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Biomedical subjects

H Seo

Publications and source records attributed to H Seo.

At least 19 recordsLinked to original sources
PubMed2006

Secretory IgA, salivary peroxidase, and catalase-mediated microbicidal activity during hydrogen peroxide catabolism in viridans streptococci: pathogen coaggregation.

Viridans streptococci can kill methicillin-resistant Staphylococcus aureus (MRSA) through the production of hydrogen peroxide (H2O2). However, several hundred viridans streptococci cells are necessary to kill 1 cfu of MRSA. We analyzed the potency of bactericidal and fungicidal effector molecules induced by catabolism of H2O2 in the oral cavity. Secretory IgA (SIgA) and an unidentified salivary component bound Streptococcus sanguinis, a viridans streprococcus, and MRSA into coaggregates. In these coaggregates, salivary peroxidase and the MRSA catalase produced singlet molecular oxygen (1O2) from H2O2 produced by viridans streptococci. SIgA converted 1O2 into ozone, which has potent bactericidal and fungicidal activity. We calculated that <10 cfu of Streptococcus sanguinis were necessary to kill 1 cfu of MRSA in the coaggregate. SIgA, Aspergillus niger catalase, and H2O2 in saliva killed Candida albicans, which is highly resistant to reagent H2O2. Together with indigenous bacteria and innate immunity, SIgA potentially constitutes a novel system that may sustain oral homeostasis.

Adult↗
PubMed2004

Comparison of computer-assisted instruction (CAI) versus traditional textbook methods for training in abdominal examination (Japanese experience).

PURPOSE: This study aimed to compare the effects of computer-assisted, text-based and computer-and-text learning conditions on the performances of 3 groups of medical students in the pre-clinical years of their programme, taking into account their academic achievement to date. A fourth group of students served as a control (no-study) group. METHOD: Participants were recruited from the pre-clinical years of the training programmes in 2 medical schools in Japan, Jichi Medical School near Tokyo and Kochi Medical School near Osaka. Participants were randomly assigned to 4 learning conditions and tested before and after the study on their knowledge of and skill in performing an abdominal examination, in a multiple-choice test and an objective structured clinical examination (OSCE), respectively. Information about performance in the programme was collected from school records and students were classified as average, good or excellent. Student and faculty evaluations of their experience in the study were explored by means of a short evaluation survey. RESULTS: Compared to the control group, all 3 study groups exhibited significant gains in performance on knowledge and performance measures. For the knowledge measure, the gains of the computer-assisted and computer-assisted plus text-based learning groups were significantly greater than the gains of the text-based learning group. The performances of the 3 groups did not differ on the OSCE measure. Analyses of gains by performance level revealed that high achieving students' learning was independent of study method. Lower achieving students performed better after using computer-based learning methods. CONCLUSION: The results suggest that computer-assisted learning methods will be of greater help to students who do not find the traditional methods effective. Explorations of the factors behind this are a matter for future research.

Abdomen↗
PubMed2004

Intrahepatic portosystemic venous shunt passing through the left inferior phrenic vein and draining into the left renal vein.

We report a case of an intrahepatic portosystemic venous shunt (IPSVS) passing through the left inferior phrenic vein and draining into the left renal vein and then to the inferior vena cava. We incidentally detected the IPSVS while performing a transcatheter arterial embolisation for the treatment of hepatocellular carcinoma. IPSVS with the left inferior phrenic vein as the draining vein is very rare. The complete pathway of this IPSVS could be clearly demonstrated by multidetector row CT during arterial portography.

Aged↗
PubMed2001

Thyrotropin modifies activation of nuclear factor kappaB by tumour necrosis factor alpha in rat thyroid cell line.

