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Mikiko Shimizu

Publications and source records attributed to Mikiko Shimizu.

At least 19 recordsLinked to original sources
PubMed2006

A developed determination of midazolam and 1'-hydroxymidazolam in plasma by liquid chromatography-mass spectrometry: application of human pharmacokinetic study for measurement of CYP3A activity.

This paper describes sensitive and reliable determination of midazolam (MDZ) and its major metabolite 1'-hydroxymidazolam (1-OHMDZ) in human plasma by liquid chromatography-mass spectrometry (LC-MS) with a sonic spray ionization (SSI) interface. MDZ, 1-OHMDZ and diazepam as an internal standard were extracted from 1ml of alkalinized plasma using n-hexane-chloroform (70:30, v/v). The extract was injected into an analytical column (YMC-Pak Pro C(18), 50mmx2.0mmi.d.). The mobile phase for separation consisted of 10mM ammonium acetate and methanol (50:50, v/v) and was delivered at a flow-rate of 0.2ml/min. The drift voltage was 100V. The sampling aperture was heated at 120 degrees C and the shield temperature was 260 degrees C. The total time for chromatographic separation was less than 16min. The validated concentration ranges of this method were 0.25-50ng/ml for both MDZ and 1-OHMDZ. Mean recoveries were 93.6% for MDZ and 86.6% for 1-OHMDZ. Intra- and inter-day coefficient variations were less than 6.5 and 5.5% for MDZ, and 6.1 and 5.7% for 1-OHMDZ at 0.3, 4, 20 and 40ng/ml. The limits of quantification were 0.25ng/ml for both MDZ and 1-OHMDZ. This method was sensitive and reliable enough for pharmacokinetic studies on healthy volunteers, and was applied for the measurement of CYP3A activity in humans after an intravenous (1mg) and a single-oral administration (2mg) of subtherapeutic MDZ dose.

Adult↗
PubMed2006

Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine.

The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Identification of the time-point which gives a plasma rabeprazole concentration that adequately reflects the area under the concentration-time curve.

OBJECTIVE: The purpose of this study is to evaluate whether a simple formula using limited blood samples can predict the area under the plasma rabeprazole concentration-time curve (AUC) in co-administration with CYP inhibitors. METHODS: A randomized double-blind placebo-controlled crossover study design in three phases was conducted at intervals of 2 weeks. Twenty-one healthy Japanese volunteers, including three CYP2C19 genotype groups, took a single oral 20-mg dose of rabeprazole after three 6-day pretreatments, i.e., clarithromycin 800 mg/day, fluvoxamine 50 mg/day, and placebo. Prediction formulas of the AUC were derived from pharmacokinetics data of 21 subjects in three phases using multiple linear regression analysis. Ten blood samples were collected over 24 h to calculate AUC. Plasma concentrations of rabeprazole was measured by an HPLC-assay (l.l.q.=1 ng/ml). RESULTS: The AUC was based on all the data sets (n=63). The linear regression using two points (C3 and C6) could predict AUC(0-infinity) precisely, irrespective of CYP2C19 genotypes and CYP inhibitors (AUC(0-infinity)=1.39xC3+7.17xC6+344.14, r (2)=0.825, p<0.001). CONCLUSION: The present study demonstrated that the AUC of rabeprazole can be estimated by the simple formula using two-point concentrations. This formula can be more accurate for the prediction of AUC estimation than that reflected by CYP2C19 genotypes without any determination, even if there are significant differences for the CYP2C19 genotypes. Therefore, this prediction formula might be useful to evaluate whether CYP2C19 genotypes really reflects the curative effect of rabeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Pharmacokinetics of low-dose nedaplatin and validation of AUC prediction in patients with non-small-cell lung carcinoma.

