Search for K_{L}→π

A search for the rare decay K_{L}→π^{0}νν[over ¯] was performed. With the data collected in 2015, corresponding to 2.2×10^{19} protons on target, a single event sensitivity of (1.30±0.01_{stat}±0.14_{syst})×10^{-9} was achieved and no candidate events were observed. We set an upper limit of 3.0×10^{-9} for the branching fraction of K_{L}→π^{0}νν[over ¯] at the 90% confidence level (C.L.), which improved the previous limit by almost an order of magnitude. An upper limit for K_{L}→π^{0}X^{0} was also set as 2.4×10^{-9} at the 90% C.L., where X^{0} is an invisible boson with a mass of 135 MeV/c^{2}.

Pharmacokinetics of a new once-daily controlled-release sarpogrelate hydrochloride compared with immediate-release formulation and the effect of food.

WHAT IS KNOWN AND OBJECTIVE: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. METHODS: A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS AND DISCUSSION: After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). WHAT IS NEW AND CONCLUSION: After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.

Screening and formulation of chemoattractant coatings for artificial reef structures.

This study was carried out to augment the colonization of marine benthic communities on artificial reef structure. Increasing marine pollution along with various natural hazards cause severe damages to marine algae and associated fauna. In recent years, artificial reefs have been deployed in coastal regions of several parts of the world in order to increase the marine productivity. They are mainly built with concrete materials, however their leachates have considerable impacts on algae. Therefore to increase the algal colonization five chemoattractants such as ferrous sulfate, zinc oxide, ammonium nitrate, sodium phosphate and ferrous lactate were screened against spores of a fouling alga, Ulva pertusa. FeSO4 / ZnO (8:2) and ferrous lactate coatings showed the highest spore attachment with 52 +/- 5.2 cm2 and 79.5 +/- 10.2 cm2 spores respectively (p<0.01). Furthermore using these chemoattractants, coating formulations were made and their performances were investigated at East coast (Ayajin harbor) and South coast (Meejo harbor) of Korea. A maximum fouling coverage (with green algae 25%, red algae 11.3% and brown algae 63.7%) was estimated from ferrous lactate coatings (p<0.01). Different composition of coating formulations and their chemoattractive properties were evaluated.

Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19.

A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.

Theophylline pharmacokinetics are not altered by lansoprazole in CYP2C19 poor metabolizers.

Lansoprazole is a potent gastric proton pump inhibitor that is metabolized by CYP2C19 but appears to induce the activity of hepatic microsomal CYP1A2 in a concentration-dependent manner. Because the inducing effect appears to be a dose-dependent phenomenon, it may be more important in poor metabolizers of CYP2C19 who have more than four times the area under the lansoprazole plasma concentration-time curve (AUC) and constitute 12% to 23% of Asian populations. Theophylline owes a significant portion of its metabolism to CYP1A2 and can cause gastric acid reflux that calls for concurrent use of proton pump inhibitors. We conducted a prospective, randomized, subject-blind, multicenter crossover study of the effect of multiple high-dose oral lansoprazole (30 mg twice a day for 7 days) on the pharmacokinetics of a single intravenous dose of theophylline (4.73 mg/kg) in healthy volunteers characterized for CYP2C19 genotype. The study compared the pharmacokinetics of lansoprazole and theophylline in five white extensive metabolizers, six Korean extensive metabolizers, and seven poor metabolizers of CYP2C19. The pharmacokinetics of lansoprazole were significantly different among groups; AUC values were 1.55+/-0.20 microg x h/mL in white extensive metabolizers, 7.01+/-0.72 microg x hr/mL in Korean extensive metabolizers, and 14.34+/-2.60 microg x h/mL in poor metabolizers (P < .001). The administration of lansoprazole did not change intravenous theophylline clearance compared with placebo in any group, and theophylline clearance exhibited no correlation with AUC of lansoprazole (rs = 0.12; P > .1). These data suggest that usual therapeutic doses of lansoprazole have no clinically significant influence on the clearance of theophylline, even in poor metabolizers of CYP2C19.

Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 µg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 µg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · µg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6.

