Possible recurrence of primary sclerosing cholangitis following living-related liver transplantation: report of a case.
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Adult↗
Biomedical subjects
E Tanaka
Publications and source records attributed to E Tanaka.
Simultaneous determination of chlorzoxazone, indicator of CYP2E1, and its metabolite in human serum using a new reversed-phase chromatographic column of 2-microm porous microspherical silica-gel.
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Chlorzoxazone↗
Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo.
OBJECTIVES: This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. BACKGROUND: Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. METHODS: A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. RESULTS: Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). CONCLUSIONS: These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.
Animals↗
Trimethadione metabolism and microsomal monooxygenases in untreated and phenobarbital-treated rhesus monkeys.
The contribution of induced cytochrome P450 (P450) isozymes (CMLa; CYP2B, CMLb; CYP2A and CMLc; CYP3A) and related enzymes to trimethadione (TMO) metabolism in phenobarbital-treated rhesus monkey were investigated. The animals received a single dose of TMO (4 mg kg-1) and plasma samples were withdrawn before this administration and again at 0.08, 0.25, 0.5, 1 and 2 h later. Phenobarbital-treatment (20 mg kg-1 day-1 for 3 days; i.p.) significantly increased the plasma dimethadione (DMO)/TMO ratios at 0.08, 0.5, 1 and 2 h one's appropriate controls. Phenobarbital treatment also increased the P450 content (1.7-fold) and activity of aniline p-hydroxylase (1.3-fold), p-nitroanisole O-demethylase (1.8-fold) and benzphetamine N-demethylase (2.3-fold). The content of CMLa, CMLb and CMLc were increased about 12.8, 2.3 and 2.7-fold by phenobarbital pretreatment, respectively. The activity of TMO N-demethylation was inhibited by anti-P450 CMLa and anti-P450 CMLb. However, the anti-P450 CMLc antibody had no effect on this activity in liver microsomes. The results of both in vivo and in vitro studies of the effects of phenobarbital treatment on TMO metabolism indicate that these effects may be attributed to the induction of CMLa. These findings suggest that plasma DMO/TMO ratio in a single blood sampling after TMO administration is very useful for determination the degree of hepatic induction in clinical study.
Aniline Hydroxylase↗
Enhanced encapsulation of amphotericin B into liposomes by complex formation with polyethylene glycol derivatives.
PURPOSE: A highly efficient method was developed for the encapsulation of amphotericin B (AmB) in liposomes, and the mechanism involved was characterized. METHODS: AmB was encapsulated in dipalmitoylphosphatidylcholine/ cholesterol (DPPC/CH, 2:1) liposomes after complex formation with distearoyl-N-(monomethoxy poly(ethylene glycol)succinyl) phosphatidylethanolamine (DSPE-PEG). Hydration of lipids was done with 9% sucrose solution. RESULTS: The encapsulated amount of AmB was 111 microg/mg lipid, which was much higher than that obtained by the same method without DSPE-PEG (14 microg/mg lipid). The amount encapsulated increased with amount of DSPE-PEG used and with PEG molecular weight. Encapsulation efficacy was also influenced by the type of PEG derivatives used and by the modification of AmB, suggesting the involvement of complex formation between AmB and DSPE-PEG. Absorption and 31P-NMR spectral analyses indicated that interactions between the amino and phosphate groups and between the polyene and PEG moieties in AmB and DSPE-PEG, respectively, play an important role in the complex formation. CONCLUSIONS: Complex formation of AmB with DSPE-PEG allows the highly efficient encapsulation of the drug in liposomes. This simple technique should be applicable to other hydrophobic drugs.
Amphotericin B↗
Serum eosinophil cationic protein as a marker of eosinophilic inflammation in asthma.
