84 results on '"Wakitani K"'
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2. JTE-522 selectively inhibits cyclooxygenase-2-derived prostaglandin production in inflammatory tissues
- Author
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Wakitani, K., Tazaki, H., Matsushita, M., and Iwamura, H.
- Published
- 2000
- Full Text
- View/download PDF
3. JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice
- Author
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Kakutani, M., Takeuchi, K., Waga, I., Iwamura, H., and Wakitani, K.
- Published
- 1999
- Full Text
- View/download PDF
4. Inhibitory effects of JTE-522, a novel prostaglandin H synthase-2 inhibitor, on adjuvant-induced arthritis and bone changes in rats
- Author
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Masaki, M., Matsushita, M., and Wakitani, K.
- Published
- 1998
- Full Text
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5. Pharmacological profile of JTE-522, a novel prostaglandin H synthase-2 inhibitor, in rats
- Author
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Matsushita, M., Masaki, M., Yagi, Y., Tanaka, T., and Wakitani, K.
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- 1997
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6. Atriopeptins: correlation between renal vasodilation and natriuresis.
- Author
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WAKITANI, K., COLE, B. R., GELLER, D. M., CURRIE, M. G., ADAMS, S. P., FOK, K. F., and NEEDLEMAN, P.
- Published
- 1985
7. Synthesis and Structure−Activity Relationships of 5,6,7,8-Tetrahydro-4H-thieno[3,2-b]azepine Derivatives: Novel Arginine Vasopressin Antagonists
- Author
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Cho, H., Murakami, K., Nakanishi, H., Fujisawa, A., Isoshima, H., Niwa, M., Hayakawa, K., Hase, Y., Uchida, I., Watanabe, H., Wakitani, K., and Aisaka, K.
- Abstract
A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [3H]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure−activity relationships of these compounds, the thienoazepine derivative
1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride2 (JTV-605) of compound1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.- Published
- 2004
8. 4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as Selective Cyclooxygenase-2 Inhibitors: Enhancement of the Selectivity by Introduction of a Fluorine Atom and Identification of a Potent, Highly Selective, and Orally Active COX-2 Inhibitor JTE-522<SUP>1</SUP>
- Author
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Hashimoto, H., Imamura, K., Haruta, J., and Wakitani, K.
- Abstract
A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [
9d , 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.- Published
- 2002
- Full Text
- View/download PDF
9. 4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors
- Author
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Hashimoto, H., Maeda, K., Ozawa, K., Haruta, J. i., and Wakitani, K.
- Published
- 2002
- Full Text
- View/download PDF
10. Inhibitory effect of JTV-803, a new cyclic guanidine derivative, on factor Xa in vitro and in vivo
- Author
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Hayashi, M., Hamada, A., Okaya, Y., Wakitani, K., and Aisaka, K.
- Published
- 2001
- Full Text
- View/download PDF
11. Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474) by a novel COX-2 inhibitor, JTE-522.
- Author
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Sasai, H, Masaki, M, and Wakitani, K
- Abstract
Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in the occurrence of sporadic colon cancer. Various Apc knockout strains of mice have been created to better understand the function of this gene. In the present study, using gene targeting, we disrupted the mouse Apc gene at the end of exon 10 to compare its effect with the effects of other types of Apc gene disruption, all of which are on exon 15. The mice expressed a mutant form of mRNA that encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In addition, these Apc(Delta474) knockout mice developed intestinal and mammary tumors. Since the most severe cases of familial adenomatous polyposis are associated with mutations on exon 15, our mutation at exon 10 was expected to result in a mild phenotype. However, the number of polyps that our mice developed was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309) mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma. Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor, showed a significantly reduced number of polyps. These results suggest that COX-2 plays an important role in polypogenesis and COX-2-selective inhibitors can be used as new preventive therapeutics against colorectal tumors.
- Published
- 2000
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12. Triglyceride-lowering effect of a novel insulin-sensitizing agent, JTT-501
- Author
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Shibata, T., Matsui, K., Yonemori, F., and Wakitani, K.
- Published
- 1999
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13. Glucose-dependent insulinotropic effects of JTT-608, a novel antidiabetic compound
- Author
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Furukawa, N., Ohta, T., Noguchi, T., Yonemori, F., and Wakitani, K.
- Published
- 1999
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14. JTT-608 controls blood glucose by enhancement of glucose-stimulated insulin secretion in normal and diabetes mellitus rats
- Author
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Ohta, T., Furukawa, N., Yonemori, F., and Wakitani, K.
- Published
- 1999
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15. Isoxazolidine-3,5-dione and Noncyclic 1,3-Dicarbonyl Compounds as Hypoglycemic Agents
- Author
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Shinkai, H., Onogi, S., Tanaka, M., Shibata, T., Iwao, M., Wakitani, K., and Uchida, I.
- Abstract
Isoxazolidine-3,5-dione
2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing activity. Dimethyl malonate10 , which was selected as a successor for2 , was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione1 .- Published
- 1998
16. Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative
- Author
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Shibata, T., Matsui, K., Nagao, K., Shinkai, H., Yonemori, F., and Wakitani, K.
- Published
- 1998
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17. An Association between the Natural Course of Shoulder Joint Destruction in Rheumatoid Arthritis and HLA-DRB1*0405 in Japanese Patients: SHORT REPORT.
- Author
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S. Wakitani, K. Imoto, N. Murata, H. Oonishi, T. Ochi, M. Yoneda
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- 1998
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18. Comparative vascular pharmacology of the atriopeptins.
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Wakitani, K, primary, Oshima, T, additional, Loewy, A D, additional, Holmberg, S W, additional, Cole, B R, additional, Adams, S P, additional, Fok, K F, additional, Currie, M G, additional, and Needleman, P, additional
- Published
- 1985
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19. Atriopeptins: A family of potent biologically active peptides derived from mammalian atria
- Author
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Geller, D.M., primary, Currie, M.G., additional, Wakitani, K., additional, Cole, B.R., additional, Adams, S.P., additional, Fok, K.F., additional, Siegel, N.R., additional, Eubanks, S.R., additional, Galluppi, G.R., additional, and Needleman, P., additional
- Published
- 1984
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20. Atriopeptins: correlation between renal vasodilation and natriuresis
- Author
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Wakitani, K., primary, Cole, B. R., additional, Geller, D. M., additional, Currie, M. G., additional, Adams, S. P., additional, Fok, K. F., additional, and Needleman, P., additional
- Published
- 1985
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21. Differential structure-activity relationships of atrial peptides as natriuretics and renal vasodilators in the dog
- Author
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Katsube, N., primary, Wakitani, K., additional, Fok, K.F., additional, Tjoeng, F.S., additional, Zupec, M.E., additional, Eubanks, S.R., additional, Adams, S.P., additional, and Needleman, P., additional
- Published
- 1985
- Full Text
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22. Integration of human sensory factors in total production system
- Author
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Sasaki, M., primary, Kishimoto, K., additional, Ohuchi, A., additional, Wakitani, K., additional, and Kaihara, T., additional
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23. Recent research in WP 3-2 of HUTOP Project-haptic interface and programless image inspection
- Author
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Hashimoto, S., primary, Wakitani, K., additional, and Anezaki, T., additional
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24. Integration of human sensory factors in total production system.