PURPOSE: The aim of this study was to determine the pharmacokinetics of low-dose nedaplatin combined with paclitaxel and radiation therapy in patients having non-small-cell lung carcinoma and establish the optimal dosage regimen for low-dose nedaplatin. We also evaluated predictive accuracy of reported formulas to estimate the area under the plasma concentration-time curve (AUC) of low-dose nedaplatin. PATIENTS AND METHODS: A total of 19 patients were administered a constant intravenous infusion of 20 mg/m(2) body surface area (BSA) nedaplatin for an hour, and blood samples were collected at 1, 2, 3, 4, 6, 8, and 19 h after the administration. Plasma concentrations of unbound platinum were measured, and the actual value of platinum AUC (actual AUC) was calculated based on these data. The predicted value of platinum AUC (predicted AUC) was determined by three predictive methods reported in previous studies, consisting of Bayesian method, limited sampling strategies with plasma concentration at a single time point, and simple formula method (SFM) without measured plasma concentration. Three error indices, mean prediction error (ME, measure of bias), mean absolute error (MAE, measure of accuracy), and root mean squared prediction error (RMSE, measure of precision), were obtained from the difference between the actual and the predicted AUC, to compare the accuracy between the three predictive methods. RESULTS: The AUC showed more than threefold inter-patient variation, and there was a favorable correlation between nedaplatin clearance and creatinine clearance (Ccr) (r = 0.832, P < 0.01). In three error indices, MAE and RMSE showed significant difference between the three AUC predictive methods, and the method of SFM had the most favorable results, in which %ME, %MAE, and %RMSE were 5.5, 10.7, and 15.4, respectively. CONCLUSIONS: The dosage regimen of low-dose nedaplatin should be established based on Ccr rather than on BSA. Since prediction accuracy of SFM, which did not require measured plasma concentration, was most favorable among the three methods evaluated in this study, SFM could be the most practical method to predict AUC of low-dose nedaplatin in a clinical situation judging from its high accuracy in predicting AUC without measured plasma concentration.

Aged↗
PubMed2006

Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein.

AIMS: We determined whether or not the extent of drug interaction of fexofenadine by itraconazole is time-dependent. METHODS: In a randomized two-phase crossover study, itraconazole was administered orally for 6 days, and, on days 1, 3 and 6, fexofenadine was administered simultaneously. On another occasion, fexofenadine was administered alone. RESULTS: Itraconazole increased fexofenadine AUC(0, infinity), and the % change for difference was 178% (95% CI 1235, 3379), 205% (95% CI 1539, 3319) and 169% (95% CI 1128, 2987) on days 1, 3 and 6 of the 6 day treatment, respectively. CONCLUSIONS: The extent of drug interaction by itraconazole was not time-dependent.

Adult↗
PubMed2006

Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19 genotypes.

OBJECTIVE: Rabeprazole as a proton pump inhibitor (PPI) is mainly reduced to rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 involvement. The aim of this study was to compare possible effects of clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of rabeprazole among CYP2C19 genotypes. METHODS: A three-way randomized, double-blind, placebo-controlled crossover study was performed. Nineteen volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole thioether were monitored up to 24 h after the dosing. RESULTS: In the control phase, the AUC(0-infinity) values for rabeprazole and rabeprazole thioether were 1,005+/-366 and 412+/-149 ng.h/ml in homozygous EMs, 1,108+/-340 and 491+/-245 ng.h/ml in heterozygous EMs, and 2,697+/-364 and 2,116+/-373 ng.h/ml in PMs, respectively. There were significant differences (p<0.001) in the AUC(0-infinity) of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. In the clarithromycin and verapamil phases, no significant differences were found in the pharmacokinetic parameters of rabeprazole compared with those in the control phase irrespective of CYP2C19 genotypes, whereas the AUC(0-infinity) of rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for CYP2C19, there were no statistical differences in the percent increase in those pharmacokinetic parameters between the clarithromycin and verapamil pretreatment phases. CONCLUSION: The pharmacokinetic parameters of rabeprazole were not altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. However, this result shows that both clarithromycin and verapamil significantly influence the disposition of rabeprazole by inhibiting the oxidation of the thioether, since the AUC(0-infinity) of rabeprazole thioether that has no effect on acid secretion increased. Therefore, the pharmacokinetic interactions between rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical significance.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans.

