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1.
J Int Med Res ; 32(2): 141-8, 2004.
Article in English | MEDLINE | ID: mdl-15080017

ABSTRACT

Autoantibodies against heat shock protein 40 (HSP40) and their clinical significance in ulcerative colitis (UC) have not been evaluated before. Twenty-six tissue specimens of inflamed areas from patients with UC, 16 from patients with Crohn's disease (CD) and 16 endoscopically normal tissues were analysed for HSP40 expression. Sera from 47 patients with UC and 44 healthy volunteers were examined for the presence of autoantibodies against HSP40 by enzyme-linked immunosorbent assay test. Immunohistochemistry showed that 17 out of 26 specimens from UC patients, one specimen from a CD patient and one normal tissue specimen were positive for HSP40. Most HSP40-positive cells expressed CD68. Higher titres of anti-HSP40 autoantibodies were detected in sera from UC patients compared with healthy volunteers. In patients with inactive disease, those with proctitis or left-sided colitis had higher titres of anti-HSP40 autoantibodies than those with total colitis. Our study suggests that autoimmunity against HSP40 may have a beneficial effect in UC patients by limiting the extent of the disease.


Subject(s)
Autoantibodies/blood , Colitis, Ulcerative/immunology , Heat-Shock Proteins/immunology , Adolescent , Adult , Aged , Female , HSP40 Heat-Shock Proteins , Humans , Male , Middle Aged
2.
Chem Pharm Bull (Tokyo) ; 49(9): 1102-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11558595

ABSTRACT

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Azoles/chemical synthesis , Azoles/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Alkylation , Animals , Antifungal Agents/therapeutic use , Aspergillus fumigatus/drug effects , Azoles/therapeutic use , Candida albicans/drug effects , Candidiasis/drug therapy , Candidiasis/microbiology , Half-Life , Hemolysis/drug effects , Imidazoles/therapeutic use , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Prodrugs/therapeutic use , Rats , Solubility , Tetrazoles/therapeutic use
3.
Chem Pharm Bull (Tokyo) ; 49(9): 1110-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11558596

ABSTRACT

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.


Subject(s)
Antifungal Agents/chemical synthesis , Imidazoles/chemical synthesis , Tetrazoles/chemical synthesis , Animals , Antifungal Agents/pharmacokinetics , Biotransformation , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Imidazoles/pharmacokinetics , In Vitro Techniques , Liver/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tetrazoles/pharmacokinetics
4.
Chem Pharm Bull (Tokyo) ; 48(12): 1935-46, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11145148

ABSTRACT

New optically active antifungal azoles, N-14-(azolyl)phenyl]- and N-14-(azolylmethyl)phenyl]-N'-[(IR,2R)-2(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(IH-1,2,4-triazol-1-yl)propyllazolones (1, 2, 3), were prepared in a stereocontrolled manner. Compounds 1-3 showed strong antifungal activity against Candida albicans in vitro. Among them, the imidazolidinones 3 showed a broad antifungal spectrum in vitro as well as potent in vivo activity against candidiasis and aspergillosis in mice. The imidazolidinones (3i, j, k) having 1H-1,2,3-triazol-1-yl, 2H-2-tetrazolyl and IH-1-tetrazolyl moieties were found to exert strong protective effect against aspergillosis.


Subject(s)
Antifungal Agents/chemical synthesis , Azoles/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Azoles/chemistry , Azoles/pharmacology , Candida albicans/drug effects , Magnetic Resonance Spectroscopy , Optical Rotation
5.
Chem Pharm Bull (Tokyo) ; 48(12): 1947-53, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11145149