- Author
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Sasaki, M., Kishimoto, K., Ohuchi, A., Wakitani, K., and Kaihara, T.
- Published
- 2002
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25. Recent research in WP 3-2 of HUTOP Project-haptic interface and programless image inspection.
- Author
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Hashimoto, S., Wakitani, K., and Anezaki, T.
- Published
- 2002
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26. Tacrolimus Triggers Transient Receptor Potential Vanilloid-1-Dependent Relapse of Pancreatitis-Related Pain in Mice.
- Author
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Terada Y, Tsubota M, Sugo H, Wakitani K, Sekiguchi F, Wada K, Takada M, Oita A, and Kawabata A
- Subjects
- Anilides pharmacology, Animals, Benzimidazoles pharmacology, Ceruletide adverse effects, Cinnamates pharmacology, Cyclopropanes pharmacology, Male, Mice, Naphthalenes pharmacology, Pain complications, Pancreatitis chemically induced, Pancreatitis complications, Recurrence, Tacrolimus antagonists & inhibitors, Hyperalgesia chemically induced, Pain physiopathology, TRPV Cation Channels physiology, Tacrolimus pharmacology
- Abstract
Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain., (© 2017 S. Karger AG, Basel.)
- Published
- 2017
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27. Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways in rats.
- Author
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Ogawa N, Ito M, Yamaguchi H, Shiuchi T, Okamoto S, Wakitani K, Minokoshi Y, and Nakazato M
- Subjects
- Adrenergic alpha-2 Receptor Antagonists administration & dosage, Adrenergic alpha-2 Receptor Antagonists pharmacology, Animals, Caprylates administration & dosage, Caprylates metabolism, Cholecystokinin blood, Dose-Response Relationship, Drug, Ghrelin blood, Glucagon-Like Peptide 1 blood, Idazoxan administration & dosage, Idazoxan pharmacology, Injections, Intraventricular, Jejunum, Male, Mesencephalon surgery, Norepinephrine metabolism, Paraventricular Hypothalamic Nucleus metabolism, Peptide YY blood, Rats, Rats, Sprague-Dawley, Time Factors, Vagotomy, Vagus Nerve surgery, alpha-Linolenic Acid administration & dosage, alpha-Linolenic Acid metabolism, Dietary Carbohydrates administration & dosage, Dietary Fats administration & dosage, Energy Intake drug effects, Food Preferences drug effects, Hypothalamus metabolism, Linoleic Acid administration & dosage, Linoleic Acid metabolism, Mesencephalon metabolism, Vagus Nerve metabolism
- Abstract
The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 μL/h) and reduced to the control level with the higher doses (150 and 200 μL/h). α-Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon-like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an α2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways. The effects of the α2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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28. Pharmacological analysis of antigen-induced late airway response in rats.
- Author
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Miyagawa N, Iwasaki H, Kato T, Tanaka M, Shibata T, and Wakitani K
- Subjects
- Albuterol pharmacology, Animals, Anti-Asthmatic Agents pharmacology, Bronchoalveolar Lavage Fluid cytology, Chromones pharmacology, Eosinophils drug effects, Eosinophils pathology, Ketotifen pharmacology, Leukocyte Count, Male, Prednisolone pharmacology, Pulmonary Edema immunology, Pulmonary Edema pathology, Rats, Rats, Sprague-Dawley, Respiratory Hypersensitivity pathology, Time Factors, Ovalbumin immunology, Respiratory Hypersensitivity immunology
- Abstract
The pharmacological and pathophysiological characteristics of rat antigen-induced late airway response (LAR) are not yet fully understood. In this study, the pharmacological properties of rat ovalbumin (OVA)-induced LAR and effects of the clinically used anti-asthmatic drugs salbutamol (beta2-agonist), ketotifen (antihistamine), pranlukast (anti-leukotriene C4/D4/E4), and prednisolone (steroid) were examined. In addition, a comparison was made of cell infiltration in bronchoalveolar lavage fluid (BALF) between immediate airway response (IAR) and LAR, and the edematous features of lung during LAR were also examined. Although infiltration of inflammatory cells into BALF was increased in both IAR and LAR, only the increase in eosinophils at 1, 3, and 6 h during LAR were significantly higher than those during IAR. Although beta2-agonist, antihistamine, and anti-leukotriene C4/D4/E4 exhibited no effects on rat LAR, steroid attenuated LAR and decreased eosinophil number in BALF. LAR and the percentage water content were both increased after antigen inhalation, suggesting that LAR is involved in pulmonary edema in rats. In conclusion, antigen-induced LAR was related to pulmonary edema and eosinophil infiltration rather than contraction of airway smooth muscle. This is the first comprehensive study of the profiles of rat antigen-induced LAR, and these analyses of LAR improve understanding of the diverse mechanisms underlying human asthmatic diseases.
