Prediction of fluoroquinolone-induced elevation in serum creatinine levels: a case of drug-endogenous substance interaction involving the inhibition of renal secretion.

The aim of this study was to examine the mechanism underlying the elevation in serum creatinine levels caused by a novel des-fluoro(6)-quinolone antibacterial agent, DX-619, in healthy subjects. hOCT2 showed a prominent uptake of creatinine (K(m) = 56.4 mmol/l) among renal organic ion transporters. DX-619 is a potent inhibitor of hOCT2 (K(i) = 0.94 micromol/l), hMATE1 (0.82 µmol/l), and hMATE2-K (0.10 micromol/l). The pharmacokinetic model involving the inhibition of hOCT2 (model 1), hOCT2, and MATE1 or MATE2-K (model 2) could predict the elevation in serum creatinine levels in individual subjects receiving DX-619. This assumes that a significant contribution of tubular secretion (59, 38, and 31%) and reabsorption ranged from 3-50, 4-30, and 5-21% in model 1, -2a (hOCT2/hMATE1), and -2b (hOCT2/hMATE2-K), respectively, for creatinine. In conclusion, DX-619, at its therapeutic dose, is able to inhibit hOCT2, hMATE1, and hMATE2-K, leading to a significant inhibition of tubular secretion of creatinine and consequently to elevation of serum creatinine levels.

Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats.

CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.

Effects of organic solvents on the time-dependent inhibition of CYP3A4 by diazepam.

The effects of organic solvents, acetonitrile, dimethyl sulfoxide (DMSO), and methanol, which are used to dissolve lipophilic test compounds and cytochrome P450 (P450) substrates, and carried into pre-incubation at 1% (v/v), on time-dependent inhibition of CYP3A4 by diazepam, were evaluated using human liver microsomes (HLM) and recombinant human P450 expressed microsomes (rCYPs). The inactivation kinetics of CYP3A4 by diazepam dissolved in acetonitrile and methanol were almost equal with k(inact)/K(I) values, 0.095 and 0.15 min(-1) mM(-1) for HLM and 1.1 and 1.4 min(-1) mM(-1) for rCYP3A4, respectively. In contrast, the inactivation by diazepam dissolved in 1% DMSO significantly decreased and the kinetic parameter could not be calculated. The formation rate of nordiazepam and temazepam metabolized from diazepam dissolved in DMSO were approximately half of those using substrate dissolved in acetonitrile and methanol in both HLM and rCYP3A4. Dixon plots revealed that the metabolism of diazepam in rCYP3A4 were inhibited by DMSO in a competitive or mixed-type manner with K(i) (inhibition constant) values of 6 and 24 mM for nordiazepam and temazepam, respectively. In conclusion, the time-dependent inhibition of CYP3A4 by diazepam was attenuated by DMSO, while acetonitrile and methanol had no effect. The metabolite formation profile under the conditions tested suggested that DMSO competitively inhibit the formation of the reactive metabolites of diazepam by CYP3A4. The effect of organic solvents should be taken into consideration when evaluating the in vitro time-dependent inhibition of new chemical entities.

Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine, clopidogrel, and prasugrel.

Mechanism-based inhibition of CYP2C19 in human liver microsomes by the thienopyridine antiplatelet agents clopidogrel, prasugrel and their thiolactone metabolites was investigated by determining the time- and concentration-dependent inhibition of the activity of S-mephenytoin 4'-hydroxylase as typical CYP2C19 activity and compared with ticlopidine and its metabolite. Clopidogrel was shown to be a mechanism-based inhibitor of CYP2C19 with the inactivation kinetic parameters, k(inact) and K(I), equal to 0.0557 min(-1) and 14.3 microM, respectively, as well as ticlopidine (0.0739 min(-1) and 3.32 microM, respectively). The thiolactone metabolite of ticlopidine and clopidogrel inhibited CYP2C19 only in a concentration-dependent manner. In contrast, neither prasugrel nor its thiolactone metabolite inhibited CYP2C19 at concentrations up to 100 microM. The oxidation of the thiophene moiety of clopidogrel to form their respective thiolactones was found to be the critical reaction that produces the chemically reactive metabolites which cause the mechanism-based inhibition of CYP2C19. Estimation of in vivo drug-drug interaction using in vitro parameters predicted clinically observed data. For clopidogrel, there was no increase in the area under the curve (AUC) at its clinical dose level as predicted by the in vitro parameters, and for ticlopidine the prediction agreed with the clinically observed AUC increase. In conclusion, clopidogrel is potent mechanism-based inhibitors of CYP2C19 as well as ticlopidine, whereas prasugrel did not inactivate CYP2C19. Administration of prasugrel would not cause a clinically relevant interaction with CYP2C19.

