Biomedical subjects

K Onodera

Publications and source records attributed to K Onodera.

At least 55 records · Page 3Linked to original sources

PubMed2000

Teratogenic and fetal toxicity following intravenous theophylline administration in pregnant rabbits is related to maternal drug plasma levels.

This study investigated the teratogenic and fetal toxicity of i.v. theophylline and its relationship to maternal plasma levels in pregnant rabbits. From days 6-18 of gestation, each dose of theophylline (15, 30 and 60 mg/kg/day at a rate of 0.5 ml/kg/min) was administered i.v. to pregnant rabbits using an automatic infusion pump. Theophylline showed reversible toxicity: accelerated respiration, sluggish startle reactions, dilation of the auricular vessels and polyuria were observed in dams treated with 60 mg/kg/day but not in animals given 15 or 30 mg/kg/day. Fetuses from the dam group treated with 60 mg/kg/day exhibited teratogenic toxicity such as cleft palate and skeletal variation of the 13th rib. Fetal toxicity was also observed including abortion, increased number of late deaths and decreased body weight appearing on day 29 of gestation. No toxicity was observed in fetuses from the dam group treated with 15 or 30 mg/kg/day. However, in the 30 and 60 mg/kg/day theophylline-treated groups, maternal plasma concentrations (Cmax) during the treatment period were approximately 56 and 106 micrograms/ml, respectively. It is therefore suggested that the risk of teratogenic and fetal toxicity caused by theophylline is dependent on its dosage. In conclusion, caution should be taken when administering theophylline or aminophylline to pregnant individuals at doses that could result in high neonate peak blood levels.

Abnormalities, Drug-Induced↗

PubMed2000

Usefulness and safety of theophylline injection form (Theodrip) for the treatment of acute asthma.

The effects of the speed of intravenous infusion on the pharmacokinetics of theophylline were studied in 9 healthy volunteers (Ex I). Subjects were intravenously administered either six 4.8 mg/kg theophylline (Theodrip, Nikken Chemicals Co., Ltd., Japan) or three matching placebo injections (4.8 ml/kg physiological saline) for 30 min (Step I) or for 15 min (Step II). In Steps I and II, Cmax was 10.8 +/- 1.1 and 10.8 +/- 0.8 micrograms/ml, respectively. These Cmaxs were concentrations yielding therapeutic effects in patients with acute asthma. Next, comparative pharmacokinetics between theophylline (Theodrip) and aminophylline were examined by a crossover method in 16 healthy volunteers (Ex II). The 90% confidence limits of the differences of mean values were within 80-120% and were 92.8-100.1% for Cmax, 99.7-105.3% for t1/2 and 100.2-104.4% for AUC. Thus, we concluded that the pharmacokinetics of the plasma theophylline after intravenous administration of Theodrip (theophylline at 4.8 mg/kg) were bioequivalent to those of aminophylline (6.0 mg/kg) for 30 min. In Ex I and II, no subjects had adverse effects and in Ex I no influence on ECG was seen. In addition, the convenience of Theodrip was compared with that of ampules of aminophylline among nurse volunteers (Ex III). The times required for set-up of Theodrip were significantly shorter than those of aminophylline ampules. On the other hand, the adverse reactions to aminophylline resulting from hypersensitivity reactions to its ethylenediamine component have been reported. Theodrip consists of 200 mg theophylline and 200 ml physiological saline in a plastic bag. Therefore, Theodrip, which does not contain ethylenediamine, is expected to have less adverse effects and be easier to handle than aminophylline.

Acute Disease↗

PubMed2000

Induction of metallothionein mRNA expression in the mouse liver after cadmium injection as measured by the reverse transcriptase-polymerase chain reaction method.

Metallothioneins (MTs) are low molecular weight proteins that have been considered to be important metal-binding proteins in the defense against cadmium (Cd) toxicity in animals. These proteins are known to be induced by the injection of heavy metals such as Cd. Previously, we developed the RT-PCR method to measure the level of MT mRNA expression. In this study, we analyzed the time course and dose response of Cd-induced MT-I mRNA expression in the male and female mouse liver. By this method, we measured hepatic MT-I mRNA expression which reached the highest peak 6 h after subcutaneous injection of 1.1 mg/kg Cd in 9-week old male and female mice compared with those of corresponding controls (0 h). There was no statistical difference in the hepatic MT-I mRNA expression between male and female mice 6 h after the injection of this dosage. However, it is notable that the MT-I mRNA expression in male mice was much higher than that in females 6 h after injection of 0.5 mg/kg Cd. Thus, the induction of hepatic MT-I mRNA expression is dependent on the sex of the mouse, the dosage and the time course of Cd.