- Published
- 2009
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- View/download PDF
29. Induction of late airway response was involved in serum antigen-specific immunoglobulin G in rats.
- Author
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Miyagawa N, Iwasaki H, Kato T, Tanaka M, Shibata T, and Wakitani K
- Subjects
- Administration, Inhalation, Animals, Asthma physiopathology, Disease Models, Animal, Histamine immunology, Histamine metabolism, Immunoglobulin E blood, Immunoglobulin G blood, Interleukin-1beta immunology, Interleukin-1beta metabolism, Leukotrienes immunology, Leukotrienes metabolism, Male, Ovalbumin immunology, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Antigens immunology, Asthma immunology, Bronchoalveolar Lavage Fluid immunology, Bronchoconstriction immunology, Immunoglobulin G immunology
- Abstract
The antigen-induced immediate airway response (IAR) has been considered a form of bronchoconstriction mainly provoked by histamine and leukotriene C4/D4/E4, which are released by stimulation by antigen-specific IgE. However, the pathophysiological features of the antigen-induced late airway response (LAR) are not yet fully understood. In the present study, sensitized rats were repeatedly exposed to ovalbumin (OVA) to induce IAR and LAR, and the immunological profiles of IAR and LAR were examined. The first antigen inhalation induced only IAR but not LAR. However, the second antigen inhalation 7 days after IAR induced LAR but not IAR. Tumor necrosis factor (TNF)-alpha level in BALF in LAR was significantly higher than that in IAR, although there were no differences in histamine, leukotriene C4/D4/E4, interleukin (IL)-1beta, or IL-13 levels between IAR and LAR. Serum antigen-specific IgE titer was high in both IAR and LAR, but serum antigen-specific IgG, IgG1, and IgG2a titers were dramatically high in LAR but not IAR. There were significant correlations between antigen-specific IgG, IgG1, and IgG2a titers and LAR. Interestingly, LAR could be induced in normal rats by transfer of serum from LAR rats, which exhibited high antigen-specific IgG, IgG1, and IgG2a titers. In conclusion, these findings suggest that repeated antigen inhalation converts IAR to LAR, and that LAR is a reaction triggered by antigen-specific IgG and involving TNF-alpha. This is the first study to directly suggest the involvement of antigen-specific IgG in the induction of LAR.
- Published
- 2008
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30. Two pharmacological phases in antigen-induced immediate airway response in rats.
- Author
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Miyagawa N, Iwasaki H, Kato T, Tanaka M, Shibata T, and Wakitani K
- Subjects
- Administration, Inhalation, Adrenergic alpha-2 Receptor Agonists, Adrenergic beta-Agonists pharmacology, Albuterol pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Benzoquinones pharmacology, Bronchial Hyperreactivity physiopathology, Chromones pharmacology, Heptanoic Acids pharmacology, Histamine H2 Antagonists pharmacology, Hypersensitivity, Immediate immunology, Ketotifen pharmacology, Leukotriene Antagonists pharmacology, Male, Ovalbumin immunology, Prednisolone pharmacology, Rats, Rats, Sprague-Dawley, Thromboxane A2 pharmacology, p-Methoxy-N-methylphenethylamine pharmacology, Anti-Asthmatic Agents pharmacology, Antigens pharmacology, Hypersensitivity, Immediate physiopathology
- Abstract
The pharmacological profiles of antigen-induced immediate airway response (IAR) in rats are not fully understood. In this study, we established an ovalbumin (OVA)-induced IAR model using noninvasive measurement in rats, and evaluated the effects of commonly used and effective antiasthmatic drugs, i.e. ketotifen (antihistamine), pranlukast (anti-leukotriene C(4)/D(4)/E(4) (LT)), seratrodast (anti-thromboxane A(2) (TXA(2))), salbutamol (beta2-agonist), and prednisolone (steroid). The rat IAR model exhibited an optimal rapid airway response, and salbutamol inhalation completely suppressed the IAR. Ketotifen inhibited only the quick phase (QP; the reaction from 3 to 6 min after challenge), while pranlukast and seratrodast suppressed only the early phase (EP; the reaction from 6 to 30 min after challenge). Prednisolone inhibited both QP and EP. Further, continuous administration of compound 48/80, which depletes connective tissue mast cells (CTMC), partially inhibited QP but not EP. In conclusion, these findings suggest that the pharmacological profiles of noninvasive rat IAR are similar to those of asthmatic patients, and that rat IAR exhibits additional, immunological diverse characteristics, i.e. QP caused by the exocytosis of mediators in CTMCs and EP mediated by LT and TXA(2), which are produced by mucosal mast cells (MMCs) and possibly by other types of cells. This is the first report about the comprehensive pharmacological profiles of rodent IAR model, and these analyses of rat IAR model may help expand our understanding of the diverse mechanisms underlying human asthmatic diseases.
- Published
- 2008
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31. Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice.
- Author
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Ueda Y, Miyagawa N, and Wakitani K
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Camphanes pharmacology, Dermatitis, Atopic immunology, Dinitrofluorobenzene immunology, Dinitrofluorobenzene pharmacology, Dioxoles pharmacology, Dose-Response Relationship, Drug, Female, Ligands, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Pyrazoles pharmacology, Quinolones pharmacology, Receptor, Cannabinoid, CB2 genetics, Receptor, Cannabinoid, CB2 metabolism, Dermatitis, Atopic metabolism, Immunoglobulin E immunology, Receptor, Cannabinoid, CB2 physiology, Skin drug effects, Skin immunology, Skin metabolism
- Abstract
Involvement of cannabinoid CB2 receptors in the IgE-mediated cutaneous reaction was investigated. Epicutaneous challenge with 2,4-dinitrofluorobenzene caused a triphasic swelling in the ear of BALB/c and C57BL/6 mice passively sensitized with anti-dinitrophenol IgE. Peak responses of the ear swelling appeared at 1 h, 24 h, and 8 days after the challenge in both strains of mice. In contrast, cannabinoid CB2 receptor-deficient mice failed to exhibit the obvious triphasic ear swelling observed in wild-type mice. Oral administration of cannabinoid CB2 receptor antagonist/inverse agonists [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR144528) at doses of 0.1-10 mg/kg significantly and dose-dependently suppressed all three phases of ear swelling in BALB/c mice. Interestingly, epicutaneous treatment with an ether-linked analogue of endogenous cannabinoids, 2-arachidonoylglycerol, caused an ear swelling that could be detected at 1 h, 24 h, and 8 days after treatment of both BALB/c and C57BL/6 mice. These results suggest that cannabinoid CB2 receptors are involved in induction of the triphasic cutaneous reaction mediated by IgE, and that cannabinoid CB2 receptor antagonist/inverse agonists may serve as anti-allergic agents in the treatment of allergic dermatitis.
- Published
- 2007
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32. Comparative study of glucocorticoids, cyclosporine A, and JTE-607 [(-)-Ethyl-N[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride] in a mouse septic shock model.
- Author
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Iwamura H, Sato M, and Wakitani K
- Subjects
- Animals, Bronchoalveolar Lavage Fluid cytology, Cytokines antagonists & inhibitors, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Leukocyte Count, Lung cytology, Lung metabolism, Male, Mice, Mice, Inbred BALB C, Peroxidase metabolism, Platelet Count, Prednisolone therapeutic use, Anti-Inflammatory Agents therapeutic use, Cyclosporine therapeutic use, Glucocorticoids therapeutic use, Immunosuppressive Agents therapeutic use, Phenylalanine analogs & derivatives, Phenylalanine therapeutic use, Piperazines therapeutic use, Shock, Septic drug therapy
- Abstract
Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)-ethyl-N-[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-gamma, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.
