Biomedical subjects

T Yuzuriha

Publications and source records attributed to T Yuzuriha.

At least 37 records · Page 2Linked to original sources

PubMed1995

Distribution of menaquinone-4, a therapeutic agent for osteoporosis, in bone and other tissues of rats.

[14C]Menaquinone-4 was administered orally once daily at a dose of 4 mg/kg for ten days to female rats of different ages to determine its blood and tissue distribution with particular attention to its distribution in bone. Animals aged 10 and 30 months were either ovariectomized or sham-operated as a control, and young rats aged 7 weeks were used as untreated controls. Blood concentrations of radioactivity at 24h after each dose during repeated administration increased daily and approached a steady rate by the seventh dose. Higher concentrations of radioactivity in blood (plasma) were observed in older animals than in the younger ones, but there was little difference between ovariectomized rats (OVX rats) and sham-operated rats (Sham rats). In tissue samples collected at 1.5 h after administration, the liver, adipose tissue, spleen and adrenals showed higher concentrations of radioactivity than the other organs and the plasma. IN bone tissues, the bone marrow (BM) and cancellous tissue (CT) of the femur showed radioactivity concentrations which were higher than that in the plasma, and these increased during repeated administration. Finally, at 24 h after the last dose, the concentrations of radioactivity in bone tissues of older animals (BM, 5,807.2 ng eq/g; CT, 5,264.8 ng eq/g in OVX rats aged 10 months and BM, 11,479.3 ng eq/g; CT, 4,023.0 ng eq/g in OVX rats aged 30 months) were several times higher than those in younger animals (BM, 2,771.6 ng eq/g; CT, 890.2 ng eq/g in 7-week-old untreated rats). The values in OVX rats were also higher than those in Sham rats. Furthermore, micro autoradiography studies of femur sections from OVX rats indicated that [14C] Menaquinone-4 localized in cancellous tissue where bone is known to be actively remodelled. The concentrations of radioactivity in cancellous tissue and bone marrow of OVX rats aged 10 and 30 months were comparable to the pharmacologically effective concentrations of Menaquinone-4 (10(-6)-10(-5) M) in in vitro studies on bone formation. These findings suggest that orally administered Menaquinone-4 distributes specifically into the bone tissues of ovariectomized rats and this is consistent with its effect as a therapeutic agent for osteoporosis.

Aging↗

PubMed1994

Expression of beta-amyloid precursor protein in the developing human spinal cord.

Human fetal spinal cords and other non-neural tissues from cases with gestational age from 6 to 21 weeks were examined with a panel of antibodies to different domains of beta-amyloid precursor proteins (beta-APPs). In the early developmental stages, the beta-APPs were expressed in three distinct layers, i.e., primitive neuroepithelial cell layer, mantle layer and marginal layer. beta-APP immunoreactivity was most prominent in cell bodies of putative neuroblasts located in the outer ventral part of the mantle layer. beta-APP expression diminished as the spinal cord matured and a weak residual immunoreactivity was detected exclusively in a subset of the anterior horn cells by 21 weeks gestational age. Throughout the gestational ages examined, no convincing beta/A4 immunostaining was seen in any of the spinal cord regions. Outside the spinal cord, beta-APP immunostaining was consistently present in (1) cell bodies and proximal nerves of immature neurons of dorsal root ganglia and in (2) myotubules, although these cells were devoid of beta/A4 immunoreactivity. Western blot analysis of fetal spinal cord revealed immunoreactive bands with apparent molecular weight between 100 and 140 kDa in the membrane-associated fraction, while soluble proteins with a molecular mass centered on 115 kDa were detected in the cytosolic fraction. Our results indicate that: (1) one or more isoforms of full length beta-APPs are expressed at very early gestational ages in the developing human spinal cord; (2) the normal metabolism of beta-APPs does not result in accumulations of beta/A4 fragments.

