Biomedical subjects

T Tamura

Publications and source records attributed to T Tamura.

At least 919 records · Page 51Linked to original sources

PubMed1990

Subcutaneous administration of recombinant human granulocyte colony-stimulating factor (KRN8601) in intensive chemotherapy for patients with advanced lung cancer.

The efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rh G-CSF, KRN8601) given subcutaneously was evaluated in patients with advanced lung cancer undergoing intensive chemotherapy. Twenty-nine and 30 patients with or without prior therapy were enrolled in this study. At dose levels of 50, 90 and 130 micrograms/m2 of rh G-CSF for 14 consecutive days after chemotherapy, the mean neutrophil nadir counts, the mean neutrophil nadir ratios and the duration of neutropenia (days of less than 1000/mm3) were significantly improved. No significant differences were seen in frequency and duration of febrile episodes (greater than 38 degrees C). When rh G-CSF is given subcutaneously, the dose required for an equal effect in alleviating neutropenia is 50% of that required when it is given intravenously. The monocyte counts in the peripheral blood were also significantly increased after chemotherapy cycles with rh G-CSF. The cumulative plasma concentration of rh G-CSF showed a decrement after 7-9 days despite maintenance of the same dose of rh G-CSF for the entire 14 days. In conclusion, 50-130 micrograms/m2 of sc rh G-CSF increased the neutrophil nadir count and shortened the duration of neutropenia in patients undergoing intensive chemotherapy for lung cancer without intolerable side effects.

Adult↗

PubMed1990

Prediction from creatinine clearance of thrombocytopenia and recommended dose in patients receiving (glycolato-O,O')-diammine platinum (II) (NSC 375101D).

Thrombocytopenia is the most serious dose-limiting toxicity of (glycolato-O,O')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues. A total of 38 patients treated with 100 mg of 254-S per m2 in a clinical phase II study were retrospectively analyzed to determine the factors influencing thrombocytopenia. Performance status, sex, age and prior chemotherapy did not affect either the percent reduction of platelets or the nadir platelet count. However, creatinine clearance (Ccr.: ml/min) was found to be a predictive variable for thrombocytopenia. There was a significant relationship between nadir platelet count and Ccr. (R2 = 0.637) or relative dose [RD = (dose of 254-S: mg/m2)/Ccr.] (R2 = 0.707). From these observations, the following equations for predicting nadir platelet count associated with administration of 254-S were proposed. [Nadir platelet count] = -64,264.7 + 2,783.4 x [Ccr.] (A) log [Nadir platelet count] = -1.6743 log [RD] + 5.32 = -1.6743 log [Dose/Ccr.] + 5.32 (B) If we administer 100 mg of 254-S per m2 to a patient with Ccr. of less than 40.3 ml/min, thrombocytopenia of grade 3 or more according to the Eastern Cooperative Oncology Group (ECOG) criteria (less than 50,000/mm3) can be predicted from equation (A). In these patients, dose modification using equation (B) is recommended.

Adult↗

PubMed1990

Cell-specific expression of the mouse glial fibrillary acidic protein gene: identification of the cis- and trans-acting promoter elements for astrocyte-specific expression.

We have determined the whole promoter sequence and the transcriptional startpoint of the mouse glial fibrillary acidic protein (GFAP) gene and characterized the promoter function. We found that the cis elements for astrocyte specific expression are located within 256 bp from the transcription startpoint. We defined by DNase I footprinting assay three trans-acting factor binding sites (GFI, GFII, and GFIII) using brain or C6 astrocytoma nuclear extracts. GFI, GFII, and GFIII have AP-2, NFI, and cyclic AMP-responsive element motifs, respectively. Mutations in GFII drastically decreased the promoter activity. Base substitution in GFI and GFIII abolished the cell-specific expression, resulting in the GFAP promoter expression even in some non-GFAP-producing cells.

Animals↗

PubMed1990

Chimeric and molecular genetic analysis of myelin-deficient (shiverer and mld) mutant mice.

The shiverer and myelin-deficient (mld) mutants are two allelic mutations. Both are characterized by hypomyelination in the CNS and deficient expression of the MBP gene. Chimeric analysis of the pathogenesis of shiverer showed that shiverer mutation acts intrinsic to the oligodendrocyte, which is the only cell type expressing the MBP gene in the CNS. Molecular genetic studies by several groups demonstrated that shiverer is a deletion mutation in the MBP gene. Consequently, no MBP is produced in the shiverer mutant. In mld, however, partial expression of the MBP gene was observed. Interestingly, MBP was expressed in a mosaic fashion in the CNS of mld mice. Molecular genetic studies revealed that the mld mutant has duplicated MBP genes in tandem on a distal part (E2-4) of chromosome 18q. The reduced expression was based on the level of mRNA. A large portion is inverted in the upstream copy, and an intact copy is located downstream. We showed in mld mutants that antisense RNA corresponding to the inverted segment is transcribed, and it forms RNA duplex, with the RNA transcribed from the normal gene located downstream.

