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. k(hydrolysis) was determined in vitro. Nephrotoxicity was estimated from blood urea nitrogen (BUN) level and myelosuppression from platelet count. RESULTS: The platelet count decreased dose-dependently, but BUN did not increase significantly. The degree of decrease in platelet count caused by oxaliplatin and the other three platinum drugs was not explained by the differences of AUC(p) and AUC for the bone marrow but was fitted by a combination of AUC(p) and the toxicity factor (r = 0.908, P < 0.001). CONCLUSION: The product of AUC(p) and the toxicity factor is a useful predictor of the degree of toxicity of oxaliplatin as has been observed with other platinum drugs.

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. METHODS: Analysis was made for all patients who were treated with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer. Regimen of FOLFIRI was compared with modified FOLFOX6 under consideration from clinical and economic standpoints. Progression free survival, response, toxicity and cancer care cost in patients with metastatic colorectal cancer was analyzed. Direct costs based on the fee schedule of the Japanese national health insurance were calculated. RESULTS: Median progression free survival was 7.7 months for FOLFIRI versus 8.4 months for modified FOLFOX6 (P = 0.48). Overall cost for first four cycles was yen756 284 for FOLFIRI and yen1 081 162 for modified FOLFOX6 (P < 0.0001). All grade alopecia was significantly more frequent with FOLFIRI than with modified FOLFOX6 (P = 0.04). All grade neuropathy was more observed with modified FOLFOX6 than FOLFIRI (P = 0.0002). CONCLUSIONS: FOLFIRI is inexpensive in the initial stage of treatment which a number of patients can receive chemotherapy than modified FOLFOX6 as first-line therapy for metastatic colorectal cancer in Japanese national insurance system.

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. R- and S-carvedilol concentrations were measured using HPLC at steady-state after oral administration of carvedilol at 1.25-20 mg o.d. or b.i.d. The data from both studies were used to estimate the population pharmacokinetic parameters and covariates using the nonlinear mixed effects model program. For 40 patients evaluated in one clinical study, the cytochrome P450 (CYP)2D6 *1, *10, and *5 genotypes were determined using allele-specific primer PCR, and individual patients' oral clearance (CL/F) of both enantiomers were estimated by the empirical Bayes method. A one-compartment model with a first-order absorption rate was established, in which body weight and alpha(1)-acid glycoprotein were significant covariates. Individual CL/F values for carvedilol were significantly lower in Japanese CHF patients with the CYP2D6 *1/*5, *5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic parameters and their covariates for each enantiomer in Japanese patients with CHF showed that the CL/F values for R- and S-carvedilol were dependent on body weight, alpha(1)-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of beta-blocker therapy in patients with CHF.

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). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats.

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. Relative mRNA levels of drug-metabolizing enzymes, transporters, nuclear receptors, and proinflammatory cytokines were analyzed with normalization to glyceraldehyde 3-phosphate dehydrogenase expression. mRNAs encoding cytochromes P450 1A2, 2E1, and 3A4, and drug transporters, Na(+)-taurocholate-cotransporting polypeptide, organic anion-transporting peptide-C, and organic cation transporter 1 showed remarkable decreases, and tumor necrosis factor-alpha showed an increase according to fibrosis stage progression. HepG2 cells and primary hepatocytes of two human individuals were treated with interleukin 1beta, interleukin 6, or tumor necrosis factor-alpha. CYP1A2 and Na(+)-taurocholate-cotransporting polypeptide mRNA levels significantly decreased in HepG2 cells with interleukin 1beta and interleukin 6 treatments. CYP2E1 and organic cation transporter 1 mRNA levels significantly decreased with tumor necrosis factor-alpha treatment only in HepG2. These results suggested that down-regulation of CYP1A2, 2E1, and 3A4, and drug transporters, Na(+)-taurocholate-cotransporting polypeptide, organic anion-transporting peptide-C, and organic cation transporter 1, manifested in livers of patients with chronic hepatitis C viral infection, was associated, at least in part, with the elevated production of proinflammatory cytokines, including tumor necrosis factor-alpha.

