Pathophysiology of dogs after 84% hepatectomy with emphasis on prostaglandin metabolites and the effect of a thromboxane A2 synthesis inhibitor and a prostaglandin I2 analog

The pathophysiological conditions following 84% hepatectomy were examined in terms of the changes in thromboxane A₂ (TxA₂) and prostaglandin I₂ (PGI₂) in canine model. OKY-046, TxA₂ inhibitor, and OP-2507, a PGI₂ analog, were administered to evaluate the possibility of extending hepatic resection. The 2-week survival rate following 84% hepatectomy significantly improved after the administration of OKY-046 and OP-2507, from 12.5% to 58.3% and 75.0%, respectively. Furthermore, OP-2507 significantly improved impaired hepatocyte and sinusoidal endothelial cell function after 84% hepatectomy, resulting in a satisfactory recovery to the preoperative levels. Within 24 h after 84% hepatectomy, the plasma levels of thromboxane B₂ (TxB₂) increased significantly, and the 6-keto-prostaglandin F_l (6-KF) levels became slightly elevated. OKY-046 and OP-2507 decreased TxB₂ and increased 6-KF in the plasma, resulting in the maintenance of sufficient blood flow in the portal vein and hepatic tissue and the mitigation of microcirculatory disorders. Moreover, the cytoprotective effects of the two drugs inhibited functional impairment of the residual liver. In conclusion, abnormal prostaglandin metabolites were produced after 84% hepatectomy, being involved in residual liver disorders. However, the administration of either an inhibitor of TxA₂ synthesis or PGI₂ analog ameliorated the functional impairment of the residual liver, which suggests their potential value for extending the resectability of the liver from what is presently feasible.An abstract of this study was presented at the 92nd Annual Meeting of the Japan Surgical Society held in 1992.     

Analytical Chiral Separation of the Stereoisomers of a Novel Carbonic Anhydrase Inhibitor and Its Deethylated Metabolite,and the Assignment of Absolute Configuration of the Human Metabolite and Chiral Degradation Products

Several approaches to the separation of four stereoisomers, 1–4, of a novel, topically active, carbonic anhydrase inhibitor, 1, with two chiral centers in the molecule and four isomers, 5–8, of its chiral metabolite, 5, were evaluated. These methods include nonchiral derivatization followed by separation on chiral stationary phases (CSPs) and chiral derivatization and separation on nonchiral columns and on CSPs. Baseline separation of stereoisomers 1–4 was achieved in less than 15 min after chiral derivatization with (S)-(+)-l-(l-naphthyl)ethyl isocyanate (NEIC) and chiral chromatography on a (R)-N-(3,5-dinitrobenzoyl)phenyl glycine (DNBPG) column under normal phase (NP) conditions. Similarly, isomers 5-8 were baseline separated in less than 20 min after derivatization with NEIC and chromatography on nonchiral (nitrophenyl) and chiral [(S)-(3,5-dinitrobenzoyl)leucine; DNBL] columns in series under the same NP chromatographic conditions. Only partial separation of the diastereomeric derivatives was observed on a variety of nonchiral columns. In addition, all other direct and indirect chiral separation approaches gave only partial separation of at least two stereoisomers within the group of 1–4 or 5–8. The details of chiral separations using various methods and separation () and capacity factors (k) of the derivatized isomers 1–8 on a series of chiral and nonchiral columns are presented. Using these methods, the absolute configuration of the human metabolite of 1 was established as S ₁ S ₂ (5), and the heat (HD) and light (LD) degradation products of 1 as R ₁ S ₂ (3) and S₁ S ₂ (5), respectively.     

Soft Drugs. XX. Design,Synthesis, and Evaluation of Ultra-Short Acting Beta-Blockers

