Background

The differences in conditions of enteric-coated acid-labile drug release and absorption between healthy subjects in bioequivalence studies and gastrointestinal patients in clinical practice can lead to significant differences in gastric stability of original PPIs and generics. Thus, pathologic duodenogastric reflux (PDGR) and the pH increasing within PPIs administration still remain unaccounted for.

Methods

Two-stage modified comparative dissolution testing of original omeprazole (OO) and four generics (G1;2;

;4) was performed. At first, we moved drugs from solution with pH 1.2 (1.2±0.05) to pH 7.0 (7.0±0.05) and measure concentration of omeprazole in solution by high-performance liquid chromatography. According to our self-developed formula, pH 7 exposure time of resistance to PDGR for omeprazole is 4 minutes, i.. the active substance should not be released within 4 minutes at pH 7. The exposure at the second stage was conducted with pH 4 (4.0±0.05), that imitated gastric pH after PPI administration. And then we also moved drugs to pH 7 with the subsequent measurement of omeprazole concentration.

Results

Omeprazole concentrations after 4, 10, 15, 20, 30, 45, 60 minutes in pH 7 solution at the first stage were different for OO and generics. For OO, these values were 4,7±0,7%; 41,4±

,0%; 62,±4,0%; 79,5±2,%; 83,5±2,%; ,6±2,%; 80,6±4,4%; for Generic1 - 0; 49,±,%; 88, ±2,%; 90,4±,7%; 88, 2±2,2%; 87,±2,0%; 85,±1,1%; for Generic2 - 0; 30,6±6,%; 66,7±,2%; 76,4±7,4%; ,±5,%; 86,0±,7%; 84,6±,%: for Generic - 80,±,6%; 83,5±1,%; 83, ±,2%; 83,±2,7%; ,±2,1%; ,1±2,0%; ,0±2,4%; for Generic4 - ,5±1,7%; 84,4±0,%; 84,2±1,2%; , ±0,%; ,±0,%; ,±0,%; ,±1,1%, respectively.

An analysis of the omeprazole concentration in pH 7 solution at the second stage revealed the following parameters after the same time: for OO - 4,4±0,6%; 40, 5±

,0%; 62,±2,0%; 80,0±,1%; 85,4±2,%; ,±,4%; 80,±,5%; for Generic1 - 0; 67,0±7,%; ,7±2,%; 91, ±4,%; ,1±1,6%; 88,±1,4%; 87,±1,2%; for Generic2 - 0; 42,2±5,6%; 75,1±7,%; ,0±6,0%; 88,4±,2%; 88, 6±1,%; 87,±1,0%; for Generic4 - 85,5±0,5%; 85,6±0,5%; 84,7±0,%; ,7±,0%; 84,4±0,%; 84,4±0,%; 84,±0,4%, respectively. Generic release and degradation were completely realized at pH 4.

Conclusion

Decreased gastric stability of Generic

and Generic4 makes PDGR and inhibited gastric acid secretion due to PPIs administration the potential causes of decreased enteric-coated acid-labile drugs stability.

抄録全体を表示

A biosynthetic pathway for (

)-methyl cinnamate formation was evaluated in Tricholoma matsutake by tracer experiments using

13C

- and ²H-labeled precursors. One hundred percent selective

13C

incorporation was observed when L-[1,2,

3

,4,5,6,7,

8

,

9

-

13C₉

, ^15/N]phenylalanine was converted to (

E

)-[1,2,

3

,4,5,6,7,

8

,

9

-

13C₉

]cinnamate and (

E

)-[1,2,

3

,4,5,6,7,

8

,

9

-

13C₉

]methyl cinnamate. Similarly, 100% selective

13C

incorporation was observed when (

E

)-[1,2,

3

,4,5,6,7,

8

,

9

-

13C₉

]cinnamate was converted to (

E

)-[1,2,

3

,4,5,6,7,

8

,

9

-

13C₉

]methyl cinnamate. In contrast, the ²H incorporation selectivities were

82

.1% and

81

.4% when L-[2,

3

,4,5,6,7,7,

8

-

2H₈

]phenylalanine was converted to (

E

)-[2,

3

,4,5,6,7,

8

-²H₇]cinnamate and (

E

)-[2,

3

,4,5,6,7,

8

-²H₇]methyl cinnamate, respectively. Thus, T. matsutake synthesizes (

E

)-methyl cinnamate from L-phenylalanine via (

E

)-cinnamate. (

E

)-cinnamate was likely formed through two pathways: one was major and the other was a minor.

