Gamma-pyrone compounds with selective and potent anti-Helicobacter pylori activity.
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Biomedical subjects
Publications and source records attributed to A Tanaka.
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Since clarithromycin is expected to be widely used to treat Helicobacter pylori infection in the near future, it is important to investigate the relationship between resistance to clarithromycin and the regimens of eradication therapy. We investigated: (1) the usefulness of susceptibility tests prior to eradication therapy, and (2) the rate of acquisition of H. pylori resistance to clarithromycin after treatment failure. Drug susceptibility tests to clarithromycin and amoxicillin were conducted by Dry Plate Test or E-test. The subjects in the first part of this study included 112 patients with H. pylori infection who received triple therapy with various combinations of drugs, including clarithromycin. The eradication rate in patients with clarithromycin-susceptible H. pylori was significantly higher than that in patients with clarithromycin-resistant H. pylori. The second part of this study included 21 patients in whom H. pylori was not eradicated by triple therapy and 12 patients in whom H. pylori was not eradicated with dual therapy including clarithromycin. Of the 33 patients showing non-eradication. 90.9% of those treated with dual therapy and 35.7% of those treated with triple therapy acquired secondary resistance of H. pylori to clarithromycin. We conclude that it is important to conduct drug susceptibility tests prior to treatment of H. pylori infection. Since the incidence of acquiring clarithromycin resistance was significantly higher in the patients showing non-eradication, it is important to choose a regimen with a higher eradication rate, such as triple therapy.
UNLABELLED: To develop PET ligands for mapping central nervous system (CNS) adenosine A2a receptors that are localized in the striatum and are coupled with dopamine receptors, 3 11C-labeled xanthine-type adenosine A2a antagonists, [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e), [11C]KF19631 ([7-methyl-11C]-(E)-1,3-diallyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanth ine), and [11C]CSC ([7-methyl-11C]-8-chlorostyrylcaffeine), were compared with [11C]KF17837 ([7-methyl-11C]-(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylx anthine). METHODS: The regional brain uptake of the tracers, the effect of the coinjected adenosine antagonists on the uptake, and the metabolism were studied in mice. In rats, the regional brain uptake of the tracers was visualized by ex vivo autoradiography (ARG). The A2a receptor binding of antagonist 1 was also measured by in vitro ARG. Imaging of the monkey brain was performed with PET with antagonist 1. RESULTS: In mice, the highest striatal uptake was found for antagonist 1 followed by antagonists 2 and 4. The uptake was inhibited by each of 3 KF compounds and by CSC, but not by an A1 antagonist KF15372. Another selective nonxanthine-type A2a antagonist SCH 58261 significantly decreased the striatal uptake of only antagonist 1, the labeled metabolites of which were less than 20% in the plasma 30 min postinjection, but were negligible in the brain tissue. In ex vivo ARG, antagonist 1 showed the highest striatal uptake and the highest uptake ratio of the striatum to the other brain regions. A high and selective binding of antagonist 1 to the striatum was also confirmed by in vitro ARG. PET with antagonist 1 visualized adenosine A2a receptors in the monkey striatum. CONCLUSION: These results indicate that antagonist 1 ([11C]KF18446) is the most suitable PET ligand for mapping adenosine A2a receptors in the CNS.