- Published
- 2004
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33. Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine derivatives: novel arginine vasopressin antagonists.
- Author
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Cho H, Murakami K, Nakanishi H, Fujisawa A, Isoshima H, Niwa M, Hayakawa K, Hase Y, Uchida I, Watanabe H, Wakitani K, and Aisaka K
- Subjects
- Animals, Azepines chemistry, Azepines pharmacology, Benzamides chemistry, Benzamides pharmacology, Binding, Competitive, Blood Platelets drug effects, Blood Platelets metabolism, CHO Cells, Cricetinae, Humans, Hypertension drug therapy, In Vitro Techniques, Kidney drug effects, Kidney metabolism, Liver drug effects, Liver metabolism, Male, Membranes, Models, Molecular, Radioligand Assay, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Thiophenes chemistry, Thiophenes pharmacology, Antidiuretic Hormone Receptor Antagonists, Arginine Vasopressin antagonists & inhibitors, Azepines chemical synthesis, Benzamides chemical synthesis, Thiophenes chemical synthesis
- Abstract
A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [(3)H]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure-activity relationships of these compounds, the thienoazepine derivative 1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride 2 (JTV-605) of compound 1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.
- Published
- 2004
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34. Effect of JTT-705 on cholesteryl ester transfer protein and plasma lipid levels in normolipidemic animals.
- Author
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Okamoto H, Iwamoto Y, Maki M, Sotani T, Yonemori F, and Wakitani K
- Subjects
- Administration, Oral, Amides, Animals, Callithrix, Cholesterol Ester Transfer Proteins, Cholesterol, HDL blood, Cholesterol, HDL drug effects, Cricetinae, Esters, Humans, In Vitro Techniques, Lipoproteins blood, Lipoproteins drug effects, Macaca fascicularis, Male, Rabbits, Species Specificity, Carrier Proteins antagonists & inhibitors, Carrier Proteins blood, Enzyme Inhibitors pharmacology, Glycoproteins, Lipids blood, Sulfhydryl Compounds pharmacology
- Abstract
This study evaluated JTT-705, S-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate, as a cholesteryl ester transfer protein (CETP) inhibitor in several animal species. In vitro, JTT-705 inhibited plasma CETP activities of humans, rabbits, hamsters, cynomolgus monkeys and marmosets with IC(50) values of 5.5, 1.0, 11.7, 2.4 and 6.3 microM, respectively. The thiol form (JTP-25203) also inhibited those activities with IC(50) values of 2.8, 0.44, 0.52, 1.3 and 1.1 microM, respectively. Following oral administration to normolipidemic animals (rabbits, hamsters and marmosets), JTT-705 reduced plasma CETP activity, increased high density lipoprotein cholesterol (HDL-cholesterol), and decreased the ratio of non-HDL-cholesterol to HDL-cholesterol (atherogenic index) in all species. In marmosets, JTT-705 increased slow alpha-migrating lipoprotein (apolipoprotein E-rich HDL) in agarose gel electrophoresis, indicating that HDL metabolism in JTT-705-treated marmosets is similar to that in CETP-deficient humans. These results indicate that JTT-705 can be expected to inhibit plasma CETP activity and improve plasma lipoprotein profiles in a wide range of animal species, including humans.
- Published
- 2003
- Full Text
- View/download PDF
35. Prior burn insult induces lethal acute lung injury in endotoxemic mice: effects of cytokine inhibition.
- Author
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Sasaki J, Fujishima S, Iwamura H, Wakitani K, Aiso S, and Aikawa N
- Subjects
- Acute Disease, Animals, Chemokine CXCL2, Cytokines antagonists & inhibitors, Endotoxemia chemically induced, Gene Expression drug effects, Lipopolysaccharides pharmacology, Lung metabolism, Lung Diseases metabolism, Male, Mice, Mice, Inbred BALB C, Monokines genetics, Monokines metabolism, Peroxidase metabolism, Phenylalanine analogs & derivatives, Phenylalanine pharmacology, Piperazines pharmacology, Prednisolone pharmacology, Survival Analysis, Time Factors, Tumor Necrosis Factor-alpha metabolism, Burns complications, Cytokines metabolism, Endotoxemia complications, Lung Diseases etiology, Lung Diseases mortality
- Abstract
Many patients who experience surgical stress, including burn injury, become susceptible to severe sepsis and septic organ dysfunction, which remains the primary contributor to morbidity and mortality in burn patients. In the present study, we developed a murine model of burn-primed sublethal endotoxemia by producing a 15% BSA full-thickness burn on the dorsum of BALB/c mice under ether anesthesia and administering 10 mg/kg of LPS intravenously on day 11 to model endotoxemia. The prior burn injury in this model induced two-peaked production of cytokines, TNF-alpha, and macrophage inflammatory protein-2 at 2 and 12 h after LPS administration, and it was associated with increased mortality. We also assessed the effect of pharmacological modulation with cytokine synthesis inhibitors prednisolone and JTE-607 and found that pretreatment with them attenuated later cytokine production and decreased mortality after LPS administration. We speculate that the prior burn injury primed the mice for the secondary insult via cytokine production. These results also suggested that an anticytokine strategy might serve as a novel prophylactic therapy for septic organ dysfunction in burn-primed patients.
- Published
- 2003
- Full Text
- View/download PDF
36. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.
- Author
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Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, and Shinkai H
- Subjects
- Amides, Animals, Carrier Proteins blood, Carrier Proteins physiology, Cell Line, Cholesterol Ester Transfer Proteins, Cholesterol, HDL blood, Disulfides chemistry, Disulfides pharmacology, Esters, Humans, Male, Rabbits, Structure-Activity Relationship, Sulfhydryl Compounds chemistry, Arteriosclerosis prevention & control, Carrier Proteins antagonists & inhibitors, Cholesterol Esters, Glycoproteins, Sulfhydryl Compounds pharmacology
- Abstract
Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.
- Published
- 2000
- Full Text
- View/download PDF
37. Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist, JTT-501, on diabetic complications in Zucker diabetic fatty rats.
