both immunoassays. Subsequently, we switched the assay for detection of everolimus blood concentrations from LTIA to ECLIA as a clinical application. Three quality control (QC) samples for LTIA were analysed using ECLIA, and 3 QC samples for ECLIA were analysed using LTIA. RESULTS: The Deming regression of ECLIA versus LTIA generated the following parameters: slope, 1.0067 and intercept, 1.7489 ng/mL, in the analysis of 230 samples. Bland-Altman analysis showed an average positive bias of 1.73 ng/mL between ECLIA and LTIA. When the clinical apparatus was switched from LTIA to ECLIA, the average everolimus blood concentration assayed by LTIA before switching was 3.57 ng/mL, whereas that by ECLIA after switching in the same patients taking the same daily dose (mean: 1.43 mg/day) was 5.85 ng/mL. The QCs assayed using LTIA were lower by an average of 67.3% (range: 55.8%-79.5%) for ECLIA, and in the same 230 samples from patients, the everolimus blood concentrations assayed by LTIA were lower by an average of 67.4% (range: 37.1%-114.5%) of ECLIA. WHAT IS NEW AND CONCLUSION: Analysis of everolimus concentrations by immunoassays with high precision and accuracy is required to ensure long-term survival of transplant recipients. Although the concentrations of QCs and calibrators of everolimus in LTIA were previously corrected to 70% concentration because of cross-reactivity with everolimus metabolites, these adjustments may need to be reviewed.


Subject(s)
Agglutination/drug effects , Everolimus/blood , Immunoassay/methods , Immunosuppressive Agents/blood , Immunoturbidimetry/methods , Latex/immunology , Diagnostic Tests, Routine/methods , Drug Monitoring/methods , Female , Humans , Kidney Transplantation/methods , Male , Middle Aged
2.
Cytopathology ; 28(6): 455-466, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29094782

ABSTRACT

Although Asian thyroid practices have implemented the American Thyroid Association guidelines, significant deviations in actual risk of malignancy (ROM) have been reported. With review of the literature from Asia, the authors examine the underlining reasons for actual ROMs reported in Asia being so different from western practice based on the author's perspective. Although the most popular diagnostic system for thyroid cytology used in Asian countries is the Bethesda system, the Japan Thyroid Association published clinical guidelines, including a national reporting system for thyroid cytology, to adapt conservative clinical management (active surveillance and strict triage patients for surgery) for low-risk thyroid carcinomas. As less aggressive clinical management is favoured in Asian societies, strict triage of patients with indeterminate thyroid nodules for surgery is usually applied, which ultimately reduces overtreatment of indolent thyroid tumours. As a result, low resection rates and high ROMs for indeterminate nodules were achieved in Asian practices using the same Bethesda system. Recently, borderline thyroid tumours were introduced in the thyroid tumour classification and significant decreases in ROMs have been reported in the indeterminate categories in western practice. However, ROM of indeterminate nodules remained high in Asian practice even after borderline tumours were deemed benign. These results suggested that the diagnostic threshold of papillary thyroid carcinoma-type nuclear features varied among practices (stricter in Asia than in western practice), and diagnostic surgery was not performed for a significant number of indeterminate nodules with benign clinical features in Asian practice, resulting in low rates of borderline tumours in surgically-treated patients.


Subject(s)
Carcinoma, Papillary/drug therapy , Cytodiagnosis , Medical Overuse/prevention & control , Thyroid Neoplasms/pathology , Thyroid Nodule/pathology , Biopsy, Fine-Needle/methods , Humans , Thyroid Cancer, Papillary , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/drug therapy
3.
Transplant Proc ; 49(8): 1786-1790, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28923626