Toxic effects of gallium arsenide (GaAs), indium arsenide (InAs) and arsenic trioxide (As2O3) were studied in male Syrian golden hamsters. GaAs (7.7 mg/kg) and As2O3 (1.3 mg/kg) particles were instilled intratracheally twice a week a total of 16 times, while InAs (7.7 mg/kg) was instilled a total of 14 times. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During the instillation period, the cumulative body weight gain of the InAs-, but not the GaAs- or As2O3-treated hamsters was suppressed significantly, when compared with the control group. Slight to severe inflammatory responses were observed in the lung for all treatment groups. The most severe inflammatory change, characterized by an accumulation of neutrophils and macrophages, exudation, thickness of the pleura and fibrotic proliferation was found in the InAs-treated hamsters. Extensive alveolar or bronchiolar cell hyperplasia with or without keratinizing squamous cell metaplasia was observed in almost all the InAs-treated hamsters. Furthermore, squamous cell metaplasia or squamous cell hyperplasia developed in some of the InAs-treated hamsters, but not in the GaAs- or As2O3-treated hamsters. Slight to mild lesions were found in the convoluted tubules of the kidney in both the GaAs and InAs groups. From the present study, the toxic potency of these particles was provisionally estimated to be in the following order: InAs > GaAs > As2O3, at the dosage level used in this study. Furthermore, there was evidence that InAs particles could induce pulmonary, renal or systemic toxicity, and as such, InAs particles may produce pulmonary precancerous change when instilled intratracheally into hamsters.
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Because of its anesthetic properties, inhalation of 30-35% Xenon is associated with uncontrolled patient motion in 3-15% of the cases. This constitutes a major setback to regional cerebral blood flow studies with Xenon-enhanced computed tomography (Xe-CT CBF). The present study attempted to determine the effects of oral premedication with hydroxyzine (H) in the control of motion. Patients scheduled for Xe-CT CBF, aged 20-55 years, were randomly allocated to 3 groups: H 50 mg (n = 41), H 100 mg (n = 36) or Placebo (n = 43). The drugs were administered orally 90 minutes before Xenon inhalation. This consisted a gas mixture of 32% Xe and 25% oxygen. Motion was classified as controlled or uncontrolled depending on whether CBF data acquisition was possible or not. Anxiolysis and sedation were evaluated by a visual analogue scale. Motion was significantly reduced in the H 50 mg (0.8% vs 2.5% in the H 100 mg and 6.7% in the Placebo group). An anxiolytic effect of hydroxyzine was suggested.
Our study was designed to determine whether supplementary information obtained with perfusion MRI can enhance accuracy. We used delayed perfusion, as represented by time to peak map on perfusion MRI, to classify strokes in 39 patients. Strokes were classified as hemodynamic if delayed perfusion extended to a whole territory of the occluded arterial trunk; as embolic if delayed perfusion was absent or restricted to infarcts; as arteriosclerotic if infarcts were small, multiple, and located mainly in the basal ganglias; or as unclassified if the pathophysiology was unclear. We compared these findings with vascular lesions on cerebral angiography, neurological signs, infarction on MRI, ischemia on xenon-enhanced CT (Xe/CT) and collateral pathway development. Delayed perfusion clearly indicated the area of arterial occlusion. Strokes were classified as hemodynamic in 13 patients, embolic in 14 patients, arteriosclerotic in 6 patients and unclassified in 6 patients. Hemodynamic infarcts were seen only in deep white-matter areas such as the centrum semiovale or corona radiata, whereas embolic infarcts were in the cortex, cortex and subjacent white matter, and lenticulo-striatum. Embolic and arteriosclerotic infarcts occurred even in hemo-dynamically compromised hemispheres. Our findings indicate that perfusion MRI, in association with a detailed analysis of T2-weighted MRI of cerebral infarcts in the axial and coronal planes, can accurately classify stroke as hemodynamic, embolic or arteriosclerotic.