Amyloid beta-Protein Precursor↗

PubMed1994

Development of radioimmunoassay for the novel platelet activating factor receptor antagonist, E6123, and its application to pharmacokinetics in laboratory animals.

A direct radioimmunoassay for the determination of E6123, a novel antagonist of platelet activating factor (PAF) receptor, was developed in order to study the pharmacokinetics at low dose. This procedure used [3H]E6123 as the radioligand and an antiserum obtained from rabbits immunized with the hapten covalently bound to bovine serum albumin. M1B, one of the main metabolites of E6123, exhibited cross-reactivity with antisera. But this metabolite had no effect on measurements of E6123, because the amount of M1B in plasma radioactivity after administration of [14C]E6123 to dogs and monkeys was low. The sensitivity limit of this assay was 25 pg/ml of plasma when 0.1 ml of plasma was used and the assay showed good accuracy and high precision. The validity of the radioimmunoassay was demonstrated by comparative analysis of a number of samples after oral and intravenous administration (1.0 mg/kg) by HPLC-UV method (r = 0.972-0.984, slope = 1.0314-1.2143). The pharmacokinetics of E6123 was studied at a dose of 30 micrograms/kg. After intravenous administration, the plasma concentration-time curves in all species fitted a two-compartment model and the terminal half-lives in guinea pigs, dogs and monkeys (both poor and extensive metabolizers) were 4.77, 1.71, 5.34 and 1.07 h, respectively. After oral administration, the maximum plasma concentrations were obtained within 0.83-3.00 h and the half-life for each animal was almost the same as that after intravenous administration. The mean bioavailabilities of E6123 in guinea pigs, dogs and monkeys (poor and extensive metabolizers) were 106.9, 45.7, 59.1 and 22.8%, respectively.

Animals↗

PubMed1994

Thrombolysis of canine femoral artery thrombus by a novel modified tissue-type plasminogen activator (E6010).

The thrombolytic activity of a novel modified tissue-type plasminogen activator (t-PA) (E6010) was examined in a canine model with copper coil-induced femoral artery thrombus. This model, in which thrombolytic activity can be easily and directly quantified by determining changes in thrombus weight, should be useful for comparing the activities of various thrombolytic agents. Using this model, the present study showed that the thrombolytic activity of bolus intravenous injection of E6010 was identical to that of continuous intravenous infusion of recombinant t-PA at the same dose. This thrombolytic activity can be explained by changes in blood concentrations of the administered thrombolytic agents. On the other hand, administration of the thrombolytic agents dose-dependently caused significant changes in the levels of hemostatic and fibrinolytic factors. These changes were not so marked with administration of E6010, and therefore we concluded that E6010 is unlikely to cause bleeding complications after administration.

Animals↗

PubMed1994

[Encephalomyelitis with cavitary necrosis of the white matter. A clinico-pathologic study].

The authors report the clinico-pathological study of an encephalomyelitis with necrotic cavitation of the white matter occurring in a 61-year-old female. The disease of sudden onset progressed slowly to the death, 20 months after the onset of the first symptoms. They stress the rarity of the entity and the difficulties to establish the diagnosis clinically. The nosological situation of the condition is discussed and compared with the previously reported cases.

Brain↗

PubMed1993

Sex differences in schizophrenia: a demographic, symptomatic, life history and genetic study.

Twenty-one male and 32 female inpatients who met the criteria of schizophrenia according to the Research Diagnostic Criteria were compared for demographic, symptomatic, life history, and genetic variables. Female schizophrenics were marginally less likely to have auditory hallucinations; They were more likely to have early loss experiences (either bereavement or separation from a parent) before the age of 16. No other differences were found between the men and women.

Adult↗

PubMed1993

Pharmacokinetic study of loprinone hydrochloride, a new cardiotonic agent, in beagle dogs.

