Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.

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.

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.

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 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.

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.

Interpretations of cytochrome P450 mechanisms from kinetic studies.

The catalytic mechanism of cytochrome P450 (P450) enzymes has generally been understood in terms of a classic cycle in which electron donation is often limiting and catalysis is understood in terms of hydrogen abstraction and rapid oxygen rebound. In the course of detailed investigations with kinetic hydrogen isotope effects we have studied two systems in which somewhat unusual isotope effects have been interpreted in terms of modifications of the general paradigm. The low isotope effects observed for N-demethylation reactions are in contrast to high values seen with P450-catalyzed C-hydroxylation and peroxidase-catalyzed N-demethylation and are consonant with a role for the P450 FeO2+ entity in base-catalyzed deprotonation of an aminium radical. With P450 2E1, kinetic deuterium isotope effects are seen on the apparent Km for the substrate (increased) but not on Vmax. The results are interpreted in terms of a mechanism where C-H bond cleavage is sensitive to deuterium substitution but a step following this is rate-limiting. This step may be product release.

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.

Effects of proton pump inhibitors on thyroid hormone metabolism in rats: a comparison of UDP-glucuronyltransferase induction.

The effects of proton pump inhibitors on thyroid hormone metabolism in rats were examined. Pantoprazole, omeprazole, and lansoprazole were administered repeatedly to female SD rats at doses of 5, 50, and 300 mg/kg/day for 1 week, and changes in UDP-glucuronyltransferase activities were examined. Increases in o-aminophenol UDP-glucuronyltransferase activity, which was measured as that responsible for the glucuronidation of thyroxine, were evident following 7-day high-dose administration of all the proton pump inhibitors tested. Of the three proton pump inhibitors investigated, o-aminophenol UDP-glucuronyltransferase activity was greatest following the high-dose administration of omeprazole. Androsterone UDP-glucuronyltransferase activity in rats treated with the proton pump inhibitors increased significantly, but these increases were smaller than those of o-aminophenol UDP-glucuronyltransferase. Pantoprazole and omeprazole treatment did not affect plasma T4 or T3 significantly, whereas lansoprazole treatment produced marked reductions in plasma T4 but did not affect plasma T3 significantly. After administration of 125I-labeled thyroid hormone to rats treated with the proton pump inhibitors, biliary excretion of radioactivity increased significantly in omeprazole- and lansoprazole-treated rats; these increases were attributed to induction of liver thyroxine UDP-glucuronyltransferase activities. The order of biliary excretion of radioactivity, as well as the o-aminophenol UDP-glucuronyltransferase activity, in the treated animals was: omeprazole > lansoprazole > pantoprazole. Therefore, repeated administration of the proton pump inhibitors increased thyroxine-metabolizing activity via induction of UDP-glucuronyltransferase, and this induction by pantoprazole was less pronounced than that by omeprazole or lansoprazole.

Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic.

The safety and pharmacokinetic properties of DQ-2556, a new parenteral cephalosporin, were evaluated using healthy volunteers after 5-minute intravenous infusion of doses of 250, 500, 1000, or 2000 mg and a 1-hour infusion of 2000 mg, and an intramuscular dose of 500 mg. The half-lives of DQ-2556 ranged from 1.64 to 2.15 hours. The peak serum concentrations and area under the curve values were linearly correlated to the doses. The mean urinary recoveries were 80.0 to 85.5% of a dose within 24 hours. Salivary concentrations of the drug were low. There was no accumulation of DQ-2556 after 9 administrations every 12 hours. DQ-2556 was well tolerated.

An evaluation of the CYP1A induction potential of pantoprazole in primary rat hepatocytes: a comparison with other proton pump inhibitors.

The ability of pantoprazole to affect the induction of cytochrome P450 (CYP) 1A subfamily was evaluated and compared with two other proton pump inhibitors, omeprazole and lansoprazole, in primary cultured hepatocytes from female Sprague-Dawley rats. The hepatocytes were cultured for 2 days, followed by treatment for 2 days with the proton pump inhibitors at 2, 5 and 10 microM, concentrations that are similar to plasma concentrations found in rats in vivo. The CYP1A inducer 3-methylcholanthrene (at 1 microM) was also evaluated as a positive control. Induction potentials of these chemicals for CYP1A were determined by 7-ethoxyresorufin O-deethylase activity and isozyme contents. The results showed that for CYP1A induction, the rank ordering in induction potential was consistently lansoprazole > omeprazole > pantoprazole. The results are consistent with the existing rat in vivo data, i.e. pantoprazole has lower CYP1A induction potential than omeprazole and lansoprazole.

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.

Functional role of coronary collaterals with exercise in infarct-related myocardium.