Highly frequent anti-idiotype antibody in cynomolgus monkeys developed against mouse-derived regions of anti-Fas antibody humanized by complementarity determining region grafting.

BACKGROUND AND PURPOSE: We investigated the immunogenicity of a humanized anti-human Fas monoclonal antibody, R-125224, in cynomolgus monkeys to estimate its efficacy, as well as its toxicity in clinical situations. EXPERIMENTAL APPROACH: R-125224 was intravenously administered to cynomolgus monkeys at single doses of 0.4, 1.2, 6 and 30 mg kg(-1), and the plasma concentrations of R-125224 and anti-R-125224 antibody (ARA) were measured. We conducted a competitive enzyme-linked immunosorbent assay to determine which part of R-125224 was recognized by ARA. We also examined the retention of radioactivity in mononuclear cells and granulocytes after the injection of [(125)I]-R-125224 to a collagen-induced arthritis monkey model. KEY RESULTS: After i.v. administration of R-125224, the elimination of the plasma R-125224 concentrations was accelerated at around 10 days post-dose, and 10 of 12 monkeys were ARA positive. From an epitope analysis of ARA, the ARA produced in monkeys recognized the mouse-derived regions located in complementarity determining regions, but could not recognize the human IgG. After the injection of [(125)I]-R-125224 to a collagen-induced arthritis monkey model, a significantly longer retention of the radioactivity in mononuclear cells compared to granulocytes was observed. CONCLUSIONS AND IMPLICATIONS: In monkeys, the development of antibodies against R-125224 is rapid and highly frequent. Our hypothesis is that this highly frequent development of ARA might be due to the binding of R-125224 to immune cells, and its circulation in monkey blood might contribute to an increase in its chances of being recognized as an immunogen.

Pharmacokinetics and disposition of recombinant human osteoprotegerin (rhOPG) after intravenous administration in female fischer rats.

1. Osteoprotegerin (OPG) is a secreted member of the tumour necrosis factor receptor (TNFR) family that leads to the suppression of the differentiation, activation and survival of osteoclasts. The objective was to investigate the in vivo pharmacokinetics and tissue distribution of full-length recombinant human OPG (rhOPG) as well as its clearance mechanism using (125)I-labelled protein ((125)I-rhOPG) after intravenous administration to female Fischer rats. 2. (125)I-rhOPG was rapidly and predominantly distributed to the liver after dosing (3 mg kg(-1)). Immunohistochemical analysis indicated that rhOPG was located in the sinusoids of the liver. 3. The hepatic uptake of (125)I-rhOPG (0.01 mg kg(-1)) was partly regulated under a saturable process. Pre-dosing of some sulfated glycans (20 mg kg(-1)), especially dextran sulfate, heparin and fucoidan, markedly inhibited the hepatic uptake of (125)I-rhOPG. The clearance of (125)I-rhOPG was markedly reduced by the conjugation of dextran sulfate. 4. The results suggested that the hepatic clearance of (125)I-rhOPG was mainly mediated by the interaction with glycosaminoglycans.

Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs.

Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg(-1)) and clopidogrel (0.77 mg kg(-1)) were 15.8 +/- 15.9 ng h ml(-1) and 0.113 +/- 0.226 ng h ml(-1), respectively, in rats, and 454 +/- 104 ng h ml(-1) and 23.3 +/- 4.3 ng h ml(-1), respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel's thiolactone and active metabolite.

Metabolism of the calmodulin antagonist DY-9760e in animals and humans.

