Structures of three new isoprenylated xanthones, cudraxanthones e, f, and g 1,2

Three new isoprenylated xanthones, cudraxanthones E, F, and G along with a known xanthone, 6-deoxyisojacareubin, were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Moraceae), collected in China. The structures of cudraxanthones E, F, and G were shown to be 1-3, respectively, on the basis of spectral evidence.     

Components of Root Bark of Cudrania tricuspidata l.1,2 Structures of Four New Isoprenylated Xanthones, Cudraxanthones A, B, C and D

Four new isoprenylated xanthones, cudraxanthones A, B and C were isolated from the N-hexane extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Japanese name "Hariguwa"; Moraceae), and cudraxanthone D from the benzene extract. The structures of cudraxanthones A, B, C and D were shown to be 1-4, respectively, on the basis of spectral and chemical evidence.     

Structures of four new isoprenylated xanthones, cudraxanthones h,i,j, and k1,2

Four new isoprenylated xanthones, cudraxanthone H,I,J, and K were isolated from the ethanol extract of the root bark of CUDRANIA TRICUSPIDATA (Carr.) Bur. (Moraceae), collected in China. The structures of cudraxanthones H,I,J, and K were shown to be 1- 4, respectively, on the basis of chemical and spectral evidence.     

Azinomycins A and B, new antitumor antibiotics. I. Producing organism, fermentation, isolation, and characterization

A strain of Streptomyces griseofuscus S42227 (FERM P-8443) was found to produce new antitumor antibiotics, called azinomycins A and B. The molecular formulas of azinomycins A and B were determined as C30H33N3O10 and C31H33N3O11, respectively. They were active against Gram-positive bacteria, Gram-negative bacteria and L5178Y cells in tissue culture.     

O-酰基-L-丝氨酸衍生物和S-酰基-L-半胱氨酸衍生物的合成研究

目的寻找能将氨基酸侧链的羟基、巯基与二元羧酸连接成酯的方法。方法分别以L 丝氨酸和L 半胱氨酸为起始物 ,采用叔丁氧羰基、苄酯或二苯甲酯形式保护 ,分别与丁二酸单苄酯、草酸单苄酯、丁二酸单叔丁酯缩合成酯 ,合成了 3个未见文献报道的化合物O (4 苄氧丁二酰基 ) N 叔丁氧羰基 L 丝氨酸苄酯 (4 )、O (2 苄氧草酰基 ) N 叔丁氧羰基 L 丝氨酸苄酯 (8)、S (4 叔丁氧丁二酰基 ) N 叔丁氧羰基 L 半胱氨酸二苯甲酯 (12 )。化合物 4经氢解合成未见文献报道的化合物O 丁二酰基 N 叔丁氧羰基 L 丝氨酸 (5 )。化合物 5经酸解得到O 丁二酰基 L 丝氨酸(6)。结果与结论目标化合物的结构经光谱确证。通过这种方法二元羧酸能与氨基酸的羟基、巯基缩合成酯     

Pradimicins M, N, O and P, new dihydrobenzo[a]naphthacenequinones produced by blocked mutants of Actinomadura hibisca P157-2

Four blocked mutants which accumulated new dihydrobenzo[a]naphthacenequinone metabolites, designated pradimicins M, N, O and P, have been isolated from cultures of mutants of Actinomadura hibisca P157-2 resulting from treatment with N-methyl-N'-nitro-N-nitrosoguanidine. The structures of the four compounds were determined by spectral analysis. Pradimicins N, O and P contain D-alanine, while pradimicin M does not. The conformations at C-5 and C-6 of these compounds are different from those of the original pradimicins.     

WS-9659 A and B, novel testosterone 5 alpha-reductase inhibitors isolated from a Streptomyces. I. Taxonomy, fermentation, isolation, physico-chemical characteristics

WS-9659 A and B, produced by Streptomyces sp. No. 9659, were extracted from cultured broth, purified by solvent extraction followed by chromatography on silica gel and then isolated as prisms (C22H24N2O, mp 161 approximately 162 degrees C, C22H23N2OCl, mp 152 approximately 153 degrees C). WS-9659 A and B have testosterone 5 alpha-reductase inhibitory activity. The IC50 values of WS-9659 A and B for partially purified rat prostate testosterone 5 alpha-reductase were 5.0 x 10(-7) M and 1.0 x 10(-5) M, respectively.     