Animals↗

PubMed1990

Lack of correlation between interferon levels induced by polyribonucleotides and their antimetastatic effect.

The inhibitory effect of poly(A)poly(U) on the pulmonary metastasis of B16-F10 melanoma was examined in comparison with that of poly(I,C)-L,C and poly(I)poly(C). The correlation between interferon (IFN) level and antimetastatic effect was also investigated. Intraperitoneal injection of poly(A)poly(U) (50 mg/kg) into C57BL/6 mice 24 h before intravenous inoculation of B16-F10 melanoma (1 X 10(5] caused a significant decrease (p less than 0.01) in the number of pulmonary nodules 14 days after tumor challenge. But poly(I,C)-L,C (1 or 0.2 mg/kg) and poly(I)poly(C) (5 mg/kg or 1 mg/kg) did not. From the kinetic study of IFN levels induced by polyribonucleotides, poly(I,C)-L,C showed the most potent IFN-inducing activity, followed by poly(I)poly(C) and poly(A)poly(U), in this order. Plasma IFN reached a peak at 6 h and still continued to be detected at 24 h after intraperitoneal injection of the polyribonucleotides. Against B16-F10 melanoma, the cytotoxicity of spleen cells stimulated by poly(A)poly(U) (50 mg/kg) was significantly (p less than 0.05) higher than that of spleen cells stimulated by poly(I)poly(C) (5 mg/kg) both at 12 and 24 h after intraperitoneal injection of those agents. The above results that there is no correlation between the IFN levels induced by polyribonucleotides and their antimetastatic effect. More extensive study of poly(A)poly(U) might give more fruitful results, which will give valuable information for future clinical trials of this lowly toxic promising agent.

Animals↗

PubMed1990

Experimental cedar pollinosis in rhesus monkeys.

In order to develop an experimental model for human cedar pollinosis, 4 rhesus monkeys (Macaca mulatta) were subcutaneously immunized with crude cedar pollen antigen, which contained 1.0 microgram or 10 micrograms protein with aluminium hydroxide gel, six times every month. All 4 animals showed immediate-type cutaneous reactivity. Serum IgE antibody responses against the pollen antigen, as quantitated by the Prausnitz-Küstner reaction, were seen in 3 of 4 monkeys. Radioallergosorbent test scores increased in 2 monkeys and remained at higher levels throughout the study. Histamine release from leukocytes was positive in all animals. In conjunctival provocation tests, they showed clinical signs such as eye-scratching after the antigen was dropped into their eyes. This reaction is similar to that observed in humans and suggests this animal model might be useful in studying human cedar pollinosis.

Allergens↗

PubMed1990

Effect of early diastolic loading on myocardial relaxation in the intact canine left ventricle.

Early transmitral flow (MiF) patterns depend strongly on the rate of fall of measured left ventricular pressure (Pm) determined by both the active decay of pressure (Pa) due to myocardial relaxation and the increase in pressure due to stretch of passive elements during filling (Pp). This study was designed to uncouple passive forces from deactivation in order to reveal the instantaneous rate and duration of myocardial relaxation. We assumed a parallel combination of passive and active elements: Pm(t,V) = Pa(t) + Pp(V), with no constraints on the form of Pa(t), where t is time and V is ventricular volume. Pp(V) was determined by a retrospective analysis of data obtained in 11 anesthetized dogs instrumented for volume clamping with a remote-controlled mitral valve, with left atrial and left ventricular micromanometers, and with an electromagnetic probe to measure MiF. The passive pressure-volume relation (both positive and negative portions) was determined by clamping at end-systolic volume or after various filling volumes, and fit to logarithmic functions. Pp(t) was then calculated from Pp(V) and V(t) (integral of MiF). Time to end relaxation (Ter) was defined as time when Pa = 0. During isovolumic relaxation, when dPp/dt = 0, dPm/dt is equal to the relaxation rate, dPa/dt. In completely isovolumic relaxations, asymptote P infinity = -7 +/- 6 mm Hg (thus, Pa is 7 mm Hg greater than Pm) and Ter = 40 +/- 15 msec, compared with 175 +/- 53 msec during normal filling. In high versus low inotropic state, Pa at the beginning of filling was greater (18.1 +/- 6.1 vs. 12.2 +/- 3.9 mm Hg), and Ter was shorter (170 +/- 42 vs. 228 +/- 43 msec). Active pressure Pa(t) during filling is not an exponential function, and at any time, it was always greater after filling than in nonfilling beats, which indicates an increase in the relaxation duration. We conclude that myocardial relaxation is modulated by filling, which slows its rate and increases its duration, and is therefore a function of both ventricular volume and time. Such a mechanism may have an important role in regulating the diastolic pressure-volume relation.