ABSTRACT

New routes for the synthesis of the optically active antifungal triazoles 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1b) and the 3-14-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone analog (1a) that possess an imidazolidine nucleus were established. The key synthetic intermediates, (2R,3R)-3-(2,2-diethoxvethyl)amino-2-(2,4-difluorophenyl)-1-(1H1,2,4-triazol-1-yl)-2-butanol (8) and (2R,3R)-2-(2,4-difiuorophenyl)-3-(2-h ydroxyethyl)amino-1-(1H-1,2,4-triazol-1-yl)-2-butanol (14), were prepared by the ring-opening reaction of the oxirane (2) with the corresponding 2-substituted ethylamines. The acetal (8) was converted to the imidazolidinones (1a, b) by condensation with the carbamates (10a, b) followed by treatment with hydrochloric acid and subsequent catalytic hydrogenation. The candidate selected for the clinical trials, 1b (TAK-456), was alternatively prepared from the hydroxyethylamino intermediate (14) via two reaction steps: condensation with the carbamate (10b) to the urea (15) and subsequent cyclization to the imidazolidinones. This newly developed synthetic route could be applied to a large scale preparation of 1b.


Subject(s)
Antifungal Agents/chemical synthesis , Azoles/chemical synthesis , Imidazoles/chemical synthesis , Tetrazoles/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Azoles/chemistry , Azoles/pharmacology , Candida albicans/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Optical Rotation , Tetrazoles/chemistry , Tetrazoles/pharmacology
6.
Chem Pharm Bull (Tokyo) ; 47(3): 360-8, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10212386

ABSTRACT

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.


Subject(s)
Antifungal Agents/chemical synthesis , Triazoles/chemical synthesis , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Magnetic Resonance Spectroscopy , Spectrophotometry, Infrared , Stereoisomerism
7.
Chem Pharm Bull (Tokyo) ; 47(3): 351-9, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10212385

ABSTRACT

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.


Subject(s)
Antifungal Agents/chemical synthesis , Imidazoles/chemical synthesis , Triazoles/chemical synthesis , Animals , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Candida albicans/drug effects , Candidiasis/drug therapy , Cryptococcus neoformans/drug effects , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Spectrophotometry, Infrared , Stereoisomerism , Triazoles/pharmacology
8.
Chem Pharm Bull (Tokyo) ; 45(2): 321-6, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9118446

ABSTRACT

2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]-4-[4-(2,2,3,3,tetrafluoropropoxy) phenyl]-3(2H, 4H)-1,2,4-triazolone [(1R,2R)-1: TAK-187] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2S)-, (1R,2S)- and (1S,2R)-1] of this compound were prepared to clarify the relationship between the stereochemistry and the biological activities. In vitro and in vivo assays of antifungal activity revealed that TAK-187 [(1R,2R)-1] is the most potent among the four stereoisomers. Furthermore, TAK-187 was found to exert strong and selective inhibitory effect on the sterol synthesis in Candida albicans as compared with that in rat liver.


Subject(s)
Antifungal Agents/chemical synthesis , Triazoles/chemical synthesis , Animals , Antifungal Agents/chemistry , Candida albicans/drug effects , Microbial Sensitivity Tests , Rats , Stereoisomerism , Triazoles/chemistry
9.
Res Commun Mol Pathol Pharmacol ; 92(2): 155-63, 1996 May.
Article in English | MEDLINE | ID: mdl-8774069

ABSTRACT

Antitumor activities of zinostatin stimalamer (YM881) were examined in human hepatoma cell lines (SK-Hep1 and HuH2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 causing a 50% inhibition of growth of SK-Hep1 and HuH2 cells were 6.7 and 27 nM, respectively. In VX2 tumor-bearing rabbits, administration of YM881 suspended in Lipiodol, an iodinated fatty acid ethylester of poppyseed oil, (YM881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs. sham-operated and Lipiodol-treated groups) inhibitory effects on tumor growth and histopathological changes at 1 and 2 weeks after administration. In contrast, Lipiodol (0.2 ml/body) tended to inhibit the growth of VX2 tumor (p < 0.1, vs. sham-operated group) at 1 week after administration, but showed only moderate effects at 2 weeks after administration. Minimal necrosis was observed at 1 and 2 weeks after administration of Lipiodol, and histopathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM881/Lipiodol suspension showed antitumor activity in VX2 tumor-bearing rabbits presumably due to the inhibition of the growth of hepatoma cells by YM881 itself. Lipiodol, on the other hand, is considered to augment the antitumor activity of YM881 by maintaining high YM881 concentrations in tumor tissue.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Maleic Anhydrides/pharmacology , Polystyrenes/pharmacology , Zinostatin/analogs & derivatives , Animals , Cell Division/drug effects , Disease Models, Animal , Drug Screening Assays, Antitumor , Humans , Iodized Oil/pharmacology , Liver Neoplasms, Experimental/drug therapy , Male , Neoplasm Transplantation , Rabbits , Suspensions , Tumor Cells, Cultured , Zinostatin/pharmacology
10.
Chem Pharm Bull (Tokyo) ; 44(2): 314-27, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8998838