Synthesis,characterization, and biological evaluation of new biotinylated 99mTc/Re‐tricarbonyl complexes

The synthesis and biological evaluation of three new biotinylated fac‐[^99mTc/Re(CO)₃]⁺ complexes with the tridentate ligands L1, L2, and L3 are reported. L1–L3 contain the chelators 2‐((5‐aminopentyl)(pyridin‐2‐ylmethyl)amino)acetic acid, 2‐(2‐aminoethylthio)‐3‐(1H‐imidazol‐4‐yl)propanoic acid, and 2‐amino‐3‐(1‐carboxy‐2‐(1H‐imidazol‐4‐yl)ethylthio)propanoic acid, respectively, which are conjugated to biotin's carboxylate via their amine group. The fac‐[Re(CO)₃(L1–L3)] complexes were synthesized and characterized by NMR and IR, where the (N,N,O) coordination for ReL1 and the (N,S,O) coordination for ReL2 and ReL3 were confirmed. The tracer complexes fac‐[^99mTc(CO)₃(L1–L3)] were synthesized in high yield and were found highly stable in 10^?3 M l ‐histidine and l ‐cysteine over 24 h. Furthermore, they exhibited high binding affinity (>90%) for avidin. Rat plasma studies showed complete cleavage of biotin from ^99mTcL1 after 1 h and a low percentage of intact ^99mTcL2 and ^99mTcL3 with no biotin cleavage metabolites present, over 24 h. Similarly, rat urine analysis showed the presence of intact ^99mTcL2 and ^99mTcL3, while ^99mTcL1 was cleaved. Biodistribution studies of ^99mTcL2 and ^99mTcL3 revealed fast blood and tissue clearance.     

PROCEEDINGS OF THE AUSTRALASIAN SOCIETY OF CLINICAL AND EXPERIMENTAL PHARMACOLOGISTS: 9th Annual Meeting, 27–28 November 1975, Melbourne