Animals↗

PubMed1990

Detection of moving flow separation in pulsatile flow and the degree of stenosis by power of Doppler shift signals.

Power ratios were derived from the principle of ultrasonic Doppler velocimetry to determine a ratio of the volume of vortices to the total vessel volume under the ultrasonic beam. This ratio also equals the ratio of the cross-sectional area of vortices to the vessel lumen. In vitro pulsatile flow experiments were performed in a Reynolds number range of 1,230-4,320 with axisymmetric constrictions with area reductions of 55%, 65%, 70%, and 85% to model carotid stenosis. Flow separation downstream from the model stenoses was detected, and the power ratio fluctuated when vortices with the forward- and reverse-flow velocity components passed by the measurement position. The power ratio estimated the degree of stenosis within 10% of error. Ensemble average of the power ratio was computed to obtain the statistically averaged separated flow region. The moving flow reattachment point was revealed downstream from the 85% stenosis at a Reynolds number of 900.

Blood Circulation↗

PubMed1990

Diastolic viscous properties of the intact canine left ventricle.

The viscoelastic model of the ventricle predicts that the rate of change of volume (strain rate) is a determinant of the instantaneous pressure in the ventricle during diastole. Because relaxation is not complete before the onset of filling, one cannot distinguish the individual effects of relaxation and viscosity unless the passive and active components that determine the ventricular pressure are separated. To overcome this problem, we used the method of ventricular volume clamping to compare the pressures in the fully relaxed ventricle at a given volume at zero strain rate (static pressure) and high strain rate (dynamic pressure). Six open-chest, fentanyl-anesthetized dogs were instrumented with micromanometers and an electronically controlled mitral valve occluder in series with the electromagnetic flow probe. We reasoned as follows: If there were significant viscosity, then the dynamic pressure would be higher than the static pressure. The static pressure was measured when the ventricle was completely relaxed following a mitral valve occlusion after an arbitrary filling volume had been achieved. The dynamic pressure was determined by delaying the onset of filling until relaxation was complete and then measuring the pressure at the same volume that was achieved when the static pressure was measured. In 19 different hemodynamic situations, the dynamic and static pressures were identical (mean difference, 0.1 +/- 0.8 mm Hg), indicating that in the passive ventricle viscoelastic effects are insignificant and do not contribute to the left ventricular diastolic pressure under normal filling rates.

Animals↗

PubMed1990

Atrial natriuretic peptide in patients with the syndrome of inappropriate antidiuretic hormone secretion and with diabetes insipidus.

To examine a possible role for atrial natriuretic peptide (ANP) in water and sodium metabolism disturbances associated with abnormal vasopressin (AVP) secretion, we measured plasma ANP concentrations in 15 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and in 17 patients with central diabetes insipidus (DI). The mean plasma ANP concentration (30.2 +/- 10.4 pmol/L) in SIADH patients who had hyponatremia, plasma hypoosmolality, hyperosmolar urinary compared to plasma sodium levels, and increased plasma AVP levels relative to plasma osmolality was significantly higher than that in normal subjects (12.6 +/- 4.9 pmol/L), although there was a considerable individual variation in plasma ANP ranging from normal to clearly elevated levels (15.1-47.0 pmol/L). When hyponatremia was corrected by water restriction or demeclocycline administration, plasma ANP levels decreased significantly and fell into the normal range (12.5 +/- 4.3 pmol/L). DI patients who complained of polyuria and polydipsia and had hypoosmolar urine, normal or elevated plasma sodium concentrations, and decreased plasma AVP levels relative to plasma osmolality, on the other hand, had a significantly lower mean plasma ANP level (7.6 +/- 2.9 pmol/L) than normal subjects. There was, again, a considerable overlap between plasma ANP levels in individual DI patients (4.2-13.9 pmol/L) and those in normal subjects. Treatment with 1-desamino-8-D-arginine vasopressin resulted in a significant increase in the mean plasma ANP level (18.6 +/- 8.0 pmol/L). There were no significant correlations between plasma ANP and AVP levels in either group of patients. The results indicate that ANP secretion is modulated by changes in plasma volume consequent to abnormal AVP secretion, which may have a pathophysiological significance in maintaining volume homeostasis.

