司帕沙星衍生物(YH37)体外抗微生物活性研究

采用微量稀释法测定了5-氨基-1-环丙基-6，8-二氟-1，4-二氢-7-（3-甲基-1-哌嗪基）-4-氧代喹啉-6-羧酸（YH37）对临床分离的人型支原体（Mh）、解脲脲原体（Uu）以及细菌标准菌株的体外敏感性。结果显示，YH37对Mh的抑制活性较强，MIC90为0．25mg／L，是司帕沙星的1／8；对Uu的MIC90为1mg／L，是司帕沙星的1／4。YH37对Mh、Uu的喹诺酮耐药株有一定的抑制活性，其MIC分别为CPLX的1／4～1／16。YH37对被测细菌的抑制活性是左氧氟沙星的1／8～1／16，是司帕沙星的1／2。     

性病门诊男性患者支原体感染耐药性分析

目的了解STD门诊男性泌尿生殖道感染解脲脲原体单纯感染与合并感染时对8种抗生素的耐药情况。方法取男性患者泌尿生殖道分泌物进行解脲脲原体、人型支原体培养及药敏试验。同时做淋球菌培养及衣原体检测。结果 Uu阳性223例．Mh阳性18例,Uu＋Mh阳性77例。分离株对罗红霉素、氧氟沙星、司帕沙星高度耐药;对交沙霉素、多西环素、米诺环素耐药率较低。单纯解脲脲原体感染患者149例、解脲脲原体合并人型支原体感染患者73例、解脲脲原体合并衣原体感染患者42例、解脲脲原体合并淋菌感染患者6例．比较认为混合感染较单纯感染耐药性增加。结论对泌尿生殖道支原体感染患者应该首选多西环素和交沙霉素。有条件可以做分泌物的多方面培养,以便更好的治疗混合感染。     

芦氟沙星、交沙霉素对70株解脲脲原体的体外药物敏感性实验及临床应用分析

目的 指导临床用药。方法 采用和肉汤稀释的方法,测定芦氟沙星和交沙霉素对70株解脲脲原体（Uu）体外抗菌作用效果,并分别用芦氟沙星和交沙霉素对70例Uu患者进行治疗。结果 交沙霉素的MIC50为0．5mg／L,MIC90嵝2mg／L,芦氟沙星的MIC50的0．06mg／L,MIC90为0．5mg／L,两者均有较强的抗Uu作用。芦氟沙星组治愈率97．1％,交沙霉素组治愈率91．4％。结论 芦氟沙星和交沙霉素均可作为临床治疗解脲脲原体（Uu）的首选药物。     

曲伐沙星对枝原体的体外活性

曲伐沙星是一种对革兰氏阳性菌、阴性菌和厌氧菌都具有强活性的新氟喹诺酮类药物。 Bebear等以 3种氟喹诺酮类药物 (司帕沙星 ,氧氟沙星 ,环丙沙星 )和多西环素、红霉素为对照 ,研究了曲伐沙星对包括人型枝原体和解脲尿枝原体在内的枝原体的体外活性。氟喹诺酮敏感性枝原体 112株 ,包括 32株肺炎枝原体 ,31株临床分离株和 1株参考菌株 (FH) ;7株生殖道枝原体 ,5株临床分离株和 2株参考菌株 (G37和M30 ) ;2 0株多西环素敏感性人型枝原体 ,19株临床分离株和 1株参考菌株 (PG2 1) ;10株多西环素耐药性人型枝原体 ;11株发酵枝原体 ,9株临床分…     

枝原体和尿原体对左氧氟沙星衍生物(YH7)的体外敏感性研究

采用微量稀释法测定了(S)-9氟-2，3-二氢-3-甲基-10-（4-（2-嘧啶）-1-哌嗪基）-7-氧代-7H-吡啶并[1,2,3-de][1,4]苯并恶嗪-6-羧酸（YH7）等氟喹诺酮及大环内酯类、四环素类抗生素对人型支原体（Mh）、口腔枝原体（M.ora）、唾液枝原体（M.sal）、解脲枝原体（Uu）的体外敏感性。结果显示：YH7对Mh、M、ora、M、sal、Uu的最低抑制浓度（MIC）分别为0.5、0.25、0.125、0.125mg/L。它的抑菌活性是氧氟沙星2-16倍，与红霉素、柱晶白霉素相当。Mh、Uu对YH7及交沙霉素不易产生诱导耐药性，而对红霉素和四环素易产生诱导耐药性。而对红霉素升四环素产生耐药的Mh和Uu菌株对红霉素和四环素交叉耐药而对YH7和交沙霉素无交叉耐药。     

五环三萜类柴胡皂苷单体对解脲脲原体四环素耐药株的作用

目的研究五环三萜类柴胡皂苷单体Bp3对解脲脲原体四环素耐药株的作用及其与四环素的相互作用。方法参照美国临床实验室标准化协会标准,采用棋盘微量稀释法,测定单用Bp3、四环素及两者联合使用时对20株四环素耐药解脲脲原体的最低抑菌浓度(MIC),计算部分抑菌浓度(FIC)指数,判定两药相互作用。结果单独用药时Bp3及四环素对解脲脲原体四环素耐药株MIC的几何均数值(GM值)分别为1.234 mg.L-1和0.948 mg.L-1,联合用药时Bp3和四环素的GM值分别降低为0.692 mg.L-1和0.271 mg.L-1。2种药物单用和联合使用时MIC值的差异均有统计学意义(P<0.05),联用时在20株耐药株均表现为协同或相加作用。结论五环三萜类柴胡皂苷单体Bp3对解脲脲原体四环素耐药株有抑制作用,且与四环素有协同或相加作用。     