BACKGROUND: The serum level of eosinophil cationic protein (ECP) has been used as a clinical marker in asthma, on the assumption that it reflects ongoing eosinophilic inflammation of the airways. However, only a few studies have investigated this issue, using bronchial secretions but not tissue specimens. OBJECTIVE: To evaluate cross-sectionally the correlation between serum ECP level or blood eosinophil count, and the degree of eosinophilia in bronchoalveolar lavage fluid (BALF) and bronchial biopsy tissue, and disease activity, in asthmatic patients. METHODS: Thirty-three adults with symptomatic asthma and six healthy controls were studied. The blood eosinophil count, ECP levels in serum and BALF, percentage of eosinophils in BALF, number of eosinophils in bronchial tissue, pulmonary function, and methacholine bronchial responsiveness of these subjects were clarified. An asthma severity score and inhaled beta2-agonist requirement (puffs/day) were also assessed for the asthmatic patients. RESULTS: The asthmatic patients, compared with the controls, had more obstructive (as tested by %FEV1, FEV1/FVC, and FEF25-75%) and more responsive airways, and showed a significant increase in the number of eosinophils in the blood, BALF, and tissue, and in the serum ECP levels. The ECP levels in BALF were below the detection limit for most of the subjects in both groups examined. In the asthmatic patients, serum ECP level demonstrated correlations with the number or percentage of eosinophils in BALF and tissue, whereas the blood eosinophil count correlated only with the percentage of eosinophils in BALF. Serum ECP level correlated with all indices of disease activity examined; %FEV1, FEV1/FVC, FEF25-75% bronchial responsiveness, severity score and beta2-agonist usage, whereas the blood eosinophil count correlated only with %FEV1 and bronchial responsiveness. CONCLUSION: The data suggest that serum ECP level reflects the intensity of eosinophilic airway inflammation, as well as the disease activity, and may be useful as an inflammatory marker in asthma.
Adult↗
Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes.
Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues and many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In the future, it may help to identify individuals at greatest risk of drug interactions and adverse events.
Cytochrome P-450 Enzyme Inhibitors↗
Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease.
Liver disease is associated with reduced metabolic capacity for drugs that are metabolized by oxidative biotransformation. Three cytochrome P450 (P450 or CYP) gene families in liver microsomes (CYP 1, CYP2 and CYP3) appear to be responsible for much of the drug metabolism that takes place. The genetic polymorphism of the CYPs responsible for debrisoquine/ sparteine (CYP2D6) metabolism and S-mephenytoin (CYP2C19) metabolism has been well documented, but information on the impairment of each isoform in liver disease is still limited. There are two types of hepatic P450 function tests. One type consists of non-genetic P450 function tests (CYP1A2, 2A6, 2C9/10, 2E1 and 3A3/4), and probe drugs include caffeine, catalysed by CYP1A2, coumarin by CYP2A6, phenytoin by CYP2C6, chlorzoxazone by CYP2E1, and nifedipine, erythromycin and lidocaine by CYP3A3/4. The second type of genetic P450 function tests (CYP2C19 and CYP2D6) involves probe drugs such as S-mephenytoin, catalysed by CYP2C19, and debrisoquine and sparteine, catalysed by CYP2D6. The metabolism of the probe drugs used in non-genetic P450 function tests in patients with liver disease falls into two categories: reduced (CYP1A2, CYP2C, 2E1 and 3A) and unchanged (CYP2C). In genetic P450 function tests there seems to be a lesser degree of inhibition in poor metabolizers (PMs) than extensive metabolizers (EMs) among patients with liver disease. There have been very few reports on changes in metabolism of the probe drugs used in genetic P450 function tests in liver disease. In this paper the subject is reviewed.
Biotransformation↗
In vivo age-related changes in hepatic drug-oxidizing capacity in humans.
Very few studies have been carried out looking at how the effects of drugs and their toxicity in humans change during their lifespan (developing and ageing). The purpose of this study is to review the literature on the changes in probe-drug metabolism, classified by cytochrome P450 (P450 or CYP) at five stages in life: neonates < 4 weeks, infants < 12 months, children < 19 years, young/mature adults 20-64 years, and elderly adults > 65 years. The main probe drugs include caffeine and theophylline, whose metabolism is catalysed by CYP1A2, tolbutamide, phenytoin and ibuprofen, catalysed by CYP2C9, amitriptyline and nortriptyline, catalysed by CYP2C19, acetaminophen, catalysed by CYP2E1 and lidocaine, midazolam and terfenadine, catalysed by 3A3/4. From the published in vivo studies two different patterns of drug metabolism can be identified: (i) activity is low immediately after birth, increases, then peaks at the young/mature adult level and, finally, decreases in old age (drugs catalysed by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A3/4) and (ii) activity increases rapidly after birth to reach a level equivalent to that in the young/mature adult, then gradually decreases and finally decreasing faster in old age (drugs catalysed by CYP2E1). Further study of the changes in P450 with age is warranted to help prevent adverse reactions and to guide us in tailoring therapy better for the individual patient.