ABSTRACT

A new series of optically active antifungal azoles, N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones (1,2) and 5(1H,4H)-tetrazolones (3), were prepared from the triflate derivative of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (13) by an SN2 displacement reaction with the anion of an azolone (17-19) and subsequent ring-opening reaction with 1H-1,2,4-triazole. The optically active oxiranylethanol 13 was synthesized from methyl (R)-lactate in a stereo-controlled manner. The azolones 1-3 prepared showed potent antifungal activities in vitro and in vivo.


Subject(s)
Antifungal Agents/chemical synthesis , Candida albicans/drug effects , Tetrazoles/chemical synthesis , Triazoles/chemical synthesis , Antifungal Agents/pharmacology , Chemical Phenomena , Chemistry, Physical , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Conformation , Stereoisomerism , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Triazoles/pharmacology , Triazoles/therapeutic use
11.
Fundam Appl Toxicol ; 26(2): 191-202, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7589908

ABSTRACT

Lansoprazole is a substituted benzimidazole which inhibits gastric acid secretion by inhibiting the hydrogen-potassium ATPase (proton pump) in the parietal cell. The finding of Leydig cell hyperplasia and Leydig cell tumors in 2-year oral studies in Sprague-Dawley rats but not in CD-1 mice prompted investigative studies to determine the mechanism for the Leydig cell changes. hCG challenge studies in Sprague-Dawley rats revealed decreased testosterone responsiveness in rats treated orally for 1 or 2 weeks with lansoprazole. After 4 weeks of daily oral treatment increases in serum LH and decreases in serum testosterone were detected within a few hours after dosing. In a study where 9-month-old male F344 rats were given testosterone supplementation via Silastic implants and then treated with lansoprazole for 6 months, a high incidence of Leydig cell tumors was seen in lansoprazole-treated, unsupplemented rats, whereas no Leydig cell tumors were seen in testosterone supplemented rats. This implied that reduction of the normal feedback inhibition at the level of the hypothalamus and/or pituitary due to reduced testosterone levels, thus giving rise to elevated levels of LH, was involved in the induction of Leydig cell tumors by lansoprazole. In vitro studies with Leydig cells from rats using various stimulators and precursors of testosterone biosynthesis demonstrated that the most sensitive site for inhibition of testosterone synthesis by lansoprazole is the transport of cholesterol to the cholesterol side chain cleavage enzyme. The IC50s for inhibition of LH or hCG-stimulated testosterone synthesis in Leydig cells from rats, mice, and monkeys were 11-12, 8, and 24.7 micrograms/ml, respectively. In vitro studies with metabolites of lansoprazole revealed that three metabolites were more potent inhibitors of testosterone synthesis than the parent drug, two of them being at least 10 times more potent. These metabolites are present in rats at substantial levels but are undetectable in humans. The lack of induction of Leydig cell tumors in mice, lower sensitivity of primate Leydig cells, and the absence of testosterone synthesis-inhibiting metabolites in man suggest that Leydig cell tumors found in rats represent a species-specific sensitivity and does not imply a risk for clinical use in man.