Adolescent↗

PubMed1990

[Preferential action of eptazocine, a novel analgesic, with opioid receptors in isolated guinea pig ileum and mouse vas deferens preparations].

Actions of eptazocine, a novel analgesic, on isolated smooth muscle preparations were investigated. Eptazocine (10(-5) M) slightly inhibited electrically-driven twitch-tension in guinea pig ileum preparations sensitive to mu- and kappa-agonists, and this effect was antagonized by 10(-7) M naloxone. Eptazocine (10(-5)-10(-4) M) inhibited such an effect by the mu-agonist morphine. In mouse vas deferens preparations having delta-, mu- and kappa-receptors, eptazocine (10(-7) M-) inhibited the twitch-tension in a dose-dependent manner, being hardly inhibited by naloxone. On the other hand, MR-2266 (10(-6) M), a relatively selective kappa-receptor antagonist, inhibited the eptazocine effect. The Ke (equilibrium dissociation constant) value of naloxone against eptazocine was 325 nM and the Ke value of MR-2266 against eptazocine was 33.2 nM, showing that MR-2266 was 9.79-fold more effective than naloxone. These results suggest that eptazocine acted as a mu-receptor antagonist and as a kappa-receptor preferential agonist in isolated smooth muscle preparations.

Analgesics↗

PubMed1990

[Protective effect of eptazocine, a novel analgesic, against cerebral hypoxia-anoxia in mice].

Cerebral protective effect of eptazocine, a mu-antagonist-kappa-agonist, was investigated using mice subjected to hypoxia-anoxia. Eptazocine (1 to 10 mg/kg) prolonged the survival time of mice subjected to KCN (3 mg/kg, i.v.) injection in a dose-dependent manner, and this effect was completely inhibited by naloxone (5 mg/kg). EKC, U50,488H, opioid kappa-agonists, also had such an effect, but were weaker than eptazocine. In mice exposed to hypobaric hypoxia (190 mmHg), eptazocine (3, 10 mg/kg) and EKC (10 mg/kg) prolonged the survival time, but morphine (5 mg/kg) and pentazocine (10 mg/kg) shortened the time. The eptazocine effect was attenuated by either naloxone (5 mg/kg) or atropine (0.5 mg/kg), different from what was seen in the case of physostigmine and diazepam, and the combination of eptazocine (1 mg/kg) and physostigmine (0.075 mg/kg) had a potentiating effect. MR-2266, a selective kappa-receptor antagonist, inhibited the eptazocine effect more potently than naloxone. These results suggest that eptazocine elicited its cerebral protective effect via its binding with opioid kappa-receptors and probably an activation of the central cholinergic system.

Analgesics↗

PubMed1990

Augmentation of wound healing by royal jelly (RJ) in streptozotocin-diabetic rats.

Chronically diabetic rats prepared by a single i.v. injection of streptozotocin were used to study whether royal jelly (RJ) possesses a hypoglycemic reaction and whether it can augment wound healing. Oral RJ administration of 10, 100 and 1000 mg/kg/day did not show any insulin-like activity (the hypoglycemic reaction). RJ, however, showed some anti-inflammatory activity by decreasing exudation and collagen formation in granulation tissue formation in the cotton pellet method. RJ also shortened the healing period of desquamated skin lesions. Thus, RJ possesses an anti-inflammatory action and is able to augment wound healing, but does not have an insulin-like action in streptozotocin-diabetic rats.

Animals↗

PubMed1990

Effects of eptazocine, a novel analgesic, on KCN-induced changes in the cerebral contents of glycolytic metabolites and high-energy phosphates in mice.

Effects of eptazocine on cerebral metabolic changes due to a sublethal dose of KCN were investigated in mice. KCN (2 mg/kg, i.v.) induced a temporary loss of consciousness being moderated by eptazocine (1-10 mg/kg) in a dose-dependent manner. The KCN injection decreased the contents of phosphocreatine (PCr), ATP and glucose and increased the contents of AMP and lactate, resulting in a 34% decrease in energy charge potential (ECP) and an increase in lactate/pyruvate (L/P) ratio. Such changes were improved by eptazocine (10 mg/kg) and EKC (3 mg/kg), but not by pentazocine (10 mg/kg) and morphine (3 mg/kg), and the improving effect of eptazocine was completely inhibited by MR-2266 (3 mg/kg), a relatively selective opioid kappa-receptor antagonist. On the other hand, eptazocine (3, 10 mg/kg) was found to increase the glucose content in normal mice, but not to give significant changes in the contents of glycolytic metabolites and high-energy phosphates. These results suggest that eptazocine may improve anoxic changes in cerebral energy metabolism.