ABSTRACT

OBJECTIVES: Using a strategy of placing a surgical drain after kidney transplantation, the duration of a lymphatic fluid leakage and prevalence of a symptomatic lymphocele were retrospectively analyzed. The risk factors for persistent lymphatic fluid leakage or asymptomatic lymphocele were evaluated using multivariate analysis to estimate the origin of the lymphatic fluid leakage. MATERIALS AND METHODS: Patients with persistent lymphatic fluid leakage and symptomatic lymphocele were defined as those with lymphatic fluid drainage >50 mL for more than 15 days and those who required a percutaneous drainage of the lymphocele, respectively. RESULTS: Persistent lymphatic fluid leakage and symptomatic lymphocele were observed in 40 (16.4%) and 10 (4.1%) of a total of 244 patients, respectively. The maximum durations of lymphatic fluid drainage from the initial drain tube and the second drainage of the symptomatic lymphocele were 48 and 28 days, respectively. Anastomosis of the graft artery to the external iliac artery was an independent risk factor to predict persistent lymphatic fluid leakage or symptomatic lymphocele after kidney transplantation (odds = 2.597, P = .008). CONCLUSION: The findings of the study suggest that the lymphatic fluid originates from the recipient's iliac lymph trunk rather than from the graft kidney.


Subject(s)
Drainage/methods , Kidney Transplantation/adverse effects , Lymphatic Vessels/pathology , Lymphocele/epidemiology , Vascular Diseases/epidemiology , Adult , Aged , Anastomotic Leak/epidemiology , Anastomotic Leak/etiology , Female , Humans , Lymphocele/etiology , Lymphocele/prevention & control , Male , Middle Aged , Multivariate Analysis , Prevalence , Retrospective Studies , Risk Factors , Vascular Diseases/etiology , Vascular Diseases/prevention & control
4.
Eur J Obstet Gynecol Reprod Biol ; 201: 140-5, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27131232

ABSTRACT

OBJECTIVE: Maternal exposure to magnesium sulphate has a neuroprotective effect in premature infants. This study aimed to examine this neuroprotective effect and the dose-response relationship in very-low-birthweight infants born between 24 and 32 weeks of gestation. STUDY DESIGN: A retrospective cohort study compared the rates of mortality and brain damage between three groups: no magnesium sulphate, low-dose (<50g) magnesium sulphate and high-dose (≥50g) magnesium sulphate. RESULTS: Japanese maternal and neonatal databases were linked using six key parameters from 2003 to 2007. Of 298,514 deliveries, 9101 were very-low-birthweight infants. Among these, full matching was possible for 5562 infants. Of the fully-matched infants, 3763 were born between 24 and 32 weeks of gestation, and 1813 (48%) were followed-up beyond 18 months. A multivariate analysis of the data, including gestational age, sex, fetal growth restriction, antenatal steroids and low pH (<7.1), showed that the low-dose group had no beneficial effects in terms of a reduction in mortality or incidence of brain damage (cerebral palsy or mental retardation). The high-dose group showed a significantly higher mortality rate [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.2-2.9]. A stratified subgroup analysis of infants born between 28 and 32 weeks of gestation showed that survivors in the low-dose group had significantly lower rates of cerebral palsy (OR 0.4, 95% CI 0.2-0.98) and brain damage (OR 0.2, 95% CI 0.1-0.9), while the high-dose group did not show any significant changes. CONCLUSION: This study found that antepartum exposure to magnesium sulphate did not reduce the infant mortality rate or influence neurological outcomes. However, among infants born between 28 and 32 weeks of gestation, rates of cerebral palsy and brain damage were found to be significantly lower among survivors in the low-dose group.


Subject(s)
Brain Diseases/prevention & control , Cerebral Palsy/prevention & control , Magnesium Sulfate/therapeutic use , Neuroprotective Agents/therapeutic use , Databases, Factual , Delivery, Obstetric , Dose-Response Relationship, Drug , Female , Gestational Age , Humans , Infant , Infant, Extremely Premature , Infant, Newborn , Infant, Premature , Infant, Very Low Birth Weight , Japan , Male , Perinatal Mortality , Pregnancy , Retrospective Studies
5.
Ann Oncol ; 27(7): 1257-66, 2016 07.
Article in English | MEDLINE | ID: mdl-27052653

ABSTRACT

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.


