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J Kawakami

Publications and source records attributed to J Kawakami.

At least 19 recordsLinked to original sources
PubMed2000

Inhibitory effect of azole antifungal agents on the glucuronidation of lorazepam using rabbit liver microsomes in vitro.

Azole antifungal agents (azoles) have inhibitory effects on the cytochrome P450. However, the effect of azoles on conjugative metabolism has not been given much attention. Lorazepam (LZP), a benzodiazepine sedative agent, is known to be metabolized by uridine 5'-diphosphate (UDP)-glucuronyltransferase. Herein we report investigation of the effect of azoles on the enzyme-kinetics of glucuronidation of lorazepam using rabbit liver microsomes in vitro. The Km and Vmax for LZP glucuronidation were determined to be 0.26+/-0.08 mM and 1.25+/-0.21 nmol/min/mg protein, respectively, when evaluated in the presence of a detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) (0.8 mg/mg protein). Azoles fluconazole, miconazole, and ketoconazole competitively inhibited the glucuronidation of LZP, with Ki values of 7.17+/-4.78 mM, 0.17+/-0.08 mM, and 0.092+/-0.026 mM, respectively. These results are comparable to the previously reported Ki values of azoles with zidovudine (AZT) glucuronidation (1.4, 0.18, and 0.08 mM for fluconazole, miconazole, and ketoconazole, respectively) [Sampol et al., Br. J. Clin. Pharmacol., 40, 83-86, 1995]. Therefore, in order to avoid possible side effects of LZP, the concomitant administration of LZP and azoles should be carefully evaluated.

Animals↗
PubMed1999

In vivo and in vitro toxicodynamic analyses of new quinolone-and nonsteroidal anti-inflammatory drug-induced effects on the central nervous system.

We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the gamma-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 microM) > FRP (0. 3 microM) > FLB (0.2 microM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

Animals↗
PubMed1998

Development and histologic characteristics of synovitis induced by trauma in the rat temporomandibular joint.

Histopathological changes caused by trauma to the rat temporomandibular joint synovium were examined by light microscopy. The trauma was induced by forced hypermobility of the condyle. Pathological changes of the synovium were found primarily in the anterior pouch of the upper joint compartment. The main findings included surface cell proliferation, increased capillary hyperemia, fibrin deposits on the surfaces of inflamed synovial membranes, and fibrinous adhesion between closely opposed synovial membranes. A gradual change from fibrinous adhesion to fibrous adhesion was also seen.

Animals↗
PubMed1998

Histologic study of synovitis induced by trauma to the rat temporomandibular joint.

OBJECTIVE: The purpose of this study was to establish and histologically examine the time course of synovitis induced by trauma to the rat temporomandibular joint. STUDY DESIGN: Synovitis of the temporomandibular joints of 8-week-old male Wister rats was induced by forced condylar hypermobility, which was administered 10 times successively once a day for 10 days. Pathologic changes were observed microscopically at 2 and 5 days and 2, 4, 6, 8, 10, and 20 weeks after treatment. RESULTS: Histologic findings from the 5th day to the 6th week after treatment were characterized by multiple layers of synovial cells, an increase of dilated vasculature, fibrin deposits, and synovial adhesion. These findings were in good agreement with those reported for the human temporomandibular joint. The pathologic changes decreased with advancing time, and synovitis was not observed at 20 weeks after treatment. CONCLUSION: The present procedure for inducing synovitis of the temporomandibular joint in rats will be useful in understanding the pathogenesis of synovitis in human temporomandibular joints.

Animals↗
PubMed1998

Three-dimensional structure of a glycosphingolipid having a novel carbohydrate linkage, Galbeta1-4(Fucalpha1-3)Glcbeta1-3Galbeta, determined by theoretical calculations.

The novel glycosphingolipid, SEGLx (Galbeta1-4(Fucalpha1-3)Glcbeta1-3GalbetaCer), which was identified by us (Kawakami Y, et al. (1993) J Biochem 114: 677-83), shows a characteristic spectrum on 1H-NMR analysis, in which the anomeric proton resonances of a reducing end galactose and a glucose are split. To elucidate the structural characteristics of SEGLx, we determined its three-dimensional (3D) structure by means of computer simulation, involving such techniques as molecular mechanics (MM2), the semiempirical molecular orbital method (AM1), molecular dynamics (Amber), and computer 3D modelling. With the hypothesis that all OH group(s) of a ceramide participate in intramolecular hydrogen bonds, two kinds of stable conformers, horizontal and right-angled ones, were formed, depending on the ceramide species. The present findings suggest that the chemical species of both the long chain base and fatty acid moieties, mainly the occurrence of OH group(s), affect the chemical shifts of the anomeric proton resonances not only of the reducing terminal galactose but also the penultimate glucose through the formation of intramolecular hydrogen bonds. Computer simulation through theoretical calculation and 3D modelling was shown to be the best means of confirming the results obtained by experimental analysis.