We have recently demonstrated that nuclear factor kappaB (NF-kappaB) mediates the tumour necrosis factor alpha (TNF-alpha)-dependent expression of the gene encoding interleukin 6 (IL-6) in rat thyroid FRTL-5 cells cultured in the presence of thyrotropin (TSH). In the present study we investigated how TSH is involved in the activation of NF-kappaB by TNF-alpha in the cells. Electrophoretic mobility-shift assay revealed that, in the absence of TSH, TNF-alpha activated a single protein-DNA complex containing the p50 subunit but not other NF-kappaB subunits such as p65. In contrast, two distinct protein-DNA complexes were activated in the presence of TSH: the faster-migrating complex contained only p50 subunit; the slower-migrating complex consisted of p65-p50 heterodimer. This TSH effect was mimicked by forskolin and thyroid-stimulating antibodies obtained from patients with Graves's disease, suggesting that an increase in intracellular cAMP is responsible for the induction of different NF-kappaBs by TNF-alpha. A transient transfection study with a luciferase reporter gene driven by multimerized NF-kappaB sites demonstrated that TNF-alpha increased the luciferase activities only in the presence of TSH, and that this increase was inhibited by the co-transfection of mutant p65, which prevented the function of wild-type p65 in a dominant-negative manner. Accordingly, TNF-alpha activated the expression of the IL-6 gene in the presence of TSH but not in its absence. Although the expression of the p105 gene, another known target for NF-kappaB, was increased by TNF-alpha in the absence of TSH, the presence of TSH further increased the mRNA level. Taken together, these observations indicate that the presence of TSH is crucial for the NF-kappaB-mediated actions of TNF-alpha on thyroid follicular cells.

Animals↗
PubMed2001

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha.

Only three of the four thyroid hormone receptor (TR) isoforms, alpha1, beta1, and beta2, bind thyroid hormone (TH) and are considered to be true TRs. TRalpha2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TRalpha (TRalpha(o/o)) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T(4)), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3',5-triiodothyronine, L-T3) given to TH-deprived and to intact TRalpha(o/o) mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TRbeta (TRbeta(-/-)). In liver, T3 produced significantly greater responses in TRalpha(o/o) and smaller responses in TRbeta(-/-) as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TRalpha(o/o), whereas they were similar in WT and TRbeta(-/-) mice, supporting the notion that TRalpha1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T(4) in TRalpha(o/o) than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive "silencing" effect of TRalpha2 in tissues expressing the TRbeta isoforms.

Animals↗
PubMed2001

Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing syndrome: possible contribution for the autonomous production of cortisol.

OBJECTIVE: To examine whether inhibition of endogenous adrenocorticotropin (ACTH) secretion in patients with Cushing syndrome affects the expression of the ACTH receptor (ACTH-R) gene in adrenocortical adenoma and attached atrophic normal gland. SUMMARY BACKGROUND DATA: ACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R. In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species. In patients with Cushing syndrome resulting from adrenocortical adenoma, there is autonomous production of cortisol from the adenoma. This strongly inhibits endogenous ACTH secretion, giving rise to the speculation that the expression of the ACTH-R gene in these patients is also suppressed. However, previous studies have shown that administration of exogenous ACTH to these patients leads to a further increase in the production of cortisol, suggesting the expression of functional ACTH-R in the adenoma. The authors, therefore, examined the expression of the ACTH-R gene in these patients. METHODS: Fourteen patients with Cushing syndrome were studied. Glucocorticoid excess resulting from autonomous production from the adenomas was ascertained, and unilateral adrenalectomy was performed. The levels of ACTH-R and cytochrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis. The entire coding region of the ACTH-R gene in these patients was sequenced. RESULTS: ACTH-R mRNA abundance in the attached atrophic normal adrenals was suppressed and invariably less than that in the normal gland obtained from a patient with renal cancer. However, the expression of ACTH-R mRNA was not suppressed in any of the adenomas. Expression of ACTH-R mRNA in the adenomas was four- to sixfold greater than that in the attached atrophic gland. No mutation in the coding sequence of the ACTH-R gene in the adenoma was detected in any of the patients. The mRNA in the adenomas appeared to be translated into functionally active receptor because intramuscular administration of ACTH resulted in significant increases in plasma cortisol before surgery but not 3 months after surgery. In addition, there was a positive linear correlation between the expressions of ACTH-R and P450scc mRNAs in the adenoma tissue. CONCLUSIONS: Suppressed ACTH secretion in patients with Cushing syndrome results in reduction of the ACTH-R mRNA expression in nonneoplastic adrenocortical cells. However, the regulatory mechanism of ACTH-R expression might be different in adenoma. Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol.

Adenoma↗
PubMed2001

Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism.