Subject(s)
Carcinoma/pathology , Carcinosarcoma/pathology , Sarcoma/pathology , Uterine Neoplasms/pathology , Adult , Aged , Carcinoma/drug therapy , Carcinoma/epidemiology , Carcinoma/radiotherapy , Carcinosarcoma/drug therapy , Carcinosarcoma/epidemiology , Carcinosarcoma/radiotherapy , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Ifosfamide , Middle Aged , Neoplasm Staging , Radiotherapy, Adjuvant , Retrospective Studies , Sarcoma/drug therapy , Sarcoma/epidemiology , Sarcoma/radiotherapy , Survival Analysis , Treatment Outcome , Uterine Neoplasms/drug therapy , Uterine Neoplasms/epidemiology , Uterine Neoplasms/radiotherapy
6.
Oncogenesis ; 5: e195, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26878389

ABSTRACT

Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the role FASN on HFD-mediated PCa progression remains unclear. We investigated the role of FASN on PCa progression in LNCaP xenograft mice fed with HFD or low-fat diet (LFD), in PCa cells, and in clinical PCa. The HFD promoted tumour growth and FASN expression in the LNCaP xenograft mice. HFD resulted in AKT and extracellular signal-regulated kinase (ERK) activation and 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation. Serum FASN levels were significantly lower in the HFD group (P=0.026) and correlated inversely with tumour volume (P=0.022). Extracellular FASN release was enhanced in the PCa cells with phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) inhibition and AMPK signalling activation. FASN inhibition resulted in decrease of PCa cell proliferation through PI3K/MAPK downregulation and AMPK activation. Furthermore, AMPK activation was associated with FASN downregulation and PI3K/MAPK inactivation. Clinically, high FASN expression was significantly associated with high Gleason scores and advanced pathological T stage. Moreover, FASN expression was markedly decreased in the PCa response to androgen deprivation therapy and chemotherapy. HFD modulates FASN expression, which may be an important mechanism in HFD-associated PCa progression. Furthermore, a critical stimulatory loop exists between FASN and the PI3K/MAPK system, whereas AMPK signalling was associated with suppression. These may offer appropriate targets for chemoprevention and cancer therapy in HFD-induced PCa.

7.
Br J Radiol ; 87(1042): 20130791, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25074719

ABSTRACT

OBJECTIVE: To evaluate the role of diffusion-weighted MRI (DW-MRI) as an imaging biomarker for upper urinary tract cancer (UUTC) that has already metastasized or will metastasize soon. METHODS: 61 patients clinically diagnosed with UUTC were prospectively enrolled in this study. All the patients underwent MRI, including DW-MRI, prior to any interventions. Correlations between apparent diffusion coefficient (ADC) and other clinicopathological variables, including metastasis-free survival, were analysed. RESULTS: Median follow-up period was 938 days. Of the 61 patients, 12 had any metastases at the initial diagnosis. 11 patients developed metastases during the follow-up period. These 23 patients were categorized as "Metastatic". Of the remaining 38 patients, 35 with a follow-up period longer than 400 days were categorized as "Localized". ADC was significantly lower in the Metastatic category than in the Localized (p = 0.0002) category. Multivariate analysis of pre-operative variables identified ADC (cut-off value, 1.08 × 10(-3) mm(2) s(-1)) and clinical T stage based on T2 weighted MRI as an independent predictive factor of metastatic UUTC. 46 patients without any metastases during the initial diagnosis were stratified into a high-risk group (16 patients with low ADC and clinical T3-4) and a low-risk group (30 patients with high ADC or clinical Ta-2). The 3-year metastasis-free survivals were 45% and 93%, respectively. CONCLUSION: In the current study, UUTC with lower ADC value is more likely to have metastatic potential. Incorporating ADC with clinical T stage helps to differentiate metastatic UUTC at the initial diagnosis. ADVANCES IN KNOWLEDGE: DW-MRI is a potential imaging biomarker reflecting metastatic propensity of UUTC.


Subject(s)
Diffusion Magnetic Resonance Imaging , Urologic Neoplasms/pathology , Biomarkers, Tumor , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Image Processing, Computer-Assisted , Kaplan-Meier Estimate , Kidney Neoplasms/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Urinary Bladder Neoplasms/pathology , Urologic Neoplasms/diagnosis , Urologic Neoplasms/mortality
8.
Br J Surg ; 99(6): 849-54, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22418853