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. Continuous administration of isoproterenol for 2 weeks produced heart failure, which is characterized by an increased heart rate, cardiac hypertrophy and downregulation of beta-adrenoceptors. The doses of racemic carvedilol and metoprolol were adjusted to obtain a similar heart rate in rats with isoproterenol-induced cardiac hypertrophy. The reduction of left ventricular weight and improvement of cAMP production induced by carvedilol were superior to those induced by metoprolol. Although heart rate, blood pressure and cAMP production were not affected by R-carvedilol, left ventricular weight was significantly reduced as a result of alpha-adrenoceptor blockade. The improvement of cAMP production by S-carvedilol was significantly higher than that induced by coadministration of R-carvedilol and metoprolol, suggesting that beta(2)-adrenoceptor blockade partly contributed to the improvement of signal transduction in rats with isoproterenol-induced cardiac hypertrophy. This study has demonstrated that the effects of carvedilol on cAMP production and cardiac hypertrophy in rats with isoproterenol-induced cardiac hypertrophy are superior to those induced by metoprolol at a similar heart rate.

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. Apparent hydrolysis rates of each drug were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to platinum was estimated as the product of the area under the plasma concentration-time curve for unchanged drug (AUC p), Kp app and the apparent hydrolysis rate constant (k hydrolysis), and toxicity factor was defined as the product of Kp app x k hydrolysis as an intrinsic drug parameter. The relationship between AUC p x toxicity factor and BUN fitted well to an Emax model. In bone marrow, this function was also correlated with platelet count. In summary, the product of AUC p x toxicity factor is a factor determining the pharmacokinetics of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this toxicity factor may be a useful parameter for predicting the degree of toxicity of platinum antitumour compounds.

[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. V. The mean oral clearance was 0.0249 (l/h), and the inter- and intraindividual variation was 30.3% and 28.3%, respectively, in the basic model. The oral clearance was significantly affected by body weight, sex, and age. The final model obtained was expressed by the following equation: oral clearance (l/h)=0.0201 x (body weight (g)/1000)(1.08)x (1-0.282 x drug product), where theophylline alcohol is 0 and Apnecut is 1. The inter- and intraindividual variations in the final model were 15.0% and 15.3%, respectively. The oral clearance of the two oral formulations differed significantly, and this difference should be considered when adjusting the theophylline dose.

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.), 2) the relationship between drug concentration and bactericidal activity and 3) the magnitude of any persistent antibiotic activity (sub-MIC effect, post antibiotic effect, etc.). In the PK/PD approach based on the MIC (static MIC approach), information concerning aspect 1) alone is treated as the quantitative PD parameter (MIC), while information concerning aspects 2) and 3) are not represented as quantified PD parameters in spite of their importance in in vivo pharmacodynamic situation. On the other hand, in the PK/PD approach based on the time-kill profile (dynamic PK/PD approach), information concerning aspects 1) - 3) can all be represented as quantitative dynamic PD parameters (epsilon; the maximum kill rate constant, gamma; the Hill coefficient and EC50; the antibiotic concentration at which 50% of the maximum effect is obtained) together with the growth rates of the organisms (lambda). We thought that the PD characterization of antibiotics should be determined by integrating the dynamic PD parameters and the growth rates, so we developed a new concept integrating these parameters so that a good approximation of the time course of in vivo antibacterial activity exhibited by a antibiotic might be predicted from these parameters and the pharmacokinetics of the drug. To achieve this, we analyzed the time-kill profiles of a wide range of antibiotics against various microorganisms and obtained the dynamic PD parameters and the growth rates for the various combinations of antibiotics and microorganisms. Then we analyzed the causal relationship between the PD characteristics of the antibiotics and the dynamic PD parameters and the growth rates. As a result, we derived the following criteria for predicting the PD characteristics of antibiotics. (i) if the epsilon/lambda is greater than about 10 and gamma is less than one, the pharmacodynamics should be concentration-dependent (ii) if the epsilon/lambda is within the range 1-2 and gamma is about 5 or more, the pharmacodynamics should be time-dependent (iii) if the epsilon/lambda is within the range 1-4 and gamma is in the range 1-12, the pharmacodynamics should be time-dependent or both time- and concentration-dependent. The PD characterization of antibiotics against various strains of different microorganisms can be predicted relatively easily and quickly by utilizing these criteria. These findings make it possible to determine the kinds of causative pathogens to which the antibiotics should be applicable in the clinical sites. Furthermore, it is expected that effective strategies for development and establishing the optimum dosage regimen of novel antibiotics could be worked out more scientifically and efficiently than ever on the basis of the PK/PD parameters corresponding to the predicted PD characters.