Subject(s)
Carcinogens/toxicity , Leydig Cell Tumor/chemically induced , Omeprazole/analogs & derivatives , Testicular Neoplasms/chemically induced , 2-Pyridinylmethylsulfinylbenzimidazoles , Animals , Chorionic Gonadotropin/pharmacology , Dose-Response Relationship, Drug , Haplorhini , Ketoconazole/toxicity , Lansoprazole , Male , Mice , Omeprazole/metabolism , Omeprazole/toxicity , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Species Specificity , Testosterone/antagonists & inhibitors , Testosterone/blood , Testosterone/pharmacology
12.
Chem Pharm Bull (Tokyo) ; 43(3): 432-40, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7774026

ABSTRACT

(2R,3R)-3-Azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols (III) were prepared from (2R,3S)-3-methyl-2-(substituted phenyl)-2-(1H-1,2,4-triazol-1-yl)methyloxiranes (21a-f) by a ring-opening reaction with 1H-1,2,3-triazole and 1H-tetrazole and evaluated for antifungal activity against Candida albicans in vitro and in vivo. The optically active oxiranes (21a--f) which serve as the key synthetic intermediates, were synthesized from 1-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxypropanoyl]morpholin e (24) and substituted phenylmagnesium bromide (23) via six steps in a stereocontrolled manner. The 3-(1H-1,2,3,-triazol-1-yl)-(IIIa) and 3-(2H-2-tetrazolyl)-2-butanol (IIId) derivatives showed strong protective effects against candidosis in mice.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Azoles/chemical synthesis , Azoles/pharmacology , Butanols/chemical synthesis , Butanols/pharmacology , Animals , Candida albicans/drug effects , Candidiasis/drug therapy , Chemical Phenomena , Chemistry, Physical , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred Strains , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
13.
Chem Pharm Bull (Tokyo) ; 43(3): 441-9, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7774027

ABSTRACT

The (2S,3S)-, (2R,3S)- and (2S,3R)-stereoisomers of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols [(2R,3R)-1a--d] were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo to clarify the relationships between stereochemistry and biological activities. The results revealed that the in vitro antifungal activity in each set of the four stereoisomers [(2R,3R)-, (2S,3S)-, (2R,3S)- and (2S,3R)-1a--d] definitely paralleled the in vivo antifungal activity against candidosis in mice, and the order of potency was (2R,3R) >> (2R,3S) > or = (2S,3S) > or = (2S,3R). In addition, the four stereoisomers in each set were assessed for sterol biosynthesis-inhibitory activities in C. albicans and rat liver. The (2R,3R)-isomer was found to exert a strong and selective inhibitory effect on the sterol synthesis in C. albicans as compared with that in rat liver.


Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Azoles/chemical synthesis , Azoles/pharmacology , Butanols/chemical synthesis , Butanols/pharmacology , Animals , Candida albicans/drug effects , Candidiasis/drug therapy , Chemical Phenomena , Chemistry, Physical , Female , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Rats , Rats, Inbred F344 , Stereoisomerism , Structure-Activity Relationship
14.
Chem Pharm Bull (Tokyo) ; 42(12): 2636-40, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7697778

ABSTRACT

Tripeptide analogues 2 and 3 containing a dioxoethylene moiety were designed based on the characteristic structure of the naturally occurring human immunodeficiency virus (HIV)-1 protease inhibitors RPI-856 A, B, C and D (1). The compounds (2, 3) prepared showed high inhibitory activity, comparable to that of RPI-856 A, against HIV-1 protease in vitro.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV-1/enzymology , Chemical Phenomena , Chemistry, Physical , HIV Protease/metabolism , HIV Protease Inhibitors/pharmacology , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oligopeptides/chemistry , Oligopeptides/pharmacology
15.
Gan To Kagaku Ryoho ; 21(2): 219-26, 1994 Feb.
Article in Japanese | MEDLINE | ID: mdl-8311492

ABSTRACT

Anti-tumor activities of zinostatin stimalamer (YM 881) were examined using human hepatoma cell lines (SK-Hep1 and HuH 2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 against SK-Hep 1 and HuH 2 cells were 6.7 and 27 mM, respectively. In VX2 tumor-bearing rabbits, administration of YM 881 suspended in iodinated fatty acid ethylesters of poppyseed oil (YM 881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs sham-operated and Lipiodol-treated groups) inhibitory effects on the growth and pathological changes 1 and 2 weeks after administration. On the other hand, Lipiodol (0.2 ml/body) showed a tendency to inhibit the growth of VX2 tumor (p < 0.1, vs sham-operated group) 1 week after administration, but it showed only moderate effects on the VX2 tumor growth 2 weeks after administration. Minimal necrosis was observed 1 and 2 weeks after administration of Lipiodol, and these pathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM 881/Lipiodol suspension showed the anti-tumor activity against VX2 tumor-bearing rabbits, presumably due to the inhibition of the growth of hepatoma cell by YM 881 per se. On the other hand, Lipiodol is considered to augment the anti-tumor activity by maintaining high YM881 concentrations in tumor tissue.