The in vitro metabolism of the calmodulin antagonist DY-9760e was investigated using liver microsomes from humans and three other animal species and compared with the in vivo metabolism in rats after intravenous administration of DY-9760e. Seven major metabolites were produced by human liver microsomes by the following metabolic pathways: N-dealkylation, phenyl hydroxylation, O-demethylation and imidazole oxidation. These metabolites were also produced by liver microsomes from monkeys, dogs and rats; additionally, a hydroxylated derivative of the indazole moiety was produced only by rat microsomes. To identify the structures of two imidazole ring metabolites whose authentic compounds could not be obtained, Escherichia coli co-expressing human cytochrome P450 CYP3A4 and NADPH-P450 reductase was used to biosynthesize these metabolites. NMR spectra elucidated the precise structures; oxidation occurred at the imidazole ring, and the subsequent ring-opening resulted in the generation of amide and formylamine groups. Glucuronide conjugates of the hydroxylated and O-demethylated derivatives were major components in rat bile. Therefore, DY-9760e metabolites generated in vitro correspond to the aglycones of the major metabolites observed in rat bile.

Urinary metabolites of DX-8951, a novel camptothecin analog, in rats and humans.

Urinary metabolites of DX-8951 ((1S,9S)-1-amino-9-ethyl-5-fluoro- 1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, CAS 171335-80-1, exatecan) in rats and humans were identified. Rats were dosed with the drug, and two major metabolites (UM-1 and UM-2) in the urine were isolated and purified by using ion-exchange column and HPLC. From NMR and mass spectra, they are suggested to be 4-hydroxymethyl metabolite (UM-1) and 3-hydroxy metabolite (UM-2) of the drug. Their chemical structures were confirmed by comparing their NMR spectra with those of chemically synthesized metabolites. Two major metabolites were found in human urine obtained in phase I trial. They were also confirmed to be UM-1 and UM-2 by LC/MS/MS by comparing their mass fragment patterns with those of synthetic metabolites.

Exercise-induced QTc-interval changes for predicting improvement in regional blood flow in ischemic myocardium and cardiac output after coronary angioplasty in patients with right bundle-branch block.

BACKGROUND: We have previously shown that QT-interval changes are more useful than ST-T changes in evaluating the severity of exercise-induced myocardial ischemia in patients with right bundle-branch block (RBBB). HYPOTHESIS: The purpose of this study was to evaluate whether the improvement in regional myocardial blood flow (RMBF) in ischemic areas and cardiac output after percutaneous transluminal coronary angioplasty (PTCA) can be predicted by exercise-induced QT-interval changes prior to PTCA. METHODS: The RMBF and cardiac output were quantified with nitrogen-13 ammonia positron emission tomography at rest and during exercise in 20 patients with RBBB and ischemic heart disease before and 6 months after PTCA, and in 9 healthy volunteers. RESULTS: Before PTCA, exercise-induced prolongation by < 20 ms or shortening of the Bazett-corrected QT (QTc) interval (454 +/- 38 to 451 +/- 41 ms, p = NS) was observed in 13 patients (Group 1) and prolongation by > or = 20 ms (429 +/- 44 to 466 +/- 50 ms, p < 0.002) was observed in 7 (Group 2). The number of regions of exercise-induced ischemia was significantly greater in Group 2 than in Group 1 (4.0 +/- 1.2 vs. 2.1 +/- 1.2, p < 0.01). The RMBF in regions of exercise-induced ischemia and cardiac output at rest was not significantly different between Groups 1 and 2, whereas during exercise both the parameters were significantly lower in Group 2 than in Group 1 (both p < 0.05). After successful PTCA, RMBF both at rest and during exercise improved significantly in Group 1 (0.67 +/- 0.04 to 0.71 +/- 0.06 ml/min/g, 0.74 +/- 0.05 to 0.84 +/- 0.08 ml/min/g; both p < 0.0001), but did not improve significantly in Group 2 (0.63 +/- 0.05 to 0.65 +/- 0.07 ml/min/g, 0.65 +/- 0.04 to 0.69 +/- 0.11 ml/ min/g; both p = NS). Cardiac output during exercise improved significantly in Group 1 (6.4 +/- 0.7 to 7.4 +/- 0.9 l/min; p < 0.002) but not in Group 2 (5.7 +/- 0.6 to 5.9 +/- 0.6 l/min; p = NS). CONCLUSIONS: Our results suggest that the marked prolongation of the QTc interval induced by pre-PTCA exercise may predict a lack of improvement in RMBF in ischemic areas and cardiac output after PTCA in patients with RBBB and ischemic heart disease.

