Future prospects for toxicokinetics: its ability to predict drug adverse events in humans.
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Animals↗
Biomedical subjects
M Tsuda
Publications and source records attributed to M Tsuda.
Poststatin, a new inhibitor of prolyl endopeptidase. VIII. Endopeptidase inhibitory activity of non-peptidyl poststatin analogues.
Non-peptidyl postatin analogues, (S)-N-substituted-2-[2-(1-acylpyrrolidinyl)]-2-oxoacetamides were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Many compounds showed stronger activity than natural poststatin, a pentapeptide. Among them, (S)-N-cyclohexyl-2-oxo-2-[2-(1-(3-phenoxybenzoyl)pyrrolidinyl)]ace tamide (22) and (S)-N-cyclohexyl-2-[2-(1-(2-naphthoyl)pyrrolidinyl)]-2-oxoacetamide++ + (19) indicated IC50 value of 5.8 and 8.2 ng/ml for prolyl endopeptidase inhibition respectively. None of these compounds possess significant inhibitory activities against cathepsin B, a cysteine protease. These results indicate that these compounds are more selective inhibitors against prolyl endopeptidase than is natural poststatin.
Magnetic Resonance Spectroscopy↗
Stereospecific synthesis of a novel farnesyl protein transferase inhibitor, valinoctin A and its analogues.
(2S,3R)-3-Amino-2-hydroxyoctanoic acid was synthesized by Curtius rearrangement of an azide derivative of (S)-malic acid. Total syntheses of valinoctin A and its analogues were achieved by a coupling of (2S, 3R)-3-amino-2-hydroxyoctanoic acid moiety with L-valine or several other amino acids moieties. 2S configuration of 3-amino-2-hydroxyoctanoic acid moiety was found to be important for the inhibitory activity and the L-valine moiety of valinoctin A was exchangeable with other L-amino acids.
Alkyl and Aryl Transferases↗
Poststatin, a new inhibitor of prolyl endopeptidase. III. Optical resolution of 3-amino-2-hydroxyvaleric acid and absolute configuration of poststatin.
3-Amino-2-hydroxyvaleric acid was prepared, and separated into its diastereomers. The relative stereochemistry was determined by 1H NMR in their oxazolidone derivatives. The threo-isomer was resolved by (S)-1-(1-naphthyl) ethylamine in the N-(p-methoxybenzyloxycarbonyl) derivative. The absolute configuration of (--)-threo-3-(p-methoxybenzyloxycarbonyl)amino-2-hydroxyvaleric acid was confirmed to be 2R, 3S. The absolute configuration of 3-amino-2- oxovaleric acid in poststatin was confirmed to be S by comparison of the four stereoisomers of methyl N, O-bis(3,5-dinitrobenzoyl)-3-amino-2-hydroxyvalerate derived from 3-amino-2-hydroxyvaleric acid and that derived from 3-amino-2-oxovaleryl moiety of poststatin by means of HPLC with chiral column.
Amino Acid Sequence↗
Poststatin, a new inhibitor of prolyl endopeptidase. IV. The chemical synthesis of poststain.
Total synthesis of poststatin was achieved by both liquid phase and solid phase methods. In both methods, the (2R,3S)-3-amino-2-hydroxyvaleric acid moiety was incorporated into protected pentapeptides, and was oxidized to (S)-3-amino-2-oxovaleric acid (postine). Deprotection of the oxidized pentapeptides gave a specimen identical with natural poststatin in physico-chemical properties and prolyl endopeptidase inhibitory activity.
Amino Acid Sequence↗
Poststatin, a new inhibitor of prolyl endopeptidase. V. Endopeptidase inhibitory activity of poststatin analogues.