Animals↗

PubMed2000

Regioisomeric distribution of cholesteryl linoleate hydroperoxides and hydroxides in plasma from healthy humans provides evidence for free radical-mediated lipid peroxidation in vivo.

We have previously reported the detection of cholesteryl ester hydroperoxides, consisting mainly of cholesteryl linoleate hydroperoxides (Ch18:2-OOH), at nm levels in plasma from healthy humans (Y. Yamamoto and E. Niki, 1989. Biochem. Biophys. Res. Commun. 165: 988-993). To elucidate their production mechanism in vivo, we examined the distribution of Ch18:2-O(O)H regioisomers in blood plasma from nine healthy young subjects using a sequential method consisting of methanol/hexane extraction in the presence of antioxidant, reductant, and internal standard, solid phase extraction to remove unoxidized cholesteryl linoleate, purification by reversed-phase high-performance liquid chromatography (HPLC), and detection by normal phase HPLC. Furthermore, we confirm that little artifactual oxidation of cholesteryl linoleate occurred during analytical procedures indicated by the absence of oxidation products of cholesteryl 11Z,14Z-eicosadienoate (Ch20:2) when provided as an exogenous substrate to the experimental procedure. We detected nm levels of all free radical-mediated oxidation products, 13ZE-, 13EE-, 9-EZ-, and 9-EE-forms of Ch18:2-O(O)H, in blood plasma, whereas the 13ZE-isomer resulting from enzymatic 15-lipoxygenase oxidation was not evident as a major product. These results indicate that free radical chain oxidation of lipids occurs even in healthy young individuals.

Adult↗

PubMed2000

Acute and subacute toxicities of theophylline are directly reflected by its plasma concentration in dogs.

The purpose of this study was to evaluate the relationship between acute and subacute toxicity and blood levels of theophylline in dogs. Theophylline was administered intravenously into dogs once (at doses of 50, 100 and 150 mg/kg) or for 4 weeks (at doses of 20, 35 and 70 mg/kg/day). In the single dose toxicity study, by increasing the dose of theophylline, plasma concentration increased and the severity of toxic symptoms were intensified. After a single dosing of theophylline, accentuated heart rate and vomiting were observed at a concentration of more than 67 micrograms/ml, and excitement, spasm and hyperpnea were observed at more than 130 micrograms/ml. Animals died after tonic convulsion at 180 micrograms/ml. In the repeated dose toxicity study, the plasma concentration of theophylline increased dependent on dosage, and was not affected by repeated dosing. Even under these conditions, the toxic symptoms were quite similar to those of the single dose, except for an additional decrease in movement, body weight reduction and myocardial lesion. These present results suggest that the severity of theophylline toxicity is dependent on its plasma concentrations rather than accumulated dosages. The blood concentration of theophylline-treated patients should be maintained within the therapeutic range in order to diminish risk.

Animals↗

PubMed2000

Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine.

Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.

Aminophylline↗

PubMed2000

Alveolar soft-part sarcoma of the cheek: report of a case with a review of the literature.

An alveolar soft-part sarcoma (ASPS) occurring in the cheek is described, with a review of the literature. The subject was a 25-year-old woman who presented with a large swelling in the left cheek. The lesion, initially diagnosed as a benign tumor on radiographic and computed tomographic examinations, was surgically excised. Histopathological examination of the mass revealed a nest-like or organoid cellular arrangement as confirmed by three-dimensional computer graphic reconstruction. The cytoplasm of the large polygonal tumor cells contained abundant diastase-resistant, PAS-positive inclusions, ultrastructurally confirmed to be crystalloid materials. The tumor cells were immunoreactive for anti-myoglobin, sarcomeric actin, and neuron-specific enolase antibodies, suggesting a myogenic origin.

Adult↗

PubMed1999

Distinct tolerance pathways in sensitized allograft recipients after selective blockade of activation signal 1 or signal 2.