Exercise-induced ST-segment depression: imbalance between myocardial oxygen demand and myocardial blood flow.

OBJECTIVE: ST-segment depression is believed as a common electrocardiographic sign of myocardial ischemia during exercise testing. Ischemia is generally defined as oxygen deprivation due to reduced perfusion. However, the exact relationship of the ischemic definition to ST-segment depression remains unclear. This study was conducted to evaluate the correlation between myocardial oxygen demand and myocardial blood flow (MBF) when ischemic (horizontal or downsloping) ST-segment depression of > or = 0.1 mV 80 ms after the J point developed during low-level exercise. METHODS AND RESULTS: Seventy-two patients with angiographically proven coronary artery disease (CAD) and 9 healthy volunteers underwent exercise positron emission tomography (PET). Myocardial oxygen demand was defined as a rate-pressure product (RPP, heart rate x systolic blood pressure) during exercise and MBF was quantified by nitrogen-13 ammonia perfusion PET. The myocardial demand-supply balance (MDSB) index was calculated from the MBF ratio (values during exercise/values at rest) against the RPP ratio (values during exercise/values at rest). The MDSB index was significantly lower in patients with ischemic ST-segment depression than in patients with non-ischemic ST depression and healthy volunteers (0.82 +/- 0.16 vs. 1.02 +/- 0.17, p < 0.0001 and vs. 0.99 +/- 0.14, p = 0.0109). Further, the presence of inadequate increase in MBF of < or = 10% (2 SD below the mean % value of healthy volunteers) during exercise in regional myocardium perfused by stenotic CAD significantly correlated with exercise-induced ischemic ST-segment depression (p = 0.0105). CONCLUSIONS: Our study could demonstrate that exercise-induced ischemic ST-segment depression is associated with myocardial ischemia due to exercise-induced imbalance between myocardial oxygen demand and global and regional MBF supply in patients with proven CAD.

Brady-tachycardia syndrome after radiotherapy for lung cancer. Assessment by computed tomography and carbon-11 methionine positron emission tomography.

A 74-year-old male who had received radiotherapy (total 54 Gy) for right lung cancer 7 months earlier developed a symptomatic brady-tachycardia syndrome requiring the implantation of a permanent pacemaker. Chest CT showed a pulmonary tumor of 2-cm diameter in the right lower lobe with direct extension into the surrounding tissue, suggesting the possibility of cardiac invasion. Carbon-11 methionine positron emission tomography (PET) indicated the absence of visible invasion of the heart with lung cancer. The bradytachycardia syndrome, therefore, was considered to be associated with sinus node injury due to radiation. Carbon-11 methionine PET metabolic imaging might play an important role in evaluating noninvasively the cause of the arrhythmia in this patient.

Evaluation of appropriate pacing with myocardial perfusion and cardiac function as a treatment of end-stage idiopathic dilated cardiomyopathy.

We sought to determine an appropriate pacing mode on the basis of myocardial perfusion and cardiac function as assessed by nitrogen-13 ammonia positron emission tomography in a patient with end-stage idiopathic dilated cardiomyopathy.

Paradoxical QRST integral changes with ventricular repolarization dispersion.

