共查询到20条相似文献,搜索用时 15 毫秒
1.
V. Dimov K. Gréen M. Bygdeman Y. Konishi K. Imaki M. Hayashi 《Prostaglandins & other lipid mediators》1983,25(2):225-235
Di-deuterated and di-tritiated 16,16-dimethyl-trans-Δ2-PGE1 has been synthesized and used for development of a GC-MS method for quantitation of corresponding unlabelled drug in patient plasma. Although these carrier/internal standard molecules only contain 2 deuterium atoms the lower limit of detection at each injection is as low as about 40 pg.The maximum plasma levels of this drug following administration of vaginal suppositories used in clinical studies (1 mg 16,16-dimethyl-trans-Δ2-PGE1 methyl ester in 0.8 g Witepsol S-52) were 100–350 pg/ml i.e. in the same order of magnitude as earlier seenf ro 16,16-dimethyl-PGE2. 相似文献
2.
V. Dimov K. Gren M. Bygdeman Y. Konishi K. Imaki M. Hayashi 《Prostaglandins & other lipid mediators》1983,25(2)
Di-deuterated and di-tritiated 16,16-dimethyl-trans-Δ2-PGE1 has been synthesized and used for development of a GC-MS method for quantitation of corresponding unlabelled drug in patient plasma. Although these carrier/internal standard molecules only contain 2 deuterium atoms the lower limit of detection at each injection is as low as about 40 pg.The maximum plasma levels of this drug following administration of vaginal suppositories used in clinical studies (1 mg 16,16-dimethyl-trans-Δ2-PGE1 methyl ester in 0.8 g Witepsol S-52) were 100–350 pg/ml i.e. in the same order of magnitude as earlier seenf ro 16,16-dimethyl-PGE2. 相似文献
3.
Frances A. Kimball James C. Cornette Gordon L. Bundy Kenneth T. Kirton 《Prostaglandins & other lipid mediators》1980,20(3):559-569
A method is described for the estimation of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 by double antibody radioimmunoassay. Plasma samples obtained from animals treated with 9-methylene-16,16-dimethyl-PGE2,1-adamantanamine salt were extracted with diethyl ether to recover the prostaglandin. The validation of sample preparation and assay procedure are presented. Rhesus females were treated by several routes of administration and the samples assayed for drug content. Maximum blood levels were probably reached 30 minutes following subcutaneous injection and within 30 seconds of an intravenous injection. Results of the acute intravenous injection indicate an initial half-life of approximately one minute in peripheral circulation. Continuous intravenous infusion at 3 increasing doses of this compound resulted in a stepwise increase in plasma drug concentrations. Vaginal administration of 9-methylene-16,16-dimethyl-PGE2,1-adamantanamine salt in suppositories produced a dose dependent increase in plasma drug concentration. Higher plasma drug concentrations were produced when the prostaglandin was delivered in H-15 base suppositories than in E-76 base suppositories. 相似文献
4.
B.J. Broughton M.P.L. Caton A.J. Christmas E.C.J. Coffee D.J. Hambling 《Prostaglandins & other lipid mediators》1981,22(1):53-64
Rat uterine stimulant activity has been determined in vivo for a series of (
)-11-deoxyprostaglandins. The most active members of the series: 11-deoxy-15 methyl-PGE1, 11-deoxy-16, 16-dimethyl-PGE1 and its 1-alcohol were 2–3 times more potent than PGE1. Gastrointestinal side effects assessed by the antagonism of morphine-induced constipation in the mouse, were generally relatively low with these compounds and consequently several members of the series had a more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester. 相似文献
5.
F.A. Kimball G.L. Bundy A. Robert J.R. Weeks 《Prostaglandins & other lipid mediators》1979,17(5):657-666
The in vivo monkey uterine stimulating potency of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 is similar to that of 16,16-dimethyl-PGE2 and approximately 15 times that of PGE2. Low doses of this compound stimulated uterine contractions when administered vaginally. Pregnancy was terminated prematurely following subcutaneous, intramuscular or vaginal suppository treatment. Estimates of potential for gastrointestinal side effects using the rat enteropooling assay and in vivo monkey effects indicate that diarrhea will be substantially reduced with retention of uterine stimulating potency. 相似文献
6.