Algorithms↗
PubMed1998

Relationship between disc displacement and morphologic features of skeletal Class III malocclusion.

The present study assessed the relationship between disc displacement and facial morphologic features in 48 patients with skeletal Class III malocclusion. Clinical examination, standardized lateral oblique temporomandibular joint radiographs, and cephalographs were used to investigate this relationship. Disc displacement was evaluated by the presence of joint sounds (clicking and crepitation) or restricted condylar translation at maximal mouth opening. Thirty-two patients with signs of disc displacement were compared with 16 patients without signs of disc displacement. Results showed that patients with signs of disc displacement had a significantly larger gonial angle and/or SN-MP of the mandible. Thus, morphologic features of patients with skeletal Class III malocclusion may represent a risk factor for the development of disc displacement.

Adult↗
PubMed1997

Analysis of the cleavage reaction of a trans-acting human hepatitis delta virus ribozyme.

The cleavage reaction catalyzed by the trans -acting genomic ribozyme of human hepatitis delta virus (HDV) was analyzed with a 13mer substrate (R13) and thio-substituted [SR13(Rp) and SR13(Sp)] substrates under single-turnover conditions. The cleavage of RNA by the trans -acting HDV ribozyme proceeded as a first order reaction. The logarithm of the rate of cleavage (kclv) increased linearly (with a slope of approximately 1) between pH 4.0 and 6.0, an indication that a single deprotonation reaction occurred. This result suggests that kclv reflects the rate of the chemical cleavage step, at least around pH 5. The amount of active complex with the SR13(Sp) substrate was almost as large as with R13 (60-80%), whereas the amount of the corresponding active complex formed with the SR13(Rp) substrate was, at most, 20% of this value (with 0.5-100 mM Mg2+ions) at pH 5.0. Nonetheless, the value of kclv for all substrates was almost the same (0.4-0.5 min-1). Neither a 'thio effect' nor a 'Mn2+rescue effect' were observed. These results suggest that Mg2+ions do not interact with pro-R oxygen directly but are essential to the formation of the active complex of the ribozyme and its substrate.

Base Sequence↗
PubMed1997

Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.

Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.

Animals↗
PubMed1997

Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.

To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorded under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo.

Animals↗
PubMed1997

Effect of acute renal failure on neurotoxicity of enoxacin in rats.

We investigated the effect of acute renal failure on the neurotoxicity of enoxacin (ENX) in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. ENX was intravenously infused to ureter ligated (UL) and control rats, and its concentration in plasma, brain and cerebrospinal fluid (CSF) was compared. Plasma concentration of ENX increased rapidly in UL rats as compared with control rats. Brain/plasma concentration ratio (Kp)-time profile of ENX was similar in UL and control rats. Brain concentration of ENX at the occurrence of convulsion did not depend on the infusion rate, suggesting that in the brain tissue it equilibrates rapidly with the site of action for clonic convulsion. Brain concentration of ENX in UL rats at the occurrence of clonic convulsion was lower than that in control rats. A similar tendency was also observed with CSF concentration. In conclusion, the potentiation of neurotoxicity of ENX with acute renal failure may be caused by not only decreased capability for renal elimination of ENX but also increased sensitivity to convulsant activity of ENX in the central nervous system.

Acute Kidney Injury↗
PubMed1997

Evolution of a phosphorothioate RNA library during in vitro selection.

We carried out an in vitro selection of aptamers from an RNA library with phosphorothioate linkages instead of normal phosphodiesters. This "thio-RNA" library had smaller dissociation rate constant (kd) to a target protein than a natural RNA library. On the basis of the results, an improved selection procedure to obtain ideal nucleic acid drugs will be discussed.

Base Sequence↗
PubMed1996

Constructing an efficient trans-acting genomic HDV ribozyme.

We have engineered a genomic HDV ribozyme to construct several trans-acting ribozymes for use in trans to cleave target RNAs. Among the 10 different combinations attempted, only HDV88-Trans had cleavage activity on the 13-nucleotide substrate, R13, in vitro. To improve the cleavage efficiency, at least in vitro, of the HDV88-Trans ribozyme (kclv = 0.022 min(-1)), we have constructed several variants that differ in forming stem II (length) in the pseudoknot secondary structure model. When cleavage rate constants were analyzed and compared among variants of HDV88-Trans, HDV88-Trans-4 yielded kclv = 1.7 min(-1). HDV88-Trans-4 thus represents the highest active genomic HDV ribozyme that functions in trans thus far constructed, and has activity under physiological conditions (pH 7.1 at 37 degrees C with 1 mM of MgCl2).