Pharmacokinetic parameters and bioavailability of a new cardiotonic agent, loprinone hydrochloride, in beagle dogs were determined by measuring plasma levels of loprinone after intravenous bolus and oral administration. The plasma half-life after intravenous administration of loprinone varied among individuals over the range 2.65-15.40 h. The bioavailability after oral administration of loprinone as a solution was 37.1%. Effects of enterohepatic circulation on the time-course of plasma levels after intravenous administration of the drug were also studied in bile-duct-cannulated beagle dogs. The amounts of loprinone and its glucuronide excreted in bile during 8 h after administration were 25.4 and 8.6% of the dose, respectively, indicating the possibility of enterohepatic circulation. The plasma half-life in bile-duct-cannulated beagle dogs was 1.98 h. These results indicate that the variation in the half-life in beagle dogs resulted from enterohepatic circulation and that the true half-life is about 2 h. The relative bioavailability after oral administration of the drug as a powder in a capsule compared with a solution was 95.7%. In addition, the amounts of loprinone and its glucuronide excreted in bile, and the AUC of plasma level after infusion for 30 min into the portal vein in bile-duct-cannulated beagle dogs were similar to those after bolus intravenous administration. These results show that the low bioavailability reflects incomplete absorption.

Administration, Oral↗

PubMed1993

Pharmacokinetics of a new thienodiazepine platelet activating factor receptor antagonist (E6123) in laboratory animals. Is there a metabolic polymorphism in the rhesus monkey?

1. The pharmacokinetics of E6123, a platelet activating factor receptor antagonist, were studied after i.v. and oral administration to rat, guinea-pig, dog and rhesus monkey. Plasma concentrations of E6123 were determined by h.p.l.c. with UV detection. 2. After i.v. dosing (1 mg/kg), the plasma concentration-time curves fitted a two-compartment model. The half-lives for the terminal phases (t1/2) in rat, dog, and guinea-pig showed very little inter-individual variation, but t1/2 in the monkey (n = 4) varied more than four-fold. The distribution parameters were very similar in rat, dog and monkey (Vc and Vss approx. 1.2 and 1.5 l/kg, respectively) but slightly higher values were found in the guinea-pig, which also showed the lowest plasma protein binding. 3. After oral dosing (1 mg/kg), the maximum plasma concentrations were obtained within 0.3-3.0 h in all species. The half-life for each individual animal was almost the same as that after i.v. dosing. The mean bioavailabilities of E6123 in rat, guinea-pig and dog were about 65, 95 and 81%, respectively, but the values for monkey were again highly variable (range 32-99%). 4. The high variability in the monkey was confirmed by i.v. administration to a further 10 animals. The mean half-lives for the terminal phase in extensive metabolizers (EMs) (n = 4) and poor metabolizers (PMs) (n = 10) were approx. 1 and 4 h, respectively. 5. The rank order for total body clearance of E6123 was: rat > monkey (EMs) > dog > guinea-pig > monkey (PMs).

Animals↗

PubMed1993

Metabolic polymorphism of E6123 in rhesus monkey.

1. The metabolic polymorphism of a new thienodiazepine platelet activating factor receptor antagonist (E6123) in rhesus monkey was studied in vivo and in vitro. 2. After i.v. dosing of 14C-E6123, the levels of radioactivity in blood, plasma and red blood cells were higher in poor metabolizers (PMs) with AUC(0-24 h) values which were about 1.3-1.5 times higher than those in extensive metabolizers (EMs). 3. After i.v. dosing of 14C-E6123, radioactivity was excreted rapidly by both EMs and PMs. However, EMs excreted the radioactivity mainly in urine whereas, for PMs, radioactivity was excreted fairly equally in urine and faeces. 4. In vivo and in vitro studies demonstrated that the metabolic polymorphism of E6123 in rhesus monkey is caused by a difference in the hydrolysis of an amide side chain. 5. Our results suggested that there are two types of the enzymes which metabolize E6123 by this route in EMs, but only one type in PMs. 6. The low affinity enzyme in EMs might be the same as the enzyme in PMs, indicating that the metabolic polymorphism of E6123 in rhesus monkey could depend on the existence of a high affinity enzyme.

