Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.     

彩色多普勒在心脏起搏器综合征诊断中的应用价值

目的 :探讨运用彩色多普勒血流显像 (CDFI)并结合心电图 (ECG)诊断起搏器综合征 (PMS)的临床价值。方法 :对具有详实临床及ECG资料的心室按需 (VVI)起搏器安置患者 6 0例及对照组 4 8例进行CDEI检查 ,观察起搏组与对照组的三尖瓣返流 (TR)的发生率、返流程度 ,并分析二者之间的相关性。结果 :起搏组出现逆传P波 (即PMS阳性 )者 15例 ,CDFI检测出现TR者 2 0例 ,明显高于对照组 ,且PMS阳性者TR发生率明显高于PMS阴性者 ,表明安置VVI起搏器后出现逆传P波与TR的发生相关性良好。结论 :CDFI对PMS的诊断具有重要意义 ,尤其将ECG与CDFI结合应用有助于诊断率的提高。     

Evidence for the presence of substance P-like immunoreactivity in the human cerebellum

Preliminary results on the localization of substance P-like immunoreactivity in the human cerebellum are presented. Cerebella from newborn and adult subjects were examined. While only sporadic positive fibres were detected in the adult tissue, the immunoreactive material appeared more abundant in the cerebella from newborn subjects. Varicose and non-varicose fibres and dot-like nerve terminals were present with different density in various regions. The paucity of immunoreactive perikarya suggests that most of the cerebellar substance P-like immunoreactive material has an extrinsic origin.     

Nd：YAG激光对牙本质钙／磷比值的影响

为探讨Ｎｄ：ＹＡＧ激光对牙本质矿物含量的影响，应用扫描电镜和能谱仪定点测量５０个上前牙标本的根管壁（激光照射工和正常对比区）的钙、磷含量，结果表明，照射区牙本质钙／磷（Ｃａ／Ｐ）比值高于对比区，当激光能量达１５Ｗ以上时变化更为显著，提示Ｎｄ：ＹＡＧ激光能提高牙本质的钙化程度。     

RP—HPLC用于紫苏油及其习用品白苏油,野苏油的鉴别

本文采用RP－HPLC方法对紫苏油及其习用品白苏油、野苏油甘油酯进行了定性定量分析。利用HPLC分析油脂也为中药材真伪鉴别提供了一条有效途径。     

乳腺癌中P73、P21的表达及其意义

目的 :通过检测 P73蛋白、P2 1蛋白在乳腺癌中的表达及其与临床病理指标的关系 ,探讨乳腺癌的生物学特性 ,分析它们在乳腺癌的发生、转移中所起的作用。方法 :应用免疫组化 S-P法检测 68例乳腺癌石蜡包埋标本中 P73、P2 1的表达情况。结果 :a.在乳腺癌 - 级与 级之间 P73蛋白阳性率分别为 1 8.75 % ( 9/48)和 60 .0 0 % ( 1 2 /2 0 ) ,差异有显著性 ( P <0 .0 5 )。随着 P73阳性表达率增高 ,乳腺癌的恶性程度增高。b.淋巴结转移组 p2 1的阳性表达率 2 3 .3 3 % ( 7/3 0 )明显低于无淋巴结转移组的阳性率 5 2 .63 % ( 2 0 /3 8) ,差异有显著性( P <0 .0 5 )。c.P73、P2 1之间无相关。结论 :P73、P2 1与乳腺癌的发生、发展有关     

INFLUENCE OF DIET ON FATTY ACID COMPOSITION OF RED CELL AND NEURAL MEMBRANES

Increasing dietary 18:2 n-6/18:3 n-3 causes similar relative changes in fatty acid profiles of phosphatidylethanolamine and phosphatidylcholine from rat neural and erythrocyte membranes.     

The epidemiology of nosocomial Pseudomonas cepacia infections: Endemic infections

Pseudomonas cepacia has recently emerged as an important nosocomial pathogen. We analyzed a national nosocomial infections database, the National Nosocomial Infections Surveillance (NNIS) system, to describe the epidemiology of endemic nosocomial P. cepacia infections. Between 1980 and 1985, the P. cepacia nosocomial infection rate was 2.4 per 100,000 patient discharges. During this period, there was a significant increase in the P. cepacia infection rate. The highest infection rate was reported from large medical school-affiliated hospitals. Over 90% of the infections were reported from medicine and surgery services. The most frequently reported site of infection was the lower respiratory tract (31%), followed by blood (20%) and the urinary tract (20%). Nosocomial P. cepacia infections are often associated with mortality, particularly when they involve the lung. These data confirm the hypothesis that P. cepacia is an emerging nosocomial pathogen and suggest that the epidemiology of endemic infections differs from that reported for epidemic inflections.     

Absence of a differential induction of cytochrome P450 2E1 by different alcoholic beverages in rats: implications for the aetiology of human oesophageal cancer

Alcohol is an important risk factor for human oesophageal cancer. There is evidence from epidemiological studies that some specific alcoholic drinks, e.g. Calvados apple brandy, are associated with a greater risk than others. Alcohol induces cytochrome P450 2E1 (CYP2E1) and the hypothesis was tested that different alcoholic beverages, containing a variety of alcoholic compounds, could differentially induce expression of cytochrome P450 enzymes. Twelve groups of five rats each were treated for 3 days with different alcoholic beverages (ethanol alone, whisky, farm-produced or commercial Calvados brandy, beer, cider, wine) adjusted to 4, 10 or 20% of ethanol in drinking water. Immunoblotting using a monoclonal antibody specific for rat CYP2E1 revealed a single protein band in liver microsomes. Densitometric quantitation of microsomal proteins demonstrated a significant two-, three- and sixfold increase in band intensity after treatment with ethanol concentrations of 4, 10 and 20% respectively, compared to control rats drinking water alone. There was a dose-dependent increase in liver microsomal metabolism of CYP2E1 substrates (para-nitrophenol and dimethylnitrosamine) in ethanol-treated rats. However, there were no significant differences in the level of CYP2E1 protein or enzymatic activity between the different alcoholic beverages at the same ethanol concentration. There was a slight increase in hepatic CYP1A-related enzymatic activities in the alcohol-treated rats compared to the controls, but no difference between the treated groups either with dose of ethanol or type of beverage. These data show that induction of CYP2E1 with acute alcohol treatment is predominantly determined by the ethanol content of the beverage. Received: 10 February 1997 / Accepted: 26 May 1997