Body surface QRST integral (QRSTI) maps have been shown theoretically to reflect disparity of intrinsic repolarization properties and have been experimentally linked to increased arrhythmia susceptibility. Paradoxically, a lower magnitude of QRSTI in patients with heart disease and at risk for arrhythmias has been reported. We hypothesized that this paradoxical reduction in QRST magnitude is a consequence of increased heterogeneity of repolarization gradients in normal hearts. We generated QRSTI using a previously published heart model to compare QRSTI for aligned and random repolarization gradients. The heart model consisted of 50,000 cubic units in an anatomically correct arrangement that included parameters to simulate anisotropic conduction and inhomogeneous distribution of refractoriness. Body surface potential maps (BSPMs) were generated on a torso surface assuming a homogeneous torso and using the boundary element method for normal alignment of repolarization gradients and spatially reassigned repolarization values that randomized repolarization directions. QT duration was measured by the subtraction of Q onset time from T offset time on the BSPM. T offset was defined as the last potential to be detected at intervals of 3 ms that was above the threshold of 0.1 mV during recovery. The time of T offset showed a consistent tendency to shift to the left posterior and to split. When slow conduction velocities were assigned, BSPMs showed delayed propagation and multiple extrema. QRSTI showed systematic magnitude decrease with increasing randomness of repolarization gradient direction. Ventricular fibrillation (VF) could be induced by successive extrastimuli under the conditions of over 70% deviation and slow conduction of 0.5 m/s for the longitudinal direction. In conclusion, a possible explanation for the paradoxical reduction in QRSTI in the presence of constant repolarization disparity is the change in alignment of repolarization gradients.

An evaluation of the cytochrome P450 induction potential of pantoprazole in primary human hepatocytes.

Primary human hepatocytes contain a full complement of human drug-metabolizing enzymes and therefore represent a relevant experimental system for the evaluation of pharmacokinetic drug-drug interaction potential in human. In this study, the cytochrome P450 (CYP) induction potential of pantoprazole (PAN) was evaluated and compared to two other proton pump inhibitors (PPIs), omeprazole (OM) and lansoprazole (LAN). Primary human hepatocytes from three donors were studied. The hepatocytes were cultured for 3 days, followed by treatment for 3 days with the PPIs at 2, 5 and 10 microM. Two other known CYP inducers, 3-methylcholanthrene at 1 microM and rifampin at 50 microM, were also evaluated. Induction potentials of these chemicals for CYP1A and CYP3A were evaluated by isozyme activity and isozyme content. 7-Ethoxyresorufin-O-deethylase and testosterone 6beta-hydroxylase activities were used as endpoints for CYP1A and CYP3A, respectively. Isozyme protein contents of CYP1A and CYP3A were evaluated via Western blotting. The results showed that for CYP1A induction, the rank ordering in induction potential was consistently OM > LAN > PAN. CYP3A induction by the PPI's were observed in two of the three hepatocyte cultures, with no apparent differences in induction potency for the three compounds. Our results on CYP1A induction suggest that PAN has a lower drug-drug interaction potential than OM and LAN.

Correlation between exercise-induced ischemic ST-segment depression and myocardial blood flow quantified by positron emission tomography.

BACKGROUND: Ischemic ST-segment depression (horizontal or downsloping) is the most common manifestation of exercise-induced myocardial ischemia. The mechanisms responsible for these types of ST-segment depression are largely unknown. We investigated the relation of these 2 types of exercise-induced ST-segment depression to changes in regional myocardial blood flow (RMBF) by using exercise positron emission tomography (PET). METHODS AND RESULTS: The RMBF was measured with nitrogen-13 ammonia PET both at rest and during low-level supine bicycle exercise in 27 patients with angiographically proven coronary artery disease and in 6 healthy volunteers. ST-segment depression was measured from the isoelectric PR segment 80 ms after the J point. Exercise-induced horizontal ST-segment depression > or =0.1 mV was observed in 9 patients and downsloping depression > or =0.1 mV was observed in 18 patients. Multivessel disease was more frequent and areas of exercise-induced ischemia were larger in patients with downsloping depression than in patients with horizontal depression (P < .02, P < .05). In patients with horizontal ST-segment depression, RMBF in ischemic areas and in surrounding areas increased by a similar amount (31%+/-29% and 32%+/-16%) with exercise. In patients with downsloping ST-segment depression, RMBF was unchanged or decreased in ischemic areas (10%+/-24%) but increased in surrounding areas (46%+/-27%) with exercise. In healthy volunteers, RMBF increased in all areas (56%+/-30%) with exercise. CONCLUSIONS: Compared with horizontal changes in ST-segment morphology, downsloping changes may better indicate severe ischemia and greater differences in the increase of blood flow with exercise in the ischemic myocardium and in the surrounding areas.