- Author
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Shibata T, Takeuchi S, Yokota S, Kakimoto K, Yonemori F, and Wakitani K
- Subjects
- Absorptiometry, Photon, Animals, Body Weight drug effects, Bone Density drug effects, Bone Diseases, Metabolic etiology, Bone Diseases, Metabolic pathology, Bone Diseases, Metabolic prevention & control, Cataract etiology, Cataract pathology, Cataract prevention & control, Chromans pharmacology, Diabetes Mellitus genetics, Diabetes Mellitus pathology, Diabetic Nephropathies pathology, Diabetic Nephropathies prevention & control, Diabetic Neuropathies pathology, Diabetic Neuropathies prevention & control, Eating drug effects, Male, Neural Conduction drug effects, Pancreas pathology, Rats, Rats, Zucker, Thiazoles pharmacology, Time Factors, Troglitazone, Diabetes Complications, Hypoglycemic Agents pharmacology, Isoxazoles pharmacology, Obesity, Receptors, Cytoplasmic and Nuclear agonists, Thiazolidinediones, Transcription Factors agonists
- Abstract
This study has investigated the effects of JTT-501, a peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR-gamma agonist. The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT-501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy. ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT-501 and troglitazone, possibly mediated by increased bone turnover and bone formation. Since JTT-501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT-501, which activates both PPAR-alpha and PPAR-gamma, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.
- Published
- 2000
- Full Text
- View/download PDF
38. JTT-608 restores impaired early insulin secretion in diabetic Goto-Kakizaki rats.
- Author
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Ohta T, Furukawa N, Komuro G, Yonemori F, and Wakitani K
- Subjects
- Animals, Blood Glucose analysis, Diabetes Mellitus, Type 2 metabolism, Glucose Tolerance Test, Insulin Secretion, Male, Perfusion, Rats, Rats, Wistar, Tolbutamide pharmacology, Butyrates pharmacology, Cyclohexanes pharmacology, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents pharmacology, Insulin metabolism
- Abstract
1. We investigated the pharmacological effects of a new antidiabetic agent, JTT-608, in comparison with the sulphonylurea tolbutamide, in Goto-Kakizaki (GK) rats, a genetic model of non-obese insulin-dependent diabetes mellitus (NIDDM). 2. In isolated perfused pancreas from GK rats, JTT-608 (200 microM) enhanced 11.1 mM glucose-stimulated insulin secretion in the first and second phases, but had little effect on insulin secretion at 2.8 mM glucose. In contrast, tolbutamide (100 microM) markedly stimulated insulin secretion at 2.8 mM glucose and enhanced the second phase of insulin secretion but not the first phase at 11.1 mM glucose. 3. In vivo JTT-608 also enhanced early insulin secretion only with glucose-loading. In contrast, tolbutamide enhanced insulin secretion both with and without glucose-loading. 4. JTT-608 (10-100 mg kg(-1)) improved oral glucose tolerance with enhanced insulin secretion in a meal tolerance test (MTT). In comparison with tolbutamide, JTT-608 improved glucose tolerance more efficiently in GK rats than in Wistar rats. 5. We conclude that in diabetic GK rats JTT-608 suppressed postprandial glucose excursions with enhanced glucose-stimulated insulin secretion, especially the first phase of insulin secretion.
- Published
- 1999
- Full Text
- View/download PDF
39. Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative.
- Author
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Shibata T, Matsui K, Nagao K, Shinkai H, Yonemori F, and Wakitani K
- Subjects
- 3T3 Cells cytology, 3T3 Cells drug effects, Administration, Oral, Animals, Blood Glucose drug effects, Blood Glucose metabolism, Cell Differentiation drug effects, Chromans pharmacology, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 metabolism, Dose-Response Relationship, Drug, Glucose metabolism, Hyperinsulinism blood, Hypertriglyceridemia blood, Insulin blood, Insulin pharmacology, Male, Mice, Mice, Inbred Strains, Oxidation-Reduction drug effects, Pioglitazone, Rats, Rats, Sprague-Dawley, Rats, Zucker, Receptors, Cytoplasmic and Nuclear drug effects, Receptors, Cytoplasmic and Nuclear metabolism, Thiazoles pharmacology, Transcription Factors drug effects, Transcription Factors metabolism, Triglycerides blood, Troglitazone, Hypoglycemic Agents pharmacology, Isoxazoles pharmacology, Thiazolidinediones
- Abstract
JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxaz olidinedione, is an isoxazolidinedione derivative which is structurally distinct from thiazolidinediones such as pioglitazone and troglitazone. We investigated the effects of JTT-501 on insulin-sensitizing activity and in rodent diabetic models. JTT-501 enhanced insulin-stimulated cell differentiation of 3T3-L1 fibroblasts with an EC50 value of 110 nM. Furthermore, JTT-501 activated peroxisome proliferator-activated (PPA) gamma and alpha receptors with the EC5-fold values of 0.28 and 5.4 microM, respectively. In the non-insulin-dependent diabetes mellitus model KK-Ay mice, JTT-501 improved hyperglycemia, hyperinsulinemia and hypertriglyceridemia, and enhanced insulin-stimulated glucose oxidation in adipose tissues. JTT-501 was also effective in the non-insulin-dependent diabetes mellitus model Zucker diabetic fatty (ZDF) rats but not in the insulin-dependent diabetes mellitus model streptozotocin-induced diabetic mice. These observations suggest that JTT-501 enhances insulin sensitivity in peripheral tissues and improves hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in non-insulin dependent diabetes mellitus models. In particular, the triglyceride-lowering activity of JTT-501 is a unique characteristic compared to the thiazolidinediones. Therefore, JTT-501 may be a promising antidiabetic agent for treating non-insulin-dependent diabetes mellitus patients with insulin resistance.
- Published
- 1999
- Full Text
- View/download PDF
40. JTT-501, a novel oral antidiabetic agent, improves insulin resistance in genetic and non-genetic insulin-resistant models.
- Author
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Shibata T, Matsui K, Yonemori F, and Wakitani K
- Subjects
- Animals, Blood Glucose drug effects, Blood Glucose metabolism, Disease Models, Animal, Glucose metabolism, Glucose pharmacokinetics, Glucose Clamp Technique, Glucose Tolerance Test, Hyperglycemia drug therapy, Hypoglycemic Agents therapeutic use, Infusions, Intravenous, Insulin blood, Insulin pharmacology, Isoxazoles therapeutic use, Leptin, Lipids biosynthesis, Male, Obesity drug therapy, Obesity genetics, Oxidation-Reduction, Phosphorylation drug effects, Proteins drug effects, Proteins metabolism, Rats, Rats, Sprague-Dawley, Rats, Zucker, Receptor, Insulin drug effects, Receptor, Insulin metabolism, Triglycerides blood, Hypoglycemic Agents pharmacology, Insulin Resistance, Isoxazoles pharmacology
- Abstract
1. We investigated whether JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxa zolidinedione) would improve insulin resistance in genetic (Zucker fatty rats) and non-genetic (high-fat fed rats) rodent models of obesity. 2. JTT-501 (10-100 mg kg(-1) day(-1)) was administered orally to Zucker fatty rats for 7-21 days. In the high-fat fed rat model, JTT-501 (100 mg kg(-1) day(-1) was administered orally for 7 days. In both models, JTT-501 improved metabolic abnormalities by enhancing insulin action during the glucose tolerance test and the euglycaemic-hyperinsulinaemic clamp study. In ex vivo assays, JTT-501 ameliorated the impaired insulin-sensitive glucose oxidation and lipid synthesis in peripheral tissues. Furthermore, JTT-501 enhanced insulin receptor autophosphorylation in hindlimb muscle. 3. JTT-501 reduced serum leptin concentrations in both models, but did not affect body weight or epididymal fat weight. 4. Our observations indicate that JTT-501 improves the metabolic abnormalities in both genetic and non-genetic insulin-resistant models by enhancing insulin action in peripheral tissues. These effects of JTT-501 are due, at least in part, to enhanced insulin receptor autophosphorylation. In addition, JTT-501 is able to reduce serum leptin concentrations in hyperleptinaemia of the insulin-resistant model. We expect JTT-501 to show promise for treating non-insulin dependent diabetes mellitus patients with insulin resistance.