抄録全体を表示

Six full-length cDNAs encoding pig cytochrome P450 (CYP) enzymes, CYP1A1, CYP2A19, CYP2, CYP233v4, CYP249, and CYP21, were isolated and sequenced. The cDNA sequences of pig CYP1A1, CYP2A19, CYP2, CYP249, and CYP21 showed high similarity to human CYP1A1 (85.4%), CYP2A13 (88.6%), (.1%), (85.%), and (.5%), respectively, and pig cDNA showed high similarity to rat (79.2%). Reverse transcription-polymerase chain reaction (RT-PCR) assays revealed hepatic gene expression of all these pig CYP enzymes: the order of expression was and > > CYP1A1 and CYP2A19 > . In the kidney, the gene was expressed at the same level as in the liver, but the CYP1A1, CYP2A19, and genes were expressed at lower levels than in the liver. Little renal gene expression of CYP249 and CYP21 was observed. We revealed for the first time the full-length cDNA sequences encoding pig CYP1A1 and five CYP enzymes belonging to the CYP2 gene family, thus making it possible to examine the gene expression levels of these CYP enzymes in pig tissues by RT-PCR.

抄録全体を表示

The effects of T- (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,-dihydro--methoxy-1H-pyrrolo[,4-]quinolin-1-one hemifumarate), a new quinoline derivative, on acetylcholinesterase (AChE) activity and acetylcholine (ACh) release were compared with those of the well-known cholinesterase inhibitors tacrine and 2020. T-, tacrine and 2020 all concentration-dependently inhibited AChE in rat brain homogenate (IC_50s = 109.4, 84.2 and 11. nM, respectively). In addition, although tacrine strongly inhibited butyrylcholinesterase (BuChE), T- and 2020 showed only weak activity on BuChE in human plasma. In ex vivo experiments, intraperitoneal administration of T- at a dose of 30 mg/kg inhibited AChE activity in the hippocampus, frontal cortex and parietal cortex of rats. The effect of T- on the extracellular ACh concentration in rat brain was measured using in vivo microdialysis. T- at doses of 10 and 30 mg/kg, i.p. increased the extracellular ACh concentration in the hippocampus and striatum in a dose-dependent manner. These findings suggest that T- activates the central cholinergic system by selectively inhibiting AChE activity, while weakly affecting peripheral BuChE activity, and that T- increases the extracellular ACh concentration in the brain, which is followed by inhibited AChE activity.

抄録全体を表示

In Japan, aseptic meningitis cases due to enterovirus infections increase every summer in various degrees with an incidence peak usually in July. During the past 11 years from 1981 through 1991, a total of , 595 enterovirus isolations from aseptic meningitis cases were reported from 54 participating laboratories. Eight enterovirus types caused large epidemics; more than 100 isolations of each type from aseptic meningitis cases were reported for every epidemic year of the respective type. They were coxsackievirus () types and 5, echovirus () types 4, 6, 7, , 18 and 30. Among these, the highest meningitisassociating frequency was reported for 30, representing .6% of the total isolations reported for the type during this period, followed by 4, 71.1%. The frequencies of , 7, 6 and CB5 were in a range from 54.5% to 44.4%, while that of 18 was 37.7% and that of CB 21.0%. During the epidemics, enterovirusassociated meningitis was most frequently reported among children of 4-7 years of age. High frequencies were also shown in infants less than 1-year of age in some types. A total of 4, 240 enteroviruses were isolated from cerebrospinal fluid of aseptic meningitis cases, representing 49.% of the cases with enterovirus isolation.

抄録全体を表示

Repetitive liquefactions in angular and subangular gravels from an alluvial fan, in the case of two earthquakes with accelerations lower than that of a former which had caused liquefaction some months before, are described. The liquefaction took place from the surface, down to a depth of approximately 10 m. Water laden with sediments spouted out for some tens of minutes after the strong motion ceased. Knowledge of the grain size distribution of the sediments inside the body of the alluvial fan roughly defines the areas of the fan prone to future liquefaction. Non-repetitive liquefaction in overconsolidated fine fluvio-lacustrine sand of glacial origin at the unusual depth of 14 m to 16 m is also described. From the observation of sand lifted up for 10 m inside a large diameter well, and of that which spouted out from several microvents, it was estimated that extra-pore pressure was close to lithostatic conditions. Nevertheless, modeling of intrinsic pore pressure buildup on the DESRA2 programme gives lower values than the experimental one. Geotechnical characteristics of the 12 m-thick sandy stratum indicate that the upper part is unusually soft, either due to water circulation or past repetitive liquefactions which prevented reconsolidation. It is suggested that excess pore pressure generated by the earthquake was also due to redistribution of pressure from adjacent sediments.