Animals↗

PubMed1993

Pharmacokinetic characterization of menaquinone-4 in dogs by sensitive HPLC determination.

A simple and sensitive assay method for a pharmacokinetic study of Menaquinone-4 in dogs was established using HPLC with fluorescence detection following extraction with organic solvent. The quantification limit of this method was 1 ng/ml of plasma. A new oily solution formulation of Menaquinone-4 was administered orally to nonfasted dogs at doses of 0.4, 4 and 40 mg/kg. The plasma concentrations reached maximum levels at 1 to 1.5 h after dosing, and then decreased slowly. AUC values up to 24 h after administration were almost dose-proportional. Menaquinone-4 was also administered to dogs in soft-capsules, for comparison with a conventional hard-capsule oral formulation and an intravenous lecithin formulation. The mean AUC for oral dosing in the soft-capsule formulation was 13.5% of that for intravenous dosing in lecithin, and was 4.6 times higher than that for oral dosing in hard-capsules. Additional dosing in fasted dogs indicated that the AUC in pre-fed dogs was about 4 times higher, suggesting that feeding before giving Menaquinone-4 raises the bioavailability. Overall Menaquinone-4 was absorbed rapidly after administration in non-fasted dogs and dose-proportional bioavailability was obtained among the doses of 0.4 to 40 mg/kg. Higher plasma concentrations were observed after administration in the soft-capsule formulation rather than in the hard-capsule formulation. These findings suggest that the soft-capsule formulation would show a good pharmacokinetic profile for elderly patients with osteoporosis.

Administration, Oral↗

PubMed1993

[Alcohol and sudden death: a survey on alcohol-related deaths at tokyo Metropolitan Medical Examiner's Office (1989)].

Seven thousand three hundred seventy-six sudden or violent manner of deaths were inspected or autopsied at Tokyo Metropolitan Medical Examiner's Office in 1989. Out of these victims, 693 (9.4%) victims were regarded as heavy drinkers on the basis of the drinking habits and the autopsy reports and 196 (2.7%) victims without past problem drinking were thought to be drunk at death from the family statements or the blood alcohol analysis. The total 889 (12.1%) alcohol-related cases (autopsy was performed on the 489 cases) were studied from epidemiological and etiological viewpoints. The average age of the alcohol-related victims (male: 811, female: 78) was 52 +/- 11 years. In middle-aged (45-54 years) men, 34% of the all sudden or violent deaths were alcohol-related. About half of the alcohol-related victims were living alone and jobless and they often died at home, particularly in the bed. In the alcohol-related victims, the blood alcohol concentration (BAC) analysis revealed that the average BAC of female was significantly higher than that of male. (2.12 +/- 1.73 mg/ml vs. 1.33 +/- 1.75, P < 0.01). This difference may be associated with sex difference in ethanol metabolism, body composition and drinking habits. Among the major causes of the alcohol-related deaths, alcoholic liver diseases accounted for 226 (25%), gastro-intestinal bleedings for 115 (13%), cardiovascular diseases for 105 (12%) and violent deaths (e.g., acute alcohol intoxication, falls, traffic accidents, suicide) for 329 (37%). By histopathological examination of the liver, about 30% of the alcoholic liver disease cases showed mainly fatty metamorphosis and 48% showed liver cirrhosis. Only 12% of the cirrhotics had either jaundice or ascites, suggesting hepatic failure. Alcoholic cardiomyopathy was suspected in only 11 cases. In conclusion, many people, particularly middle-aged men, lose their lives due to heavy drinking and there are many pathologically unexplainable sudden deaths of alcoholics.

Adult↗

PubMed1992

Thrombolytic effects of a novel modified tissue plasminogen activator, E6010, on coronary thrombosis in the pig.

This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t-PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respectively. The time to recanalization after 0.4 mg/kg of E6010 was 22 +/- 11 min (mean +/- S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 +/- 0.3 vs. 9.4 +/- 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, alpha 2-plasmin inhibitor and plasminogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic action of E6010 following single intravenous bolus injection.