BACKGROUND: CD4-targeted therapy or blocking of CD28-B7 T-cell costimulation may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways after the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig). METHODS AND RESULTS: Lewis rats sensitized with Brown Norway skin grafts reject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 monotherapy uniformly produced permanent cardiac graft acceptance, whereas CTLA4Ig produced indefinite graft survival in about 50% of sensitized rats. Spleen cells (100 x 10(6)) from CD4 mAb-treated rats conferred donor-specific tolerance after transfer into new sets of recipients. This tolerant state could be then transferred with regulatory cells in an infectious manner into new cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300 x 10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviving grafts in both groups were largely protected from signs of chronic rejection. CONCLUSIONS: CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-mediated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance and attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not required for tolerance maintenance, and it does not necessarily lead to chronic injury.

Abatacept↗

PubMed1999

Characterization of the murine mafF gene.

Small Maf proteins are obligatory heterodimeric partner molecules of mammalian Cap'n'Collar proteins that together control a wide variety of eukaryotic genes. Although both MafK and MafG are expressed in overlapping but distinct tissue distribution patterns during embryonic development, the physiological consequences of loss-of-function mutations in either gene are modest. This suggested that compensation by the third small Maf protein, MafF, might be a major reason for such mild phenotypes and that further analysis of MafF might therefore provide important insights for understanding small Maf regulatory function(s). We therefore cloned, mapped, transcriptionally and developmentally characterized, and finally disrupted the mafF gene. We show that murine mafF is transcriptionally regulated by three different promoters and is most abundantly expressed in the lung. The lacZ gene inserted into the mafF locus revealed prominent expression sites in the gut, lung, liver, outflow tract of the heart, cartilage, bone membrane, and skin but not in hematopoietic cells at any developmental stage. Homozygous mafF null mutant mice were born in a normal Mendelian ratio and displayed no obvious functional deficiencies, indicating that MafF activity may be dispensable even in tissues where the expression of other small Maf proteins is quite low.

Amino Acid Sequence↗

PubMed1999

The structure and unusual pH dependence of plastocyanin from the fern Dryopteris crassirhizoma. The protonation of an active site histidine is hindered by pi-pi interactions.

Spectroscopic properties, amino acid sequence, electron transfer kinetics, and crystal structures of the oxidized (at 1.7 A resolution) and reduced form (at 1.8 A resolution) of a novel plastocyanin from the fern Dryopteris crassirhizoma are presented. Kinetic studies show that the reduced form of Dryopteris plastocyanin remains redox-active at low pH, under conditions where the oxidation of the reduced form of other plastocyanins is inhibited by the protonation of a solvent-exposed active site residue, His87 (equivalent to His90 in Dryopteris plastocyanin). The x-ray crystal structure analysis of Dryopteris plastocyanin reveals pi-pi stacking between Phe12 and His90, suggesting that the active site is uniquely protected against inactivation. Like higher plant plastocyanins, Dryopteris plastocyanin has an acidic patch, but this patch is located closer to the solvent-exposed active site His residue, and the total number of acidic residues is smaller. In the reactions of Dryopteris plastocyanin with inorganic redox reagents, the acidic patch (the "remote" site) and the hydrophobic patch surrounding His90 (the "adjacent" site) are equally efficient for electron transfer. These results indicate the significance of the lack of protonation at the active site of Dryopteris plastocyanin, the equivalence of the two electron transfer sites in this protein, and a possibility of obtaining a novel insight into the photosynthetic electron transfer system of the first vascular plant fern, including its molecular evolutionary aspects. This is the first report on the characterization of plastocyanin and the first three-dimensional protein structure from fern plant.

Amino Acid Sequence↗

PubMed1999

Novel insight into the copper-ligand geometry in the crystal structure of Ulva pertusa plastocyanin at 1.6-A resolution. Structural basis for regulation of the copper site by residue 88.