OBJECTIVES: We conducted a randomized controlled trial of the effects of remote ischemic preconditioning (RIPC) in children undergoing repair of congenital heart defects. BACKGROUND: Remote ischemic preconditioning reduces injury caused by ischemia-reperfusion in distant organs. Cardiopulmonary bypass (CPB) is associated with multi-system injury. We hypothesized that RIPC would modulate injury induced by CPB. METHODS: Children undergoing repair of congenital heart defects were randomized to RIPC or control treatment. Remote ischemic preconditioning was induced by four 5-min cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Measurements of lung mechanics, cytokines, and troponin I were made pre- and postoperatively. RESULTS: Thirty-seven patients were studied. There were 20 control patients and 17 patients in the RIPC group. The mean age and weight of the RIPC and control patients were not different (0.9 +/- 0.9 years vs. 2.2 +/- 3.4 years, p = 0.4; and 6.9 +/- 2.9 kg vs. 11.5 +/- 10 kg, p = 0.06). Bypass and cross-clamp times were not different (80 +/- 24 min vs. 88 +/- 25 min, p = 0.3; and 55 +/- 13 min vs. 59 +/- 13 min, p = 0.4). Levels of troponin I postoperatively were greater in the control patients compared with the RIPC group (p = 0.04), indicating greater myocardial injury in control patients. Postoperative inotropic requirement was greater in the control patients compared with RIPC patients at both 3 and 6 h (7.9 +/- 4.7 vs. 10.9 +/- 3.2, p = 0.04; and 7.3 +/- 4.9 vs. 10.8 +/- 3.9, p = 0.03, respectively). The RIPC group had significantly lower airway resistance at 6 h postoperatively (p = 0.009). CONCLUSIONS: This study demonstrates the myocardial protective effects of RIPC using a simple noninvasive technique of four 5-min cycles of lower limb ischemia and reperfusion. These novel data support the need for a larger study of RIPC in patients undergoing cardiac surgery.

Child, Preschool↗
PubMed2006

Sensitive determination of omeprazole and its two main metabolites in human plasma by column-switching high-performance liquid chromatography: application to pharmacokinetic study in relation to CYP2C19 genotypes.

A simple and sensitive column-switching high-performance liquid chromatographic method was developed for the simultaneous determination of omeprazole and its two main metabolites, 5-hydroxyomeprazole and omeprazole sulfone, in human plasma. Omeprazole, its two metabolites and lansoprazol as an internal standard were extracted from 1 ml of alkalinized plasma sample using diethyl ether-dichloromethane (45:55, v/v). The extract was injected into a column I (TSK-PW precolumn, 10 microm, 35 mm x 4.6 mm i.d.) for clean-up and column II (Inertsil ODS-80A column, 5 microm, 150 mm x 4.6mm i.d.) for separation. The mobile phase consisted of phosphate buffer-acetonitrile (92:8 v/v, pH 7.0) for clean-up and phosphate buffer-acetonitrile-methanol (65:30:5 v/v/v, pH 6.5) for separation, respectively. The peak was detected with an ultraviolet detector set at a wavelength of 302 nm, and total time for chromatographic separation was approximately 25 min. The validated concentration ranges of this method were 3-2000 ng/ml for omeprazole, 3-50 ng/ml for 5-hydroxyomeprazole and 3-1000 ng/ml for omeprazole sulfone. Mean recoveries were 84.3% for omeprazole, 64.3% for 5-hydroxyomeprazole and 86.1% for omeprazole sulfone. Intra- and inter-day coefficient variations were less than 5.1 and 6.6% for omeprazole, 4.6 and 5.0% for 5-hydroxyomeprazole and 4.6 and 4.9% for omeprazole sulfone at the different concentrations. The limits of quantification were 3 ng/ml for omeprazole and its metabolites. This method was suitable for use in pharmacokinetic studies in human volunteers, and provides a useful tool for measuring CYP2C19 activity.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

Doppler tissue imaging in the assessment of atrioventricular conduction time: validation of a novel technique and comparison with electrophysiologic and pulsed wave Doppler-derived equivalents in an animal model.

Accurate assessment of atrioventricular conduction time (AVCT) is crucial for early detection of evolving fetal heart block. Simultaneous pulsed wave Doppler (PD) interrogation of left ventricular inflow and outflow is mainly used to study fetal AVCT. Limitations of this modality include its dependency on loading conditions and merging early and late diastolic inflow waves at faster heart rate (HR). Sequential analysis of atrioventricular myocardial motion by Doppler tissue imaging (DTI) might be more useful in this regard. In 15 open-chest pigs, AVCT was measured by PD, DTI, and electrocardiogram at baseline HR and during incremental atrial pacing up to 200 beats/min. Electromechanical delay and pre-ejection period were assessed at baseline and maximal HR. DTI-derived AVCT correlated better with PR intervals and allowed measurements at faster HRs than did PD (P < .05). Pre-ejection period prolonged with faster HR (P < .001), unlike electromechanical delay. In conclusion, DTI allows more accurate measurement of AVCT over a wider HR range than does PD.