ABSTRACT

BACKGROUND: The effects of anastomotic complications after laparoscopically assisted gastrectomy (LAG) have not been studied widely. The aims of this observational study were to identify potential factors that predict anastomotic complications and investigate the impact of anastomotic complications in patients undergoing gastrectomy for early gastric cancer. METHODS: The study included consecutive patients with histologically proven T1 gastric adenocarcinoma treated by LAG with regional lymphadenectomy between August 1997 and March 2008, who had not received neoadjuvant chemotherapy. Anastomotic complications included anastomotic leakage, stricture and remnant gastric stasis of grade II or higher (modified Clavien classification) and were identified by clinical assessment and confirmatory investigation. Predictive factors for the development of anastomotic complications were identified by univariable and multivariable analyses. Long-term survival with or without anastomotic complications was examined. RESULTS: Anastomotic complications occurred in 37 (9·3 per cent) of 400 patients. Multivariable analysis indicated surgeon experience as the only independent predictor of anastomotic complications (hazard ratio 4·40, 95 per cent confidence interval 2·04 to 9·53; P < 0·001). Patients with anastomotic complications had a significantly worse overall 5-year survival rate than those without (81 versus 94·2 per cent; P = 0·009). CONCLUSION: Anastomotic complications after LAG lead to worse long-term survival.


Subject(s)
Adenocarcinoma/surgery , Gastrectomy/adverse effects , Laparoscopy/adverse effects , Stomach Neoplasms/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Anastomotic Leak/etiology , Anastomotic Leak/mortality , Constriction, Pathologic/etiology , Constriction, Pathologic/mortality , Female , Gastrectomy/mortality , Gastroparesis/etiology , Gastroparesis/mortality , Humans , Kaplan-Meier Estimate , Laparoscopy/mortality , Length of Stay , Male , Middle Aged , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Treatment Outcome
9.
J Clin Pharm Ther ; 36(2): 208-16, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21366650

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. METHODS: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). RESULTS: There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC(0-12)) and maximum plasma concentration (C(max)) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co-administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose-adjusted AUC(0-12) and C(max) of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole. WHAT IS NEW AND CONCLUSION: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Cytochrome P-450 CYP3A/genetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Polymorphism, Genetic , Tacrolimus/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles/therapeutic use , Anti-Ulcer Agents/therapeutic use , Area Under Curve , Cytochrome P-450 CYP2C19 , Drug Interactions , Female , Genotype , Humans , Immunosuppressive Agents/therapeutic use , Lansoprazole , Male , Pharmacogenetics , Polymorphism, Single Nucleotide , Rabeprazole , Tacrolimus/therapeutic use , Time Factors
10.
Fish Physiol Biochem ; 36(4): 969-77, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20127411

ABSTRACT

This paper reports the effect of feeding probiotic diets on blood profiles in rainbow trout. Two experiments were performed: in the first, fish of average weight 75 g were offered either a commercial feed or the same incorporated with 10(9) CFU g(-1) of lactic acid bacteria Lactobacillus rhamnosus for 30 days; in the second study performed for a similar duration, fish of average weight 126 g were offered formulated diets that either contained the same bacteria in heat-killed or freeze-dried form (nearly 10(11) CFU g(-1)), or the basal diet without the bacteria. Blood samples were collected at different times after commencement of probiotic feeding to determine the total cholesterol, triglyceride contents, the plasma alkaline phosphatase activity, plasma protein and hematocrit value. The plasma cholesterol significantly increased upon probiotic feeding in the first experiment. A significant elevation (P<0.05) of plasma cholesterol and triglyceride and alkaline phosphatase activity level was found in the freeze-dried probiotic fed groups at 20 and 30 days postfeeding. This was concomitant with the increased plasma protein and hematocrit values in FD group at 20 and 30 days. Likewise, the heat-killed probiotic fed group registered significantly high values of triglycerides, alkaline phosphatase activity, and plasma protein compared to the control diet fed groups after 20 days of feeding. Thus, alterations in the blood profiles could serve as supplementary information when examining the benefits of probiotics for fish.