Adenosine Monophosphate↗

PubMed1990

Transient expression of chimeric CAT genes injected into early embryos of the domesticated silkworm Bombyx mori.

In order to establish a transient expression system for genes introduced into early embryos of the silkworm, Bombyx mori, we tested various promoters ligated with CAT reporter genes. The embryos into which we injected supercoiled plasmid DNA of pFb(-860/+10)CAT containing the Bombyx fibroin promoter region ligated to the CAT gene showed a reasonably high CAT activity beginning around 30 h after oviposition. This high activity was observed only when the plasmid was injected before termination of the early nuclear cleavage stage, which was about 8 h after oviposition, but not after this stage. This means that the expression of injected DNA is closely related to the presence of cleavage nuclei in early embryos. Promoters originating from insect genes, like the Bombyx sericin-1 gene, Drosophila hsp70 and Drosophila copia LTR, functioned as strong promoters in the embryos. On the contrary, promoters from mammalian virus genes, such as the SV40 early and Moloney murine leukemia virus LTR genes, functioned as weak promoters. Moreover, linearized DNAs showed no or weak activity of expression in embryos. From these results, we conclude that the silkworm embryo transient expression system is a useful tool for studying the mechanism of regulation of insect genes.

Animals↗

PubMed1990

Selective aromatase inhibition by pyridoglutethimide, an analogue of aminoglutethimide.

The inhibitory effects of pyridoglutethimide (3-ethyl-3-(4-pyridyl)piperidine-2,6-dione), an analogue of aminoglutethimide, on aromatase and other cytochrome P-450-dependent steroid-metabolizing enzymes were studied in vitro. Pyridoglutethimide and aminoglutethimide showed competitive inhibition of human placental aromatase activity with apparent Ki values of 1.7 and 0.7 mumol/l, respectively. Both pyridoglutethimide and aminoglutethimide inhibited the aromatase activity of uterine leiomyoma and cultured choriocarcinoma Enami cells as well as immunopurified human placental aromatase cytochrome P-450 by more than 90%, with IC50 values of 10-19 and 5-7 mumol/l, respectively. These results might suggest that the inhibitors interacted directly with the aromatase cytochrome P-450 of these tissues. Aminoglutethimide inhibited bovine adrenal cholesterol side-chain cleavage activity with an IC50 value of 40 mumol/l and inhibited 21-hydroxylase activity slightly, but did not inhibit 17 alpha-, 11 beta- and 18-hydroxylase at concentrations up to 100 mumol/l. On the other hand, pyridoglutethimide had no inhibitory effect on any of these enzymes at concentrations up to 50 mumol/l, although it inhibited 11 beta- and 18-hydroxylase slightly at 100 mumol/l. These results indicated that pyridoglutethimide was an aromatase inhibitor of a comparable potency to aminoglutethimide, but that it did not inhibit other steroid hydroxylases.

Aminoglutethimide↗

PubMed1990

Depression of calcium pump activity in renal cortex of vitamin D-deficient rats with secondary hyperparathyroidism.

To examine the hormonal regulation of the ATP-dependent Ca2+ pump in the kidneys, the ATP-dependent Ca2+ uptake by the basolateral membrane vesicles in the renal cortex was measured using radioactive calcium (45Ca2+) in rats with vitamin D deficiency or rats undergoing thyroparathyroidectomy. The Vmax of the Ca2+ pump activity was increased not only by administering calcitriol, but also by normalizing the serum calcium level in vitamin D-deficient rats. PTH suppressed the Ca2+ pump activity in normocalcemic vitamin D-deficient rats. Thyroparathyroidectomy did not affect the Ca2+ pump activity in the kidneys of normal rats. It was concluded that the ATP-dependent Ca2+ pump activity was depressed by secondary hyperparathyroidism in vitamin D-deficient rats.

Adenosine Triphosphate↗

PubMed1990

Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury.

An increase in extracellular K+ concentration ([K+]c) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin, a potent depressant of neuronal discharges, and of 0.5 to 20 mM cobalt, a blocker of Ca++ channels. While a small short-lasting [K+]c increase (1.40- to 2.15-fold) was observed after a mild insult, a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt, indicating that neuronal discharges are the source of this increase. In contrast, the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++, suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]c, the extracellular concentration of glutamate ([Glu]c) was measured along with [K+]c. The results indicate that a relatively specific increase in [Glu]c (as compared with other amino acids) was induced concomitantly with the increase in [K+]c. Furthermore, the in situ administration of 1 to 25 mM kynurenic acid, an excitatory amino acid antagonist, effectively attenuated the increase in [K+]c. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.

Animals↗