Aging↗
Pharmacokinetic interactions between acute alcohol ingestion and single doses of benzodiazepines, and tricyclic and tetracyclic antidepressants -- an update.
Recent reports of interactions between alcohol and benzodiazepines, tricyclic and tetracyclic antidepressants during their acute concomitant use are reviewed. Acute ingestion of alcohol (ethanol) with tranquilizers or hypnotics is responsible for several pharmacokinetic interactions that can have significant clinical implications. In general, metabolism of these drugs is delayed when combined with alcohol but some reports have suggested otherwise. The amount of alcohol consumed, the presence or absence of liver disease, and differences in the dosage and administration of these drugs may account for the observed discrepancies. In recent years, the cytochrome P450 (P450 or CYP) isoenzyme that catalyses the metabolism of these drugs has also been identified. However, since changes in the pharmacogenetic metabolism of benzodiazepines and tricyclic and tetracyclic antidepressants are mainly governed by CYP2C19 and CYP2D6, caution is needed when used together with alcohol.
Antidepressive Agents↗
Evolution of hepatitis G virus infection and antibody response to envelope protein in patients with transfusion-associated non-A, non-B hepatitis.
The clinical significance and course of acute hepatitis G virus (HGV) infection were studied by measuring HGV RNA and antibody to HGV envelope protein E2 (HGV-E2 antibody). A total of 59 patients with transfusion-associated non-A, non-B hepatitis, who were followed-up for more than 1 year, were selected retrospectively. HGV RNA was measured by reverse transcriptase (RT) and nested polymerase chain reaction (PCR) was performed, using primer sets, in the 5'-non-coding region of the HGV genome. HGV-E2 antibody was measured by enzyme-linked immunosorbent assay (ELISA) using recombinant E2 protein. Of the 59 patients, 51 (86%) were infected with hepatitis C virus (HCV) and 12 (20%) were infected with HGV; 11 of the 12 with HGV infection were also infected with HCV. HGV viraemia was cleared during the follow-up period in seven of the 12 patients with HGV infection. All these seven patients seroconverted for HGV-E2 antibody just before or just after the clearance of HGV viraemia. In contrast, all five patients without clearance of HGV viraemia were negative for HGV-E2 antibody (P = 0.0013). Of seven patients with continuous HGV viraemia at 1 year from the onset of acute hepatitis, four with HCV RNA showed chronic elevation of alanine aminotransferase (ALT) but three without HCV RNA did not. The severity of acute hepatitis was similar between patients with both HGV and HCV infections and in those with HCV infection alone. The majority of patients with HGV infection cleared the virus during long-term follow-up. Appearance of HGV-E2 antibody was associated with the clearance of HGV viraemia. An abnormal ALT level was noted to depend on HCV infection but not on HGV infection in both the acute and chronic phases of transfusion-associated hepatitis.
Acute Disease↗
Serotonin inhibits synaptic glutamate currents in rat nucleus accumbens neurons via presynaptic 5-HT1B receptors.