A comparison of the effects of prostaglandins and some relaxant drugs on isolated preparations of human bronchus and guinea-pig trachea. I. S. McKnight and Diana M. Temple Effects of prostaglandins on an isolated blood vessel. J. D. Horowitz, and M. L. Mashford Prostaglandin biosynthesis in rat renal papilla: effect of catecholamines. Abraham Danon, Lucas C. T. Chang*, Alan S. Nies? and John A. Oates. Modification by capsaicin and compound 48/80 of dye leakage induced by irritants in the rat. P. T. Arvier, L. A. Chahl and R. J. Ladd The biological activity of C-terminal partial sequences of substances. P. R. W. Bury and M. L. Mashford. Purification of a vasodilator peptide in Cohn Fraction III-O of human plasma proteins. J. D. Horowitz and M. L. Mashford. The effects of clonidine on reflex sympathetic constrictor and heart rate responses evoked by a Valsalva-like manoeuvre in the unanaesthetized rabbit. P. I. Korner and P. A. Blombery The effects of acute administration of propranolol on the ‘Valsalva'-reflex sympathetic constrictor responses of the rabbit. P. A. Blombery, A. Bobik and P. I. Korner Circulatory response to haemorrhage in relation to the pattern of accompanying humoral reaction. Janina Staszewska-Barczak and G. J. Dusting Cardiovascular actions of verapamil (Isoptin) in the dog with particular reference to myo-cardial contractility. J. A. Angus*, D. R. Richmond, P. Dhumma-Upakorn, L. B. Cobbin and A. H. Goodman Effect of metoprolol on resting, post-exercise and mental stress blood pressure levels and pulse rates in hypertensive patients. Hendrika J. Waal-Manning Blind indirect measurement of blood pressure during isometric exercise and mental arithmetic. G. Nyberg The uptake and metabolism of histamine by blood vessels. A. Foldes and I. S. de la Lande Histamine H₂-receptors in human peripheral circulation. P. Chipman and W. E. Glover Histamine receptors in the coronary circulation of the dog. G. Heise, R. W. Giles and D. E. L. Wilcken Effect of phentolamine on the potentiating action of serotonin in the rabbit ear artery. P. R. Carroll, W. E. Glover and D. Morgans Effect of anaesthetics on drug responses in the cardiovascular system of greyhounds. D. L. Wilkinson and G. C. Scroop Perhexiline maleate, a new anti-anginal drug. M. L. Mashford and J. D. Horowitz Measurement of plasma nortriptyline. K. P. Maguire, B. A. Scoggins*, G. D. Burrows and B. Davies Cardiac effects of tricyclic antidepressants. P. Dumovic, G. D. Burrows, J. Vohra,* B. Davies and B. A. Scoggins? The effect of antidepressants upon cardiovascular response to noradrenaline in anaesthetized dogs. P. Dhumma-Upakorn and L. B. Cobbin Cardiovascular effects of a new antidepressant, H 102/09, in the anaesthetized dog. L. B. Cobbin and P. Dhumma-Upakorn Plasma levels of lignocaine and monoethylglycinexylidide during and after prolonged lignocaine infusions. R. L. Nation, E. U. Triggs and M. Selig Clinical pharmacology of pancuronium bromide in man. A. A. Somogyi, E. J. Triggs and C. A. Shanks Influence of temperature on the effect produced by a general anaesthetic at the postsynaptic membrane. O. P. Hamill, P. W. Gage and I. Spence Metabolism of etidocaine in man: a comparison with lignocaine. D. Morgan, J. Thomas and J. Vine Hexachlorophene absorption in premature infants and surgical patients. D. G. Ferry and M. T. S. Roberts Pharmacokinetic studies of tolmetin in man. M. L. Selley, J. Glass*, E. J. Triggs and J. Thomas The effect of non-steroidal anti-inflammatory drugs on ATP levels and histamine release from rat peritoneal cell suspension rich in mast cells. R. O. Day, J. E. Ray, G. D. Champion and D. N. Wade Single dose comparison of analgesic action of acetylsalicylate and sodium salicylate in rheumatoid arthritis. G. D. Champion, R. O. Day, N. Fagan, G. G. Graham, A. L. Haski, L. J. Hills, B. McManus and P. D. Paull The pharmacokinetics of salicylate in patients with rheumatoid arthritis. G. Graham, G. D. Champion, R. O. Day and P. D. Paull The effect of enteric coating of aspirin tablets on occult gastrointestinal blood loss. G. D. Champion, A. B. Corrigan, R. O. Day, G. C. Graham, A. Haski, J. Hewson, G. Howe* and P. D. Paull Serum salicylate levels in patients receiving a continuous dosage regime of different acetylsalicylate preparations. P. J. Keary, M. R. Laurent and D. G. Ferry Naproxen-aspirin drug interactions studied with response surface analysis. F. W. Stitt* and J. H. Vaughan? α-Methyldopamine as a false transmitter in the corpus striatum. E. L. Conway, B. Jarrott and W. J. Louis Pharmacokinetics of clonazepam in man. J. M. Bradfield, G. A. Smith, J. H. Tyrer and M. J. Eadie The elimination kinetics of diphenylhydantoin. W. D. Hooper, F. Bochner, J. H. Tyrer and M. J. Eadie Bioavailability of carbamazepine in oral dosage forms. L. M. Cotter, G. A. Smith, M. J. Eadie and J. H. Tyrer Plasma anticonvulsant concentration during pregnancy. C. M. Lander, M. J. Eadie, V. E. Edwards and J. H. Tyrer Betel nut constituents as inhibitors of GABA uptake. G. A. R. Johnston, P. KrogsgaardLarsen and A. L. Stephanson Octopamine receptors and their structural specificity. D. F. H. Dougan and D. N. Wade Distribution of haloperidol in human blood. K. F. Ilett, I. E. Hughes and L. B. Jellett Factors which influence drug metabolism in man: tolbutamide. S. M. Pond, D. J. Birkett and D. N. Wade Temperature transitions of the microsomal hydroxylation system. D. J. Birkett Receptor assays for therapeutic and side effects of spirolactones. J. W. Funder, J. Hood and J. Mercer Further characterization of two distinct drug binding sites on human serum albumin using fluorescent probes. G. Sudlow, D. N. Wade and D. J. Birkett The prevention of drug-induced blood dyscrasias. I. S. Collins Patterns of drug overdose admissions to a general hospital. K. B. McManus, S. Pond, D. N. Wade and D. J. Birkett Some β-adrenoreceptor mediated actions of NAB365 (clenbuterol) in anaesthetized guineapigs. Karin Bolimer and Stella R. O'Donnell A study of prolonged forced expiration in electroplexy. P. C. Tresise* and B. P. Murphy? Effect of oral ephedrine in asthma. J. W. Patenon*, M. E. Pickup and C. S. May Potentiation of β-receptor mediated responses to adrenaline and (-)-isoprenaline by hydrocortisone in the anaesthetized cat. E. Malta, R. G. Goldie, C. Raper and E. J. Cornish β-Adrenoceptor agonistic and antagonistic actions of compounds related to soterenol in isolated guinea-pig atrial and tracheal preparations. C. Raper and E. Malta Intravenous bolus injection of salbutamol in the management of asthma. J. W. Patenon*, S. G. Spiro, C. S. May and A. J. Johnson Effect of isoprenaline inhalation on plasma cyclic AMP levels in asthmatic subjects. P. W. Trembath, M. C. F. Pain and J. Shaw The blood-bathed everted aorta: a sensitive method for the detection of catecholamines in the circulating blood. K. K. F. Ng, S. Duffy, W. J. Louis and A. E. Doyle Extraneuronal accumulation of noradrenaline in the guinea-pig respiratory tract. Nili Saar and Stella R. O'Donnell Adrenergic innervation of the ovarian suspensory ligament in the guinea-pig. S. Mohsin, B. L. Opperman, J. N. Pennefather and D. A. Taylor The effects of angiotensin II and sar¹-ala⁸-angiotensin II (saralasin) on cyclic 3′5′-adenosine monophosphate (cAMP) content of working rat heart. G. M. Maxwell The release of purines from intrinsic neurons in the taenia coli of the guinea-pig. B. M. Paddle D. G. Satchell Increased lever pressing behaviour in adult rats after neonatal 6-hydroxydopamine treatment. D. W. Peterson and R. Laverty Effect of chronic administration of L-dopa on dopamine-β-hydroxylase in the rat. Ann J. Culvenor and B. Jarrott     