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

Background: 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. Using a prospective cohort, we aimed to evaluate pharmacists' role in the community. Methods: We created a patient registry system for community pharmacies to monitor long-term medication use by patients with chronic conditions. Patient drug adherence and potential problems were monitored through regular home visits or telephone calls by the pharmacist at least once a month between patient hospital visits. Patient data were collected and stored in an internet-based system. Results: Over a one-year follow-up, 28 out of 37 registered patients from 14 community pharmacies were continuously monitored. In total, we extracted 19 problems relating to medication use, 17 to physical complaints, eight to patient concerns, and two others. Conclusion: The registry system was useful for identifying medication-related problems as well as patient concerns and changes in their condition. Pharmacists might play a key role in improving patient care in the community.

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. An electronic search was conducted using MEDLINE (1966-September 2006), the Cochrane Library (issue 3, 2006), and Japana Centra Revuo Medicina (1981-September 2006). Medical subject headings used in the searches were azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, tacrolimus, inflammatory bowel disease, and neoplasms. We imposed no language limitation in the searches. Additionally, a manual search of reference listings from all articles retrieved from the electronic databases was performed. Using data obtained from control groups or population-based studies, the incidence of newly developed malignancy in patients with IBD treated with immunosuppressive agents was compared with that of patients with IBD who were not receiving immunosuppressive agents. Statistical analysis for the change in risk of developing malignancy was performed using the weighted mean difference (WMD) normalized to per person-year and its 95% confidence interval. RESULTS: Nine cohort studies met the inclusion criteria for this meta-analysis. Analysis of these studies showed no discernible difference (WMD -0.3 x 10(-3)/person-year; 95% CI -1.2 x 10(-3) to 0.7 x 10(-3)) in the incidence of any kind of malignancy in patients with IBD who received immunosuppressants compared with those who did not receive immunosuppressants. No significant difference in WMD was observed when the data from patients with either Crohn's disease (CD) or ulcerative colitis (UC) were analyzed separately. CONCLUSIONS: Our findings suggest that the administration of immunosuppressive agents in patients with either CD or UC probably does not confer a significantly increased risk of malignancy compared with patients with IBD who are not receiving these agents.

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. The daily dose of warfarin, concentrations of S- and R-warfarin in plasma, and prothrombin time expressed as the international normalized ratio were used as the pharmacokinetic and pharmacodynamic indices. Data were evaluated by a multivariate analysis method. RESULTS: Three missense mutations (47 G>C, 113 A>C, and 1338 A>G) in VKORC1 were newly identified in the Japanese population. The 113 A>C (Asp38Ser) variant decreased the warfarin dose requirement from 3.33 +/- 1.54 mg/d (n = 122) to 1.5 mg/d (n = 1). The variants -1639 G>A in the 5'-upstream region, 1173 C>T in intron 1, and 1542 G>C in intron 2 were in complete linkage disequilibrium, and the frequency of the -1639 G>A variation was only 0.8%, which contrasts with the frequency (39.8%-45.8%) reported previously for white persons. The dose of warfarin was larger in the VKORC1 -1639 GA genotype group (4.55 +/- 1.75 mg/d, P < .001) than in the -1639 AA group (2.94 +/- 1.15 mg/d). The mean daily dose of warfarin was lower in subjects with CYP2C9*1/*3 (1.86 +/- 0.80 mg/d, P = .007) than in subjects with CYP2C9*1/*1 (3.36 +/- 1.43 mg/d). When the relative contributions of the VKORC1 variants, CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3, as well as the clinical characteristics of the patients, diagnoses, and concurrent medications, were compared, the VKORC1 -1639 GA genotype group accounted for 16.5% and CYP2C9 variants accounted for 13.4% of variation in warfarin dose. CONCLUSION: The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of -1639 G>A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin.

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. The mobile phase was hexane:isopropanol:diethylamine (78:22:1, v/v). The excitation and emission wavelengths were set at 284 and 343 nm, respectively. The limits of quantification for the S(-)- and R(+)-carvedilol enantiomers in plasma and blood were both 0.5 ng/ml. Intra- and inter-day variations were less than 5.9%. As an application of the assay, concentrations of carvedilol enantiomer in plasma and blood samples from 15 patients treated with carvedilol for congestive heart failure were determined.