We identified ZAKI-4 (also designated as DSCR1L1) as a thyroid hormone responsive gene in cultured human skin fibroblasts. Recently it has been reported that ZAKI-4 belongs to an evolutionary conserved family of proteins that function as calcineurin inhibitor. In human, ZAKI-4 and calcineurin are highly expressed in brain, where thyroid hormones play essential roles in the development during fetal and neonatal periods. In the present study, we examined the temporal and spatial expression patterns of ZAKI-4 messenger RNA (mRNA) in control and hypothyroid rat brains. Northern blot analysis revealed that ZAKI-4 mRNA was detected in both cerebral cortex and cerebellum as early as embryonic day (E)18. In the cerebral cortex, the expression level gradually increased with age, reaching a plateau at postnatal day (P)7 and remained constant thereafter until P30. A similar pattern of increase with age was also observed in hypothyroid rats; however, the magnitude of the increase was significantly reduced. In control rats, the fold increase in ZAKI-4 mRNA level from E18 to P17 was 10.8; whereas in hypothyroid rats, it was 7.4. In cerebellum the expression level did not change with age or by thyroid status. In situ hybridization revealed that ZAKI-4 mRNA is widely expressed in neurons throughout the brain. It is noteworthy that the expression in the neurons of layer VI of the cerebral cortex was more evident in control rats than that in hypothyroid rats from P17 to P30. Though not influenced by hypothyroidism, there were several regions of the brain in which ZAKI-4 mRNA was strongly expressed. These regions were the mitral cell layer of the olfactory bulb, the substantia nigra, and the hippocampus, where calcineurin is also abundantly expressed. Therefore, it may be hypothesized that ZAKI-4 plays an important role in the development and function of the brain by modulating calcineurin function; and decrease in ZAKI-4 mRNA expression in the specific brain areas may explain, in some parts, the mechanism of abnormal brain development by hypothyroidism.

Animals↗
PubMed2001

The human homolog of Diminuto/Dwarf1 gene (hDiminuto): a novel ACTH-responsive gene overexpressed in benign cortisol-producing adrenocortical adenomas.

To elucidate the molecular mechanism of the pathogenesis of benign functioning adrenocortical adenomas causing Cushing's syndrome, we employed suppression PCR-based cDNA subtractive hybridization to identify novel genes that are differentially expressed in the adenoma. In this report we describe the adenoma-specific overexpression of the human homolog of the Diminuto/Dwarf1 (hDiminuto) gene. Northern blot analysis revealed that hDiminuto mRNA was overexpressed in the adenoma tissue of 14 patients with Cushing's syndrome in comparison to the adjacent nontumorous adrenal gland. In situ hybridization using hDiminuto cRNA probe showed its abundant expression in the tumor cells, whereas the nontumorous cells showed a low level of expression. As the atrophic adjacent gland may not represent the normal architecture, we examined the expression pattern of hDiminuto mRNA in normal human adrenal cortex. In situ hybridization revealed that it was expressed in all layers of the normal adrenal cortex. In situ apoptosis detection by the TUNEL method revealed that a low level of hDiminuto expression in the atrophic, adjacent gland was associated with numerous TUNEL-positive cells in all layers of cortex. In contrast almost no apoptotic cell was detected in the tumor or in the normal adrenal cortex where hDiminuto expression was abundant. These results are compatible with a recent report that hDiminuto acts as an antiapoptotic factor in neurons. The expression of hDiminuto in the normal adrenal cortex was most abundant in the zona fasciculata, suggesting its possible regulation by ACTH/cAMP. Indeed, forskolin treatment of H295R human adrenocortical cells resulted in a significant induction of the mRNA in a time- and dose-dependent manner. To further demonstrate the physiological regulation, an in vivo experiment was carried out in dexamethasone-treated rats. ACTH administration to these rats increased the mRNA expression. These results led us to speculate that the overexpression of hDiminuto in the adenoma could be due to the abundant expression of ACTH receptor, as we previously described. Diminuto is involved in steroid synthesis and cell elongation in plants. We, therefore, hypothesize that hDiminuto might be involved in the molecular events of adrenocortical tumorigenesis by facilitating steroid synthesis and cell growth.