J.N. Martin M. Bygdeman M. Ramadan K. Gréen A. Leader V. Lundström N. Wiqvist 《Prostaglandins & other lipid mediators》1976,11(1):123-132
Thirty patients in the 13th–20th week of gestation underwent therapeutic abortion utilizing vaginally administered 16,16-dimethyl-PGE2 (free acid) suppositories. The first 15 patients obtained individual doses in the range of 400–1200 μg given every three hours (mean total dose 4.2 mg). In the following 15 patients a fixed dose schedule was used (800 μg followed by 1000 μg every three hours; mean total dose 5.3 mg). All but one of the 30 patients aborted. The mean induction-abortion interval for all patients was 16.8±6.9 hours (mean ± S.D.) With the fixed dose regime the success rate was 100% and the induction-abortion interval 16.0±5.9 hours. Because gastro-intestinal side effects were minimal, neither anti-emetic nor anti-diarrheic medication was required. A slight elevation of temperature was noted in five patients. The uterine response to the vaginal administration of this compound was characterized by a gradual increase in uterine tonus followed by sustained stimulation. The results are interpreted to suggest that the vaginal administration of 16,16-dimethyl-PGE2 is a useful alternate method for the induction of second trimester abortion. Moreover, this compound seems to cause fewer gastro-intestinal side effects than other prostaglandins administered by the vaginal route at our department. 相似文献
7.
Ana B. Fernández-Martínez María I. Arenas Jiménez Francisco J. Lucio Cazaña 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2012,1821(4):672-683
We have previously shown in HK-2 cells that ATRA (all-trans-retinoic acid) up-regulates HIF-1α (hypoxia-inducible factor-1α) in normoxia, which results in increased production of renal protector VEGF-A (vascular endothelial growth factor-A). Here we investigated the role of COXs (cyclooxygenases) in these effects and we found that, i) ATRA increased the expression of COX-1 and COX-2 mRNA and protein and the intracellular levels (but not the extracellular ones) of PGE2. Furthermore, inhibitors of COX isoenzymes blocked ATRA-induced increase in intracellular PGE2, HIF-1α up-regulation and increased VEGF-A production. Immunofluorescence analysis found intracellular staining for EP1-4 receptors (PGE2 receptors). These results indicated that COX activity is critical for ATRA-induced HIF-1α up-regulation and suggested that intracellular PGE2 could mediate the effects of ATRA; ii) Treatment with PGE2 analog 16,16-dimethyl-PGE2 resulted in up-regulation of HIF-1α and antagonists of EP1-4 receptors inhibited 16,16-dimethyl-PGE2- and ATRA-induced HIF-1α up-regulation. These results confirmed that PGE2 mediates the effects of ATRA on HIF-1α expression; iii) Prostaglandin uptake transporter inhibitor bromocresol green blocked the increase in HIF-1α expression induced by PGE2 or by PGE2-increasing cytokine interleukin-1β, but not by ATRA. Therefore only intracellular PGE2 is able to increase HIF-1α expression. In conclusion, intracellular PGE2 increases HIF-1α expression and mediates ATRA-induced HIF-1α up-regulation. 相似文献
8.
Prostaglandin D2 was found to be a potent inhibitor of B-16 melanoma cell replication . The inhibition was dose-dependent between 3×10?9M and 3×10?6M (IC50~ 0.3 μM after 6 days). On a molar basis, PGD2 was a better inhibitor than PGA2 or 16,16-dimethyl-PGE2-methyl ester (di-M-PGE2) and in higher concentrations (10?6?10?7M), comparable to retinoic acid. In higher concentrations, PGD2 inhibited DNA, RNA and protein synthesis. The B-16 melanoma cell line which we used synthesized arachidonic acid metabolites which comigrated with PGA2, PGD2, PGE2 and PGF2α on a thin layer chromatography system. 相似文献
9.
A. Leader M. Bygdeman K. Gren J.N. Martin Jr. N. Wiqvist 《Prostaglandins & other lipid mediators》1975,10(4):357-364
Twenty-one women in the 10th–12th week of pregnancy were treated prior to vacuum aspiration with vaginal suppositories containing 16, 16-dimethyl-PGE2 (free acid). An average total dose of 3.4 mg led to abortion or adequate cervical dilatation in all patients. Based upon previous experience with the compound, no prophylactic anti-emetic or anti-diarrhetic medication was given. Gastrointestinal side effects were minimal. Excessive bleeding was not observed. In two cases, slight temperature elevation was noted prior to abortion. The low incidence of side effects in combination with the effectiveness of the compound help to make this method an attractive therapeutic adjunct to vacuum aspiration beyond the 10th week of gestation. Under the experimental conditions of this study, the results suggest that vaginally administered 16, 16-dimethyl-PGE2 can be a safe and effective method for cervical dilatation before vacuum aspiration. 相似文献
10.