We evaluated the regional myocardial blood flow in collateral dependent infarct-related areas to examine the functional role of coronary collaterals. Regional myocardial blood flow was measured by positron emission tomography with 13N-ammonia at rest and during low-grade exercise (bicycle ergometer fixed at 25 W for 6.5 min). The study was performed in 24 subjects, consisting of 19 patients with prior myocardial infarction, and five normal individuals. Regional myocardial blood flow was calculated using the radioactivity in myocardial tissue measured by positron emission tomography and the radioactivity in arterial blood. Concerning the infarct related area, the exercise caused myocardial blood flow to decrease by 18.4% (P < 0.01) in the collateral-dependent areas (n = 8) of angiographically positive collaterals, and to increase by 14.4% (P = not significant) in the areas (n = 10) of negative collaterals. Four patients in whom the myocardial blood flow in all walls, including the normal areas, decreased with exercise were excluded from this evaluation. Myocardial blood flow in collateral-dependent infarct-related areas appeared to decrease transiently by low-grade exercise. Our results suggest that collaterals increase the incidence of exercise-induced ischemia, but may protect the infarct related but viable myocardium from necrosis.

Possible effect of pigment on the pharmacokinetics of ofloxacin and its excretion in hair.

The mechanism of excretion of the antimicrobial ofloxacin in human scalp hair was investigated. When black and white hairs were taken from a patient with grizzled hair, who had been treated with ofloxacin, a much larger quantity of the drug was detected in the black hair. To study this difference and to elucidate the cause, ofloxacin (6, 20, and 60 mg/kg/day, b.i.d.) was administered ip for 5 weeks to albino and pigmented rats, whose backs had been depilated beforehand. In the last week of administration, the time-plasma concentration profile of ofloxacin was determined. One week after the last dosing, the newly grown hair on the depilated area was collected, and the drug concentration in hair was measured. The concentration in hair of the pigmented rats correlated significantly with the daily dose, area under the plasma concentration curve (AUC), and maximum plasma concentration (Cmax) at steady state, whereas that in the albino rats correlated with the dose and Cmax only, because AUC did not increase linearly with the dose in the albino rats. Moreover, the drug concentration in the hair of the pigmented rats was always much larger than that in the hair of the albino ones, although AUC and Cmax did not differ greatly between both rat groups. The findings suggest that ofloxacin is excreted in the hair in relation to the dose administered, and that the mechanism of the excretion is closely linked with the presence of melanin.

Comparative simulation of excitation and body surface electrocardiogram with isotropic and anisotropic computer heart models.

Comparative simulations between isotropic and anisotropic computer heart models were conducted to study the effects of myocardial anisotropy on the excitation process of the heart and on body surface electrocardiogram. The isotropic heart model includes atria, ventricles, and a special conduction system, and is electrophysiologically specified by parameters relative to action potential, conduction velocity, automaticity, and pacing. The anisotropic heart model was created by incorporating rotating fiber directions into the ventricles of the isotropic heart model. The orientation of the myocardial fibers in the ventricles of the model was gradually rotated counterclockwise from the epicardial layer to the endocardial layer for a total rotation of 90 degrees. The anisotropy of conduction velocity and intracellular electric conductivity was included in the simulation. Comparative simulations of the normal heart, LBBB, and RBBB showed no significant differences between the two models in the excitation processes of the whole heart or in the body surface electrocardiograms. However, it was easier to induce ventricular fibrillation in the anisotropic model than in the isotropic model. The comparative simulation is useful for investigating the effects of myocardial anisotropy at the whole heart level and for evaluating limitations of the isotropic heart model.

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.

[Intraocular penetration of DR-3355, a new quinolone derivative].

We studied the intraocular penetration of DR-3355, a new quinolone derivative in white mature rabbits. DR-3355 concentration in the aqueous humor reached the maximum, 1.06 micrograms/ml, at 2 hours after oral administration of 20 mg/kg in single dose. Six hours after it was 0.37 micrograms/ml. At 2 hours, the concentration ratio in the aqueous humor and serum was 23.3%. The pharmacokinetic parameters of DR-3355 levels in both of the aqueous humor and serum were: Cmax, 1.02 micrograms/ml and 4.56 micrograms/ml; Tmax, 1.42 hours and 1.47 hours; T 1/2, 0.96 hours and 1.57 hours; and AUC, 3.91 micrograms.hr/ml and 19.70 micrograms.hr/ml, respectively. At 2 hours after oral administration, the ocular tissue concentrations were 3.84-16.10 micrograms/g in the outer parts of the eye, and 0.70-13.52 micrograms/g or ml in the inner parts of the eye. Those concentrations decreased to about 1/2 to 1/32 in the outer parts, and 1/2 to 1/7 in the inner parts of the eye at 6 hours. Those ocular tissue concentrations of DR-3355 exceeded the MIC90 of the compound against various bacteria of ocular pathogens, such as Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae and Serratia marcescens.

[Clinical use of beta-blocker an as antiarrhythmic agent].

It has been reported that beta-blocker treatment reduces the incidence of sudden cardiac death after myocardial infarction, possibly due to antiischemic and antiarrhythmic effects. Beta adrenoceptor blocking drugs are administered, as an antiarrhythmic agent in patients with hyperthyroidism, atrial fibrillation, atrial flutter and ventricular tachyarrhythmias. Even low dose beta-blocker administration reduces the incidence of PVC's. Beta blockers are expected to decrease the ventricular rate of persistent tachyarrhythmias resulting from excessive cardiac sympathetic tone. Existence of denervated areas in myocardium in the cases of ventricular tachyarrhythmias may be shown in the cardiac scintigram as abnormal myocardial uptake of 123I-MIBG.

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.