- Published
- 1998
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41. Profile of JTE-522 as a human cyclooxygenase-2 inhibitor.
- Author
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Wakitani K, Nanayama T, Masaki M, and Matsushita M
- Subjects
- Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Dinoprostone metabolism, Humans, Isoenzymes metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear enzymology, Leukocytes, Mononuclear metabolism, Lipopolysaccharides pharmacology, Membrane Proteins, Prostaglandin-Endoperoxide Synthases metabolism, Time Factors, Benzenesulfonates pharmacology, Cyclooxygenase Inhibitors pharmacology, Isoenzymes drug effects, Oxazoles pharmacology, Prostaglandin-Endoperoxide Synthases drug effects
- Abstract
Inhibitory activity and the mechanism of action of JTE-522 (4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamid e), a novel selective cyclooxygenase (COX)-2 inhibitor, on human COX-1 and COX-2 were investigated and compared with those of reference compounds. In an enzyme assay, JTE-522 inhibited yeast-expressed human recombinant COX-2 with an IC50 value of 0.085 microM. In contrast, JTE-522 did not inhibit human COX-1 prepared from human platelets at concentrations up to 100 microM. In a cell-based assay, JTE-522 diminished lipopolysaccharide-induced prostaglandin E2 production in human peripheral blood mononuclear cells (COX-2) (IC50 value = 15.1 nM). On the other hand, JTE-522 was less potent at inhibiting calcium ionophore-induced thromboxane B2 production in washed human platelets (COX-1) (IC50 value = 6210 nM). JTE-522 showed highly selective inhibition of human COX-2, and its activity was more selective than that of other COX-2 inhibitors (NS-398 and SC-58635). Human recombinant COX-2 activity was attenuated by JTE-522 in a dose-dependent and time-dependent manner. In contrast, the inhibitory activity of JTE-522 on human COX-1 was not affected by preincubation time. COX-2 inhibition by JTE-522 could not be recovered by gel filtration. These results indicate that JTE-522 is a highly selective, time-dependent and irreversible inhibitor of human COX-2.
- Published
- 1998
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42. Inhibitory effect of OP-41483.alpha-CD, a prostacyclin analog, on peripheral vascular lesion models in rats.
- Author
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Wakitani K, Takakuwa T, Sugioka M, Fujitani B, and Aishita H
- Subjects
- Alprostadil analogs & derivatives, Alprostadil pharmacology, Analysis of Variance, Animals, Epinephrine pharmacology, Epoprostenol pharmacology, Ergotamine pharmacology, Femoral Artery, Ischemia physiopathology, Laurates pharmacology, Male, Platelet Aggregation Inhibitors pharmacology, Rats, Rats, Inbred Strains, Thrombosis physiopathology, Vasoconstriction, Blood Pressure drug effects, Cyclodextrins pharmacology, Epoprostenol analogs & derivatives, Ischemia drug therapy, Platelet Aggregation drug effects, Thrombosis drug therapy, alpha-Cyclodextrins
- Abstract
The effect of a chemically stable prostacyclin analog, OP-41483 alpha-cyclodextrin clathrate (OP-41483.alpha-CD), on vascular lesions, platelet aggregation and blood pressure were examined and compared with those of prostaglandin E1 alpha-cyclodextrin clathrate (PGE1.CD) in in vivo rat models. 1) In the laurate (1 mg/leg, i.a.)-induced arterial thrombotic model, OP-41483.alpha-CD (1 microgram/kg/min, i.v.) prevented the progression of femoral arterial vascular lesions and enhanced the development of collaterals in the femoral artery. PGE1.CD did not inhibit the progression of vascular damages. 2) In the model of vasoconstriction induced by epinephrine (0.05 mg/tail, s.c.) and ergotamine (2 mg/kg, s.c.), OP-41483.alpha-CD and PGE1.CD, at 1 microgram/kg/min, inhibited the progress of of tail gangrene and lessened the decrease in tail cutaneous blood flow. 3) OP-41483.alpha-CD (1 microgram/kg/min) suppressed the ADP (0.1 mg/kg/min, i.v.)-induced decrease in the number of circulating platelets without affecting the change in blood pressure. In contrast, PGE1.CD (3 micrograms/kg/min) inhibited ADP-induced thrombocytopenia with a decrease in blood pressure. These results indicate that OP-41483.alpha-CD has antiplatelet and cutaneous blood flow improving activities that are greater than its hypotensive effect and may be of therapeutic potential in peripheral vascular diseases.
- Published
- 1992
- Full Text
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43. [Effects of ONO-1016, inhibitor of C1-/HCO3- exchange, on the brain water content and local cerebral blood flow following cerebral ischemia in spontaneously hypertensive rats].