Correlation between myocardial blood flow and fasting glucose metabolism in ischemic heart disease. Quantitative assessment by nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose positron emission tomography.

Ischemic myocardium avidly incorporates fluorine-18 fluorodeoxyglucose (F-18 FDG) in the fasting state, in contrast to the relative absence of F-18 FDG uptake in normal myocardium with sufficient blood flow in the fasting state. Although many studies have attempted to use F-18 FDG uptake to discriminate ischemic but viable myocardium from scarred myocardium, little is known clinically about the correlation between blood flow and F-18 FDG uptake in ischemic myocardium. We studied the critical level of blood flow that causes avid F-18 FDG uptake in myocardium in 9 patients. All patients had angiographically proven ischemic heart disease but no diabetes. Regional myocardial blood flow (RMBF) was measured quantitatively by positron emission tomography (PET) using nitrogen-13 ammonia in the resting state, in which the normal value was 80.2 +/- 13.0 ml/min/100 cm3. The F-18 FDG uptake in myocardium was assessed with the differential uptake ratio (DUR) scale. We constructed circumferential profiles of radioactivity uptake in myocardium for each study, and chose 780 sections of myocardium in which the relation between the two factors could be analyzed. In moderately ischemic to normal myocardium with RMBF of 50 to 90 ml/min/100 cm3, RMBF and F-18 FDG uptake were negatively correlated (r = -0.44, p < 0.01). When RMBF was 50 to 60 ml/min/100 cm3 (n = 121), the peak DUR value of F-18 FDG uptake was 4.0 +/- 2.0. The two factors were not correlated when RMBF was less than 50 ml/min/100 cm3 or 90 ml/min/100 cm3 or higher. Our results suggest that RMBF and F-18 FDG uptake values as measured with PET may provide valuable information on the possible benefit of intervention in ischemic heart disease.

Effects of DU-6859a, a new quinolone antimicrobial, on theophylline metabolism in in vitro and in vivo studies.

In vitro and in vivo studies were conducted to investigate the drug interaction between a new quinolone antimicrobial, DU-6859a, and theophylline (TP). The effect of DU-6859a on TP metabolism was evaluated in vitro by measuring the rate of TP metabolite formation by using human liver microsomes. DU-6859a inhibited the metabolism of TP, especially the formation of 1-methylxanthine, in vitro, but to a lesser extent than other drugs that are known to interact with TP. TP was administered alone (200 mg twice a day [b.i.d.] for 9 days) or in combination with DU-6859a (50 or 100 mg b.i.d. for 5 days) to six healthy subjects. DU-6859a administered at a dose of 50 mg resulted in no changes in serum TP concentrations, and slight increases in serum TP concentrations were observed at a dose of 100 mg. Moreover, the administration of 100 mg of DU-6859a resulted in decreases in all urinary TP metabolites, with significant differences. It appears that although DU-6859a has a weak inhibitory effect on TP metabolism in vitro, its concomitant use with TP at clinical dosage levels does not cause any adverse effects, showing only a slight increase in blood TP concentrations and a decrease in urinary metabolites.

Exercise-induced ST-segment changes permit prediction of improvement in left ventricular ischemic dysfunction after revascularization: evaluation with positron emission tomographic measurements of regional myocardial blood flow and cardiac output.