A new type of ultra-short acting -blocker which might prove advantageous in treating acute arrhythmias was designed, synthesized and investigated. Based on the soft drug inactive metabolite approach, the inactive phenylacetic acid metabolite of both metoprolol and atenolol was reactivated by esterification with sulfur-containing aliphatic alcohols. Since the sulfur-containing moieties are labile to the ubiquitous esterases, the new compounds should be inactivated by a one step enzymatic cleavage back to the inactive phenylacetic acid derivative. Pharmacological and pharmacokinetic profiles of the new compounds were evaluated in rats and rabbits. Isoproterenol-induced tachycardia was inhibited with short-term infusion of each compound. This tachycardia blocking effect rapidly disappeared upon termination of infusion, while -blocking activity was 2–4-fold longer after comparable doses of the short-acting -blocker, esmolol. The rapid recovery from the -receptor blockade is believed due to fast hydrolysis of the soft drugs in the body. This is supported from in vitro results showing the t_l/2 of esmolol is about 10-fold longer than the new soft drugs in rat, rabbit, dog and human blood. Hydrolysis studies in phosphate buffered solutions indicated that the esters are labile to base-catalyzed hydrolysis. However, the relative t_1/2 values measured in biological media compared to phosphate buffered solution clearly support rapid enzymatic cleavage of the soft drugs. Interestingly, one of the soft -blockers, the sulfonyl ester derivative, showed a unique property of exhibiting good -receptor blocking activity without significant hypotensive action.     

海洋生物柳珊瑚的化学成分及生物活性研究进展

柳珊瑚中含有许多结构新颖、生物活性多种多样的次生代谢产物，从而引起了人们对其化学成分及药理活性研究的极大兴趣。本文综述了1998年至2001年问有关柳珊瑚中化学成分及生物活性研究的最新进展，并在此基础上对这类海洋生物潜在的药用前景进行了展望。     

Synthesis of [2H8]‐enterolactone and [2H10]‐enterodiol

Enterolactone and enterodiol are the main mammalian metabolites of dietary butyrolactone type lignans. The study of biological properties and potential health effects of these compounds requires isotopically labelled compounds as standards for quantitative measurements. An expedient deutero‐labelling method for enterolactone is to use the D₃PO₄·BF₃/D₂O complex at room temperature which will exchange all eight aromatic hydrogens, even from inactivated meta positions, to form [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone in 74% yield and 99% isotopic purity. [2,4,5,6,9,9,2′,4′,5′,6′‐²H₁₀]‐Enterodiol was prepared from [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone by reduction with LiAlD₄ which introduces two more deuterium atoms into the molecule. Copyright © 2003 John Wiley & Sons, Ltd.     

海洋微生物活性代谢产物的研究进展

研究海洋微生物活性物质 ,不但能发现结构新颖的化合物 ,而且能寻找到新的强效抗生素和抗病毒等活性的新药以及其它有用物质 ,这一新兴领域的研究在理论上和维护人类健康方面都有重大意义。本文综述了 2 0 0 0年以来对海洋微生物 (包括海洋细菌、蓝细菌、放线菌、真菌 )活性代谢产物的研究进展 ,共引用文献 6 9篇 ,包括 12 9个活性代谢产物。重点描述了这些化合物的相关生理活性 ,产生它们的微生物及微生物的采集地。     

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.     

Halichondria属软海绵次生代谢产物及其生物活性

Halichondria属软海绵分布广泛,含多种生物活性成分,引起人们的深入研究。近30年来,已从Halichon-dria属软海绵中分离得到了许多结构新颖,有抗菌、抗肿瘤和抗病毒等生物活性的次生代谢产物,如大环内酯、聚醚、生物碱、内酰胺、萜类、甾醇、鞘类脂糖苷等。在调研国内外相关资料的基础上,按化合物的结构类型简要介绍了1978—2003年Halichondria属软海绵次生代谢产物及其生物活性的研究概况,为进一步的研究工作提供参考。     

Quantification of glutamate and glutamine using constant‐time point‐resolved spectroscopy at 3 T

Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant‐time point‐resolved spectroscopy (CT‐PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time‐domain basis set was constructed taking into account metabolite T₂ relaxation times and dephasing from B₀ inhomogeneity. Metabolite concentrations were estimated by fitting the basis one‐dimensional CT‐PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom‐built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol‐treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol‐exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time. Copyright © 2012 John Wiley & Sons, Ltd.     

Inhibition of human catechol-O-methyltransferase-mediated dopamine O-methylation by daphnetin and its Phase II metabolites

1.?Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC).

2.?Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC₅₀ values for daphnetin (0.51～0.53?μM) and 8-O-methyldaphnetin (22.5～24.3?μM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (K_i) between daphnetin (competitive, 0.37?μM) and 8-O-methyldaphnetin (noncompetitive, 25.7?μM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro–in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin.

3.?With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.