Nicotine produces profound behavioral effects in humans, but little is known about the sites of its action. There is a hypothesis that frontal lobe and limbic/cingulate cortical structures might be the sites. In this study, we examined the effects of cigarette smoking on feeling and cerebral blood flow (CBF) in human subjects. Young and healthy 9 cigarette smokers (all males, 24-33 years, average, 26.4) were included. After prohibiting them from smoking for 15 hours, CBF was measured using a Xenon CT-CBF system. Fifteen minutes later after allowing them to smoke two pieces of cigarette, the second CBF measurement was performed. Subtraction CBF map was created to display the changes after smoking. CT images were taken at three levels so as to include the cerebral lobes, basal ganglia, limbic system, brainstem and cerebellum. Arterial nicotine increased up to the levels 8 times higher than before smoking. The increases of blood pressure and pulse rate were minimal. Arterial carbon dioxide level and hematocrit did not change. Feeling after smoking was variable in individual subject. In 8 subjects with a relatively high feeling, CBF increased mainly in the frontal lobe, hippocampus, uncus, thalamus and caudate nucleus. CBF did not change in the parietal, temporal and occipital lobes, and in the putamen, insula, brainstem and cerebellum. In two subjects with uncomfortable feeling, CBF did reduce in the whole brain. The CBF increase in frontal lobe and limbic structures seems to be secondary to nicotine-induced neuronal activation in each structure. Mesocorticolimbic dopamine system, which is believed to influence learning, memory or emotional performance, appears to be a target for nicotine. The CBF reduction in the whole brain might be due to cerebral vasoconstriction or be secondary to a systemic hypotension.
It is suggested that mastication stimulates the brain and accelerates its energy-consuming metabolism. This study was designed to determine its effects on regional cerebral blood flow (rCBF) using xenon-enhanced computed tomography (Xe-CT). Seven male volunteers, aged 24-57 years, inhaled 30% xenon in a 4 minutes wash-in and 4 minutes wash-out protocol. CT was scanned every 54.5 seconds. The subjects were instructed to chew a gum continuously at a rate of 1 bite per second except at the time of CT scanning (5.5 seconds). A second CBF was done 20 minutes later. Subtraction (mastication-baseline) maps were created. CT images were taken at three levels so as to include the cortex, basal ganglia, limbic system, brainstem and cerebellum. The results demonstrated a significant rCBF increase in the fronto-temporal cortex, caudate nucleus, thalamus and minor increase in the rolandic areas, insula, cingulate and cerebellum. Further studies are needed to validate the clinical significance of these findings.
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BACKGROUND: We encountered two cases of Chinese herb-induced Fanconi syndrome in Japan. One component of the chinese medicine was "Kan-mokutsu" (Aristolochia manshuriensis) in which aristolochic acids (AAs) were detected. METHODS: Renal biopsy showed flattening of proximal tubular epithelial cells and paucicellular interstitial fibrosis without glomerular lesions, all of which were in accordance with Chinese herb nephropathy (CHN). To date, many cases of CHN have been reported mainly as progressive renal failure in western countries. RESULTS: However, our cases were different from those in that they presented Fanconi syndrome. The detected AAs in our cases consisted of aristolochic acid (AA)-I, II and D. In contrast, in Belgium, the incriminated agent was Aristolochia fangchi which consisted of AA-I, B, C, and aristolactum. CONCLUSION: These findings could indicate that different components of AAs could cause different clinical lesions, or that the amount of ingested AAs might reflect clinical pictures, that is to say, our patients took lower volume of Chinese herbs and might be in an early stage of CHN. Furthermore, it is likely that susceptibility to this substance may be different among races. CHN would include two clinical aspects: subacute renal failure and adult-onset Fanconi syndrome. It is important to bear in mind that CHN could present Fanconi syndrome.