Subject(s)
Food, Formulated/microbiology , Lacticaseibacillus rhamnosus , Oncorhynchus mykiss/blood , Probiotics/pharmacology , Alkaline Phosphatase/blood , Analysis of Variance , Animals , Aquaculture/methods , Blood Proteins/analysis , Cholesterol/blood , Hematocrit , Probiotics/administration & dosage , Triglycerides/blood
11.
Kyobu Geka ; 63(1): 29-33, 2010 Jan.
Article in Japanese | MEDLINE | ID: mdl-20077829

ABSTRACT

Two cases of induction chemoradiation followed by surgical resection were reported. A 53-year-old man and a 68-year-old man who had been suffering form alleviate pain in their left shoulder and arms were referred to our hospital. Physical examination revealed Horner's syndrome on the left side in both patients. A transcutaneous needle biopsy confirmed non-small-cell lung cancer. Under the diagnosis of superior sulcus tumor in stage IIIB (T4N0M0), induction chemotherapy and radiation were given. After tumor reduction, they underwent resection through cervical anterior approach because subclavian vessel invasion was suspected. The clavicle was divided for the resection and reconstruction of subclavian artery in case 2. For the treatment of anterior superior sulcus tumors, anterior approach provides a safe and effective exposure.


Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Pancoast Syndrome/therapy , Aged , Combined Modality Therapy , Humans , Male , Middle Aged
12.
Fish Physiol Biochem ; 36(3): 687-697, 2010 Sep.
Article in English | MEDLINE | ID: mdl-19680766

ABSTRACT

Epigallocatechin-3-gallate (EGCG), a very potent antioxidant derived from green tea, was compared with vitamin E in terms of its effects on antioxidant defense and immune response of rainbow trout, by means of a feeding trial of eight weeks. Two of the experimental diets were supplemented with EGCG at either 20 or 100 mg kg(-1) diet (which contained only 30% of the intended levels) and the third was provided with 100 mg kg(-1) vitamin E but not EGCG. The control diet was not supplemented with the test components. Observation of tissue levels indicated that the high amount of EGCG helped to increase the availability of the lipid-soluble antioxidant vitamin E. The lower levels of lipid hydroperoxide in the liver of fish fed the higher amount of EGCG suggested that it was an effective antioxidant. Considering the immune indices, EGCG and vitamin E at 100 mg (actual amounts 31.9 and 94.1 mg kg(-1) diet, respectively) had identical capabilities in improving phagocytic activity and controlling hydrogen peroxide production by leucocytes. However, EGCG could possibly be more effective at enhancing serum lysozyme activity and the alternative complement activity. This work revealed the potential of EGCG as an antioxidant and an immunostimulant for rainbow trout, at least at the inclusion level of 32 mg kg(-1) diet.


Subject(s)
Antioxidants/pharmacology , Catechin/analogs & derivatives , Complement Pathway, Alternative/drug effects , Oncorhynchus mykiss/immunology , Vitamin E/pharmacology , Analysis of Variance , Animals , Catechin/pharmacology , Dietary Supplements , Flow Cytometry , Lipid Peroxides/metabolism , Liver/metabolism , Muramidase/blood , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism
13.
Xenobiotica ; 39(12): 939-45, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19795924

ABSTRACT

The objective of this study was to elucidate the effects of CYP3A5, ABCB1, NR1I2 and NR3C1 BclI gene polymorphisms on prednisolone exposure for 65 Japanese renal transplant recipients in the maintenance stage one year after transplantation. Prednisolone dosage ranged from 2.5 to 15.0 mg day(-1) based on individual immunosuppressive states. The dose-adjusted area under the plasma concentration-time curve (AUC(0-24)) and the maximal plasma concentration (C(max)) of prednisolone in recipients with the BclI G allele were significantly higher than in those with the CC genotype (p = 0.029 and 0.021, respectively), but there were no significant differences in the half-life and T(max) of prednisolone between the two groups. None of the CYP3A5, ABCB1 or NR1I2 allele variants had any significant influence on the dose-adjusted AUC(0-24) of prednisolone. The NR3C1 BclI polymorphism was important in the inter-individual variability of prednisolone pharmacokinetics. The transactivation of the CYP3A4 promoter by prednisolone via the glucocorticoid receptor might be especially responsive for intestinal CYP3A4.