Subject(s)
Carcinoma, Hepatocellular/pathology , Iodized Oil/administration & dosage , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms/pathology , Zinostatin/administration & dosage , Animals , Cell Division/drug effects , Hepatic Artery , Humans , Infusions, Intra-Arterial , Liver Neoplasms, Experimental/pathology , Rabbits , Tumor Cells, Cultured/drug effects , Zinostatin/pharmacology
16.
J Virol ; 68(1): 233-9, 1994 Jan.
Article in English | MEDLINE | ID: mdl-8254733

ABSTRACT

A synthetic peptide, RPI 312, that specifically inhibits the protease of the human immunodeficiency virus type 1 (HIV-1) showed a potent inhibition on virus production, maturation, and infectivity. Treatment with this agent prevented the cleavage of Gag protein at the site between p17 and p24 in HIV-1 chronically infected MOLT-4 cells as well as in the released virus. Passage of HIV-1 in the presence of gradually increasing concentrations of this protease inhibitor resulted in emergence of a variant that could evade the drug effects. In the resistant variant the maturation of Gag proteins appeared normal, but its infectivity was reduced compared with that of the parent virus. The nucleotides coding the amino acids at and around the cleavage site between Gag proteins p17 and p24 were not changed. One point mutation (A-->G) at site 2082 of the pol gene that resulted in one amino acid change at site 84 of the protease from isoleucine to valine (I-84-->V) could be detected in the resistant variant. An HIV-1 infectious DNA clone with the I-84-->V mutation also showed reduced sensitivity to this protease inhibitor. The findings that the resistant variant had lower infectivity and was still affected by higher doses of the drug support the speculation that resistance to protease inhibitors may not be as problematic as other drug resistance.


Subject(s)
Drug Resistance, Microbial/genetics , HIV Protease Inhibitors/pharmacology , HIV Protease/genetics , HIV-1/genetics , Oligopeptides/pharmacology , Point Mutation/genetics , Viral Proteins , Amino Acid Sequence , Base Sequence , Cells, Cultured , Cloning, Molecular , Gene Products, gag/biosynthesis , Gene Products, gag/genetics , Genes, pol/genetics , HIV Antigens/genetics , HIV Core Protein p24/genetics , HIV Protease/drug effects , HIV-1/drug effects , HIV-1/enzymology , HIV-1/pathogenicity , Humans , Isoleucine/genetics , Molecular Sequence Data , Protein Processing, Post-Translational/drug effects , Valine/genetics , Virulence/drug effects , gag Gene Products, Human Immunodeficiency Virus
17.
Meat Sci ; 36(3): 423-34, 1994.
Article in English | MEDLINE | ID: mdl-22061635

ABSTRACT

The colour of meat and rice flour pastes containing known amounts of myoglobin and the colour of intact beef and pork samples were analyzed with tissue spectrophotometer TS-200. The differences in the spectra of myoglobin among three types of derivatives were successfully distinguished with this instrument. In addition, there is a close relationship between I(HB) value, a parameter for estimating the content of pigments in animal tissues, and myoglobin content in model systems (rice flour paste and meat paste). Especially, the I(HB) value is proportional to myoglobin content in intact beef and pork meat whose myoglobin is mostly in the state of oxymyoglobin and/or deoxymyoglobin: y = 208·26 x + 6·72, where y is the I(HB) value, x is the myoglobin content (%) and r = 0·94.