抄録全体を表示

Nine isoquinoline alkaloids belonging to the protoberberine, proaporphine and bisbenzyl-isoquinoline series were isolated from Caryomene olivascens (Menispermaceae). Four compounds are new : (-)-2-norlimacine (4), (-)-caryolivine (6), (+)-1, 2-dehydro-2-norlimacusine () and N-formylstepharine (). The last one is the first N-formyl derivative to be reported in the proaporphine group. Its biogenetic origin is discussed. Structures were established on the basis of 360 MHz (FT) nuclear magnetic resonance measurements and also by chemical correlation in the case of .

抄録全体を表示

Objective: This study was conducted to determine whether to perform endovascular intervention or bypass surgery as a treatment option for critical limb ischemia (CLI) with lesions in the popliteal artery or below.Subjects and Methods: A total of 150 patients (164 limbs) with CLI underwent endovascular intervention or bypass surgery for lesions in the popliteal artery or below at our department between May 1995 and June 2011. Therapeutic outcomes were examined by surgical technique. An indication for endovascular intervention was established with the combination of (1) poor general condition, and (2) a stenotic or occlusive lesion ≤5 cm.Results: The bypass group (group ) comprised 119 patients (99 males, 20 females) with 131 affected limbs at 46 to years of age (mean: 70 years). The endovascular intervention group (group ) comprised 31 patients (25 males, 6 females) with 33 affected limbs at 47 to years of age (mean: 72 years). There was no significant difference in patient demography between the two groups. Regarding preoperative complications, hypertension was observed in 54% and 61% of the subjects in groups and , respectively, diabetes in 36% and 55%, renal dysfunction in 29% and 58%, ischemic heart disease in 27% and 32%, and cerebrovascular disorder in 18% and 23%; renal dysfunction accounted for a significantly higher percentage in group . As for early postoperative complications, subjects in group experienced wound infections (6 patients), hemorrhage (2), thrombosis (2), pneumonia (1), and another complication (1), and those in group experienced wound infections (1) and another complication (1). The hospital mortality rate was 0.% (1 patient) for group and 0% for group . The -year cumulative primary patency rate was 72% for group and 54% for group ; the rate was significantly higher for group . The -year secondary patency rate was % for group and 60% for group . The -year limb salvage rate was 86% for group and % for group ; there was no significant difference between the two groups. The 5-year survival rate was 57% for group and 42% for group ; the survival rate was significantly lower for group .Conclusion: For the study population of CLI patients with lesions in the popliteal artery or below, the patency rate was higher for the bypass group than for the endovascular intervention group, whereas there was no difference in the limb salvage rate. Based on the findings in prognosis for survival, the indication for endovascular intervention at our department is believed to be appropriate. (*English translation of Jpn J Vasc Surg 2013; : 715-718)

抄録全体を表示

The possibility of attenuation of microseismic waves due to the presence of an upward folding of the ocean bottom into the liquid is discussed in this paper. The upward folding of the ocean bottom has been idealized by means of an irregularity in the form of a rectangle intruding into the liquid and the evaluation of the displacement component at any point of the solid medium has been carried out in two stages. First, the change in the incident mode of the surface wave due to the presence of the rectangular irregularity has been determined, and second, the subsequent change of the resulting displacement components due to the termination of the liquid layer and the step change in elevation of the solid medium at the continental margin has been discovered. Finally, numerical calculation has been made to determine the attenuation of the microseismic waves of different periods due to the presence of the rectangular irregularity at the ocean bottom.

抄録全体を表示

One method currently being considered for the disposal of high level radio-active waste is burial in the seabed. When a hot object is buried in soil, the temperature of the soil adjacent to the object is raised and there is transient heat flow away from the object. The rise in the temperature of the soil causes excess pore pressures to be generated and transient pore water diffusion also takes place. A finite element formulation of the coupled heat flow and consolidation problem is presented. The computer implementation of this formulation is found to compare favourably with analytical solutions based on the same physical principles.