Subject(s)
Asian People/genetics , Kidney Transplantation/physiology , Prednisolone/pharmacokinetics , Adult , Aged , Area Under Curve , Genotype , Humans , Middle Aged , Polymorphism, Genetic
14.
Xenobiotica ; 39(5): 407-14, 2009 May.
Article in English | MEDLINE | ID: mdl-19274604

ABSTRACT

Mycophenolic acid (MPA), converted from the prodrug mycophenolate mofetil (MMF), is generated by intestinal and hepatic esterases. The role of carboxylesterase (CES) in MMF hydrolysis was examined in vitro using human liver microsomes. V(max) and K(m) values of MMF hydrolysis in pooled human liver microsomes were 1368 +/- 44 nmol min(-1) mg(-1) protein and 1030 +/- 65 microM, respectively. Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC(50) values of 77.1, 3.59 and 0.0312 microM, respectively. Eighty Japanese renal transplant recipients that received repeated-doses of MMF, tacrolimus and prednisolone,were evaluated for MPA pharmacokinetics 28 days after transplantation to investigate the relationship between MPA pharmacokinetics and CES2 genetic polymorphisms. No significant differences in MPA pharmacokinetics were observed between CES2 A4595G, C8721T orA-1548G genotype groups. CES2 allelic variants also did not appear to affect plasma MPA concentrations between individuals. In conclusion, the study demonstrated that while CES1 and/or CES2 are involved in the hydrolysis of MMF to MPA, CES2 allelic variants appeared to make only a minor contribution to inter-personal differences in MPA pharmacokinetics.


Subject(s)
Carboxylesterase/genetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Microsomes, Liver/enzymology , Mycophenolic Acid/pharmacokinetics , Adult , Alleles , Asian People/genetics , Carboxylesterase/antagonists & inhibitors , Carboxylesterase/metabolism , Enzyme Inhibitors/pharmacology , Humans , Immunosuppressive Agents/administration & dosage , Isoflurophate/pharmacology , Microsomes, Liver/drug effects , Mycophenolic Acid/administration & dosage , Nitrophenols/pharmacology , Phenylmethylsulfonyl Fluoride/pharmacology , Polymorphism, Genetic , Prednisolone/administration & dosage , Prednisolone/pharmacokinetics , Tacrolimus/administration & dosage , Tacrolimus/pharmacokinetics
15.
J Clin Pharm Ther ; 34(6): 683-92, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20175802

ABSTRACT

OBJECTIVE: The aim of this study was to elucidate the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activating angiotensin receptor blocker (ARB) telmisartan and the non-PPAR-gamma activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients. METHODS: Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation. RESULTS: Dose-adjusted maximum and trough plasma concentration of MPA co-administered with telmisartan were the lowest in all groups. The mean dose-adjusted area under the concentration curve from 0 to 12 h (AUC(0-12)) and AUC(0-6) of MPA co-administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng x h/mL/mg, P = 0.0353 and 63 vs. 96 ng x h/mL/mg, P = 0.0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co-administered with telmisartan was higher than that without ARBs, but not significantly (14.2 vs. 9.1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg). CONCLUSIONS: The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate-glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR-gamma target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Benzoates/pharmacology , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Tetrazoles/pharmacology , Valine/analogs & derivatives , Adult , Area Under Curve , Benzimidazoles/pharmacokinetics , Benzoates/pharmacokinetics , Biphenyl Compounds , Drug Interactions , Female , Humans , Male , Middle Aged , Mycophenolic Acid/pharmacokinetics , Telmisartan , Tetrazoles/pharmacokinetics , Valine/pharmacokinetics , Valine/pharmacology , Valsartan
16.
Neuroscience ; 159(1): 127-35, 2009 Mar 03.
Article in English | MEDLINE | ID: mdl-19010396

ABSTRACT

Activation of N-methyl-d-aspartic acid (NMDA) glutamate receptors (NMDARs) is required for long-term potentiation (LTP) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular mechanisms of learning and memory. We demonstrate here that a brief bath co-application of a low concentration of NMDA, an agonist of NMDARs, and the selective antagonist of NR2B-containing NMDARs, (alpha R, beta S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), to hippocampal slices from young adult rats produced a slowly developing LTP persisting at least for 6 h following a transient depression of synaptic transmission in CA1 synapses. The LTP was likely to occur at postsynaptic site and was initiated by activation of NMDARs, and its development was mediated by cAMP-dependent protein kinase (PKA) activation and protein synthesis. This chemically induced LTP and the tetanus-induced late phase of LTP (L-LTP) were mutually occluding, suggesting a common expression mechanism. Thus, we have demonstrated that a brief bath co-application of NMDA with Ro25-6981 to a slice offers an alternative to electrical stimulation as a stimulation method to induce L-LTP. The chemically induced LTP did not require the low-frequency test stimulation typically used to monitor the strength of synapses during and after drug application. Thus, the LTP may occur at a large fraction of synapses in the slice and not to be confined to a small fraction of the synapses where electrical stimulation can reach and induce LTP. Therefore, this chemically induced LTP may be useful for assessing the biochemical and morphological correlates and the molecular aspects of the expression mechanism for L-LTP that has been proven to correlate to hippocampal long-term memory.


Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Hippocampus/drug effects , Long-Term Potentiation/drug effects , N-Methylaspartate/pharmacology , Phenols/pharmacology , Piperidines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Analysis of Variance , Animals , Biophysics , Drug Combinations , Electric Stimulation/methods , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Male , Rats , Rats, Wistar
17.
J Clin Pharm Ther ; 33(2): 193-201, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18315786

ABSTRACT

OBJECTIVE: The aim of this study was to investigate drug interactions between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) and tacrolimus, as well as the impact of CYP3A5 and UGT2B7 genetic polymorphisms on these drug interactions in 71 Japanese renal transplant recipients. METHODS: Recipients received combination immunosuppressive therapy consisting of tacrolimus and MMF. On day 28 after transplantation, the concentrations of MPA and tacrolimus were measured by high-performance liquid chromatography and microparticle enzyme immunoassay respectively. RESULTS: Acute rejection was over twice more common in recipients with a total area under the observed plasma concentration-time curve (AUC(0-12)) of MPA <70 microg x h/mL than in those with higher values AUC(0-12) values (17% vs. 7%). Using this cut-off AUC value, sensitivity was 70.6% and specificity 55.6% for acute rejection (AR). There was no change in AUC(0-12), maximum plasma concentration, trough plasma concentration, or oral clearance of tacrolimus with variation in dosage or AUC of MPA. There were also no significant differences in the MPA pharmacokinetic parameters among three tacrolimus C(0) groups: 5 < or = C(0) < 10, 10 < or = C(0) < 15 and 15 < or =C(0) < 20 ng/mL. Furthermore, there were no significant differences in MPA pharmacokinetic parameters between the UGT2B7*1/*1 and *1/*2 genotype groups having the CYP3A5*1 allele or the CYP3A5*3/*3 genotype. CONCLUSION: Therapeutic dosages of MMF, do not significantly influence tacrolimus pharmacokinetics, and vice versa. Consequently, MPA and tacrolimus can be safely combined; however, it is necessary to monitor the plasma concentrations of each immunosuppressive agent to minimize acute rejection.


Subject(s)
Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/blood , Prodrugs/pharmacokinetics , Tacrolimus/pharmacokinetics , Adult , Area Under Curve , Asian People/genetics , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , Drug Interactions , Female , Genotype , Glucuronosyltransferase/genetics , Humans , Immunosuppressive Agents/blood , Immunosuppressive Agents/therapeutic use , Male , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use , Polymorphism, Genetic , Prodrugs/therapeutic use , Tacrolimus/blood , Tacrolimus/therapeutic use
18.
Dev Comp Immunol ; 31(4): 372-82, 2007.
Article in English | MEDLINE | ID: mdl-17045337

ABSTRACT

This study elucidates the immune modulation including the expression of cytokine genes following dietary administration of three selected probiotic bacteria--Lactobacillus rhamnosus, Enterococcus faecium and Bacillus subtilis to fish, rainbow trout Oncorhynchus mykiss. They were fed for 45 days on either a basal control diet or one of the three probiotic diets containing the specific bacteria in freeze-dried form at a density of 10(9)CFUgfeed-1. The non-specific immune parameters examined--superoxide anion production by the head kidney leukocytes and the alternate complement activity of serum was improved by probiotic feeding. Besides this, the relative gene expressions of interleukin-1beta1, tumor necrosis factor 1 and 2 and transforming growth factor-beta were up regulated in the spleen and the head kidney. The comparatively better performance of E. faecium could possibly be linked to their suitable ambient temperature conditions. Thus, probiotic bacteria delivered in feed exerts its influence on the immune system of fish, both at cellular and molecular levels.