Base Sequence↗
PubMed1996

Selection in vitro of trans-acting genomic human hepatitis delta virus (HDV) ribozymes.

In an effort to identify the functional structure as well as new active variants of the trans-acting genomic ribozyme of human hepatitis delta virus (HDV), we applied an in vitro selection procedure. A total of 14 rounds of selection and amplification was repeated and various mutant ribozymes in G10 and G14 pools analyzed. Active ribozymes which were isolated in the present study (from G10 and G14) all possessed conserved bases (that were identified earlier) in the cis-acting molecule. A dominant clone G10-68 variant was accumulated in generation 14. Interestingly, when base substitutions were analyzed in G10-68 variant, we found that this variant appears to be close to antigenome-like HDV ribozyme molecule. Further investigations of G10-68 confirmed that each mutated base was the most appropriate nucleotide at every position of the HDV ribozyme.

Base Sequence↗
PubMed1996

Neurotoxic convulsions induced by histamine H2 receptor antagonists in mice.

Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2 receptor antagonists (H2 blockers). Four H2 blockers, cimetidine (721-1236 nmol), ranitidine (477-954 nmol), famotidine (7.4-44 nmol), and nizatidine (226-603 nmol) were administered intracerebrally (i.c.) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (+/-)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after i.c. administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. Ed50 values for convulsive occurrence after i.c. administration of four H2 blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 microM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2 blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2 blockers may be associated with the blockade of H2 receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.

Animals↗
PubMed1996

Effect of renal failure on neurotoxicity of ranitidine in rats.

We investigated the effect of acute renal failure on the neurotoxicity of ranitidine in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. Ranitidine was infused into the ureter ligated (UL) and control rats at the rate of 3.25 mg/min through the jugular vein until the onset of clonic convulsion. In UL rats, the onset time of convulsion was shorter and ranitidine concentrations in plasma and cerebrospinal fluid (CSF) were lower than those of control rats. However, the ranitidine concentration in the brain at the onset of convulsion was not different between the UL and control rats. From these findings, we concluded that acute renal failure is one of the risk factors for ranitidine neurotoxicity, and the increased sensitivity to the drug on the central nervous system may contribute to the increased toxicity of ranitidine in renal failure.

Acute Kidney Injury↗
PubMed1996

Neurotoxic convulsions induced by theophylline and its metabolites in mice.

To evaluate the risk of neurotoxicity induced by theophylline and its main metabolites, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1,3-dimethyluric acid (1,3-DMUA) and 1-methyluric acid (1-MUA), we compared their convulsive potency to central nervous system (CNS) after intracerebral administration to mice. All compounds studied induced clonic convulsion in a dose-dependent manner, and the ED50 values for convulsion were 490, 546, 1107, 360 and 620 nmol/kg for theophylline, 1-MX, 3-MX, 1,3-DMUA and 1-MUA, respectively. These compounds were also administered intravenously to mice by constant rate infusion until the onset of convulsion. Clonic convulsion was induced by i.v. infusion of theophylline, 1-MX and 3-MX, while convulsion was not observed during 1,3-DMUA or 1-MUA infusion for 60 min. This finding may be due to the poor blood-brain barrier permeability of both 1-MUA and 1,3-DMUA as compared with theophylline, 1-MX and 3-MX. However, it may be also necessary to consider the possibility of 1,3-DMUA-induced-neurotoxicity judging from its intrinsic convulsive potency.

Animals↗
PubMed1996

Lack of potentiation with felbinac patch on the convulsive toxicity of enoxacin in rats.

We investigated the possible potentiation of the convulsive toxicity of enoxacin (ENX) by the concomitant topical application of a felbinac (FLB) patch in rats. A felbinac patch (Seltouch; 0.5%, 3 cm x 4 cm) was attached on the back of rats where their hair has been removed. ENX was infused from the left jugular vein at 8 h after the application of FLB patch under an unanesthetized and unstrained condition. Blood, CSF and brain samples were collected at the occurrence of convulsion, and ENX concentrations of each part were determined. As a result, no significant potentiation by FLB patch was found in the onset time of convulsion or in the ENX concentration of each part. Moreover, based on the assumption that there are no inter-species differences in ENX concentration in the brain at the occurrence of a convulsion (Cbr), the predicted plasma ENX concentration required to elicit convulsions in humans, which was estimated from the Cbr and Kp value of ENX in the brain of rats, was 20 times higher than the therapeutic plasma level.

Administration, Cutaneous↗