K. Gréen F.A. Kimball B.A. Thronburgh A.J. WickremaSinha 《Prostaglandins & other lipid mediators》1980,20(4):767-780
Comparisons were made of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 levels in plasma determined by three assay methods. Plasma samples from Rhesus monkeys treated with 200 μg/kg 9-deoxo-16,16-dimethyl-9-methylene-PGE2 intravenously were analyzed by radioimmunoassay (RIA) and by high pressure liquid chromatography (HPLC). In a second experiment known amounts of 11β-3H-9-deoxo-16,16-dimethyl-9-methylene-PGE2 were added to human plasma at several concentration levels. The samples were analyzed by RIA, HPLC and gas chromatography-mass spectrometry (GC-MS). A limited number of comparisons have been made between RIA and GC-MS analysis of plasma samples from human subjects treated with 9-deoxo-16, 16-dimethyl-9-methylene-PGE2. The results indicated that the three assay methods generally give comparable estimations of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 content in plasma. 相似文献
11.
Hydroxyl Radical-Mediated Oxidation of Serotonin: Potential Insights into the Neurotoxicity of Methamphetamine 总被引:1,自引:1,他引:0
Monika Z. Wrona Zhaoliang Yang Michelle McAdams Susan O'Connor-Coates Glenn Dryhurst 《Journal of neurochemistry》1995,64(3):1390-1400
Abstract: When incubated with a hydroxyl radical (HO?)-generating system (ascorbic acid/Fe2+-EDTA/O2/H2O2), 5-hydroxytryptamine (5-HT; serotonin) is rapidly oxidized initially to a mixture of 2,5-, 4,5-, and 5,6-dihydroxytryptamine (DHT). The major reaction product is 2,5-DHT, which at physiological pH exists as its keto tautomer, 5-hydroxy-3-ethylamino-2-oxindole (5-HEO). Rapid autoxidation of 4,5-DHT gives tryptamine-4,5-dione (T-4,5-D), which reacts with the C(3)-centered carbanion of 5-HEO to give 3,3′-bis(2-aminoethyl)-5-hydroxy-[3,7′-bi-1H-indole]-2,4′,5′-3H-trione (7). The latter slowly cyclizes to 3′-(2-aminoethyl)-1′,6′,7′,8′-tetrahydro-5-hydroxyspiro[3H-indole-3,9′-[9H]pyrrolo[2,3-f]quinoline]-2,4′,5′(1H)- trione (9). A minor amount of T-4,5-D dimerizes to give 7,7′-bi-(5-hydroxytryptamine-4-one) (7,7′-D). In the presence of GSH, the reaction of T-4,5-D with 5-HEO is diverted and, in the presence of sufficient concentrations of this tripeptide, completely blocked. This is because GSH preferentially reacts with T-4,5-D to give 7-S-glutathionyltryptamine-4,5-dione (11). The results of this investigation suggest that 5,6-DHT, 5-HEO, 7, and 9 are products unique to the HO?-mediated oxidation of 5-HT. Thus, the observation of other investigators that 5,6-DHT is formed in the brains of rats following a large dose of methamphetamine (MA) suggests that this drug might evoke HO? formation. However, the present in vitro study indicates that 5,6-DHT is a rather minor, unstable product of the HO?-mediated oxidation of 5-HT and suggests that detection of 5-HEO, 7/9, and 11 in rat brain following MA administration could provide additional support for HO? formation. Furthermore, one or more of the intermediates and major products of oxidation of 5-HT by HO? might, in addition to 5,6-DHT, contribute to the MA-induced degeneration of serotonergic neurons. 相似文献
12.
A.P. Tulloch 《Chemistry and physics of lipids》1979,23(1):69-76
Methyl [17-2H2]oleate was prepared by stepwise reduction from 17-oxooleate in 24% yield. Methyl [18-2H3], [16-2H2], [14-2H2] and [12-2H2] oleates were synthesized from appropriately deuterated octylbromides by conversion to deuterated 7-hexadecyn-1-ols and chain extention to deuterated stearolates followed by semihydrogenation; overall yields were about 17%. 相似文献
13.
