Establishing a Pharmacy-Based Patient Registry System: A Pilot Study for Evaluating Pharmacist Intervention for Patients with Long-Term Medication Use.

In Japan, an increasing number of patients are prescribed a large amount of long-term medications by large hospitals that are then dispensed by a community pharmacy. This practice often leads to considerable wastage of medicine. As part of their professional role, community pharmacists are expected to contribute more to the appropriate use of medication by patients.

[Study of factors affecting drug extraction during continuous hemofiltration and hemodiafiltration, and the contribution of extraction to systemic clearance].

The aim of this study was to elucidate the factors affecting dialysis clearance and the need for additional doses of drugs during and after continuous hemofiltration (CHF) and hemodiafiltration (CHDF). We performed a literature search of MEDLINE using the terms hemofiltration OR hemodiafiltration AND pharmacokinetics to obtain the clearances of CHF and CHDF in a clinical setting. The relationships between molecular weight, the unbound fraction (fuB), ultrafiltration flow rate (UFR) and dialysis flow rate were analyzed.

Effect of nuclear receptor downregulation on hepatic expression of cytochrome P450 and transporters in chronic hepatitis C in association with fibrosis development.

Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dependent on fibrosis stage (F), and that for stage 3 patients (F3) was about 50% less than that for F1 patients. Levels of expression of AhR, together with CAR and PXR, were lowest in livers of F3 patients.

A population approach to eplerenone pharmacokinetics and saturable protein binding.

Eplerenone deviates from linear pharmacokinetics at doses above the therapeutic dose range. In addition, saturable protein binding of eplerenone is observed in in vitro plasma protein binding studies. The purpose of the present study was to clarify the factors contributing to the nonlinear pharmacokinetics of eplerenone.

Population pharmacokinetics of R- and S-carvedilol in Japanese patients with chronic heart failure.

Carvedilol is a beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were conducted to evaluate the population pharmacokinetics and pharmacodynamics of R- and S-carvedilol, and associated covariates, in patients with CHF. Fifty-eight patients (male=45, female=13) with New York Heart Association class I-IV CHF were enrolled in two clinical studies.

Clinical and economic evaluation of first-line therapy with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer.

Objective: Recently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m(2)) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.

Pharmacokinetics and toxicodynamics of oxaliplatin in rats: application of a toxicity factor to explain differences in the nephrotoxicity and myelosuppression induced by oxaliplatin and the other platinum antitumor derivatives.

Purpose: We previously reported that the product of the area under the plasma concentration-time curve (AUC(p)) and a toxicity factor, which in turn was defined as the product of the apparent ratio of tissue to plasma concentration (Kp(app)) and the apparent hydrolysis rate constant (k(hydrolysis)), was a determinant of the different degrees of toxicities induced by platinum drugs, cisplatin, carboplatin and nedaplatin. We tested this model with oxaliplatin.

Methods: Oxaliplatin was administered to rats by intravenous bolus or infusion, and the linearity of pharmacokinetics, total clearance and the Kp(app) at steady state were determined.

Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer.

Purpose: To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients.

Methods: We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets.

Results: The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1-3) (P = 0.

New concept and a theoretical consideration of the mechanism-based pharmacokinetics/ pharmacodynamics (PK/PD) modeling for antimicrobial agents.

Pharmacodynamic (PD) characterization (concentration-dependent, time-dependent, etc.) of antibiotics is determined by aspects of the pharmacodynamic interaction between antibiotics and microorganisms. There are three major aspects of the pharmacodynamic interaction between antibiotics and microorganisms; 1) the minimum drug concentration required for the exhibition of antibacterial activity (MIC: minimum inhibitory concentration, MBC: minimum bactericidal concentration, etc.

Stereoselective first-pass metabolism of verapamil in the small intestine and liver in rats.

Verapamil (VP) is used as a racemate but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of VP and its main metabolite, norverapamil (NVP).

Comparison of pharmacodynamics between carvedilol and metoprolol in rats with isoproterenol-induced cardiac hypertrophy: effects of carvedilol enantiomers.

A recent clinical study has shown that carvedilol has a significantly more favorable effect than metoprolol on survival rate in patients with heart failure. This may be due to actions of carvedilol such as beta(2)-adrenoceptor blockade, alpha-adrenergic receptor blockade and other properties such as anti-oxidant effects that are not yet fully understood. We compared the effects of racemic carvedilol, metoprolol and carvedilol enantiomers on cardiac hypertrophy at similar heart rate in rats with isoproterenol-induced cardiac hypertrophy.

Decreased expression of cytochromes P450 1A2, 2E1, and 3A4 and drug transporters Na+-taurocholate-cotransporting polypeptide, organic cation transporter 1, and organic anion-transporting peptide-C correlates with the progression of liver fibrosis in chronic hepatitis C patients.

Patients with chronic hepatitis C viral infection underwent liver biopsies and laboratory studies for evaluation and to determine subsequent treatment. Changes in status of drug metabolism and disposition may vary with chronic hepatitis C stage and should be assessed. Total RNA was extracted from liver biopsy specimens (n = 63) and reverse transcribed to yield cDNA.

[Population pharmacokinetic analysis of two theophylline formulations in premature neonates and infants with apnea].

A study was conducted to clarify differences in the theophylline pharmacokinetics of two orally available products, theophylline alcohol and Apnecut, in premature neonates and infants using population pharmacokinetic analysis. Fifty-two patients with apnea hospitalized at the National Center for Child Health and Development were enrolled (total number of plasma concentration points=90). Population pharmacokinetic analysis under steady-state conditions was performed using NONMEM ver.

Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats.

The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in their toxicity. The relationships between the pharmacokinetics of these drugs and developed parameters for predicting their nephrotoxicity and myelosuppression were investigated. The drugs were administered to male Wistar rats by intravenous bolus or infusion, and linearity of pharmacokinetics, total clearance and the apparent ratio of tissue concentrations of unchanged drug to plasma concentration (Kp app) at steady state were determined.

Selective binding of tamsulosin to genetic variants of human alpha1-acid glycoprotein.

We investigated the characteristics of binding of tamsulosin to alpha(1)-acid glycoprotein (AGP) genetic variants. The binding of tamsulosin to each of the human AGP variants was determined by ultrafiltration, and the binding characteristics for each variant were compared using binding parameters and inhibition of the binding by disopyramide and warfarin. The affinities of tamsulosin binding to a F1/S variant mixture and total AGP variants were relatively high (dissociation constants 1.

Comparison of pharmacokinetics of individual teicoplanin components in patients.

Teicoplanin is a glycopeptide antibiotic comprising six closely related major components whose activities against specific microbial species differ. In order to clarify the significance of monitoring these components separately for determining the therapeutic effectiveness of teicoplanin, we measured the total and unbound concentrations of the main teicoplanin components in plasma and the unbound fractions in patients. Teicoplanin components in plasma were determined separately by high-performance liquid chromatography following a co-extractive clean-up procedure.

Clinical characteristics influencing the effectiveness of metformin on Japanese type 2 diabetes receiving sulfonylureas.

In this study, we described the effectiveness of metformin on Japanese type 2 diabetes patients receiving sulfonylureas and the clinical characteristics of the patients whose glycemic control were significantly improved with metformin administration. Our results showed that the reduction of glycohemoglobin (HbA1C), serum concentration of total cholesterol, and diastolic blood pressure was statistically significant through the administration of metformin. The clinical characteristics of the patients who responded to metformin therapy exhibited lower systolic blood pressure in addition to higher HbA1C value just before administration of metformin when compared with DeltaHbA1C (HbA1C 6 months after administration of metformin--HbA1C before administration of metformin).

Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease.

Background: There is a concern as to whether long-term administration of immunosuppressants in patients with inflammatory bowel disease (IBD) would increase the risk of malignancy.

Objective: To compare the risks of developing malignancy between patients with IBD treated with immunosuppressive agents and patients with IBD not receiving these agents.

Methods: A systematic literature review was conducted, and a meta-analysis was performed on data retrieved from cohort studies that followed patients with IBD who received immunosuppressive agents for more than a year and documented the incidence of newly developed malignancy.

Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration.

Aims: To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients.

Methods: Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available.

VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients.

Objectives: To compare the genetic and clinical factors that cause large interpatient variability and ethnic differences in warfarin efficacy, we investigated variations of the VKORC1, CYP2C9, and CYP2C19 genes in Japanese subjects. Furthermore, we evaluated the genetic variations and clinical data as contributors of variation in warfarin maintenance dose.

Methods: Gene variations of VKORC1, CYP2C9, and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed.

Determination of KRN321 in rat serum by ELISA and correlation between ELISA and in vitro bioassay.

KRN321, darbepoetin alfa, is a hyperglycosylated analog of recombinant human erythropoietin (rHuEPO, epoetin alfa). We carried out the validation study by using a commercially available ELISA assay kit to establish the ELISA quantitation method for KRN321 in rat serum for the implementation of the pharmacokinetic studies with a lower limit of quantitation at 100 pg/mL and quantitation range from 100 to 4,000 pg/mL. We also established the in vitro bioassay method as an index of biological activity using UT-7/Epo, derived from a human leukemia cell line with a lower limit of quantitation, at 10 ng/mL.

Enantioselective and highly sensitive determination of carvedilol in human plasma and whole blood after administration of the racemate using normal-phase high-performance liquid chromatography.

A highly sensitive HPLC method for enantioselective determination of carvedilol in human whole blood and plasma was developed. Carvedilol and S-carazolol as an internal standard extracted from whole blood or plasma were separated using an enantioselective separation column (Chiralpak AD column; 2.0 diameter x 250 mm) without any chiral derivatizations.

Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes.

Background: Alterations of hepatic drug metabolism in patients with renal failure are poorly understood. In this study, the effects of uremic substances that can be removed by hemodialysis on in vitrohepatic drug metabolism were studied using human liver microsomes and hepatocytes.

Methods: The metabolism of various compounds that undergo oxidation and glucuronidation in the liver was studied using human liver microsomes and hepatocytes in the presence of 11 uremic substances removable by hemodialysis.

Improved quantitative determination of total and unbound concentrations of six teicoplanin components in human plasma by high performance liquid chromatography.

Total and unbound concentrations of six teicoplanin components in human plasma were determined by high-performance liquid chromatography with a coextractive cleanup technique. Unbound concentrations of teicoplanin components were estimated after ultrafiltration of plasma. For determination of each component in plasma, plasma was deproteinized with acetonitrile and the supernatant was shaken for 60 s with chloroform under acidic conditions.

Impairment state of cognitive performance and the affecting factors in outpatients following gastrointestinal endoscopy after single-dose diazepam.

Diazepam is commonly used as premedicant for endoscopic procedures. Wide interindividual differences have been observed in the residual cognitive effects of the drug after gastrointestinal endoscopy. Our aim was to clarify the major factors, including pharmacokinetic factors, contributing to this wide variation in residual cognitive effect after gastrointestinal endoscopy in the study.