Subject(s)
Cytokines/biosynthesis , Cytokines/genetics , Immunity, Innate/genetics , Immunologic Factors/physiology , Oncorhynchus mykiss/genetics , Oncorhynchus mykiss/immunology , Probiotics/administration & dosage , Animal Feed/microbiology , Animals , Bacillus subtilis/immunology , Enterococcus faecium/immunology , Immunologic Factors/metabolism , Interleukin-1beta/biosynthesis , Interleukin-1beta/genetics , Lacticaseibacillus rhamnosus/immunology , Oncorhynchus mykiss/microbiology , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/genetics
19.
Int J Clin Pharmacol Ther ; 44(12): 605-13, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17190370

ABSTRACT

OBJECTIVE: Lansoprazole and tacrolimus are substrates of ATP binding cassette (ABC) transporters such as P-glycoprotein (ABCBI/multidrug resistance 1) and cytochrome P450 (CYP). The purpose of this study was to investigate the implication of the ABCB1 C3435Tpolymorphism on the pharmacokinetics of (R)-lansoprazole, the major enantiomer, in CYP2C19 extensive metabolizers (EMs) and on gastroesophageal symptoms in renal transplant recipients receiving tacrolimus. MATERIALS: 24 recipients who were CYP2C19 EMs were studied. METHODS: Oral administration of 30 mg lansoprazole was started 2 days before transplantation. On Day 2 before and Day 28 after transplantation, the plasma concentrations of (R)-lansoprazole and tacrolimus were measured. RESULTS: Pretransplantation, there were no significant differences in the pharmacokinetic parameters of (R)-lansoprazole between the 3 ABCBI C3435T genotypes. However, after renal transplantation, the peak plasma concentration (Cma ) and area under the plasma concentration-time curve (AUCO-24) of (R)-lansoprazole in patients with the ABCB1 C3435T C allele significantly increased, but not in patients with the TT genotype. These pharmacokinetic variations in (R)-lansoprazole did not influence the AUC of tacrolimus. There were no significant differences in the frequency of gastroesophageal symptoms among the three ABCB] C3435Tgenotypes. CONCLUSIONS: (R)-lansoprazole concentrations significantly increased in CYP2C19 extensive metabolizers with the ABCB1 C3435T C allele, but not TT genotype, after renal transplantation. However, the clinical relevance of this observation may be minor because these pharmacogenetic changes were not associated with the occurrence of gastroesophageal complications.


Subject(s)
2-Pyridinylmethylsulfinylbenzimidazoles/therapeutic use , Aryl Hydrocarbon Hydroxylases/genetics , Gastroesophageal Reflux/drug therapy , Mixed Function Oxygenases/genetics , Organic Anion Transporters/genetics , Polymorphism, Genetic , 2-Pyridinylmethylsulfinylbenzimidazoles/blood , 2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Administration, Oral , Adult , Alleles , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/pharmacokinetics , Anti-Ulcer Agents/therapeutic use , Area Under Curve , Aryl Hydrocarbon Hydroxylases/metabolism , Asian People/genetics , Cytochrome P-450 CYP2C19 , Dexlansoprazole , Female , Gastroesophageal Reflux/ethnology , Gastroesophageal Reflux/genetics , Genotype , Half-Life , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Japan , Kidney Transplantation , Lansoprazole , Male , Middle Aged , Mixed Function Oxygenases/metabolism , Tacrolimus/administration & dosage , Tacrolimus/pharmacokinetics , Tacrolimus/therapeutic use
20.
BJOG ; 113(5): 605-7, 2006 May.
Article in English | MEDLINE | ID: mdl-16579804

ABSTRACT

Women with complete atrioventricular heart block without a permanent pacemaker normally receive temporary pacing for labour and birth. Here, we report seven women who were managed without pacing. All women had a temporary pacing lead inserted prior to induction of labour, but none of the women required pacing during labour or birth. Our experience suggests that women with complete atrioventricular block and without permanent pacing do not routinely require temporary pacing for labour and birth.


Subject(s)
Heart Block/therapy , Pacemaker, Artificial , Pregnancy Complications, Cardiovascular/therapy , Prenatal Care/methods , Adult , Female , Humans , Obstetric Labor Complications/therapy , Pregnancy
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