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To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1* 6/* 28 and SLCO1B1* 15/* 15 genotypes. A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m2) on days 1, 8 and 15 in combination with docetaxel (60 mg/m2) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1* 6/* 28 and SLCO1B1* 15/* 15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic ( UGT1A1* 6/* 28) and transport ( SLCO1B1* 15/* 15) capabilities. [ABSTRACT FROM AUTHOR]

Pravastatin is mainly taken up from the circulation into the liver via organic anion-transporting polypeptide 1B1 ( SLCO1B1 gene product). We examined the contribution of genetic variants in the SLCO1B1 gene and other candidate genes to the variability of pravastatin efficacy in 33 hypercholesterolemic patients. In the initial phase of pravastatin treatment (8 weeks), heterozygous carriers of the SLCO1B1*15 allele had poor low-density lipoprotein cholesterol (LDL-C) reduction relative to non-carriers (percent reduction: −14.1 vs −28.9%); however, the genotype-dependent difference in the cholesterol-lowering effect disappeared after 1 year of treatment. Cholesterol 7α-hydroxylase ( CYP7A1) and apolipoprotein E ( APOE) are known to contribute to lipid metabolism. Homozygous carriers of the CYP7A1 -204C allele or heterozygotes for both CYP7A1 -204C and APOE ε4 alleles showed significantly poorer LDL-C reduction compared to that in other genotypic groups after 1 year of treatment (−24.3 vs −33.1%). These results suggest that the SLCO1B1*15 allele is associated with a slow response to pravastatin therapy, and the combined genotyping of CYP7A1 and APOE genes is a useful index of the lipid-lowering effect of pravastatin. [ABSTRACT FROM AUTHOR]

The article focuses on the study relevant to the recommendation of the Japanese Society of Hypertension on calcium channel blockers (CCBs) as second line drugs next to the renin-angiotensin (Ang) system (RAS) inhibitor for hypertension with chronic kidney disease (CKD) treatment. It aims to find out the long-term effects of CCBs on arterial augmentation in CKD. It includes 26 non-diabetic CKD patients with amlodipine treatment and 27 patients on benidipine. The findings were discussed briefly.

The article discusses a comparative study between non-diabetic chronic kidney disease (CKD) patients treated with amlodipine and benidipine. The results revealed the superiority of benidipine over amlodipine in renoprotection as the anti-hypertensive supplement to the RAS inhibitor when similar blood pressure levels are attained. The study suggests that the influence on augmentation index (AI) varies among types of calcium chemical blockers (CCB) in patients with CKD.

Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large inter-patient variability in the clinical efficacy of metformin. The sequences of the 5′-flanking and coding regions of the two genes of interest were screened by single-strand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, −43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% ( P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to develop a population pharmacodynamic (PPD) model to describe uric acid (UA)–lowering effects in patients treated with febuxostat based on electronic medical records in 2 independent hospitals (university and city hospitals). Interhospital differences in the PPD model were also evaluated. We conducted the following 2 approaches to build the PPD models. A PPD model was developed separately using individual hospital data, and structural models and covariates between the two hospitals were compared (approach A). Another PPD model was developed using all available data from both hospitals, and differences between the 2 hospitals were evaluated by performing a covariate analysis on all PPD parameters (approach B). PPD analyses were performed by NONMEM using data from 358 patients. In both approaches, one indirect response model was established. In approach A, 2 diuretics (loops and thiazides) and renal function tests (Scr or BUN) were selected as covariates for the UA baseline level (serum UA levels just before the febuxostat treatment), whereas 2 diuretics and BUN were selected in approach B. A covariate analysis indicated that loops and thiazides increased UA baseline levels by 7%–14% and 6%–11%, respectively. In approach B, “hospital” was identified as a significant covariate for the UA baseline level; the baseline level was 7% higher in the city hospital. A PPD analysis may provide a precise description of the time course of the UA‐lowering effects of febuxostat and quantitatively detect an interhospital difference in the UA baseline level. [ABSTRACT FROM AUTHOR]

Health-related quality of life ( HRQOL) is an important measure of how disease affects patients' daily life. Conventional in-center hemodialysis ( CHD) patients have been found to have decreased HRQOL. Recent study reported that at-home hemodialysis ( HHD) improved the long-term HRQOL compared with CHD; however, there have been no data from Japanese HHD patients. A sample of 80 Japanese hemodialysis patients (46 HHD and 34 CHD) was matched for age, sex, and cause of end-stage renal disease. Patient HRQOL was measured using two health surveys: Medical Outcomes Study 36 Item Short Form Health Survey- Version 2 and Kidney Disease Quality of Life- Short Form. HHD patients reported better scores on seven out of eight domains (all domains except general heath) of the Medical Outcomes Study 36 Item Short Form Health Survey- Version 2, as well as better Kidney Disease Quality of Life- Short Form scores with respect to symptoms and problems, effect of kidney disease, and work status. No significant differences were observed for burden of kidney disease, cognitive function, quality of social interaction, sexual function, or sleep. More than 65% of HHD patients stated that they were not bothered at all by limitations on food and water intake. Japanese HHD patients demonstrate significantly higher HRQOL scores. However, while their HRQOL and employment rate were high and they were able to enjoy fewer dietary restrictions, kidney disease remained a great burden. [ABSTRACT FROM AUTHOR]