Animals↗

PubMed1991

Thrombolytic properties of a novel modified human tissue-type plasminogen activator (E6010): a bolus injection of E6010 has equivalent potency of lysing young and aged canine coronary thrombi.

The thrombolytic properties of a novel modified human tissue plasminogen activator (E6010), in which cystein 84 in the epidermal growth factor domain is replaced by serine and that has a prolonged biological half-life, were examined. The thrombolytic efficacies of E6010 and recombinant human tissue plasminogen activator (rt-PA) on the duration of coronary artery thrombus were evaluated in a canine model (123 anesthetized dogs) with copper coil-induced left anterior descending coronary artery thrombus. Thrombi established for periods of 1, 3, or 6 h, as documented by coronary arteriography, were employed. A single bolus i.v. injection of E6010 or rt-PA and an i.v. infusion of rt-PA over 60 min were compared (n = 6). Thrombolytic efficacy was evaluated by three criteria: time to reperfusion (TR), reperfusion rate at 60 min (RR), and reocclusion rate at 60 min after reperfusion (OR). With a bolus i.v. injection of E6010 at a dose of 0.2 mg/kg or an i.v. infusion of rt-PA at a dose of 0.6 mg/kg/h, these parameters were as follows: TR, 30.0 +/- 15.3 and 27.5 +/- 4.8 min; RR, 100 and 100%; OR, 17 and 33% for 1-h aged thrombi; TR, 30.0 +/- 9.5 and 35.0 +/- 8.2 min; RR, 83 and 50%; OR, 20 and 67% for 6-h aged thrombi. These data indicate that a bolus injection of E6010 is almost equally efficacious in lysing thrombi aged both 1 and 6 h. On the other hand, in the case of rt-PA, the thrombi aged 6 h were lysed significantly less than the thrombi aged 1 h. Plasma half-lives of E6010 were t1/2 alpha, 4.8 +/- 0.95 (estimated by antigen level) and 3.0 +/- 0.78 min (estimated by activity), and t1/2 beta, 51 +/- 5.4 (antigen level) and 22 +/- 7.0 min (activity). The half-lives of rt-PA were t1/2 alpha, 3.6 +/- 0.23 (antigen level) and 2.1 +/- 0.61 min (activity), and t1/2 beta, 36 +/- 2.3 (antigen level) and 7.0 +/- 3.5 min (activity). We conclude that a bolus injection of E6010 may have a more potent and longer-lasting effect than i.v.-infused rt-PA in clot lysis therapy.

Aging↗

PubMed1991

[Prolonged traumatic coma caused by diffuse axonal lesions].

A 22-year old male patient was admitted for deep coma probably of traumatic origin. There was neither fracture of the skull nor expansive intracranial lesion. The patient survived for 6 years and 8 months without any change in consciousness. Post-mortem neuropathological examination showed lesions which predominated in the white matter and had features that were compatible with diffuse axonal injury. The mechanism responsible for these lesions seems to be stretching and shearing of axones at the moment of impact. The exceptionally long duration of survival probably accounts for the severity of the lesions observed.

Adult↗

PubMed1991

[Diffuse axonal injury (DAI) in an autopsy case of head trauma with long survival].