Adenoma↗
PubMed2001

Overexpression of glutathione-S-transferase A1 in benign adrenocortical adenomas from patients with Cushing's syndrome.

Benign adrenocortical adenoma is a major primary cause of Cushing's syndrome. Although numerous studies have been performed, the molecular mechanism of adrenocortical adenoma is yet to be elucidated. In this study we endeavored to identify genes differentially regulated in adrenocortical adenoma by suppression PCR-based complementary DNA (cDNA) subtractive hybridization. The cDNA population in atrophied nontumorous adrenal gland adjacent to the adenoma was subtracted from that in the adenoma. Then adenoma-specific cDNAs were amplified by PCR. We cloned several cDNAs that are selectively up-regulated in the adenoma, one of which was identified to encode glutathione-S-transferase A1 (GSTA1). Northern blot analysis revealed that GSTA1 messenger ribonucleic acid was abundantly expressed in the adenoma compared with that in the adjacent atrophied nontumorous gland. Western blot analysis and immunohistochemistry showed high expression of GSTA1 also at the protein level. In concordance with this finding, GST activity was significantly higher in the adenoma than in the adjacent atrophied nontumorous gland. To clarify the role of GSTA1 in adrenocortical cells, GST activity in the H295R human adrenocortical cell line was inhibited by ethacrynic acid. Inhibition of GSTs interfered with proliferation of the cells. We, therefore, hypothesize that overexpression of GSTA1 in adrenocortical adenomas might be involved in the growth of tumor cells. We also speculate that this overexpression might be an adaptive response to excess cortisol production.

Adenoma↗
PubMed2001

Homeobox protein Gsh-1-dependent regulation of the rat GHRH gene promoter.

Although GHRH is known to play a pivotal role in the regulation of the GHRH-GH-IGF-I axis, the molecular mechanism of GHRH gene expression has not yet been examined. Here we studied the transcriptional regulation of the GHRH gene 5'promoter using an in vitro experimental model system. We especially focused on the role of homeobox transcriptional factor Gsh-1, because a dwarf phenotype and abolished GHRH expression was observed in Gsh-1 knockout mice. First, we cloned human Gsh-1, which showed 87.3% homology with mouse Gsh-1 at the nucleotide level. When the 5'-promoter region of the rat GHRH gene was introduced into the human placental cell line JEG-3, in which we found the endogenous expression of Gsh-1 as well as GHRH mRNA, substantial transcriptional activity of the promoter was recognized. Promoter activity was further enhanced by overexpression of Gsh-1 protein, whereas it was substantially reduced by elimination of Gsh-1 binding sites. EMSA confirmed the actual binding of Gsh-1 on the multiple binding sites of GHRH gene promoter. Finally, coexpression of CREB-binding protein significantly enhanced the Gsh-1-induced GHRH gene expression, suggesting the cooperative role of the coactivator protein. Because Gsh-1 is found to be expressed in the hypothalamus of the adult rat, our data provide evidence that the Gsh-1 homeobox protein plays a key role in the expression of the GHRH gene.

Animals↗
PubMed2001

Ultrastructure of aortic elastic fibers in copper-deficient Sika deer (Cervus nippon Temminck).

Light microscopic and transmission and scanning electron microscopic observations were performed on the aortas of two 4- and 6-year-old deer affected with cervine ataxia and two 6-month- and 4-year-old healthy deer. Examination of the aortas from affected deer by transmission electron microscopy revealed the absence of distinct elastic laminae in the internal elastic lamina and tunica media, but discontinuous and irregular clumps of elastin were present. Scanning electron microscopy disclosed immature architecture of elastic fibers in the aortas from the copper-deficient deer, and the architecture was similar to that of a 6-month-old healthy deer.

Animals↗
PubMed2001

Tumor necrosis factor alpha induces expression of genes for matrix degradation in human chondrocyte-like HCS-2/8 cells through activation of NF-kappaB: abrogation of the tumor necrosis factor alpha effect by proteasome inhibitors.