Thirty analogues of poststatin were synthesized, and their inhibitory activities against prolyl endopeptidase, human leukocyte elastase and cathepsin B were measured. The alpha-ketone was essential and the S configuration was preferable to the R configuration in the beta-substituted-beta-amino-alpha-oxopropionic acid moiety of poststatin analogues for endopeptidase inhibitory activity. The analogue in which the D-leucine residue of poststatin was replaced by L-leucine showed strong inhibitory activity to cathepsin B. Introduction of an aromatic group into the P4 position and proline into the P2 position increased inhibitory activity to elastase. Benzyloxycarbonyl-L-homophenylalanyl-(RS)- 3-amino-2-oxovaleryl-D-leucyl-L-valine was about 6 times more active to prolyl endopeptidase than natural poststatin.
Cathepsin B↗
Poststatin, a new inhibitor of prolyl endopeptidase. VI. Endopeptidase inhibitory activity of poststatin analogues containing pyrrolidine ring.
Several pyrrolidine-containing analogues of poststatin were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Replacement of the postine residue with 2-oxo-2-(2-pyrrolidinyl)acetic acid increased the selectivity and inhibitory activity against prolyl endopeptidase. Benzyloxycarbonyl-L-phenylalanyl-(S)-2-oxo-2- (2-pyrrolidinyl)acetyl-D-phenylalanine was about 46 times as active to propyl endopeptidase as natural poststatin.
Cathepsin B↗
Poststatin, a new inhibitor of prolyl endopeptidase. VII. N-cycloalkylamide analogues.
Poststatin analogues containing (S)-2-oxo-2-(2-pyrrolidinyl)acetyl moiety in P1 were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Introduction of non-peptidyl cycloalkylamine component in P1, was effective and P3-acyl groups must be widely modifiable for prolyl endopeptidase inhibition. Acyl-L-phenylalanyl-(S)-2-oxo-2-(2-pyrrolidinyl)acetyl-cycloalkylamid e type compounds showed IC50 value of nano to subnano g/ml as prolyl endopeptidase inhibitor and were shown no significant inhibitory activities against cathepsin B, a cysteine protease.
Cathepsin B↗
Kimura disease: CT and MR findings.
The lesions of Kimura disease showed slightly high and very high intensity on T2-weighted MR, and low and intermediate intensity, respectively, on T1-weighted images. The degree of enhancement also differed between the two cases. These discrepancies may be attributable to differing degrees of fibrosis and vascular proliferation.
Adolescent↗
[Teratogenicity study of magnesium chloride hexahydrate in rats].
Teratogenicity of magnesium chloride hexahydrate (MgCl2.6H2O) was examined in rats. Magnesium chloride hexahydrate dissolved in distilled water was given to pregnant Wistar rats by gavage once a day from day 6 through 15 of pregnancy at doses of 0, 200, 400 and 800 mg/kg/day. The pregnant rats were sacrificed on day 20 of pregnancy and their fetuses were examined for malformation. Magnesium chloride hexahydrate caused no increased incidences of fetal malformation, and no toxic signs in the pregnant rats and the fetuses. It was concluded that magnesium chloride hexahydrate has no teratogenicity in rats when given by gavage. The no observed adverse effect level was estimated to be over 800 mg/kg/day for both pregnant rats and rat fetuses.
Abnormalities, Drug-Induced↗
[Disorders of organic acid metabolism].
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Alkaptonuria↗
Diagnostic usefulness of postexercise systolic blood pressure response for detection of coronary artery disease in patients with electrocardiographic left ventricular hypertrophy.
Patients with left ventricular (LV) hypertrophy often have a positive result on exercise testing despite a normal coronary arteriogram. This indicates that exercise-induced ST depression is not always an accurate indicator of the presence of coronary artery disease (CAD) in such patients. We evaluated the usefulness of the postexercise systolic blood pressure (BP) response for detection of CAD in 51 patients with both electrocardiographic evidence of LV hypertrophy and positive ST depression on treadmill exercise testing. Coronary cineangiograms showed normal coronary arteries in 23 patients (45%) (group 1) and significant CAD in 28 patients (55%) (group 2). The systolic BP ratio (systolic BP at 3 minutes of recovery divided by systolic BP at peak exercise) was significantly higher in group 2 than in group 1 (1.01 +/- 0.19 vs 0.80 +/- 0.09; p < 0.001). Analysis of the relative cumulative frequency revealed that a systolic BP ratio of 0.86 was the cutoff point for distinguishing a patient with CAD from one with normal coronary arteries. The sensitivity, specificity, and accuracy of a systolic BP ratio > or = 0.86 for detection of CAD in patients with LV hypertrophy were 79%, 83%, and 82%, respectively. Our results suggest that the use of an abnormal BP ratio, in combination with ST depression, improves the accuracy of treadmill exercise testing for detecting CAD in patients with electrocardiographic evidence of LV hypertrophy.