18.
Endocrinol Jpn ; 35(1): 83-92, 1988 Feb.
Article in English | MEDLINE | ID: mdl-3396515

ABSTRACT

Thermogenesis of brown adipose tissue (BAT) of genetically obese mice, KKAY mice, was examined by measuring the BAT mitochondrial guanosine diphosphate (GDP) binding as an index of thermogenesis and comparing it with that of normal C57BL mice. No great difference in GDP binding was observed in KKAY and C57BL mice fed a stock diet. However, when they were given a sucrose solution, the increase in BAT mitochondrial GDP binding of KKAY mice (+22%) was much lower than that of C57BL mice (+106%). A high fat diet increased BAT mitochondrial GDP binding in KKAY mice to the same extent (+82%) as in C57BL mice. When the mice were fasted for 48 h, BAT mitochondrial GDP binding of C57BL mice decreased by 70%, while that of KKAY mice showed no change. Both acute exposure to cold and norepinephrine injections increased GDP binding in KKAY mice by 90% and 131%, respectively. These results indicate that low BAT thermogenesis in response to sucrose intake may be a cause of obesity in KKAY mice, and this may be brought about by defects in the central nervous system.


Subject(s)
Adipose Tissue, Brown/physiopathology , Body Temperature Regulation , Diabetes Mellitus/physiopathology , Mice, Inbred C57BL/physiology , Mice, Obese/physiology , Adipose Tissue, Brown/metabolism , Aging , Animals , Body Weight , Diabetes Mellitus/congenital , Diabetes Mellitus/metabolism , Fasting , Female , Guanosine Diphosphate/metabolism , Male , Mice , Mitochondria/metabolism , Sucrose/pharmacology
19.
Life Sci ; 42(11): 1123-30, 1988.
Article in English | MEDLINE | ID: mdl-3347142

ABSTRACT

The dose dependent effect of ipriflavone (7-isopropoxy-isoflavone) on the femoral bone in streptozotocin-induced diabetic rats was studied by microdensitometric analysis. Diabetic rats showed severe hyperglycemia, glucosuria, hypoinsulinemia, associated with increased urinary calcium and hydroxyproline. Microdensitometric analysis revealed decreases in femoral length, bone width, and bone density. The dietary administration of ipriflavone (about 270 mg/kg/day) to the diabetic rats for 6 weeks prevented reduction of the cortical thickness index in the diaphysis and depletion of bone density in the distal metaphysis, and also reduced the inner diameter of the diaphysis; diabetic state was not improved. A simple correlation and linear regression analysis revealed that ipriflavone also significantly reduced the inner diameter in the diaphysis at a dose of 90 mg/kg/day, but not at one of 25 mg/kg/day. These results suggest that ipriflavone suppresses the depletion of the femoral bone through inhibition of bone resorption in a dose dependent fashion; its minimum effective dose is 90 mg/kg/day in experimental diabetes.


Subject(s)
Bone Resorption/drug effects , Diabetes Mellitus, Experimental/physiopathology , Flavonoids/pharmacology , Isoflavones/pharmacology , Animals , Body Weight/drug effects , Diabetes Mellitus, Experimental/urine , Dose-Response Relationship, Drug , Eating/drug effects , Femur/drug effects , Male , Rats , Rats, Inbred WKY
20.
J Bone Miner Res ; 1(2): 207-11, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3503539

ABSTRACT

The fetal long bone culture system developed by Raisz for the assessment of bone resorption was modified to improve the sensitivity, by using radii and ulnae separately, based on the observation of the consistently higher release of 45Ca from the radii than ulnae. Effects of ipriflavone (TC-80), an isoflavonoid derivative currently under clinical trial for its effect on osteoporosis, on bone resorption were examined in this new system. Ipriflavone and its metabolites (5 out of 6) at 10 micrograms/ml or more inhibited basal 45Ca release from bones. The inhibitory effects were still demonstrated in the presence of submaximal concentration of parathyroid hormone (12.5 ng/ml). The effect of ipriflavone on bone resorption was apparently not due to its toxicity on bone cells, since the inhibition was reversible.


Subject(s)
Bone Resorption/drug effects , Flavonoids/pharmacology , Isoflavones/pharmacology , Animals , Calcium/metabolism , Culture Techniques , Female , Isoflavones/metabolism , Parathyroid Hormone/pharmacology , Pregnancy , Radius/drug effects , Radius/embryology , Rats , Rats, Inbred Strains , Ulna/drug effects , Ulna/embryology
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