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. RESULTS: The formation of resorufin from ethoxyresorufin was inhibited by 3-indoxylsulfate and 3-indoleacetic acid. The formation of 6beta-hydroxytestosterone from testosterone was inhibited only by 3-indoxylsulfate. These uremic substances reduced the maximum metabolic rate but not the affinity, suggesting that the inhibitory mechanism was noncompetitive. The inhibition of formation of resorufin and 6beta-hydroxytestosterone by 3-indoxylsulfate was also observed in human hepatocytes. The elimination of nicardipine in liver microsomes was decreased significantly in the presence of 3-indoxylsulfate and 3-indoleacetic acid. CONCLUSION: The hepatic metabolism of certain drugs may be inhibited directly by uremic substances such as 3-indoxylsulfate that accumulate in the plasma in patients with chronic renal failure.

Comparison of pharmacokinetics and pharmacodynamics of docetaxel and Cisplatin in elderly and non-elderly patients: why is toxicity increased in elderly patients?

PURPOSE: Following phase I studies of docetaxel and cisplatin in patients with non-small-cell lung cancer, the recommended doses of docetaxel were different for elderly (> or = 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients. PATIENTS AND METHODS: Twenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m(2) for elderly and non-elderly patients, respectively. All patients received 25 mg/m(2) of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients. RESULTS: There were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was -11.2% (95% CI, -21.8 to -0.5%). CONCLUSION: The pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.

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. Sixty-one outpatients undergoing gastrointestinal endoscopy participated in the study. Cognitive effects were evaluated in the diazepam group (n=52) by the digit symbol substitution test (DSST) twice before and 30 min after an intravenous administration of 5 mg diazepam; in the intervening time gastrointestinal endoscopy was performed. Plasma concentrations of diazepam were determined by HPLC. The control group (n=9) was tested by DSST in the same manner. The cognitive effects according to the change in DSST score was significantly decline in the diazepam group compared with the control group (by 0.2 versus -4.6; P=0.014). This prospective study confirmed that cognition was significantly impaired after gastrointestinal endoscopy by premedication to subjects with 5 mg diazepam. There were very wide variations in change in DSST score. However we could not identify the independent variables that best predicted DSST score difference in a multiple regression analysis for age, plasma albumin level, and plasma diazepam concentration 30 min after intravenous administration. We should pay attention to patients' individual states in cognitive performance following gastrointestinal endoscopy after single-dose diazepam.

Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients.

OBJECTIVE: Our objective was to clarify risk factors associated with the development of severe hepatotoxicity during antituberculosis chemotherapy in Japanese children. METHODS: In a retrospective analysis in a 350-bed referral children's hospital in a metropolitan area, the medical charts of all pediatric patients who received antituberculosis chemotherapy between January 1995 and November 1999 were surveyed. Univariate and multivariate analyses were performed to find any demographic parameters (ie, sex, age, height, and body weight), clinical characteristics (ie, nutritional or developmental status, co-infection with hepatitis viruses [B or C] or human immunodeficiency virus, presence of extrapulmonary tuberculosis, or medical history of liver disease), or individual antituberculosis agents used that would be associated with the likelihood of development of severe hepatotoxicity during antituberculous chemotherapy. Severe hepatotoxicity (defined as an elevation of ALT and AST levels that were greater than 5 times the respective reference values) was attributed to the chemotherapy when it developed in children with normal pretreatment values for these parameters and no other potential causes were identified. Those who had abnormal ALT or AST values before treatment were excluded from analysis. RESULTS: Among the 117 patients surveyed (58 males and 59 females; age range, 0 to 16 years), 18 were excluded from the analysis because of abnormal baseline ALT and AST values. Severe hepatotoxicity developed in 8 of the 99 eligible children, and all 8 of those children were younger than 5 years old. The univariate analysis revealed that the children in whom hepatotoxicity developed were significantly (P <.05) younger, were predominantly male, had extrapulmonary tuberculosis, and were given pyrazinamide more often than those who had no hepatotoxicity. However, the multivariate logistic regression analysis revealed that only age and the administration of pyrazinamide would have a significant contribution (P <.05) to the development of severe hepatotoxicity, with odds ratios of 143 (95% confidence interval, 4.2 to 4934.9) and 0.60 (95% confidence interval, 0.39 to 0.90), respectively: the estimated probability of development of hepatotoxicity in a typical pediatric patient at 1, 5, and 10 years receiving pyrazinamide with rifampin (INN, rifampicin) and isoniazid would be 0.95, 0.72, and 0.16, respectively. CONCLUSIONS: This study indicated that intensive monitoring of hepatotoxicity should be performed for younger children (<5 years) receiving pyrazinamide for antituberculosis chemotherapy.