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PURPOSE: Interview survey is the often selected method to investigate falls among the elderly. However, the reliability of data obtained by that method has not be confirmed. The aim of this study is to clarify the number of intervals of recollection that should be specified to ensure accurate data when we investigate falls by using interview surveys among the elderly. METHODS: We carried out a total health survey among the elderly in Shigenobu town, and reported about the frequency of falls and its relating factors. Sex, age, walking ability over a distance of 1 km and hospitalization experience for past 1 year were related to falls significantly. In this study, we set 3 groups matching for the above factors in addition to history of falls during the preceding a year, and for one year we asked about falls every month for the first group (116 participants), every 3 months for the second group (116 participants) respectively. The third group (118 participants) was asked once at the end of this study. These three groups totaled 350 persons who were participants of physical fitness measurements that we carried out in Shigenobu town. The existence of falls was investigated by mail, and the nonrespondents were questioned by direct telephone calls. RESULTS: For reasons such as death, moving out, hospitalization and answer denial, persons whose answer was not obtained were excluded from the analysis. Finally, 87.1% in the 1st group, and 89.7% in the 2nd group and 96.6% in the 3rd group were analyzed. Statistically significant difference for the above factors related to falls did not exist among the 3 groups. Annual incidence for falls tended to be more frequent in the 1st group that in the 3rd group (20.5% in the 1st group, 15.9% in the 2nd group and 6.4% in the 3rd group) in males. In females, such a difference was not observed. (26.3% in the 1st group, 18.3% in the 2nd group and 20.9% in the 3rd group). CONCLUSIONS: There were no significant differences for the factors related to falls in 3 groups, therefore, the groups had almost similar backgrounds. In men, the difference of annual reported incidence between the 1st group and the 3rd group may be due to differences in the method of recollection.
To elucidate the effect of epinephrine and the combination with heat on malignant cells, using two melanoma cell lines, HM6KO and G361, we have examined the cytotoxicity and induction of 72-kD stress protein (HSP72) after the treatments. After epinephrine treatment, in both cell lines, cell survival rates decreased gradually in a concentration-dependent manner. After the combination treatment, cell survival rates decreased more than those when two treatments were done separately. The cytotoxicity of epinephrine was more enhanced in G361 than in HM6KO by heat. After epinephrine treatment, in both cell lines, the level of HSP72 did not elevate. After combination treatment, in HM6KO, the level of HSP72 were higher than those of heat alone. In G361, the kinetics of HSP72 level was similar to that of heat alone. These results suggest that epinephrine has a cytotoxicity to melanoma cells and the cytotoxicity is enhanced by the combination. In addition, it is probable that epinephrine does not have HSP72 inducibility in HM6KO and G361, and the different kinetics of HSP72 between the cell lines in the combination treatment may play an important role to determine the degree of enhancement.
For the purpose of reducing the risk of lung injury while separating adhesions in repeated pulmonary resections, the inhibitory effect of hyaluronate based bioresorbable membrane (HA membrane) on postoperative adhesions was investigated in a new pleural adhesion model in rats. First of all, a novel post-thoracotomy adhesion model in rats was successfully established by using a combination of mechanical, chemical and ischemic injuries of the pleura during operation. After undergoing the same adhesion-inducing procedures, one of two groups was treated with HA membrane inserted between the lung and the parietal pleura, and the other group underwent infusion of saline only. The severity of the adhesion formation was macroscopically lower in the HA membrane-treated rats, and they had favorable mesothelial regeneration microscopically. Additionally, the activity of type 1 plasminogen activator inhibitor (PAI-1) in the intrapleural lavage fluid (ILF) was measured at 24 hours postoperatively because this is the main influence on adhesion formation after surgery. PAI-1 activity was 23.37+/-2.57 U/ml in the saline-treated group and 17.85+/-3.06 U/ml in the HA membrane-treated group. The result suggests that the HA membrane inhibits postoperative adhesion formation through a significant repression of PAI-1 activity.
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An 84-year-old man was referred to our hospital because of fever, cough, and hemoptysis. The patient had acute respiratory failure (PaO2 < 40 mmHg) on admission, with diffuse interstitial infiltration and bilateral pleural effusion. The bronchoalveolar lavage fluid was bloody, and contained a high percentage of eosinophils (32%). A diagnosis of acute eosinophilic pneumonia was established, and the patient made a rapid recovery after corticosteroids were administered. When the DLST (drug lymphocyte stimulation test) was performed after the corticosteroid therapy was stopped, it was positive for serrapeptase, which had been prescribed for chronic cystitis for 3 months before the onset of the pneumonia. This was a case of drug (serrapeptase)-induced pneumonitis manifesting as acute eosinophilic pneumonia.