Neurons in the nucleus accumbens septi in brain slices from adult male rats were studied with patch clamp recording in the whole-cell conformation. Cells filled with Lucifer Yellow were identified as medium spiny neurons. Electrical stimulation close to the recorded cell evoked excitatory and inhibitory synaptic currents. In the presence of picrotoxin or bicuculline, stimulation at a holding potential of -90 mV evoked an inward excitatory current that was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), identifying it as an excitatory postsynaptic current (EPSC) mediated by glutamate acting at AMPA/kainate receptors. Serotonin (5-hydroxytryptamine, 5-HT; 3-100 microM in the bath) decreased the EPSC in about 90% of the cells. The action of 5-HT was mimicked by N-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP), but not by (+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT) or (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI). The 5-HT effect was antagonized by pindolol or cyanopindolol, but not by spiperone, ketanserin or tropisetron. Taken together, these results indicate that 5-HT acts at 5-HT1B receptors. The effect of 5-HT was potentiated by cocaine (0.3-3 microM) or the selective serotonin reuptake inhibitor citalopram. Miniature synaptic currents recorded in the presence of tetrodotoxin were inhibited by CNQX, identifying them as spontaneous miniature EPSCs. 5-HT reduced the frequency of these miniature EPSCs without affecting their amplitude, which indicates a presynaptic site of action. This presynaptic inhibition by 5-HT might be involved in the behavioural effects of cocaine.
Animals↗
Hopelessness in a community population: factorial structure and psychosocial correlates.
The factorial structure of the Beck Hopelessness Scale (BHS; A. T. Beck, A. Weissman, D. Lester, & L. Trexler, 1974) was examined in a nonclinical sample (N = 154) in Japan, and the relationships between dimensions of hopelessness and psychosocial variables were analyzed. A semistructured interview was used, as well as a questionnaire consisting of the BHS, the Eysenck Personality Questionnaire (EPQ; H. J. Eysenck & S. B. Eysenck, 1975), and the Parental Bonding Instrument (PBI; G. Parker, H. Tupling, & L. B. Brown, 1979). A factor analysis with principal components solution after oblimin rotation yielded 2 factors--Doubt About a Hopeful Future (Factor 1) and Belief About a Hopeless Future (Factor 2). Significant, positive correlations were found between Factor 2 and (a) the number of emotional symptoms of depression in a 4-day depressive episode and (b) scores on the Neuroticism subscale of the EPQ. The Factor 1 score was significantly and negatively correlated with the Extraversion subscale of the EPQ and the Paternal Care subscale of the PBI.
Adolescent↗
Changes in the enzymatic activities of beagle liver during maturation as assessed both in vitro and in vivo.
1. We have examined changes in caffeine and trimethadione (TMO) metabolism in vivo, agents which are used as probe drugs. In this study the total body clearance (Cl) of caffeine and TMO was low 1 week after birth (week 1), increased rapidly from week 3, peaked and then decreased gradually until reaching the level for the mature, adult dog. The elimination half-life (t1/2) of caffeine and TMO was prolonged during week 1; however, it then gradually became shorter. Gradually it became longer and reached the level for the adult dog. The apparent volume of distribution (Vd) of caffeine did not change throughout the study. However, the Vd of TMO was only high during week 1. 2. The in vitro changes in a variety of typical substrates for seven different cytochrome P450 (CYP) isozymes were examined. In this study three different patterns of metabolism can be identified: (1) activity is low immediately after birth, increases, peaks and then decreases to the adult dog level (p-nitroanisole; CYP1A1, caffeine; CYP1A2, benzphetamine; CYP3A/2B(?), aniline; 2E1 and TMO; CYP2C9/2E1/3A4); (2) activity generally increases rapidly soon after birth, continues to increase, peaks and then gradually decreases to the adult level (phenytoin; CYP2C9); and (3) activity is high (about the same level as the adult) immediately after birth, decreases and then gradually increases to the adult level (erythromycin; CYP3A4/5). 3. The results of these in vivo and in vitro studies suggest that changes in enzyme activity are due to differences in P450 isoenzymes during development.
Alanine Transaminase↗
Acquisition versus loss of Helicobacter pylori infection in Japan: results from an 8-year birth cohort study.
Studies of the pattern of change in the epidemiology of Helicobacter pylori infection are scarce. A longitudinal cohort study consisted of 644 children and adults, and two independent cross-sectional surveys were conducted in rural Japan between 1986 and 1994. The anti-H. pylori IgG seroconversion rates were 1.1% and 1% per year for children and adults, respectively. The seroreversion rate per year was 1.8% for children and 1.5% for adults. The cohort study was confirmed by the two cross-sectional studies. H. pylori prevalence fell in all age groups in both children (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.2-1.0, P = .05) and adults (OR = 0.4, 95% CI = 0.3-0.6, P = .001). The rate of loss of H. pylori infection was greater than the acquisition. Data regarding acquisition and loss of H. pylori infection are critical to understanding the epidemiology of the infection and to developing treatment and vaccination strategies.