Nonlinear pharmacokinetics of aprindine in guinea pigs.

After intravenous bolus administration of aprindine (AP) to conscious guinea pigs, the semilogarithmic plasma concentration versus time curve was linear at a dose of 2 mg/kg, but convex at doses of 5 and 10 mg/kg. AP concentrations immediately after administration (C(p0)) were almost identical, irrespective of the dose received. The areas under the plasma concentration-time curves (AUCs) were proportional to the AP doses. At 2 mg/kg, the plasma total clearance (CL(tot)) of AP was high (279+/-80 mL/h), and its volume of distribution (Vd(ss)) was large (245+/-99 mL). Total blood clearance and time-averaged blood clearance (CL(ave)) values for AP were similar to those for R(+) propranolol (PL) after intravenous coadministration of R(+) PL (0.25 mg/kg) and AP (2 or 10 mg/kg). An in vitro serum protein binding study showed that the unbound fraction of AP was concentration-dependent. In guinea pigs pretreated with turpentine oil (2 mL/kg/day), the elimination of AP after intravenous doses of 2 and 5 mg/kg closely followed first-order kinetics, while C(p0) and AUC increased in proportion to the AP doses. The bound fraction of AP in the serum was larger after turpentine oil pretreatment than in normal guinea pig serum in vitro. From these observations, the nonlinear pharmacokinetics of AP observed in guinea pigs can be attributed to nonlinear serum protein binding.

Uptake of lamivudine by rat renal brush border membrane vesicles.

Uptake of lamivudine, a nucleoside analogue antiviral agent, by brush border membrane vesicles (BBMV) prepared from rat renal cortex was investigated. Initial uptake of lamivudine by BBMV was stimulated in the presence of an outward pH gradient. Determination of the kinetic parameters of the initial uptake yielded apparent Km and Vmax values of 2.28 mm and 1.56 nmol (mg protein)(-1) (20 s)(-1), respectively. The pH-driven uptake of lamivudine was inhibited by organic cations such as trimethoprim and cimetidine. The inhibitory effect of trimethoprim on lamivudine uptake was competitive, with an apparent Ki of 27.6 microM. The uptake of lamivudine was also inhibited by nitrobenzylthioinosine, a representative inhibitor of nucleoside transport, and by other nucleoside analogues, such as azidothymidine and dideoxycytidine, that are excreted by renal tubular secretion. These findings suggest that efflux of lamivudine at the brush border membrane of renal tubular epithelium is mediated by an H+/lamivudine antiport system, which may correspond to the H+/organic cation antiport system, and that this system is also involved in the renal secretion of other nucleoside analogues.

[A systematic review of the clinical effectiveness of azathioprine in patients with ulcerative colitis].

To clarify the effectiveness and safety of azathioprine (AZA) and 6-mercaptopurine (6MP) in the induction and maintenance of remission in ulcerative colitis (UC) by using a systematic review of published studies. Studies were searched for from within the 1966 to March 2003 MEDLINE database, Cochrane Library 2003 issue 1, and the 1981 to March 2003 Japana Centra Revuo Medicina database. References from published studies and reviews were also obtained. Randomized, placebo-controlled trials of oral AZA or 6MP therapy in adult patients with active or quiescent UC were included. Ratios for the induction and maintenance of remission, the steroid-sparing effect, and the incidence of adverse drug reactions (ADRs) were compared and evaluated between the two study arms and expressed by the odds ratio (OR) specific for the individual studies and the meta-analytic summary for the OR. We could find no randomized controlled trial for 6MP therapy. However, four clinical trials for AZA therapy were included in this meta-analysis. For the induction of remission, the pooled OR of the response to AZA therapy compared with placebo in active UC was 1.45 (95% Confidence Interval (CI): 0.68 to 3.08). For the maintenance of remission, the pooled OR for AZA therapy was 2.26 (95% CI: 1.27 to 4.01). The number needed to treat (NNT) to prevent one recurrence was 6 patients. The pooled OR for AZA therapy's ADRs compared with placebo was 2.11 (95% CI: 0.92 to 4.84). From the viewpoint of effectiveness and safety, this meta-analysis suggests that AZA might be useful in the maintenance of remission in UC patients.