Synthesis, base-catalyzed hydrolytic reactivity, and anticancer evaluation of O-aryl phosphorodiamidates as a novel class of pro(phosphorodiamidic acid mustards).

Bis(2-chloroethyl)phosphoramidic dichloride [MP(O)Cl2, M = N(CH2CH2Cl)2] has been used as the starting material for the synthesis of O-aryl phosphorodiamidates having the general structure MP(O)(NHR)OAr: 9, R = H, Ar = 4-NO2C6H4; 10, R = H, Ar = C6F5; 11, R = C6H5, Ar = C6F5; 12, R = 4-MeC6H4, Ar = C6F5; and 13, R = 4-EtOC6H4, Ar = C6F5. The phosphorodiamidic chloride precursor to 13 (14) was also isolated. Kinetics for the base-catalyzed hydrolysis of compounds 9--13 were investigated by UV and NMR methods and are considered in connection with service of these compounds as pro(phosphorodiamidic acid mustards) [MP(O)(NHR)OAr leads to MP(O)(NHR)OH] via an E1cB mechanism involving the intermediacy of a mustard-bearing metaphosphorodiimide [MP(O)=NR]. Anticancer screening tests against L1210 lymphoid leukemia in mice indicated that 9--14 are inactive; similar negative results were obtained with the KB cell culture, except in the case of 14 which was marginally active.     