A. Leader M. Bygdeman K. Gren J.N. Martin Jr. N. Wiqvist 《Prostaglandins & other lipid mediators》1975,10(2):357-364
Twenty-one women in the 10th–12th week of pregnancy were treated prior to vacuum aspiration with vaginal suppositories containing 16, 16-dimethyl-PGE2 (free acid). An average total dose of 3.4 mg led to abortion or adequate cervical dilatation in all patients. Based upon previous experience with the compound, no prophylactic anti-emetic or anti-diarrhetic medication was given. Gastrointestinal side effects were minimal. Excessive bleeding was not observed. In two cases, slight temperature elevation was noted prior to abortion. The low incidence of side effects in combination with the effectiveness of the compound help to make this method an attractive therapeutic adjunct to vacuum aspiration beyond the 10th week of gestation. Under the experimental conditions of this study, the results suggest that vaginally administered 16, 16-dimethyl-PGE2 can be a safe and effective method for cervical dilatation before vacuum aspiration. 相似文献
14.
Göran Hansson 《Prostaglandins & other lipid mediators》1979,18(5):745-771
The metabolism of the prostaglandin F2α analogues, 15-methyl-Δ4--PGF1α and 16,16-dimethyl-Δ4--PGF1α, has been investigated in the cynomolgus monkey and the human female. The two analogues, tritium labelled in the 9β-position, were administered by intramuscular injections into the monkeys and by subcutaneous injections into the human. Excretion of tritium labelled products were followed in urine (in both species) and feces (in monkeys only) and several metabolites were identified by GC/MS. The analogues were found to be resistant to the 15-hydroxy dehydrogenase and furthermore the degradation by β-oxidation was delayed. About 13% of the given dose of 15-methyl-Δ4--PGF1α was excreted unchanged into urine and feces from the monkey. The corresponding figure for 16,16-dimethyl-Δ4--PGF1α was about 20%. In addition, a large part of the metabolites had the carbon skeleton intact and were only metabolized by ω-oxidation. The relative resistance to degradation of these two analogues is likely to be the basis for their prolonged pharmacological activity. 相似文献
15.
The formation of 3H2O from L-4-3H-phenylalanine is used as an index of tyrosine hydroxylase activity in synaptosomes from rat hippocampus, hypothalamus, and striatum. The reactions are linear with respect to time (up to 20 min) and with respect to protein concentration (up to 0.2 mg/ml). Formation of 3H2O from L-4-3H-phenylalanine is inhibited by standard tyrosine hydroxylase inhibitors (α-methyl-p-tyrosine, L-3-iodotyrosine, dopamine, L-norepinephrine, and L-apomorphine) and by the tyrosine hydroxylase substrate L-tyrosine as well as by synaptosomal lysis. The blank 3H2O produced from L-4-3H-phenylalanine (0.02% of total DPM) is 10-fold less than the blank 3H2O produced from L-3,5-3H-tyrosine. The Km values of tyrosine hydroxylase for phenylalanine determined by the production of 3H2O from L-4-3H-phenylalanine are 3.1, 1.3, and 1.2 μm in hippocampal, hypothalamic and striatal synaptosomes respectively. The results indicate that analysis of 3H2O formed from L-4-3H-phenylalanine is a sensitive and reliable method for quantitating synaptosomal tyrosine hydroxylase activity from tissues with low levels of tyrosine hydroxylase such as synaptosomes from hippocampus and hypothalamus. 相似文献
16.
A.P. Tulloch 《Chemistry and physics of lipids》1979,25(3):225-235
Deuterated oleates have been synthesized by semihydrogenation of acetylenic intermediates. [11-2H2]Oleate was prepared by two-carbon chain extension of the C16 alcohol obtained from [1-2H2]octyl bromide and 7-octyn-1-ol. [8-2H2] and [7-2H2]oleates were both prepared from dimethyl suberate, tetradeutero intermediate C16 alcohols were synthesized from [1,8-2H4] and [2,7-2H4]octane diols by monobromination, conversion to deuterated 9-decyn-1-ols and reaction with octyl bromide. Oxidation gave [8-2H2]-9-octadecynoate and [2,7-2H2]-9-octadecynoate, after semihydrogenation of the latter, deuterons at C-2 were removed by exchange with aqueous alkali. [6-2H2] and [5-2H2]oleates were obtained from methyl 5-tetradecynoate, semihydrogenation, deuterium exchange at C-2 and two malonate extensions gave [6-2H2]oleate; reduction with lithium aluminum deuteride, two malonate extensions and semihydrogenation gave the [5-2H2] ester. [4-2H2] and [3-2H2]oleates were both obtained from methyl 7-cis-hexadecenoate, exchange of the α protons and chain extension gave the [4-2H2] ester and reduction with lithium aluminum deuteride and chain extension gave the [3-2H2] ester. 相似文献
17.