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension. Furthermore, daily variations of blood pressure are relatively large in patients treated with hemodialysis, partly due to ultrafiltration. Twenty hypertensive patients with end-stage renal diseases whose blood pressure was controlled by a single antihypertensive agent, either angiotensin receptor antagonist (ARB) or calcium channel blocker (CCB), were enrolled into the study. Home blood pressure measurements were also performed. Average systolic and diastolic blood pressures were similar between two agents. However, variations of systolic blood pressure during ARB treatment were greater than those of CCB, and maximal differences in daily systolic blood pressure during treatment with ARB (19 ± 7 mmHg) were greater than those with CCB (14 ± 6 mmHg, p < 0.01). Systolic blood pressure measured after hemodialysis under ARB therapy (110 ± 6 mmHg) was lower than that of CCB (118 ± 6 mmHg, p < 0.05). Daily variations of diastolic blood pressure were similar between ARB and CCB periods. Our results indicate that variations of systolic blood pressure during ARB treatment are larger than CCB, and suggest that CCB is useful to obtain the better quality of blood pressure control, improving blood pressure stability by preventing substantial drops in blood pressure in hypertensive patients with end-stage renal diseases. [ABSTRACT FROM AUTHOR]

Our previous study indicated that the exchange from an angiotensin receptor blocker (ARB) to aliskiren reduced morning blood pressure and albuminuria in hypertensive patients with diabetic nephropathy. We extended the above study and assessed the effects of exchanging from an ARB to aliskiren on home blood pressure in hypertensive patients with diabetic nephropathy on chronic hemodialysis. The patients who were persistently hypertensive despite antihypertensive therapy, including ARB, were considered as candidates for the exchange from the ARB to aliskiren. Patients' age and durations of diabetes and hemodialysis were averaged as 62 ± 9 years old, 15 ± 8 and 7 ± 3 years, respectively. Aliskiren decreased morning systolic blood pressure (149 ± 14 to 144 ± 13 mm Hg, n = 30, P < .01) and plasma renin activity (3.5 ± 1.1 to 1.2 ± 0.6 ng/mL/h, P < .01) without changes in serum potassium. Aliskiren also reduced interdialytic weight gain (2.7 ± 0.6 to 2.5 ± 0.5 kg/interval, P < .05) and attenuated the magnitude of intradialytic declines in systolic (−20 ± 11 to −17 ± 10 mm Hg, P < .05) and diastolic blood pressure (−9 ± 6 to −5 ± 5 mm Hg, P < .01). The exchange from an ARB to aliskiren is safe and useful to control home blood pressure in hypertensive hemodialysis patients with diabetic nephropathy. Aliskiren reduced both intradialytic blood pressure drops and interdialytic weight gain in patients with DN. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a leading disease that requires renal replacement therapy. The progression of renal dysfunction in DN is faster than the other renal diseases. While antihypertensive therapy reduces albuminuria, a good indicator for the progression, hypertension in DN is treatment resistant. Among patients with DN who took angiotensin receptor blockers (ARBs), 27 patients who exhibited poor control of albuminuria were enrolled into the study. Angiotensin receptor blocker was exchanged to aliskiren (150-300 mg/d) and clinical parameters were followed for 6 months. Exchange to aliskiren decreased albuminuria (1.57 ± 0.68 to 0.89 ± 0.45 g/gCr, P < .01) without changes in estimated glomerular filtration rate and office blood pressure (BP). Body weight and hemoglobin A1c were not altered. Aliskiren also reduced plasma renin activity (2.0 ± 0.9 to 1.2 ± 0.6 ng/mL/h, P < .01). While evening BP was unchanged, morning systolic BP (139 ± 8 to 132 ± 7 mm Hg, P < .01) and diastolic BP (81 ± 7 to 76 ± 6 mm Hg, P < .05) were decreased significantly after 6 months. Our results indicated that aliskiren decreased BP, especially morning BP in hypertensive patients with DN. The present data suggest that aliskiren exerts renoprotective actions including reduction in albumin excretion for patients with DN. [ABSTRACT FROM AUTHOR]