We tested the ability of human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP or P450) isoforms to catalyze the N-demethylation of nirvanol-free (S)-mephenytoin [(S)-MP] in vitro. In mixed HLMs, the kinetics of (S)-MP N-demethylation suggested two contributing activities. A high-affinity/low-capacity component exhibited a KM of 174.1 microM and a Vmax of 170.5 pmol/mg protein/min, whereas a low-affinity/high-capacity component exhibited a KM of 1911 microM and a Vmax of 3984 pmol/mg protein/min. The activity of the high-affinity component was completely abolished by sulfaphenazole, with little effect on the low-affinity component. Of the recombinant P450 isoforms tested, only CYP2B6 and CYP2C9 formed nirvanol from (S)-MP. The KM value (150 +/- 42 microM) derived for recombinant CYP2C9 was close to that obtained for the high-affinity/low-capacity component in mixed HLMs (KM = 174.1 microM). The predicted contribution of this activity at concentrations (1-25 microM) achieved after a single 100-mg dose of racemic MP is approximately 30% of the rate of nirvanol formation. At concentrations of >1000 microM, we estimate that >90% of the rate can be explained by the low-affinity activity (CYP2B6). Therefore, the N-demethylation of (S)-MP to nirvanol may be a useful means of probing the activity of CYP2B6 in vitro when concentrations of >1000 microM are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of >1000 microM are rarely encountered.

Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms.

The human clearance of omeprazole and lansoprazole is conducted primarily by the hepatic cytochrome P450 (CYP) system. Efficacy data indicate few differences between these two drugs, but they may exhibit discrete drug interaction profiles. To compare the potency and specificity of these drugs as inhibitors of CYP isoforms, we performed in vitro studies with human liver microsomal preparations. Both drugs were potent, competitive inhibitors of CYP2C19, as measured by the conversion of S-mephenytoin to 4-hydroxymephenytoin (k(i) = 3.1 +/- 2.2 microM for omeprazole, K(i) = 3.2 +/- 1.3 microM for lansoprazole). For omeprazole, the highest concentration at which >70% inhibition of CYP2C19 was observed with no significant inhibitory effect on other isoforms was at least 20 times greater than K(i). Both drugs were competitive inhibitors of CYP2C9-catalyzed conversion of tolbutamide to 4-hydroxytolbutamide (K(i) = 40.1 +/- 14.8 microM for omeprazole, K(i) = 52.1 +/- 1.4 microM for lansoprazole) and were noncompetitive inhibitors of CYP3A-catalyzed conversion of dextromethorphan to 3-methoxymorphinan (K(i) = 84.4 +/- 4.0 microM for omeprazole, K(i) = 170.4 +/- 7.1 microM for lansoprazole). Lansoprazole was at least 5 times more potent (K(i) = 44.7 +/- 22.0 microM) than omeprazole (k(i) = 240.7 +/- 102.0 microM) as an inhibitor of CYP2D6-mediated conversion of dextromethorphan to dextrorphan. No inhibition of CYP1A2, assessed by measuring the conversion of phenacetin to acetaminophen, was noted. Our data suggest that whereas the inhibitory profiles of these two drugs are similar, lansoprazole may be the more important in vitro inhibitor of CYP2D6. Since its inhibition is very potent and has a broad "window of selectivity," omeprazole seems to be a useful, selective inhibitor of CYP2C19.

In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6.

AIMS: To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. METHODS: Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Ki values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. RESULTS: TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) was marginal. CONCLUSIONS: TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.

Pityriasis lichenoides-like mycosis fungoides in children.

We report three children with clinical features of pityriasis lichenoides (scaly red to brown papules and macules) in whom there were histopathological findings of mycosis fungoides (disproportionate epidermotropism, Pautrier's microabscesses, and wiry and coarse collagen bundles). Immunohistochemical staining revealed a prevalence of T lymphocytes in the infiltrate. T-cell receptor gene rearrangement analysis in lesional skin demonstrated rearrangement of the gamma chain in all cases. Human T-cell lymphotropic virus type 1 serology was negative in the two patients in whom this test was performed. Thus, lesions resembling pityriasis lichenoides can be an unusual and potentially misleading presentation of mycosis fungoides.

Identification and characterization of human cytochrome P450 isoforms interacting with pimozide.