Adolescent↗
A Fourier rebinning algorithm incorporating spectral transfer efficiency for 3D PET.
This paper presents a Fourier rebinning algorithm for three-dimensional image reconstruction in PET that incorporates the concept of spectral transfer function. It suggests the need for discarding low-frequency components in the rebinning. It also includes the correction for rebinning efficiency which was evaluated by simulations as a function of oblique angle of projections. The performance was optimized by high-pass filters and axial smoothing. The algorithm yields satisfactory images with negligible axial cross-talk for a maximum oblique angle up to 26.6 degrees. The statistical noise was evaluated in terms of 'noise equivalent number of oblique angles', and reasonable results were obtained in view of the theoretical expectation. Ring artefacts due to noise are negligibly small.
Algorithms↗
Comparative toxic effects of iobitridol and iohexol on the kidney.
RATIONALE AND OBJECTIVES: The authors compare the toxic effects of iobitridol and iohexol, which are nonionic contrast media with equivalent osmolalities and viscosities on the kidney. METHODS: In a rat acute renal failure (ARF) model, iobitridol or iohexol (both at the dose of 2.87 g I/kg) were injected to rats after pretreatment with indomethacin and N omega-nitro-L-arginin methyl ester. The effects on histopathology, creatinine clearance, and urinary N-acethyl-beta-D-glucosaminidase (NAG) activity were assessed. In a rat renal slice system, the slices were exposed to iobitridol or iohexol (both at the concentration range of 17.5-70 mg iodine/mL) for 60 min. The accumulation of para-aminohippuric acid (PAH), an organic anion, and the intracellular potassium content as the indicators of renal tubular injury were measured to assess the direct effects of iobitridol and iohexol on renal tubules. RESULTS: In the ARF model, no significant difference was detected between the effects of iobitridol and those of iohexol on the creatinine clearance and urinary NAG activity 24 hours after the injection. However, iobitridol produced a lower degree and incidence of renal tubular injury of renal proximal tubules (P < 0.001) and distal tubules (P < 0.05) compared with iohexol. In the rat renal slice system, the iobitridol treatment had significantly less effect on the PAH accumulation compared with iohexol (P < 0.001). There were no changes in the intracellular potassium content. CONCLUSIONS: These findings suggest that iobitridol has significantly less toxic effects on the kidney compared with iohexol under the condition of our experiment.
Analysis of Variance↗
A microangiographic technique using synchrotron radiation to visualize dermal circulation in vivo.
Conventional angiography cannot resolve dermal small vessels with a diameter of 200 microm or less. In vitro microangiography is currently characterized by better spatial resolution than conventional angiography but does not allow visualization of the blood stream in dermal vessels in vivo. In this study, we introduce a novel synchrotron radiation microangiographic system for visualizing the structure of and blood flow in dermal microvessels in vivo repeatedly. We used monochromatic synchrotron radiation with an energy just above the k-edge of iodine (33.3 keV) as an x-ray and a high-definition television camera system with a high-sensitivity image pick-up tube for detection. The 33.3-keV monochromatic synchrotron radiation allows detection of a small amount of iodine, and the high-definition television camera system can resolve small vessels with high-spatial resolution and no loss of sensitivity. We performed synchrotron radiation angiography of superficial inferior epigastric arteries and their branches in nine rats, and of the caudal artery in 14 rats, and compared angiographic images taken by the current system with those taken by a conventional angiographic system in seven rats. With this new microangiographic technique, we could visualize small dermal vessels with a diameter as low as 50 microm. In addition, repeated angiograms at baseline and under increasing body temperature could be obtained. This new microangiographic approach is expected to be very useful for the assessment of dermal circulation in patients.
Angiography↗