Abstract: Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3′-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64±4.02 versus 9.75±6.58 and 0.64±0.75 versus 1.48±1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy. [Copyright &y& Elsevier]

Aim. Height is an important determinant of augmentation index (AI) that anticipates cardiovascular prognosis. There is a scanty of the data whether short height predicts survival in patients with end-stage renal diseases, a high risk population. Methods. Fifty two hypertensive patients with type 2 diabetic nephropathy receiving hemodialysis and 52 patients with nondiabetic nephropathy were enrolled. In addition to AI estimated with radial artery tonometry, classical cardiovascular risk factors were considered. Patients were followed for 2 years to assess cardiovascular prognosis. Results. Cox hazards regression revealed that both smoking and shortness in height independently contributed to total mortality and indicated that smoking as well as the presence of left ventricular hypertrophy predicted cardiovascular mortality. Our findings implicated that high AI, the presence of diabetes, and low high-density lipoprotein cholesterol were significant contributors to cardiovascular events. Conclusions. Our findings provide new evidence that shortness in height independently contributes to total mortality in hemodialysis patients. [ABSTRACT FROM AUTHOR]

Abstract: Bronchial asthma is characterized by chronic airways inflammation and reversible airflow limitation. In patients with asthma, symptoms generally worsen during the early hours of the morning, and pulmonary function often deteriorates at the same time, suggesting a role for chronopharmacotherapy. Several drugs for asthma have been developed based on chronopharmacology. Most medications employed for the chronotherapy of asthma are administered once at night with the goal of preventing chronic airway inflammation or development of airflow limitation. In addition to bronchodilators, the inhaled glucocorticosteroid ciclesonide is now available with once-daily dosing, which also improves patients'' compliance. Numerous investigations have demonstrated the usefulness of chronotherapy for asthma, especially for patients with nocturnal asthma. This review focuses on chronotherapy of asthma, and also provides a molecular biological explanation for the influence of asthma medications on the clock genes. [Copyright &y& Elsevier]

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension, and their blood pressure elevates in winter. However, seasonal changes in daily variations of blood pressure are poorly assessed in patients treated with hemodialysis. Thirty hypertensive patients with end-stage renal diseases were enrolled in the study. Dry weight and antihypertensive medications were altered when they were necessary. Home blood pressure measurements were performed at least for 1 week in each season; April–May 2008, July–August 2008, October–November 2008, and January–February 2009. Both morning and evening systolic blood pressures (SBPs) showed significant seasonal changes ( p < 0.01), with the highest blood pressure in winter (162 ± 18 and 135 ± 22 mmHg in morning and evening). Morning diastolic blood pressure (DBP) also exhibited seasonal changes ( p < 0.05), with the highest blood pressure in fall ( 78 ± 8 mmHg). Evening DBP did not manifest seasonal deviations. Morning-evening differences in SBP and DBP were the greatest in winter (28 ± 21 and 10 ± 9 mmHg in SBP and DBP, p < 0.01), and the smallest in summer (16 ± 12 and 6 ± 5 mmHg). Daily variations of SBP and DBPs in spring (19 ± 12 and 7 ± 6 mmHg) and fall (20 ± 13 and 9 ± 8 mmHg) were between those of summer and winter. Our results indicate that not only averaged blood pressure but also variations of blood pressure in winter are larger than the other seasons, and suggest that these blood pressure variations participate in cardiovascular events in hypertensive patients with end-stage renal diseases. [ABSTRACT FROM AUTHOR]

Although the patients with diabetic nephropathy suffered high cardiovascular risk, augmentation index (AI) in diabetic nephropathy has been poorly characterized. Cross-sectional studies were performed on 26 diabetic and 27 nondiabetic nephropathic patients. Home blood pressure was examined. In addition, blood pressure, pulse rate, and AI were measured in both supine and sitting positions. Patient backgrounds such as age, sex, sitting blood pressure, and pulse rate were similar between two groups. Circadian variations of home blood pressure were preserved in nondiabetic patients, but disappeared in diabetes. Changing from supine to sitting position induced greater decrements of systolic blood pressure (ΔSBP −9 ± 8 mmHg) and AI (ΔAI −7 ± 10) in the diabetic group than in nondiabetic patients (ΔSBP −4 ± 12 mmHg, ΔAI −2 ± 9). Multivariate regression analysis revealed that AI in a sitting position correlated positively to SBP and inversely to pulse rate. Of interest, AI in supine position related positively to age, the presence of diabetes and SBP, and inversely to pulse rate. The present data indicate autonomic dysfunction in patients with diabetic nephropathy. Furthermore, our findings provide the evidence that autonomic dysfunction elicits an inadequate physiological arterial contraction in response to postural change, thereby reducing AI that results in the fall of SBP. Finally, the present results suggest that AI in supine, but not sitting position, is suited for detecting cardiovascular risk in diabetes. [ABSTRACT FROM AUTHOR]