The crystal structure of plastocyanin from a green alga, Ulva pertusa, has been determined at 1.6-A resolution. At its copper site, U. pertusa plastocyanin has a distorted tetrahedral coordination geometry similar to other plastocyanins. In comparison with structures of plastocyanins reported formerly, a Cu(II)-Sdelta(Met92) bond distance (2.69 A) is shorter by about 0.2 A and a Cu(II)-Sgamma(Cys84) distance is longer by less than 0.1 A in U. pertusa plastocyanin. These subtle but significant differences are caused by the structural change at a His-Met loop (His87-Met92) due to an absence of a O(Asp85)-Ogamma(Ser88) hydrogen bond which is found in Enteromorpha prolifera plastocyanin. In addition, poplar and Chlamydomonas reinhardtii plastocyanins with a glutamine at residue 88 have a weak cation-pi interaction with Tyr83. This interaction lengthens the Cu(II)-Sdelta(Met92) bond of poplar and C. reinhardtii plastocyanins by 0.14 and 0.20 A, respectively. As a result of structural differences, U. pertusa plastocyanin has a less distorted geometry than the other plastocyanins. Thus, the cupric geometry is finely tuned by the interactions between residues 85 and 88 and between residues 83 and 88. This result implies that the copper site is more flexible than reported formerly and that the rack mechanism would be preferable to the entatic theory. The His-Met loop may regulate the electron transfer rate within the complex between plastocyanin and cytochrome f.

Amino Acid Sequence↗

PubMed1999

Mucin-producing tumors of the pancreas: clinicopathological features, surgical treatment, and outcome.

Mucin-producing tumors (MPTs) of the pancreas are increasingly being recognized. To evaluate the appropriate surgical treatment and predict the prognosis of MPTs, we performed a retrospective clinicopathological study in 51 patients, 27 with benign tumors and 24 with borderline/malignant tumors. Three of the malignant tumors showed stromal invasion and lymph node metastasis on histological examination. Of the 24 patients with borderline/malignant tumors, 2 died of MPTs and 4 died of other diseases. At the last follow-up, 35 patients were alive and well. The 5-year postoperative survival rate was 90% for patients with benign tumors, and 78% of these with borderline/malignant tumors. Five of the patients with borderline/malignant tumors had multicentric tumors. Three of these patients underwent resection of the rest of the pancreas, 5, 6, and 8 years, respectively, after the first operation. Extended radical resection is required for malignant MPT with invasion of the pancreatic stroma. We prefer to perform pancreatogastrostomy or Imanaga's procedure to allow examination of the body and tail of the pancreas by endoscopic retrograde pancreatography after resection of the pancreatic head. Careful follow-up for a long period may be the most prudent approach for detecting multiple MPTs in the residual pancreas after surgical treatment.

Adenocarcinoma, Mucinous↗

PubMed1999

Papillary adenoma of the distal common bile duct.

A 73-year-old man with a papillary adenoma located in the distal common bile duct is reported. He underwent pylorus-preserving pancreatoduodenectomy. The lesion in the common bile duct featured papillary proliferation of the epithelium and fibrous elements with diffuse infiltration by inflammatory cells. Positive staining for MIB-1 (Ki-67) and p53 was identified in the nuclei of the proliferative epithelium. These findings suggested the malignant potential of this lesion. Further progress in imaging diagnostic techniques should increase the frequency with which such lesions are discovered. Even now, if mural irregularities and defects are found in the extrahepatic biliary system, especially the distal common bile duct, the possibility of such borderline biliary adenoma should be taken into consideration when making a diagnosis.

Adenoma, Bile Duct↗

PubMed1999

Effect of dietary xylitol on growth and inflammatory responses in immune stimulated chickens.

It has been argued that stimulation of the immune system depresses performance. Accordingly, an experiment was conducted to determine the effect of dietary xylitol (150 g/kg diet) on growth and selected inflammatory responses in male broiler chickens. During the final 6 d of the experimental periods, chicks were injected with antigens: Escherichia coli lipopolysaccharide (LPS) on days 1, 3 and 5 and with Sephadex-G50 superfine on days 2 and 4 to stimulate macrophage functions. The immune stimulation reduced body weight gain and food intake, but enhanced alpha 1 acid glycoprotein (AGP) concentration and interleukin (IL-1) like activity in plasma. Feeding the xylitol diet partially, but significantly, prevented the reductions in body weight gain and food intake, without affecting the early stage of inflammatory responses triggered by LPS and Sephadex injections.

Animal Feed↗

PubMed1999

Angiolipoma of the colon with right lower quadrant abdominal pain.