氧化亚氮对七氟醚吸入浓度的影响

目的了解新鲜气流中加入氧化亚氮对七氟醚吸入浓度的影响。方法20例ASAⅠ～Ⅱ级的患儿于全身麻醉下行择期骨科手术,运用自身对照方法分别先后吸入纯氧(Ⅰ组)和氧气-氧化亚氮(Ⅱ组),充分去氮,静脉诱导气管插管,控制呼吸,维持PETCO235～40mmHg。调节新鲜气体流量:Ⅰ组氧气2L/min;Ⅱ组氧气和氧化亚氮各1L/min。七氟醚蒸发器开至2%刻度,于吸入麻醉开始、麻醉后30s、1min、2min、3min直至达到目标浓度时的各个时间点测定患者七氟醚的吸入浓度及达到目标浓度的时间、MAP、HR、SPO2、PETCO2。结果(1)两组七氟醚吸入浓度逐渐升高,麻醉后6minⅠ组浓度明显高于Ⅱ组(P<0.05)。(2)吸入浓度达到目标吸入浓度的时间Ⅰ组明显短于Ⅱ组(P<0.01)。结论新鲜气流中加用氧化亚氮可减慢吸入七氟醚浓度的上升速度,应用纯氧可更快达到目标吸入浓度。     

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M

The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.     

厦门市86例吸毒人员的16项人格因素量表分析

目的:采用卡特尔16项人格因素量表(16PF)分析吸毒人员的人格特征.方法:使用16PF对厦门市86名吸毒人员进行人格分析,并与常模比较;进一步分析吸毒人员不同性别之间的人格特征.结果:男、女吸毒人员与正常成年人对照存在明显的人格偏差:除男性O因子分,女性M及Q1因子分无显著性差异(P＞0.05)外,其它各因子分之间均有统计学差异(P＜0.05);不同性别吸毒人员的人格之间也有差异,在M因子分方面,女性高于男性,除此以外,A、C、E、F、G、I、L、N、Q、Q1、Q2、Q3因子分均是男性吸毒者较女性高(P＜0.05);在B、Q因子分之间无统计学差异,其它各因子之间均有显著性差异(P＜0.05);结论:吸毒人员有明显的人格偏离,不同性别的人格特征表现不同,在强制性戒毒及心理疏导的同时,要注意人格特点的影响.     

Mispairing of a site specific major groove (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl DNA Adduct of butadiene diol epoxide with deoxyguanosine: formation of a dA(anti).dG(anti) pairing interaction

The (2S,3S)-N6-(2,3,4-trihydroxybutyl)-2'-deoxyadenosyl (BDT) adduct arising from alkylation of adenine N6 by butadiene diol epoxide (BDE) was placed opposite a mismatched deoxyguanosine nucleotide in the complementary strand of the oligodeoxynucleotide 5'-d(CGGACXAGAAG)-3'.5'-d(CTTCTGGTCCG)-3'. This oligodeoxynucleotide contains codon 61 (underlined) of the human N-ras protooncogene. The BDT adduct was at the second position of codon 61, and this was named the ras61 S,S-BDT-(61,2) A.G adduct. NMR spectroscopy revealed the presence of two conformations of the adducted mismatched duplex. In the major conformation, the mismatched base pair X6.G17 was oriented in a "face-to-face" orientation, in which both the modified nucleotide X6 and its complement G17 were intrahelical and in the anti conformation about the glycosyl bond. Hydrogen bonding was suggested between X6 N1 and G17 N1H and between X6 N6H and G17 O6. The presence of the BDT moiety allowed formation of a stable A.G mismatch pair. The identity of the minor conformation could not be determined. If not repaired, the resulting mismatch pair would generate A-->C mutations, which have been associated with this adenine N6 BDT adduct [Carmical, J. R., Nechev, L. N., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2000) Env. Mol. Mutagen. 35, 48-56].     

Hydrogen peroxide-induced endothelium-dependent relaxation of rat aorta involvement of Ca2+ and other cellular metabolites.