Animals↗
PubMed2006

Sensitive determination of itraconazole and its active metabolite in human plasma by column-switching high-performance liquid chromatography with ultraviolet detection.

A simple and sensitive column-switching high-performance liquid chromatographic method for the simultaneous determination of itraconazole (ITZ) and its active metabolite, hydroxyitraconazole (HIT) in human plasma is described. ITZ, HIT, and an internal standard, R051012, were extracted from 1 mL of alkalinized plasma sample using n-heptane-chloroform (60:40, vol/vol). The extract was injected onto column I (TSK precolumn BSA-ODS/S, 5 microm, 10 x 4.6 mm ID) for clean-up and column II (Develosil C8-5 column, 5 microm, 150 x 4.6 mm ID) for separation. The mobile phase consisted of phosphate buffer-acetonitrile (68:32 vol/vol, pH 6.0) for clean-up and phosphate buffer-acetonitrile (35:65 vol/vol, pH 6.0) for separation. The peaks were monitored with an ultraviolet detector set at a wavelength of 263 nm, and total time for chromatographic separation was about 24 minutes. The validated concentration ranges of this method were 3 to 500 ng/mL for ITZ and 3 to 1000 ng/mL for HIT. Mean recoveries were 59.7% for ITZ and 72.8% for HIT. Intraday and interday coefficients of variation were less than 4.6% and 5.0% for ITZ, and 4.6% and 4.9% for HIT at the different concentrations. The limit of quantification was 3 ng/mL for both ITZ and HIT. This method was suitable for therapeutic drug monitoring of ITZ and HIT, and was applied to pharmacokinetic studies in human volunteers.

Adult↗
PubMed2006

Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status.

AIMS: Rabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes. METHODS: A two-way randomized double-blind, placebo-controlled crossover study was performed. Twenty-one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing. RESULTS: During placebo administration, the mean AUCs(0,infinity) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml-1h , 1214 (975, 1453) ng ml-1 h and 2762 (2482, 3042) ng ml-1 h (P<0.001), respectively. Fluvoxamine treatment increased AUC(0,infinity) of rabeprazole and rabeprazole thioether by 2.8-fold (P<0.001) and 5.1-fold (P<0.01) in homozygous EMs, and by 1.7-fold (P<0.01) and 2.6-fold (P<0.01) in heterozygous EMs, and significantly prolonged the elimination half-life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine-mediated percentage increase in AUC(0,infinity) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes. CONCLUSIONS: The present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein.

AIMS: Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. METHODS: In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. RESULTS: Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine. CONCLUSIONS: Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Determination of rabeprazole and its active metabolite, rabeprazole thioether in human plasma by column-switching high-performance liquid chromatography and its application to pharmacokinetic study.

A new sensitive column-switching high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed for the simultaneous determination of rabeprazole, a proton pump inhibitor, and its active metabolite, rabeprazole thioether in human plasma. Rabeprazole, its thioether metabolite and 5-methyl-2-[(4-(3-methoxypropoxy)-3-methyl pyridin-2-yl) methyl sulfinyl]-1H-benzimidazole, as an internal standard were extracted from 1 ml of plasma using diethyl ether-dichloromethane (9:1, v/v) mixture and the extract was injected into a column I (TSK-PW precolumn, 10 microm, 35 mmx4.6mm I.D.) for clean-up and column II (C18 Grand ODS-80TM TS analytical column, 5 microm, 250 mmx4.6 mm I.D.) for separation. The peak was detected with an ultraviolet detector set at a wavelength of 288 nm, and the total time for chromatographic separation was approximately 25 min. Mean absolute recoveries were 78.0 and 88.3% for rabeprazole and rabeprazole thioether, respectively. Intra- and inter-day coefficient variations were less than 6.5 and 4.5% for rabeprazole, 3.6 and 5.3% for rabeprazole thioether, respectively, at the different concentration ranges. The validated concentration ranges of this method were 1-1000 ng/ml for rabeprazole and 3-500 ng/ml for rabeprazole thioether. The limits of quantification were 1 ng/ml for rabeprazole and 3 ng/ml for rabeprazole thioether. The method was suitable for therapeutic drug monitoring and was applied to pharmacokinetic study in human volunteers.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism.