BACKGROUND/AIM: An angiolipoma is a common benign neoplasm with a characteristic vascular component that occurs in the subcutaneous tissue and rarely in the gastrointestinal tract. We report on a 69-year-old man with a submucosal angiolipoma in the cecum. METHODS: This patient was treated with a laparoscopy-assisted ileocecostomy, and a side-to-side anastomosis was performed extracorporeally. RESULTS: A light microscopic study supported the diagnosis of an angiolipoma of the colon. After 5 years of follow-up, the patient has no symptoms or signs of recurrence. CONCLUSION: The colonic angiolipoma was successfully removed using a minimally invasive laparoscopic technique.

Abdominal Pain↗

PubMed1999

[The roles of histamine H3 receptors in the behavioral disorders and neuropsychopharmacological aspects of its ligands in the brain].

Histamine H3 receptors exist in the presynapse of histaminergic nerve terminals, and they regulate the synthesis and release of histamine. A high density of histamine H3 receptors is observed in the cerebral cortex, the amygdala, the striatum, the hippocampus, the thalamus and the hypothalamus. In this review, we describe signal transduction mechanisms of histamine H3 receptors and discuss the structure-activity relationship of histamine H3-receptor ligands, including new compounds that possess high selectivities and affinities. Possible roles of histamine H3 receptors on neurobehavioral disorders such as Alzheimer's disease, Down syndrome, attention deficit hyperactive disease, epilepsy, stress, anxiety, Parkinson's disease, etc. were also described. Recent pharmacological studies revealed that BP2.94, a histamine H3 receptor agonist, has anti-inflammatory and analgesic action. BP2.94 may be useful for the treatment of migraine and is now in clinical trial. Histamine H3 receptor antagonists such as GT2016 and FUB181 may provide clinical candidates for the treatment of dementia, attention deficit hyperactive disorder and epilepsy.

Animals↗

PubMed1999

Evaluation of the histamine H1-antagonist-induced place preference in rats.

The place preferences by some histamine H1 antagonists, such as tripelennamine, optical isomers of chlorpheniramine (dl-, d- and l-forms) and pyrilamine, in rats were evaluated with the conditioned place preference paradigm. In the present study, tripelennamine and all of the optical isomers of chlorpheniramine, but not pyrilamine, produced a significant place preference. The degree of the place preference induced by optical isomers of chlorpheniramine (6.0 mg/kg) did not correlate with the H1-antagonistic potency of these drugs, suggesting that H1-antagonist-induced place preferences are not mediated by H1-receptor blockade. The tripelennamine (3.0 mg/kg)- and dl-chlorpheniramine (6.0 mg/kg)-induced place preferences were completely abolished by pretreatment with the dopamine D1-receptor antagonist SCH23390 (0.05 mg/kg). Furthermore, the doses of H1 antagonists that induced a place preference significantly reduced the levels of DOPAC, which may be mediated by inhibition of dopamine uptake, in the limbic forebrain (including the nucleus accumbens and olfactory tubercle). These results suggest that some H1 antagonists induce rewarding effects, which may be mediated by the activation of dopamine D1 receptors, followed by the inhibition of dopamine uptake.

Animals↗

PubMed1999

Effects of epinastine on the antitussive and rewarding effects of dihydrocodeine in mice.

The effects of chlorpheniramine and epinastine on dihydrocodeine were examined in mice. Orally administered dihydrocodeine (3-30 mg/kg) dose-dependently inhibited the number of capsaicin-induced coughs. The dose-dependent antitussive effects of dihydrocodeine were enhanced by each corresponding dose of chlorpheniramine or epinastine delivered at a ratio generally similar to that found in over-the-counter antitussive preparations (dihydrocodeine:histamine H1 antagonist = 3:1). The ED50 value of dihydrocodeine in combination with chlorpheniramine was nearly the same as that for dihydrocodeine in combination with epinastine. On the other hand, while combination treatment with dihydrocodeine (3 mg/kg i.p.) and chlorpheniramine (1 mg/kg s.c.) significantly potentiated place preference, no potentiation was observed with the combination of dihydrocodeine (3 mg/kg i.p.) and epinastine (1 mg/kg s.c.). These results suggest that epinastine may be a useful constituent opioid-containing antitussive preparation that would not enhance the potential for psychological dependence.

Animals↗