The authors reported a clinico-pathological case survived 11 months after a traffic accident. A 41-year-old man had been hit by a motor car and was found in a state of semicoma. On admission, his consciousness level was III-100 to 200 (Japan Coma Scale). Pupils were isocoric; light reflex was present. Linear fracture of occipital bone was disclosed by Skull X-ray and subarachnoid hemorrhage was revealed on CT scan. This comatose state, lasting 24 hours, slowly improved and eventually he presented the so-called Korsakoff's syndrome until his death. He could not recognized his relatives, only uttered some meaningless words. He was unable to obey simple verbal orders. The patient was incontinent and right pyramidal sign was positive. On repeated CT scans, cerebral ventricles gradually increased in size; especially the enlargement of the fourth ventricle was remarkable. He expired of septic shock caused by bed sores. At autopsy brain weighed 1190 g. Old gloss contusional scars were observed on the bilateral frontal lobes including the orbital area and on the left temporal pole. Gliding contusions were revealed in the subcortical white matter beneath the left superior frontal convolution. Fibrillary gliosis was noted in this region, the deep white matter underlying the left temporal pole and the tissue surrounding the anterior horn of the left lateral ventricle. Nerve fibers were fragmented and lacerated at corpus callosum, anterior commissure and posterior limb of the left internal capsule. Bilateral pyramidal tracts showed mild myelin pallor at the brainstem. Loss of Purkinje cells were observed. This case would correspond to mile type of diffuse axonal injury proposed by Adams and Gennarelli. (ABSTRACT TRUNCATED AT 250 WORDS)

Accidents, Traffic↗

PubMed1991

Enzymatic hydrolysis of indometacin farnesil, a prodrug of indomethacin, by carboxylesterase in cultured synovial cells.

The hydrolysis of indometacin farnesil (IMF) in the synovial cells of rat and human and the subcellular fractions of rat liver were investigated in relation to the inhibition of prostaglandin E2 (PGE2) production in the synovial cells. The inhibition of PGE2 production in cultured human synovial cells by anti-inflammatory drugs was potent in the order of IND, IMF and acetyl salicylic acid. However, when the cells were pretreated with IMF, the inhibitory activity of IMF was retained even after the compound was washed out from the medium. No duration of the inhibition was seen in the pretreatment of the cells with IND or acetyl salicylic acid. These results suggest that IMF incorporated into the synovial cells was hydrolyzed gradually to IND. In fact, IMF was taken up by rat synovial cells in culture and considerable amount of IND, which increased with culture period, was found out in the cells. Furthermore, the IMF hydrolase activity was found in microsomal and lysosomal fractions of rat liver, and the hydrolase was identified as carboxylesterase by using bis-(p-nitrophenyl) phosphate, a specific inhibitor of carboxylesterase.

Animals↗

PubMed1989

A high-performance liquid chromatographic method for the determination of polyphosphoinositides in brain.

A simple high-performance liquid chromatographic method for the determination of endogenous phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2) in brain has been developed. PIP and PIP2 were derivatized with 9-anthryldiazomethane to yield (9-anthryl)PIP and di(9-anthryl)-PIP2. The derivatives were separated on a reversed-phase column using isocratic elution and detected with a uv detector. The detection limits of PIP and PIP2 were 0.25 micrograms. The method with uv detection was sufficiently sensitive to measure the concentrations of PIP and PIP2 in rat brain. The levels of PIP and PIP2 were increased in developing rat brain and were decreased after 10 min of ischemia.

Animals↗

PubMed1989

Calcitonin gene-related peptide-binding sites of porcine cardiac muscles and coronary arteries: solubilization and characterization.

Calcitonin gene-related peptide (CGRP)-binding sites were solubilized, using digitonin, from the porcine spinal cord, atria, and coronary arteries. The specific binding of 125I-human alpha-CGRP to the solubilized binding sites was inhibited by human alpha- and beta-CGRP and by rat alpha-CGRP, but not by angiotensin II or human calcitonin. Scatchard plot analysis of saturation gave the same KD value for CGRP in the crude membrane fractions of the tissues examined. The affinity of CGRP to the binding sites was decreased by solubilization in the atria and coronary arteries, but not in the spinal cord. Affinity labeling followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed distinct molecular sizes of the specific binding sites among the tissues; 70K for the spinal cord, 70K and 90K for the coronary arteries, and 70K and 120K for the atria. These results indicate that the molecular characteristics of the specific binding sites of CGRP in the cardiovascular system are distinct from those in the central nervous system.

Animals↗