抄録全体を表示

長期的に見ると、景気のトレンドが低下し、在庫投資や設備投資の変動が小さくなっている。その背景には、経済のサービス化、グローバル化、DX、研究開発投資の拡大などの経済構造の変化がある。こうした中で、第 16 循環の山（2018 年 10 月）付近においては、景気動向指数（一致指数）と実質GDPの動きに乖離が見られたが、その要因としては、外需の減少ペースが景気を一気に冷え込ませるような急激なものではなかったことが大きい。加えて、労働市場では、人口減少下で女性や高齢者を中心に労働市場に参入する人が増え、雇用所得環境を下支えしていた。コロナショック後は、賃上げのモメンタムが強まっている。今後、労働市場の構造変化がどのように進むのか、それが景気循環にどのような影響を与えるのか、注視していく必要がある。 こうした景気循環の特徴の変化やその背景にある経済構造の変化を踏まえると、景気循環を適切に捉えるためには、第一に、景気循環の転換点を敏感に捉える必要があることに変わりはないが、一方で、第二に、生産に過度に重点を置かず、より幅広い指標を観察すること、第三に、経済の全体的な動向を捉えるという観点から、実質GDPの動向にも留意すること、が必要となろう。

抄録全体を表示

Does the demonstration of recollection with the slave boy in the Meno really constitute the proof of recollection thesis? Socrates seems there to be asking leading questions I take it that Plato intended to make it uncertain whether the boy is really recollecting his second denial of knowledge 'ou manthano' (85A4-5) can mean 'I am not learning', suggesting that he is not recollecting We can never know the truth about his learning, because the demonstration is a Gorgian type of epideixis (1-2), which produces only persuasion However, it is one thing to know whether the boy is recollecting, and quite another to know whether learning is recollection The demonstration is meant to make Meno recollect the latter truth (6-A) Throughout the demonstration Socrates addresses questions to Meno, thereby making him consider whether the boy is really recollecting (6-7, 12-, 84A-4, 10-D1) Socrates' remark after the demonstration is that Meno knows that the boy will regain knowledge (85-D1), which means that Meno has been successfully made to recollect that recollection thesis is correct According to Cebes' explanation in the Phaedo (73A7-2), recollection is helped by the use of proper questions and diagrams, and according to the Republic (510D5-511A1, 529D7-530A), mathematicians should not seek truth in diagrams or models made by such masters as Daedalus, but make use of them simply as images The boy's learning is a beautiful image of true learning created by Socrates, an offspring of Daedalus We should not seek truth concerning learning in this image, but make use of it to find truth about true learning Socrates' proper questions with the help of this image made Meno recollect that learning is recollection However, inquirers are rather misled by perceptual images when the object of inquiry has no lustre in its earthly image(Phaedrus 250), as is the case with virtues, knowledge, education and learning In order to establish that learning is recollection, it is then necessary to have recourse to another kind of proof, in which one relies on rational thinking Plato embarks on this task in the Phaedo Recollection itself can be taken to be an image or metaphor (eikon) of learning, presented by Socrates, just as the torpedo is an image of Socrates, presented by Meno (80A-) But they are different in that while the latter is intended to stop inquiry, recollection is a metaphor that stimulates inquiry and helps to develop new ideas expressible in literal paraphrases ('the illustrative thesis' in Pender, Images of Persons Unseen, Sankt Augustin 2000) In the Phaedo Plato continues his quest for the truth about learning, with the help of recollection as the image of learning, and thereby develops such new ideas as the existence of Forms and the immortality of the soul His further inquiry about knowledge, the object of learning, in the Theaetetus is taken to be its further continuation

抄録全体を表示

A sample of [

3H

] tobrarnycin (5, 000 Ci/Mole) has been synthetized and incubated with
the bacterial ribosome and its subunits. The results obtained show that this antibiotic has
two types of binding sites. The primary one is probably responsible for the inhibition of
protein synthesis whereas the secondary one is probably related to the misreading and reading
tiirough of the messenger RNA.

抄録全体を表示

This paper applies the fuzzy cluster analysis to six international stock markets (i.., France, Germany, the U.S., Canada, Japan, and China). We analyze the similarity values calculated from the monthly stock returns, using both Zadeh's and Ward's clustering methods. These two methods induce different partition trees. Both the Minkowski distance and cophenetic correlation coefficient choose Zadeh's method over Ward's method. The optimal partition tree and the associated optimal number of clusters suggest (1) the similarity of European countries, (2) the institutional regularity of the Chinese stock market, and () the strong influence of the U.S. These implications are consistent with standard economic theory, and are preserved under the addition of three countries (i.., the U.K., Mexico, and South Korea).

抄録全体を表示