利福霉素类抗生素的晶型与血（尿）药浓度

目的：探讨利福霉素类抗生素的衍生物（利福平,利福定,利福喷丁）的晶型与血（尿）药浓度的关系。方法：通过正常人空腹口服各不同型晶粉,定时收集血、尿标本,用杯碟法测定血、尿药含量。结果：同一药物的不同晶型粉,显示出各自不同的结构图形、溶解度及生物有效度的特性。结论：凡是稳定的晶型均具恒定的结构及生物有效度,利福霉素类药物的含水量,对其晶型的稳定性至关重要,干燥失重,不是越低越好。     

血液制品丙肝病毒与艾滋病毒检测

目的了解１９９３～１９９５年度临床使用的新鲜冰冻血浆（ＦＦＰ）和血液制品中艾滋病毒（ＨＩＶ）、丙肝病毒（ＨＣＶ）的感染情况。方法用ＥＬＩＳＡ、ＷＢ和ＰＣＲ对１１０批ＦＦＰ、人血丙种球蛋白、人血白蛋白检测了抗ＨＣＶ、ＨＣＶＲＮＡ、抗ＨＩＶ（１＋２）、ＨＩＶ－１ＲＮＡ。结果所有血制品抗ＨＣＶ的平均阳性率为１９．１％,ＨＣＶＲＮＡ为１７．３％;１９９３～１９９４年度ＦＦＰ的抗ＨＣＶＨＣＶＲＮＡ阳性率比１９９５年度高（３０％、２６％和０．５％）;人血丙球的抗ＨＣＶ和ＨＣＶＲＮＡ阳性率明显高于人血白蛋白（３０％、２０％和０．５％）;８９批抗ＨＣＶ阴性血制品ＨＣＶＲＮＡ的阳性率为５．６％,所有血制品的抗ＨＩＶ（１＋２）和ＨＩＶ－１ＲＮＡ均阴性。结论１９９３～１９９５年度临床上所使用的血制品,特别是１９９３～１９９４年度的ＦＦＰ,有传播ＨＣＶ的危险,这与当时没有对所有供血者进行抗ＨＣＶ筛检有关。     

Synthesis and analgesic and anti-inflammatory activities of 1,2-benzothiazine derivatives

Three 1,2-benzothiazine derivatives were synthesized, and their analgesic/anti-inflammatory efficacy and their effects on gastric irritation were evaluated. Among the three compounds, 39 exhibited the most potent analgesic action, but the effect was weaker than that of piroxicam. Nonetheless, the compound showed 4 times more potent analgesic action with less gastric damage than did ibuprofen. These compounds did not show anti-inflammatory effect at an oral dose of 5 mg/kg.     

New flavonol glycosides from leaves ofSymplocarpus renifolius

A study was carried out to evaluate flavonol glycosides in leaves ofSymplocarpus renifolius (Araceae). From the water fraction of the MeOH extract, three new flavonol glycosides were isolated along with three known compounds, kaempferol-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-7-O-β-D-glucopyranoside, quercetin-3-O-β-D-glucopyranosy-l-(1→2)-β-D-glucopyranoside, and caffeic acid. The structures of the new flavonol glycosides were elucidated by chemical and spectral analyses as quercetin-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-7-O-β-D-glucopyranoside, isorhamnetin-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-7-O-β-D-glucopyranoside, and quercetin-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-7-O-(6^IIII-trans-caffeoyl)-β-D-glucopyranoside.     

Glutathione conjugates of 2- or 6-substituted 5,8-dimethoxy-1,4-naphthoquinone derivatives: Formation and structure

Thirty-four glutathione conjugates of 5,8-dimethoxy-1,4-naphthoquinones (DMNQ) were synthesized and their structure was determined. The yield of GSH conjugate was dependent on size of alkyl group; the longer the size of alkyl group was, the lower was the yield. It was also found that the length of alkyl side chain influenced the chemical shift of quinonoid protons; the quinonoid protons of 2-glutathionyl DMNQ derivatives with R=H to propyl, 6.51-6.59 ppm vs. other ones with R=butyl to heptyl, 6.64-6.68 ppm. This was explained to be due to a folding effect of longer alkyl group. Glutathione (GSH) reacted with DMNQ derivative first to form a 1,4-adduct (2- or 3-glutathionyl-1,4-dihydroxy-5,8-dimethoxynaphthalenes) and then, the adduct was autooxidized to 2- or 3-glutathionyl-DMNQ derivatives. Moreover, GSH reduced DMNQ derivatives to their hydrogenated products. It was suggested that such an organic reaction might play an important role for a study of metabolism or toxicity of DMNQ derivatives in the living cells.     

Synthesis andin vitro antibacterial activity of C-3′ pyridinium cephalosporin derivatives

The quaternary ammonium cephalosporin derivatives were prepared with various pyridines substituted at the 3 or/and 4 position. Their in vitro antibacterial activities were determined and substituent effect on pyridine nucleus was studied. Preparation of substituted pyridines are also described.     

Pharmacokinetic Analysis and Antiepileptic Activity of Tetra-Methylcyclopropane Analogues of Valpromide

Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). Results. The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their non-active acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. Conclusions. In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the position to the carbonyl, such as in the case of TMCD, or a substitution in the and in the positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.     

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus,and their distribution in immature rats

We studied the potential of both stereoisomers of 17-[¹²³I]iodovinyloestradiol (E- andZ-[¹²³I]IVE) and of 11-methoxy-17-[¹²³I]iodovinyloestradiol (E-andZ-[¹²³I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17-[¹²³I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their¹²³I-labelled analogues were studied in immature female rats. All four 17-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE E-IVE. Neither of these 17-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[¹²³I]MIVE being higher than that ofE- andZ-[¹²³I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [¹²³I]MIVE. The uterus-to-blood uptake ratio was higher for^E-[¹²³I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [¹²³I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[¹²³I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.     

Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

Summary Three chemical classes of serotonin 5-HT₄ receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT₄ receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3–5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded K_i values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT₃ receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (K_i, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID₅₀, 231 vs 0.5 g/kg, i.v.). No significant binding (K_i>10 mol/l) of DAU 6285 to serotonergic 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, and 5-HT₂ receptors as well as to adrenergic ₁, ₂, dopaminergic D₁, D₂ or muscarinic M₁–M₃ receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT₄ receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT₃ receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT₄ receptors. Send offprint requests to A. Dumuis at the above address     

Effect of oxidized derivatives of cholesterol on uptake and degradation of very low-density β-lipoproteins by human and rabbit hepatocytes

Research Institute of Cardiology, Tomsk Scientific Center, Academy of Medical Sciences of the USSR. Research Institute of Experimental Cardiology, All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 3, pp. 254–256, March, 1991.