Using human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP450) isoforms, we identified the major route of pimozide metabolism, the CYP450 isoforms involved, and documented the inhibitory effect of pimozide on CYP450 isoforms. Pimozide was predominantly N-dealkylated to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI). The formation rate of DHPBI showed biphasic kinetics in HLMs, which suggests the participation of at least two activities. These were characterized as high-affinity (K(m1) and Vmax1) and low-affinity (K(m2) and Vmax2) components. The ratio of Vmax1 (14 pmol/min/mg protein)/K(m1) (0.73 microM) was 5.2 times higher than the ratio of Vmax2 (244 pmol/min/mg protein)/K(m2) (34 microM). K(m2) was 91 times higher than K(m1). The formation rate of DHPBI from 25 microM pimozide in nine human livers correlated significantly with the catalytic activity of CYP3A (Spearman r = 0.79, P = .028), but not with other isoforms. Potent inhibition of DHPBI formation from 10 microM pimozide was observed with ketoconazole (88%), troleandomycin (79%), furafylline (48%) and a combination of furafylline and ketoconazole (96%). Recombinant human CYP3A4 catalyzed DHPBI formation from 10 microM pimozide at the highest rate (V = 2.2 +/- 0.89 pmol/min/pmol P450) followed by CYP1A2 (V = 0.23 +/- 0.08 pmol/min/pmol P450), but other isoforms tested did not. The K(m) values derived with recombinant CYP3A4 and CYP1A2 were 5.7 microM and 36.1 microM, respectively. Pimozide itself was a potent inhibitor of CYP2D6 in HLMs when preincubated for 15 min (Ki = 0.75 +/- 0.98 microM) and a moderate inhibitor of CYP3A (Ki = 76.7 +/- 34.5 microM), with no significant effect on other isoforms tested. Our results suggest that pimozide metabolism is catalyzed mainly by CYP3A, but CYP1A2 also contributes. Pimozide metabolism is likely to be subject to interindividual variability in CYP3A and CYP1A2 expression and to drug interactions involving these isoforms. Pimozide itself may inhibit the metabolism of drugs that are substrates of CYP2D6.

Congenital multiple plaque-like glomangiomyoma.

Congenital glomus tumor is a rare clinical variant of glomus tumor, and glomangiomyoma is the least frequent histologic type of glomus tumor. We report a case of congenital multiple plaque-like glomangiomyoma in a 38-year-old man with multiple nodules and plaques on his left arm and forearm. Histopathologic study showed an angiomatous, nonencapsulated tumor with numerous highly folded dilated vascular lumina scattered throughout the dermis. The lumina were lined by a single layer of flat endothelial cells, and one to several rows of glomus cells were observed adjacent to the endothelial cells. Around large vessels, there was a gradual transition from glomus cells to elongated mature smooth muscle cells with thin and long "blunt-ended" nuclei. Immunohistochemically, there were strong positive reactions for cytoplasmic alpha-smooth muscle actin in glomus cells and smooth muscle cells, vimentin in glomus cells and endothelial cells, and desmin in the smooth muscle cells only. To our knowledge, this is the first case report of congenital multiple plaque-like glomus tumor with the microscopic appearance of a glomangiomyoma.

Selective transport of cesium ion in polymeric CTA membrane containing calixcrown ethers.

A series of calixcrown ethers for which the cavity size of the crown ring is varied from crown-6 to crown-7 to crown-8 were examined for the transport abilities toward alkali metal ions. These ligands were incorporated into supported liquid membranes (SLMs) and into polymer inclusion membranes (PIMs) composed of cellulose triacetate (CTA) as a support and 2-nitrophenyl octyl ether (NPOE) and tris(2-butoxyethyl) phosphate (TBEP) as a plasticizer. In both membrane systems, calixcrown-6 showed the best selectivity toward a cesium ion over other alkali metal ions. The polymeric CTA membrane showed more rapid transport rate as well as higher durability than did the SLMs.

A Study of the Survival Rate of Childhood Cancer in Korea.

PURPOSE: It is known that the prognosis of childhood cancer is relatively good, however actual representative nationwide data on childhood cancer, particularly of survival rate, are rare. In this study we attempted to establish the overall survival rate of major childhood cancer. MATERIALS AND METHODS: The primary source of data of childhood cancer under 15 years of age were the registry files of the Central Cancer Registry Report (Ministry of Health & Welfare) from 1993 to 1997. The above data was compared to death case data files of the same period obtained from the Korea National Statistical Office using the personal identification code. We calculated the 1, 3, and 5 year survival rates using the life table of SPSS and Kaplan-Meier method and compared the survival rate of disease according to prognostic factors. RESULTS: A total of 6,720 cases of pediatric cancer from the Central Cancer Registry files were computerized and sorted by personal identification (ID) code to extract duplicated cases as well as cases with incomplete data. The final number of cases entered in this study was 4,983. 1) The number of confirmed death cases was 1,448 (29.1%). 2) The disease distribution showed that the most common pediatric cancer was leukemia (1,468/4,983, 29%), followed by brain tumors (503/4,983, 10%), lymphoma (315/4,983, 6%), Wilms tumor (165/4,983, 3%), etc. in order by number of patients. 3) The 5 year survival rate of disease was as follows: overall 62%, acute lymphocytic leukemia 61%, acute non-lymphocytic leukemia 32%, malignant lymphoma 72%, neuroblastoma 47%, medulloblastoma 51%, Astrocytoma 66%, Wilms tumor 83%, etc. CONCLUSION: We analyzed and report the 5 year survival rate of overall childhood cancer and of each of the twelve major childhood cancers from in Korea 1993 to 1997 to provide basic data on childhood cancer statistics.