- Author
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Ishikawa T, Setoyama K, Wakitani K, Kubo M, Maekawa T, Sakabe T, and Takeshita H
- Subjects
- Animals, Blood-Brain Barrier, Brain metabolism, Brain Edema metabolism, Ischemic Attack, Transient physiopathology, Male, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Bicarbonates antagonists & inhibitors, Body Water metabolism, Brain drug effects, Cerebrovascular Circulation, Ischemic Attack, Transient metabolism
- Abstract
The effects of ONO-1016, as an inhibitor of C1-/HCO3-exchange, on the brain edema and circulatory failure following cerebral ischemia were examined in stroke-prone spontaneously hypertensive rats (SHR-SP). SHR-SP were divided into three groups: control (sham-operation), non-treated, ONO-1016 group, respectively. Cerebral ischemia was produced by bilateral carotid artery occlusion (BCAO) for 1 hr and then following reperfusion. The brain water content and local cerebral blood flow (LCBF) were determined by dry-wet method and 14C-iodoantipyrine method 2 hr after start of reperfusion. ONO-1016 was given intravenously at a dose of 100 micrograms/kg/min prior to ischemia. The brain water content increased in septum (SP), amygdala (AM) in both non-treated and ONO-1016 groups compared from those in control group. However, brain water contents in SP and midbrain were lower in ONO-1016 group than those in non-treated group. LCBFs decreased to 50-80% in SP, cerebral cortex (CT), striatum (ST), hippocampus (HC) and AM in non-treated group, while LCBFs decreased to 60-80% in SP, CT, ST, AM in ONO-1016 group when compared from those in control group. Decrease of LCBF in ST and HC in ONO-1016 group were less severe than those in non-treated group. From these results, ONO-1016 may prevent the brain edema formation associated with hypoperfusion during reperfusion period after ischemia in SHR-SP.
- Published
- 1991
44. Anti-thrombotic effect of ONO-8809, a novel TXA2/PG endoperoxide receptor antagonist.
- Author
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Wakitani K, Matsumoto R, Imawaka H, Kamanaka Y, Naka M, Hamanaka N, Okegawa T, and Kawasaki A
- Subjects
- Animals, Bridged Bicyclo Compounds therapeutic use, Death, Sudden etiology, Disease Models, Animal, Dogs, Electric Stimulation, Electrocardiography drug effects, Fatty Acids, Monounsaturated therapeutic use, Male, Mice, Mice, Inbred Strains, Molecular Structure, Prodrugs therapeutic use, Receptors, Thromboxane, Bridged Bicyclo Compounds pharmacology, Coronary Thrombosis prevention & control, Fatty Acids, Monounsaturated pharmacology, Fibrinolytic Agents, Prodrugs pharmacology, Receptors, Prostaglandin antagonists & inhibitors
- Published
- 1991
45. Studies on antiplatelet effects of OP-41483, a prostaglandin I2 analog, in experimental animals. II. Mechanism of its antiplatelet effect.
- Author
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Fujitani B and Wakitani K
- Subjects
- Adenosine Diphosphate blood, Adenylyl Cyclases metabolism, Animals, Binding, Competitive drug effects, Blood Platelets enzymology, Blood Platelets metabolism, Calcium blood, Cyclic AMP biosynthesis, Cyclic AMP metabolism, Dideoxyadenosine pharmacology, Epoprostenol metabolism, Guinea Pigs, In Vitro Techniques, Male, Microsomes drug effects, Microsomes metabolism, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors metabolism, Thrombin pharmacology, Thromboxanes biosynthesis, Blood Platelets drug effects, Epoprostenol pharmacology, Platelet Aggregation Inhibitors pharmacology
- Abstract
The mechanism for the inhibition of platelet functions by a prostaglandin I2 analog, OP-41483, was studied with guinea pig platelets. OP-41483, and PGI2 as well, inhibited aggregation, ADP release and thromboxane formation of platelets with IC50 values of 4.3-5.8 ng/ml and 0.6-0.9 ng/ml, respectively. The ligand binding study using [3H]-OP-41483 suggested that OP-41483 bound with different affinities to two classes of binding sites on platelets. The dissociation constant of OP-41483 for the higher affinity site corresponded to the IC50 values of its antiplatelet effect. PGI2 as well as OP-41483 displaced [3H]-OP-41483 previously bound to platelets, thus indicating that both agents exerted their antiplatelet effects by binding to the same site on platelets. OP-41483 and PGI2 activated adenylate cyclase and raised cyclic AMP levels in platelets. However, their inhibitory effect on platelet aggregation was not fully antagonized by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA), at a concentration completely inhibiting the increase of cyclic AMP. Moreover, this DDA-resistant effect of OP-41483 disappeared in the presence of calcium chloride (10(-4)-10(-3) M). OP-41483 and PGI2 inhibited thrombin-induced Ca++ influx into platelets. The inhibition of Ca++ influx was not reversed by DDA. Based on these results, we speculate that the inhibitory effects of OP-41483 and PGI2 on platelet functions are produced through dual mechanisms: one mediated by activation of adenylate cyclase and the other by an inhibition of Ca++ influx; and these two mechanisms seem to be independent of each other.
- Published
- 1990
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46. Studies on antiplatelet effect of OP-41483, a prostaglandin I2 analog, in experimental animals. I. Effect on platelet function and thrombosis.
- Author
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Fujitani B and Wakitani K
- Subjects
- Animals, Electric Stimulation, Electrocoagulation, Extracorporeal Circulation, Guinea Pigs, Hematocrit, Heparin pharmacology, In Vitro Techniques, Male, Platelet Function Tests, Rabbits, Epoprostenol pharmacology, Platelet Aggregation Inhibitors pharmacology, Thrombosis prevention & control
- Abstract
Antiplatelet and antithrombotic effects of OP-41483, a PGl2 analog, were studied in experimental animals, and the following results were obtained: 1) With 10 min-intravenous infusion to guinea pigs, OP-41483 inhibited platelet adhesiveness and platelet aggregation at 300-1000 ng/kg/min and 1000 ng/kg/min, respectively. In these effects, OP-41483 was 1-3 times more potent than carbacyclin and 3 times less potent than PGl2. 2) With oral administration to guinea pigs, OP-41483 given as its alpha-cyclodextrin clathrate (OP-41483 alpha-CD) inhibited platelet adhesiveness at doses higher than 1.0 mg/kg (expressed in terms of OP-41483), whereas PGl2 and carbacyclin did not at 10 mg/kg. OP-41483 alpha-CD also inhibited platelet aggregation after a single dose of 3 mg/kg and repeated doses of 3 mg/kg/day for 7 days. 3) In the electrically induced thrombosis model of guinea pig mesenteric artery, OP-41483 (300-1000 ng/kg/min, i.v.-infusion) and OP-41483 alpha-CD (1.0-3.0 mg/kg, p.o.) inhibited thrombus formation, but heparin (1.0-10 U/kg/min, i.v.-infusion) did not. 4) In the rabbit extracorporeal circulation thrombosis model, OP-41483 (100 and 300 ng/kg/min, i.v.-infusion) inhibited thrombus formation in the extracorporeal shunt and prevented the decrease in platelet count, hematocrit and fibrinogen level in circulating blood. Heparin (1.0-3.0 U/kg/min, i.v.-infusion) also inhibited the thrombus formation and the decrease in fibrinogen level, but did not inhibit the decrease in hematocrit and platelet count.