BACKGROUND: Prediction of the recovery of left ventricular (LV) ischemic dysfunction after revascularization is important in patients with coronary artery disease (CAD). We investigated whether the improvement in LV ischemic dysfunction after revascularization could be predicted preoperatively by exercise-induced ST-segment changes. METHODS AND RESULTS: Regional myocardial blood flow (RMBF) and cardiac output were measured with nitrogen 13-ammonia positron emission tomography at rest and during low-level exercise in 28 patients with angiographically proven CAD before and after successful revascularization and in 9 normal subjects. Before revascularization, exercise-induced upsloping ST-segment depression <1 mm 80 msec after the J-point was observed in 11 patients (group 1), horizontal depression of 1 to 1.5 mm was observed in 9 patients (group 2), and downsloping depression > or =1.5 mm was observed in 8 patients (group 3). The number of regions of critical CAD was greater in group 3 than in groups 1 and 2 (3.6 +/- 1.4 vs 1.6 +/- 0.7 and 2.2 +/- 1.1, p < 0.001, p < 0.02). Increase of RMBF in regions of critical CAD with exercise was lower in group 3 than in groups 1 and 2 (0.15 +/- 0.01 vs 0.22 +/- 0.01 and 0.18 +/- 0.02 ml/min per gram, p < 0.0001, p < 0.01). After revascularization, RMBF in regions of critical CAD both at rest and during exercise improved in groups 1 (0.49 +/- 0.15 to 0.60 +/- 0.18, 0.70 +/- 0.26 to 0.86 +/- 0.33 ml/min per gram, both p < 0.05) and 2 (0.50 +/- 0.15 to 0.62 +/- 0.19, 0.67 +/- 0.26 to 0.89 +/- 0.31 ml/min per gram, both p < 0.02), but was unchanged in group 3 (0.47 +/- 0.09 to 0.47 +/- 0.15, 0.62 +/- 0.17 to 0.64 +/- 0.23 ml/min per gram, both p = NS). Cardiac output at rest improved in groups 1 (4.98 +/- 0.43 to 5.35 +/- 0.50 L/min, p < 0.02) and 2 (5.08 +/- 0.52 to 5.53 +/- 0.28 L/min, p < 0.02), but was unchanged in group 3 (4.76 +/- 0.48 to 4.88 +/- 0.82 L/min, p = NS). CONCLUSIONS: Our results suggest that marked downsloping ST-segment depression induced by preoperative low-level exercise may predict a lack of improvement in LV ischemic dysfunction after revascularization.

Relation between exercise-induced myocardial ischemia as assessed by nitrogen-13 ammonia positron emission tomography and QT interval behavior in patients with right bundle branch block.

Exercise-induced myocardial ischemia is difficult to detect with ST-T changes in patients with right bundle branch block (RBBB). We sought to predict exercise-induced myocardial ischemia with QT interval behavior during exercise in patients with RBBB. Twenty-two patients with angiographically proven coronary artery disease and RBBB and 9 healthy volunteers underwent nitrogen-13 ammonia positron emission tomography with bicycle ergometer exercise at a fixed workload of 25 W. Regional myocardial blood flow (RMBF) and electrocardiographic changes were measured both at rest and after 5 minutes of exercise. The QT interval was measured from the onset of the QRS complex to the offset of the T wave in lead V5. The deltaQT and deltaRMBF, which indicated values after 5 minutes of exercise minus values at rest, were negatively correlated (r = -0.74, p <0.001). Exercise-induced shortening of the QT interval (422 +/- 27 to 381 +/- 38 ms, p = 0.0020) was observed in 15 patients (group 1) and no change or prolongation (411 +/- 45 to 420 +/- 37 ms, p = NS) was observed in 7 patients (group 2). Multivessel disease was significantly more frequent but collateral circulation was significantly less in group 2 than in group 1 (p <0.01, p <0.05, respectively). Cardiac output at rest was significantly lower in groups 1 and 2 than in healthy volunteers (4.52 +/- 0.83 and 4.51 +/- 0.84 vs 6.20 +/- 0.83 L/min; p = 0.0014, p = 0.0003). Although RMBF at rest did not differ significantly among groups 1 and 2 and healthy volunteers (0.63 +/- 0.20 vs 0.69 +/- 0.13 and vs 0.77 +/- 0.14 ml/min/g), RMBF after 5 minutes of exercise was significantly lower in group 2 than in group 1 and healthy volunteers (0.78 +/- 0.11 vs 0.96 +/- 0.20 and vs 1.20 +/- 0.18 ml/min/g; p = 0.0289, p <0.0001). The number of regions of critical coronary artery disease was significantly greater in group 2 than in group 1 (4.0 +/- 1.2 vs 2.1 +/- 1.3, p = 0.0039). Our results suggest that the absence of QT interval shortening during exercise may indicate severe myocardial ischemia induced by exercise in patients with RBBB and coronary artery disease.