Introduction: To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes. Case Report: A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. Conclusion: The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities. [ABSTRACT FROM AUTHOR]

We determined whether human peripheral blood mononuclear cells (PBMCs) could be used to analyze clock genes by studying their mRNA expressions in human bronchial epithelium (BEAS‐2B) and PBMCs following stimulation by the glucocorticoid homologue dexamethasone (DEX) in vitro. PBMCs were obtained at 10:00 h from two diurnally active (&nvsim;07:00 to 23:00 h) healthy volunteers and were evaluated for h Per1 mRNA expression following DEX stimulation in vitro using real time‐PCR analysis. DEX stimulation of human BEAS‐2B cells and PBMCs in vitro led to a remarkable increase of h Per1 mRNA. The glucocorticoid rapidly affected the expression of h Per1 mRNA in PBMCs, suggesting that human PBMCs may be a useful surrogate marker for the investigation of drug effects on clock genes. [ABSTRACT FROM AUTHOR]

To assess the contribution of OATP-C to the hepatobiliary transport of bilirubin, a pharmacogenomic evaluation with regard to polymorphisms of three candidate genes, OATP-C, MRP2, and UGT1A1, was performed. Serum total and direct (conjugated) bilirubin levels were used as phenotypic indexes. Pharmacokinetic variables of pravastatin, a typical substrate for OATP-C, were obtained from our previous study. Among 23 volunteers, two variants (Val417Ile and Ser789Phe) were observed in the MRP2 gene. While there was no apparent effect of these two variants and the UGT1A1*28 on direct bilirubin levels, the OATP-C variants were associated with differences in unconjugated bilirubin levels. Subjects with the OATP-C*15 allele had higher bilirubin levels; unconjugated bilirubin levels in *1b/*1b (n = 3), *1b/*15 (n= 7), and *15/*15 (n = 1) subjects were 0.40 ± 0.10, 0.77 ± 0.35, and 0.70 (mg/dL), respectively. In addition, the correlation between unconjugated bilirubin levels and pharmacokinetic parameters of pravastatin revealed that the subjects with higher bilirubin levels had lower non-renal clearance values, and then higher serum concentrations of pravastatin. Large clinical studies are needed to confirm a role of OATP-C in the carrier-mediated uptake of bilirubin in the human liver. [Copyright &y& Elsevier]

A letter to the editor in response to the article "Multiple gene polymorphisms and warfarin sensitivity," is presented.

MicroRNA (miRNA) are non-coding small RNA that regulate gene expression. MiR-328 is reported to influence breast cancer resistance protein (BCRP) expression in cancer cells. As a large inter-individual difference in BCRP levels is observed in various human tissues, the contribution of miR-328 to these differences is of interest. We hypothesized that DNA methylation in the miR-328 promoter region is responsible for the difference in miR-328 levels, leading to inter-individual variability in BCRP levels in human placenta. The association between placental miR-328 and BCRP levels was analyzed, and then DNA methylation in the miR-328 5'-flanking region and regulatory mechanisms causing inter-individual differences in miR-328 and BCRP levels were examined. MiR-328 expression was significantly correlated with BCRP mRNA (Rs = -0.560, P < 0.01) and protein (Rs = -0.730, P < 0.01) levels. It was also up-regulated by the demethylating agent 5-aza-2’-deoxycytidine in BCRP-expressing cells. Luciferase assays with differentially methylated reporter constructs indicated that methylation in the miR-328 5’-flanking region including a predicted CpG island remarkably decreased transcriptional activity compared to that in unmethylated constructs. We selected CCAAT/enhancer binding protein α (C/EBPα), located within the predicted CpG island, by in silico analysis. To elucidate the role of C/EBPα in miR-328 expression, a chromatin immunoprecipitation assay, promoter deletion analysis, and electrophoretic mobility shift assay (EMSA) were performed. C/EBPα-binding site-truncated constructs showed significantly decreased promoter activity, and EMSA indicated that the C/EBPα-binding sites were located in the CpG island. Finally, the methylation patterns of several CpG dinucleotides proximal to two C/EBPα-binding sites in the miR-328 5’-flanking region were correlated negatively with miR-328 levels, and positively with BCRP levels in human placental samples. These results suggest that methylation patterns in the miR-328 5’-flanking region are involved in the inter-individual difference in BCRP levels in human placenta. [ABSTRACT FROM AUTHOR]