Adult↗
A positive regulatory gene, pvdS, for expression of pyoverdin biosynthetic genes in Pseudomonas aeruginosa PAO.
In response to iron limitation Pseudomonas aeruginosa PAO induces production of pyoverdin, a low-molecular-weight siderophore able to capture ferric ion with a very high affinity. The pvd genes involved in the pyoverdin biosynthesis are organized in a chromosomal region termed the pvd region, and expression of some pvd genes is regulated at the transcriptional level. Two sets of promoter regions for the pvd genes were defined that were transcriptionally derepressed under iron-limiting conditions. Analysis of transcription from such promoters in Escherichia coli led to isolation and identification of a positive regulatory gene, pvdS, for expression of the pvd genes, and pvdS was localized in the pvd region. A genomic pvdS mutant of PAO, constructed by allelic exchange mutagenesis, produced no pyoverdin and did not allow transcription from the pvd promoters. Nucleotide sequence analysis revealed that PvdS shows considerable similarity to FecI of E. coli, a positive regulator for transcription of the fec (ferric citrate transport system) operon. The promoter region of pvdS has the sequence that matches well the consensus binding site for the E. coli Fur protein, a global negative regulatory protein that represses the transcription of the iron-repressible genes. Consistent with the presence of such a consensus sequence, addition of iron repressed transcription of the pvdS gene in P. aeruginosa.
Amino Acid Sequence↗
Blockade of morphine-induced place preference by diazepam in mice.
The effects of diazepam on morphine-induced place preference were examined in mice. Pretreatment with diazepam (2 mg/kg i.p.) 30 min prior to morphine injection significantly abolished the morphine (5 mg/kg s.c.)-induced place preference, and this effect of diazepam was antagonized by pretreatment with flumazenil. In addition, pretreatment with diazepam prevented the morphine (5 mg/kg s.c.)-induced increase in dopamine turnover in the limbic forebrain. These results suggest that pretreatment with diazepam may suppress the rewarding effects of morphine.
3,4-Dihydroxyphenylacetic Acid↗
Degradation of polyetherurethane by subcutaneous implantation into rats. II. Changes of contact angles, infrared spectra, and nuclear magnetic resonance spectra.
In vivo degradation of polyetherurethanes (PEUs) was studied using two kinds of PEUs, U-3 and U-8, coated on a base film of ethylene/vinyl alcohol copolymer (EVAL). U-3 is a nonsegmented PEU prepared from 4,4'-diisocyanatodiphenylmethane (MDI) and poly(tetramethylene oxide) (PTMO 1000). U-8 is a segmented PEU prepared from MDI, PTMO 1000, and 1,4-butanediol. Previous studies of PEUs were conducted using gel permeation chromatography and scanning electron microscopy. In this study, the explanted materials were examined with contact angle measurement, ATR-FTIR, and nuclear magnetic resonance (NMR) spectroscopies. All data obtained by these methodologies indicate that the PTMO/MDI oligomers diffused to the material surface in the early stage of implantation. Then, the low-molecular-weight fraction of the oligomers leached out from the surface to the exudate. Degradation became dominant after 2-4 weeks. In the case of PU-8, the PTMO fraction decreased approximately 35-40% from the surface at 24 weeks postimplantation. In the case of PU-3, the loss of coating material (U-3) on the base film (EVAL) was observed after 10 weeks. The PTMO fraction of the surface U-3 remained on EVAL at 6 weeks postimplantation, however, it was 64% of the initial material. The molecular weight of the U-3 remaining on EVAL also decreased. Degradation of U-3 occurred more rapidly than that of U-8. The data obtained with our materials were insufficient in determining evidence of oxidative degradation with IR or NMR spectra.