- Published
- 1990
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- View/download PDF
47. Effect of a prostacyclin analog OP-2507 on acute ischemic cerebral edema in cats.
- Author
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Terawaki T, Takakuwa T, Iguchi S, Wakitani K, Kira H, Okegawa T, Kawasaki A, and Masuda Y
- Subjects
- Animals, Blood Pressure drug effects, Brain pathology, Brain Edema etiology, Brain Edema pathology, Cats, Female, Heart Rate drug effects, Infusions, Intravenous, Male, Specific Gravity, Stereotaxic Techniques, Time Factors, Brain Edema drug therapy, Brain Ischemia complications, Epoprostenol therapeutic use
- Abstract
We evaluated the inhibitory activity of a novel prostacyclin analog, OP-2507 (15-cis-(4-n-propylcyclohexyl)-16,17,18,19,20-pentanor-9-deo xy-6,9 alpha- nitriloprostaglandin F1 methyl ester) on the brain edema induced by occlusion of the middle cerebral artery in cats. Middle cerebral artery occlusion for 4h caused a decrease of regional cerebral blood flow. The specific gravity of the cerebral cortex measured 4h after the middle cerebral artery occlusion as an index of cerebral edema showed a significant reduction. Intravenous infusion of OP-2507 at infusion rates of 10 and 50 ng/kg per min was started 30 min before the middle cerebral artery occlusion and was continued for 4.5 h. While OP-2507 did not affect the blood pressure, heart rate and regional cerebral blood flow before and after the middle cerebral artery occlusion, the reduction of the specific gravity of cerebral cortex was significantly prevented by OP-2507 treatment at both doses. Prostacyclin prevented the reduction of the specific gravity only at the higher dose of 50 ng/kg per min. The present results indicate the potential usefulness of OP-2507 in acute ischemic cerebral disorders.
- Published
- 1988
- Full Text
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48. Comparison of the activities of prostacyclin and its stable analogs on the platelet aggregation and cardiovascular systems.
- Author
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Kawasaki A, Ishii K, Wakitani K, and Tsuboshima M
- Subjects
- Animals, Dogs, Drug Stability, Humans, Hypertension physiopathology, Prostaglandins, Synthetic pharmacology, Rats, Structure-Activity Relationship, Blood Pressure drug effects, Epoprostenol pharmacology, Platelet Aggregation drug effects, Prostaglandins pharmacology
- Published
- 1980
49. Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046).
- Author
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Hiraku S, Taniguchi K, Wakitani K, Omawari N, Kira H, Miyamoto T, Okegawa T, Kawasaki A, and Ujiie A
- Subjects
- Animals, Arachidonic Acid, Arachidonic Acids metabolism, Blood Platelets metabolism, Cerebral Infarction prevention & control, Death, Sudden, Dogs, Epoprostenol biosynthesis, Epoprostenol metabolism, Female, Guinea Pigs, Isomerases metabolism, Male, Prostaglandin-E Synthases, Prostaglandin-Endoperoxide Synthases metabolism, Rabbits, Rats, Rats, Inbred Strains, Vasodilator Agents, Acrylates pharmacology, Cytochrome P-450 Enzyme System, Intramolecular Oxidoreductases, Methacrylates pharmacology, Thromboxane-A Synthase antagonists & inhibitors
- Abstract
The effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046) on thromboxane A2 (TXA2) synthetase in vitro and on experimental animal models of sudden death and cerebral infarction were studied. IC50 values of OKY-046 for the TXA2 synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 microM, respectively. OKY-046 at concentrations up to 1 mM, however, did not inhibit prostacyclin (PGI2) synthetase from bovine aorta microsomes or cyclooxygenase and PGE2 isomerase from sheep seminal vesicle microsomes. Similarly, platelet 12-lipoxygenase was not affected by OKY-046. Evidence for a re-direction of arachidonate metabolism from thromboxane synthesis toward PGI2 synthesis was obtained using rat peritoneal cells. Namely, OKY-046 increased PGI2 production accompanied by an inhibition of TXA2 production at a concentration of more than 1 microM. OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs. OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced sudden death and also decreased the incidence of cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits. Aspirin also decreased the incidence of cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that OKY-046 may be valuable for the treatment of cerebrovascular and cardiovascular diseases associated with vasoconstriction and thrombosis due to TXA2.
- Published
- 1986
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50. Vasodilator properties of a family of bioactive atrial peptides in isolated perfused rat kidneys.
- Author
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Wakitani K, Currie MG, Geller DM, and Needleman P
- Subjects
- Animals, Atrial Natriuretic Factor, Chickens, Cyanogen Bromide, Heart Atria analysis, In Vitro Techniques, Male, Molecular Weight, Muscle Contraction drug effects, Muscle, Smooth drug effects, Peptide Fragments pharmacology, Rabbits, Rats, Rats, Inbred Strains, Kidney blood supply, Muscle Proteins pharmacology, Vasodilator Agents
- Abstract
The isolated Krebs-perfused rat kidney was used for the quantitative and qualitative evaluation of the family of peptides derived from rat atrial extracts. Renal resistance changes were measured in perfused rat kidneys continuously infused with norepinephrine. The low molecular weight peptide fraction from rat atrial extracts was purified to obtain six peptides. The 21 amino acid peptide, designated atriopeptin I, was previously demonstrated to be natriuretic and to relax intestinal but not vascular smooth muscle strips (in vitro) and to be an extremely weak renal spasmolytic in the isolated perfused rat kidney. On the other hand, the 23 amino acid peptide (which has a Phe-Arg carboxy-terminal extension on atriopeptin I), designated atriopeptin II, and atriopeptin III (the Phe-Arg-Tyr carboxy-terminal extension) were natriuretic and spasmolytic (in vitro) on both intestinal and vascular smooth muscle. Both atriopeptin II and III produced a profound concentration-dependent decrease in renal resistance in the norepinephrine-constricted rat kidney preparation. A comparative study of the six peptides isolated from atrial extracts indicates that the Phe-Arg or Phe-Arg-Tyr carboxy-terminal extension of the basic 21 amino acid sequence is essential for the renal vasorelaxant activity. A purified high molecular weight peptide (designated atriopeptigen) is impotent relative to the low molecular weight atriopeptin II and III as a renal spasmolytic in isolated perfused rat kidneys and reduces renal resistance only after in vitro proteolytic cleavage. Thus, the low molecular weight peptides atriopeptin II and III appear to be the active species that mediate the renal vasodilation produced by atrial extracts.
- Published
- 1985
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