Tumor necrosis factor alpha (TNF-alpha) has been suggested to induce chondrocytic chondrolysis in both inflammatory and degenerative joint diseases. However, its intracellular signaling pathway leading to the chondrolysis has not been studied in detail. Thus, we investigated whether TNF-alpha activates a transcription factor nuclear factor kappaB (NF-kappaB) in human chondrocyte-like cells (HCS-2/8) and induces the expression of genes involved in the degradation of cartilage matrix. Treatment of the cells with TNF-alpha markedly increased the levels of matrix metalloproteinase 1 (MMP-1), MMP-3, intercellular adhesion molecule 1 (ICAM-1), and cyclo-oxygenase 2 (COX-2) messenger RNAs (mRNAs). The increase in the mRNAs was associated with the activation of p65/p50 heterodimer NF-kappaB. IkappaB-alpha and IkappaB-beta, cytoplasmic molecules preventing the nuclear translocation of NF-kappaB, were degraded rapidly by TNF-alpha followed by their synthesis to the basal level. Treatment with proteasome inhibitors inhibited the degradation of both IkappaB-alpha and IkappaB-beta and prevented the TNF-alpha-dependent nuclear translocation of p65. Furthermore, the inhibitors completely prevented the TNF-alpha-dependent induction of MMP-1, MMP-3, ICAM-1, and COX-2 mRNAs. Thus, it is shown that the activation of p65/p50 NF-kappaB by TNF-alpha plays a cardinal role in inducing the expression of MMP-1, MMP-3, ICAM-1, and COX-2 genes, which are involved in matrix degradation and inflammatory reaction in chondrocytes, leading to chondrocytic chondrolysis.

Blotting, Western↗
PubMed2001

Somatic gene alteration of AIB1 gene in patients with breast cancer.

AIB1 (amplified in breast cancer 1) is a coactivator which stimulates the transcriptional activity of the liganded-estrogen receptor (ER). It has been reported that AIBI gene is amplified and overexpressed in some breast cancer cell lines. AIB1 contains a stretch of homopolymeric glutamines (poly-Q). We reported that the poly-Q shows polymorphism, which provides an opportunity to study somatic gene alteration such as loss of heterozygosity (LOH). In the present study, we aimed to investigate the frequency of somatic gene alteration in Japanese patients with breast cancer. Amplification of AIB1 gene was detected only in 1 (2.6%) of 39 breast cancer tissues by DNA dot blot analysis. On the other hand, LOH was found in 2 (8%) breast cancer tissues out of 25 patients showing heterozygosity in peripheral blood mononuclear cells (PBMC). Taken together, both LOH and amplification of AIB1 gene were identified in breast cancer patients, raising the possibility that AIB1 have oncogenic as well as antioncogenic potential for the pathogenesis of breast cancer.

Adult↗
PubMed2001

Effects of estrogen on tail suspension-induced disuse atrophy in ovariectomized rats: evaluation of the expression of interleukin-6 mRNA in the femur.

It is known that estrogen deficiency results in osteoporosis in human and experimental animals. However, how this deficiency affects the development of disuse bone atrophy is not well understood. Recently, it has been reported that estrogen affects the production of cytokines such as interleukin 6 (IL-6) which acts as local bone-resorbing factor. We thus studied how estrogen deficiency caused by ovariectomy and estrogen supplements affects the expression of IL-6 mRNA in the femur of tail-suspended rats. Five-week old female Wistar rats were ovariectomized and divided into two groups. One group received an intramuscular injection of estradiol dipropionate once a week (OVX-E2 group), and the other received the vehicle alone (OVX group). After the third injection, the rats were subjected to tail suspension in metabolic cages for 1, 3, 5 and 7 days. The wet weight of femurs significantly decreased after day 3 of tail-suspension in the OVX group. However, no significant decrease was observed in the OVX-E2 group. The expression of IL-6 mRNA estimated by RT-PCR (reverse transcription coupled polymerase chain reaction) in the femur significantly increased on day 5 after tail suspension in the OVX group. In the OVX-E2 group, that level significantly decreased on day 1 after the commencement of tail suspension. During suspension the level tended to be lower than that in the OVX group, a significant difference being observed on days 5 and 7 of suspension. The present results suggest that estrogen administration to OVX rats prevents both IL-6 production in the femur and the development of disuse bone atrophy induced by tail suspension.