BACKGROUND: We assess whether remote ischemic preconditioning (rIPC) of the recipient can modify ischemia-reperfusion (IR) injury in the donor heart following orthotopic heart transplantation from brain dead donors and to examine potential mechanisms of protection. METHODS: Sixteen pigs weighing from 26 to 34.2 (mean 29.2) kg, randomized to control group (n=5), ischemic preconditioning (rIPC) group (n=6), and to receive rIPC with prior glibenclamide administration (Glib + rIPC) group (n=5) underwent orthotopic heart transplantation with the support of hypothermic (32 degrees C) cardiopulmonary bypass (CPB). The hearts were harvested from donor animal rendered brain dead by balloon compression via a craniotomy. Preconditioning of the recipients was induced by four 5-min cycles of lower limb ischemia. Myocardial infarction (MI) was induced following heart transplantation by 30 min of left anterior descending (LAD) artery occlusion following by 2 hr of regional reperfusion. The extent of myocardial infarction was assessed by triphenyltetrazolium (TTC) staining. RESULTS: Preconditioning of the recipient reduced the mass of MI (6.75+/-6.3 g in rIPC vs. 18.1+/-5.8 g in control, P=0.01), MI to area at risk (ARR) mass ratio by 57% (15.6%+/-15.2% vs. 36.3%+/-13.4%, P=0.04). The protective effect of preconditioning was abolished by pretreatment with glibenclamide. CONCLUSIONS: Remote ischemic preconditioning of the recipient, decreases ischemia-reperfusion injury in the brain dead donor heart following orthotopic heart transplantation via a Katp channel-dependent mechanism. This study suggests that a circulating effector persists after the rIPC stimulus is applied, and excludes an ongoing afferent neurogenic mechanism of cardioprotection.

Animals↗
PubMed2005

Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol.

PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-beta-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) -based dosing. PATIENTS AND METHODS: Fifty-nine patients with advanced non-small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m(2) of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10(-4) x total 6-beta-OHF] - [4.02 x alpha-1 acid glycoprotein] - [0.172 x AST] - [0.125 x age]) and the target AUC of 2.66 mg/L . h. RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m(2) (mean, 58.1 mg/m(2)). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L . h) and 0.40 mg/L . h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L . h) and 0.22 mg/L . h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION: The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.

Aged↗
PubMed2005

Isovolumic but not ejection phase Doppler tissue indices detect left ventricular dysfunction caused by coronary stenosis.

BACKGROUND: Isovolumic acceleration (IVA) obtained by tissue Doppler echocardiography (TDE) is a sensitive and relatively load-independent index for assessing systolic ventricular function. IVA also has the ability to describe the force-frequency relationship during incremental atrial pacing in vivo. OBJECTIVE: We sought to assess the ability of IVA to detect global left ventricular (LV) dysfunction induced by coronary constriction. METHODS: In 6 open-chest anesthetized pigs we examined right ventricular and LV long-axis function by TDE (4-chamber view) with simultaneous invasive measurements of intraventricular pressure, maximum dP/dt, minimum dP/dt, and tau by microtip catheter. A pneumatic cuff was placed around the proximal portion of left anterior descending coronary artery (LAD) and distal flow was monitored by transonic flow probe. Mean arterial pressures were monitored by indwelling cannula. Baseline studies assessed force-frequency relationships with TDE and invasive measurements during incremental pacing from 100 to 200/min (20/min increments every 10 minutes). The protocol was repeated 10 minutes after balloon inflation to reduce LAD blood flow by 50%. RESULTS: Compared with baseline, LV pressure decreased significantly (P = .03, 2-way analysis of variance) as did maximum dP/dt (P < .004) with LAD constriction. At the same time IVA and isovolumic velocity at the LV free wall were significantly reduced (P < .002 and P = .04, respectively) and both IVA and isovolumic velocity were correlated with dP/dt (r = 0.45, P < .002, and r = 0.35, P < .02, respectively). TDE systolic indices were unchanged in the right ventricle. CONCLUSION: IVA detects changes in global LV systolic function during LAD constriction and may be a useful clinical tool to diagnose ischemia.

Animals↗