In phenylephrine-precontracted rings, H2O2 produced an endothelium-dependent relaxation at concentrations of 4.4 x 10(-7) to approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) markedly attenuated the relaxant effects of H2O2. Complete inhibition of the H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i) in endothelial cells, with 10 microM acetyl methyl ester of bis (o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). These relaxant effects of H2O2 were nearly abolished by 15 x 10(-5)M N(G)-monomethyl-arginine (L-NMMA) or 5 x 10(-5) M N(G)-nitro-L-arginine (L-NAME) and were attenuated markedly by the presence of either 10(-6) M Fe2+, 10(-6) M Fe3+, or 5 x 10(-6) M methylene blue. These inhibitory effects of L-NMMA or L-NAME could be reversed partly by 5 x 10(-5) M L-arginine. These Fe(2+)- and Fe(3+)-induced inhibitions of H2O2-stimulated relaxation were reduced significantly by either 1.0 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO). In addition, 17-octadecynoic acid (2.5 microM) or proadifen (10 microM) (both antagonists of cytochrome P450 metabolism of fatty acids) markedly decreased the H2O2 relaxant effects. Proadifen (10 microM) produced concentration-dependent impairment of vasorelaxation to acetylcholine. A variety of amine antagonists and a cyclo-oxygenase inhibitor all fail to interfere with or attenuate the H2O2-induced relaxations. Our observations suggest that, at suitable pathophysiologic concentrations, H2O2 could induce release of an endothelium-derived relaxing factor, probably nitric oxide, from endothelial cells. The H2O2 relaxant effects are clearly Ca(2+)-dependent and require formation of cyclic guanosine monophosphate (cGMP). These vasorelaxing effects of H2O2 appear to be induced by H2O2 itself. Hydrogen peroxide may stimulate production of some unknown metabolites metabolized by cytochrome P450-dependent enzymes.     

Functional analysis of the human variants of breast cancer resistance protein: I206L, N590Y, and D620N.

Previous studies have shown that the V12M and Q141K variants of breast cancer resistance protein (BCRP) can affect expression and function of the transporter. In this study, the effects of the I206L, N590Y, and D620N variants on protein expression, plasma membrane localization, and transport activity of BCRP were investigated. Wild-type BCRP and the three variants were stably expressed in human embryonic kidney (HEK) cells. Confocal microscopy analysis showed that the three variants were predominantly routed to the plasma membrane of HEK cells. The expression level of I206L in the plasma membrane was approximately 45% of that of wild-type protein, whereas the N590Y and D620N levels were increased approximately 3.6-fold and 2.4-fold, respectively, as determined by immunoblotting. All three variants transported mitoxantrone, pheophorbide a, and BODIPY FL-prazosin. After normalization for differences in BCRP expression, I206L, N590Y, and D620N exhibited approximately 2-fold, 0.3-fold, and 0.5-fold wild-type efflux activities, respectively. The variants also conferred resistance to mitoxantrone and topotecan. Mitoxantrone and topotecan resistance by I206L and N590Y was approximately 2-fold and 0.3-fold of the wild-type BCRP resistance levels, respectively. Although D620N conferred a topotecan resistance similar to that of the wild-type protein, its level of mitoxantrone resistance was decreased by 50%. After normalization to BCRP expression levels, ATPase activities of I206L were not significantly different from those of wild-type protein, whereas N590Y and D620N exhibited approximately 30% and 50% of wild-type ATPase activities, respectively. These results suggest that I206L has the lowest protein expression and the highest activity, whereas N590Y and D620N display higher expression and lower activity, relative to wild-type BCRP.     

FR-900452, a specific antagonist of platelet activating factor (PAF) produced by Streptomyces phaeofaciens. I. Taxonomy, fermentation, isolation, and physico-chemical and biological characteristics

A PAF antagonist, designated as FR-900452, was isolated from fermentation products of Streptomyces phaeofaciens and the molecular formula was determined as C22H25N3O3S. The compound inhibited PAF-induced rabbit platelet aggregation with an IC50 of 3.7 X 10(-7)M, but was much less active against collagen-, arachidonic acid- or ADP-induced aggregation (IC50; 6.4 X 10(-5), greater than 10(-4) or greater than 10(-4)M, respectively).     

Metabolism of the analgesic drug ULTRAM ® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites

1. Metabolism of the analgesic agent tramadol hydrochloride has been investigated after a single oral administration of tramadol to three male volunteers (100 mg/subject), and a urine pool (4-12h) was obtained. 2. Unchanged tramadol and a total of 23 metabolites, consisting of 11 Phase I metabolites (M1-11) and 12 conjugates (seven glucuronides, five sulphates), were profiled, characterized and tentatively identified in urine on the basis of API ionspray-MS and MS/MS data. 3. Of the metabolites, five (M1-5) had been previously identified. 4. The metabolites were formed via the following six metabolic pathways: (1) O -demethylation, (2) N -demethylation, (3) cyclohexyl oxidation, (4) oxidative N -dealkylation, (5) dehydration and (6) conjugation. 5. Pathways 1-3 appear to be major routes, forming seven O -desmethyl/ N -desmethyl and hydroxycyclohexyl metabolites. 6. Pathways 1-3 in conjunction with pathway 6 produced seven glucuronides along with five sulphates. 7. In addition, the in vitro metabolism of tramadol was conducted using a human liver microsomal fraction in the presence of an NADPH-generating system. Unchanged tramadol (82% of the sample) plus eight metabolites (M1, M2, M4-6, tramadol- N -oxide (M31), OH-cyclohexyl-M1 (M32) and dehydrated tramadol- N -oxide), were profiled and tentatively identified on the basis of MS and MS/MS data.     

加味大柴胡汤对梗阻性黄疸大鼠肝损伤及JNK、Bcl-2表达的影响#br#

摘要：目的　探讨加味大柴胡汤对梗阻性黄疸大鼠肝损伤及JNK、Bcl-2 mRNA和蛋白表达的影响。方法　将90只SD雄性大鼠按随机数表法分为假手术组（S组）、梗阻性黄疸组（O组）及干预组（M组）,每组30只。S组与O组每日定时生理盐水10 µL/g灌胃,M组以生药量1 g/mL的加味大柴胡汤10 µL/g灌胃,各组按时间点分别于术后3 d、7 d、10 d取材,每次每组分别随机取10只大鼠。检测各组血清天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、血清总胆红素（TBIL）水平,实时荧光定量PCR（qPCR）和Western blot分别检测肝组织JNK、Bcl-2的mRNA及蛋白表达情况。结果　O组与M组血清AST、ALT、TBIL均较S组升高,且M组均低于O组（P＜0.05）。O组、M组JNK的mRNA及蛋白水平均高于S组,且M组均低于O组（P＜0.05）;O组、M组Bcl-2的mRNA及蛋白水平均低于S组（P＜0.05）,且M组均高于O组（P＜0.05）。结论　加味大柴胡汤能够改善梗阻性黄疸大鼠肝损伤,促进肝组织修复,这可能与下调JNK蛋白表达,促进Bcl-2蛋白表达,从而减弱内质网应激,抑制肝细胞的凋亡有关。     

Metabolic fate of the new synthetic cannabinoid 7’N‐5F‐ADB in rat,human, and pooled human S9 studied by means of hyphenated high‐resolution mass spectrometry

New psychoactive substances (NPS) are an important issue in clinical/forensic toxicology. 7’N‐5F‐ADB, a synthetic cannabinoid derived from 5F‐ADB, appeared recently on the market. Up to now, no data about its mass spectral fragmentation pattern, metabolism, and thus suitable targets for toxicological urine screenings have been available. Therefore, the aim of this study was to elucidate the metabolic fate of 7’N‐5F‐ADB in rat, human, and pooled human S9 (pS9). The main human urinary excretion products, which can be used as targets for toxicological screening procedures, were identified by Orbitrap (OT)‐based liquid chromatography–high resolution‐tandem mass spectrometry (LC–HRMS/MS). In addition, possible differentiation of 7’N‐5F‐ADB and 5F‐ADB via LC–HRMS/MS was studied. Using the in vivo and in vitro models for metabolism studies, 36 metabolites were tentatively identified. 7’N‐5F‐ABD was extensively metabolized in rat and human with minor species differences observed. The unchanged parent compound could be found in human urine but metabolites were far more abundant. The most abundant ones were the hydrolyzed ester (M5), the hydrolyzed ester in combination with hydroxylation of the tertiary butyl part (M11), and the hydrolyzed ester in addition to glucuronidation (M30). Besides the parent compound, these metabolites should be used as targets for urine‐based toxicological screening procedures. Two urine‐paired human plasma samples contained mainly the parent compound (c = 205 μg/L, 157 μg/L) and, at a higher abundance, the compound after ester hydrolysis (M5). In pS9 incubations, the parent compound, M5, and M30 were detectable among others. Furthermore, a differentiation of both compounds was possible due to different retention times and fragmentation patterns.