A method is described for the fractionation of prostaglandins and their metabolites in urine. Following acidification and extraction on Amberlite XAD-2, samples were separated by chromatography on the lipophilic anion exchanger diethyl-aminohydroxypropyl Sephadex LH-20 into fractions containing neutral compounds, monocarboxylic, dicarboxylic and polycarboxylic acids. The compounds in resulting fractions were further separated by reversed phase partition chromatography. As an application, the metabolic profiles in urine of [9β-3H]-labeled prostaglandin F2α1 and prostaglandin analogs 15-methyl-PGF2α and 16,16-dimethyl-PGF2α were investigated in the cynomolgus monkey. It was demonstrated that the resolution of individual prostaglandin metabolites by reversed phase partition chromatography was considerably simplified by initial group separation on the anion exchanger, and several metabolites were much purified. A glucuronic acid conjugate of the main metabolite of 15-methyl-PGF2α (dinor-15-methyl-PGF2α) was tentatively identified using computerized gas chromatography - mass spectrometry. 相似文献
18.
A synthesis of 5-thio-D-galactose, in the form of its crystalline, anomeric methyl glycopyranosides, is described. Compounds prepared as intermediates included ethyl 2,3-di-O-(tert-butyldimethylsilyl)-5,6-O-carbonyl-β-D-galactofuranoside, the corresponding 5,6-dideoxy-5,6-epithio derivative, and ethyl 2,3,6-tri-O-acetyl-5-S-acetyl-5-thio-β-D-galactofuranoside. On methanolysis, the latter afforded methyl 5-thio-α-D-galactopyranoside which, in turn, was transformed into methyl 5-thio-β-D-galactopyranoside. Acetolysis proved to be less satisfactory for incorporation of the sulfur atom into a pyranose ring-form. Characteristics of the 13C-n.m.r. spectra of derivatives of 5-thio-D-galactose are described, including the fact that 1JC,H values for the anomeric pyranosides differ by only 1–3 Hz, as compared with ≈ 10 Hz for their oxygen analogs. 相似文献
19.
The location of paired and unpaired 13C atoms in the 16,16′-biphytanyl components of the lipids of Caldariella acidiophila following incorporation of acetate-[1,2-13C2] shows that the overall process of isoprenoid biosynthesis in this archaebacterial species follows a normal pattern and that the head-to-head linkage of the two tetraprenyl chains occurs stereoselectively. 相似文献
20.
Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been shown to play a role in prostate cancer. In PGE2-treated LNCaP cells, up-regulation of HIF-1α requires the internalization of PGE2, which is in sharp contrast with the generally accepted view that PGE2 acts through EP receptors located at the cell membrane. Here we aimed to study in androgen-independent PC3 cells the role of intracellular PGE2 in several events linked to prostate cancer progression. To this end, we used bromocresol green, an inhibitor of prostaglandin uptake that blocked the immediate rise in intracellular immunoreactive PGE2 following treatment with 16,16-dimethyl-PGE2. Bromocresol green prevented the stimulatory effect of 16,16-dimethyl-PGE on cell proliferation, adhesion, migration and invasion and on HIF-1α expression and activity, the latter assessed as the HIF-dependent activation of (i) a hypoxia response element-luciferase plasmid construct, (ii) production of angiogenic factor vascular endothelial growth factor-A and (iii) in vitro angiogenesis. The basal phenotype of PC3 cells was also affected by bromocresol green, that substantially lowered expression of HIF-1α, production of vascular endothelial growth factor-A and cell proliferation. These results, and the fact that we found functional intracellular EP receptors in PC3 cells, suggest that PGE2-dependent intracrine mechanisms play a role in prostate cancer Therefore, inhibition of the prostaglandin uptake transporter might be a novel therapeutic approach for the treatment of prostate cancer. 相似文献