Animals↗
Effects of 2,5-di(tert-butyl)-1,4-hydroquinone on intracellular free Ca2+ levels and histamine secretion in RBL-2H3 cells.
The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca2+ level ([Ca2+]i) and histamine secretion of rat basophilic leukemia (RBL-2H3) cells were examined. DTBHQ (0.1-10 mumol/l) alone induced rapid and sustained increases in [Ca2+]i in a concentration-dependent manner. In cells sensitized with anti-dinitrophenyl IgE, DTBHQ (10 mumol/l) further increased the antigen (dinitrophenylated BSA)-induced Ca2+ response. In the absence of external Ca2+ with addition of 1 mmol/l EGTA, both DTBHQ (10 mumol/l) and the antigen (10 microgram/ml) induced transient increase in [Ca2+]i. In sensitized cells, both DTBHQ (10 mumol/l) and antigen (10 micrograms/ml) elicited histamine secretion, although the response was far stronger in the latter case. The DTBHQ-induced histamine secretion was markedly enhanced by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate (TPA) (10 ng/ml) whereas TPA alone did not cause any increase. Moreover, DTBHQ enhanced the antigen-induced histamine secretion. The results suggest that DTBHQ increases [Ca2+]i and enhances antigen-induced histamine secretion while DTBHQ alone does not cause as much histamine secretion as antigen, which support the idea that calcium signals are necessary but are not sufficient for maximum histamine secretion in RBL-2H3 cells.
Adenosine Triphosphatases↗
GAP-43 mRNA suppression by the ribozyme in PC12 cells and inhibition of evoked dopamine release.
We constructed a ribozyme designed to cleave the GAP-43 mRNA and which contained a bacteriophage T7 transcription terminator at its 3' site to maintain stability. The ribozyme was overexpressed in PC12 cells by pEF-BOS, a powerful mammalian expression vector. Consequently, PC12 cells overexpressing the GAP-43 ribozyme revealed a drastic decrease in the levels of GAP-43 mRNA expression, and the evoked dopamine release was significantly suppressed in these cell lines. These results support the previous observations that GAP-43 is associated with Ca-dependent dopamine release in PC12 cells, and the ribozyme expression system used in the present study was demonstrated to be useful for suppression of the functions of specific mRNAs and exploration of specific gene products.
Animals↗
Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain.
Using electrophoretic mobility-shift assay (EMSA), we examined changes in DNA-binding activities of transcriptional factor-activated protein-1 (AP-1), which is a Fos-Jun protein complex, onto its responsive element TRE in the hippocampus and amygdaloid nucleus of rats stimulated with pentylenetetrazol (PTZ) injection, and also investigated the effects of a single administration of the immunosuppressant cyclosporin A (CsA). In EMSA with nuclear extracts from the rat brain, the TRE-binding activity of AP-1 in the hippocampus and amygdaloid nucleus markedly increased 2 h after the PTZ injection (75 mg/kg, i.p.). These PTZ-induced increases of the TRE-binding protein in these regions were completely suppressed, by pretreatment with CsA (5 mg/kg, s.c.) 1 h before the PTZ injection. In addition, the administration of CsA significantly ameliorated PTZ-induced convulsion. This therapeutic effect of single CsA pretreatment may be based, in part, on the effects on the TRE-binding activity of AP-1 in the brain. Since single pretreatment of CsA in the present study had no effect on the PTZ-induced induction of c-fos mRNA, c-jun mRNA, Fos protein nor Jun protein, the inhibitory effects of single CsA administration on PTZ-induced TRE-binding activity in the brain may be related to the effects of CsA on AP-1 itself. These results suggest that an immune response via activation of transcriptional factor in the brain tissue is involved in the convulsion.
Amygdala↗