Animals↗
PubMed2001

Changes in mRNA levels of alkaline phosphatase and tartrate-resistant acid phosphatase in femur of ovariectomized rats: effects of estrogen and unloading.

Our previous studies demonstrated that estrogen (E2) prevents the development of disuse atrophy of the femur in tail-suspended rats. To elucidate the mechanisms of this E2 action, we investigated the effects of E2 on the expression of alkaline phosphatase (ALP, a marker for bone formation) and tartrate-resistant acid phosphatase (TRAP, a marker for bone resorption) in the femur of ovariectomized and tail-suspended rats. One group of ovariectomized rats received estradiol dipropionate (OVX-E2), and the other the vehicle alone (OVX). Each group was subjected to tail-suspension. After 1, 3, 5 or 7 days of suspension, ALP and TRAP mRNA levels were determined by Northern blot analysis. The ALP mRNA level was not altered by suspension in the OVX group, but it gradually increased in the OVX-E2 group, the highest level being observed at day 5 of suspension. In contrast, TRAP mRNA significantly increased at days 5 and 7 in the OVX group, while it is decreased significantly from day 3 to 7 in the OVX-E2 group. These results indicate that E2 prevents disuse atrophy of the femur in an ovariectomized and tail-suspended rat model by stimulating bone formation and by inhibiting bone resorption.

Acid Phosphatase↗
PubMed2000

TNF-alpha-dependent activation of NF-kappa B in human osteoblastic HOS-TE85 cells is repressed in vector-averaged gravity using clinostat rotation.

Effects of vector-averaged gravity on tumor necrosis factor (TNF)-alpha-dependent activation of nuclear factor kappa B (NF-kappa B) in human osteoblastic HOS-TE85 cells were investigated by culturing the cells using clinostat rotation (clinorotation). Cell cultures were rotated for 72 h at 40 rpm in a clinostat. At the end of clinorotation, the cells were treated with TNF-alpha for 30 min under stationary conditions. Electrophoretic mobility shift assays revealed that TNF-alpha-dependent activation of NF-kappa B was markedly reduced in the clinorotated cells when compared with the cells in control stationary cultures or after horizontal rotation (motional controls). The NF-kappa B-dependent transactivation was also impaired in the clinorotated cells, as evidenced by a transient transfection assay with a reporter plasmid containing multimerized NF-kappa B sites. Consistent with these findings, the TNF-alpha-dependent induction of endogenous NF-kappa B-responsive genes p105, I kappa B-alpha, and IL-8, was significantly attenuate in clinorotated cells. These results demonstrate that vector-averaged gravity inhibits the responsiveness of osteoblasts to TNF-alpha by repressing NF-kappa B activation.

Base Sequence↗
PubMed2000

In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin.

AT-1362 was found to be a potent, selective, and competitive inhibitor of thrombin, with a Ki value of 6.7 nM. In a rat model of venous thrombosis induced by partial stasis and endothelial disruption, the ID(50) values (a dose required to obtain 50% inhibition of thrombus formation over each vehicle group) of AT-1362 and argatroban were 0.03 mg/kg i.v. plus 0.5 microg/kg/minute and 0. 13 mg/kg i.v. plus 8.7 microg/kg/minute, respectively, and the antithrombotic effect of AT-1362 without prolongation of bleeding time lasted for 2 hours and disappeared 4 hours after oral administration of 30 mg/kg. In the rat tail transection model, the BT(2) values (a dose causing two-fold prolongation of the bleeding time over each vehicle group) of AT-1362 and argatroban were 0.56 mg/kg i.v. plus 9.3 microg/kg/minute and 1.1 mg/kg i.v. plus 73.3 microg/kg/minute, respectively. The reduction of thrombus formation and the prolongation of bleeding time were correlated with an ex vivo activated partial thromboplastin time (APTT) for both drugs. AT-1362 at 0.3 mg/kg i.v. plus 5 microg/kg/minute and argatroban at 0.6 mg/kg i.v. plus 40 microg/kg/minute significantly (p<0.05 and p<0.01, respectively) improved the vessel patency in a FeCl(2)-induced carotid artery thrombosis model in rats. These results suggest that AT-1362 may be a potent antithrombotic agent for the treatment of thrombotic diseases.

Administration, Oral↗