宁波地区841例泌尿生殖道感染患者支原体培养及药敏分析

目的了解宁波地区解脲脲原体和人型支原体感染情况及对抗生素的敏感性,为临床治疗提供依据。方法对841例泌尿生殖道感染患者泌尿生殖道分泌物标本采用解脲脲原体和人型支原体培养及药敏试剂盒进行检测结果841例泌尿生殖道感染患者中,支原体总的阳性率为42.8%,其中单一Uu感染占阳性标本的71.9%,单一Mh感染占阳性标本的5.8%,Uu＋Mh混合感染占阳性标本的22.2%,支原体对抗生素的敏感性高低为：强力霉素〉美满霉素〉交沙霉素〉克拉霉素〉阿奇霉素〉司帕沙星〉罗红霉素〉左氧氟沙星〉氧氟沙星结论泌尿生殖道支原体感染主要由Uu引起,解脲脲原体和人型支原体对喹诺酮类抗生素抗药性较高,医生应根据药敏结果,合理选择治疗药物。     

解脲脲原体感染情况及其耐药性分析

目的 以解脲脲原体（Uu）的培养结果分析解脲脲原体近年来在我地区的感染情况及其耐药状况。方法 用选择性培养基培养的方法检测解脲脲原体,以中国医学科学院皮肤病研究所推荐的方法B0做药敏试验。结果832例受检者中,共有185例解脲脲原体阳性,阳性率为22,2％,其中男性453例中54例阳性,阳性率11．9％;女性379例中131例阳性,阳性率为34．6％,185例解脲脲原体对常用的10种的耐药率均有所增加。结论 我地区解脲脲原体感染呈上升趋势,尤以女性患者为主（P〈0．01）;解脲脲原体对传统的治疗药物如红霉素、罗红霉素、阿奇霉素等的耐药率明显上升,其中对红霉素（ERY）耐药率最高,司帕沙星（SPA）、罗红霉素（ROX）次之,美满霉素（MIN）、强力霉素（DOX）对其有较好的抑制作用。     

泌尿生殖道沙眼衣原体体外药物敏感性测定

目的　检测泌尿生殖道沙眼衣原体对 6种常用抗菌药米诺环素、阿奇霉素、克拉霉素、司帕沙星、氟罗沙星、左氧氟沙星的药物敏感性。方法　用 Mc Coy细胞培养法 ,以加入抗菌药后沙眼衣原体在细胞内不生长的最低浓度为最小抑菌浓度 (MIC) ,复板后在无抗菌药情况下仍不生长的最低浓度为最小杀菌浓度(MBC)。结果　米诺环素 MIC90 =0 .0 16 mg/ L,MBC90 =0 .0 32 mg/ L;阿奇霉素 MIC90 =0 .5 mg/ L,MBC90 =1.0 mg/ L ;克拉霉素 MIC90 =0 .0 32 mg/ L ,MBC90 =0 .12 8mg/ L ;司帕沙星 MIC90 =0 .0 32 mg/ L ,MBC90 =0 .0 6 3mg/ L ;氟罗沙星 MIC90 =2 .0 mg/ L ,MBC90 =8.0 mg/ L ;左氧氟沙星 MIC90 =0 .5 mg/ L ,MBC90 =2 .0 mg/L。结论　实验中未发现对这 6种抗菌药产生耐药的菌株 ,但氟罗沙星的 MIC90 与 MBC90 已在较高水平。此外 ,米诺环素的抑菌浓度已较以前报道升高。     

泌尿生殖道感染支原体的分布和耐药性变迁分析

目的：了解本地区解脲脲原体和人型支原体感染泌尿生殖道的分布情况,分析支原体对抗菌药物的耐药性变迁,指导临床合理用药。方法：对2013年-2018年间疑似泌尿生殖道感染并送检支原体培养病人的临床资料收集进行回顾性分析,统计支原体的临床分布,评价支原体对12种常规检测抗菌药物的耐药变迁情况。结果：1 087份临床标本中,检出支原体566例,总感染率52.07%,其中解脲脲原体占比最多（74.73%）,解脲脲原体和人型支原体混合感染占22.97%,人型支原体最少（2.30%）。女性和男性标本阳性率分别63.07%和30.22%,女性更容易感染。支原体检出率总体呈逐年下降趋势。对解脲脲原体耐药率最低的抗菌药物依次为交沙霉素（0.24%）、美满霉素（0.71%）和强力霉素（1.89%）,且均常年维持在很低的比例。而氧氟沙星、左氧氟沙星及司帕沙星的耐药率较高但呈下降趋势。结论：解脲脲原体是引起泌尿生殖道感染的主要支原体,对疑似支原体感染的患者需要进行支原体的分离培养鉴定和药敏检测。经验用药建议首选美满霉素、强力霉素和新型大环内酯类抗菌药物交沙霉素。     

Antihypertensive and cardiovascular effects of the new calcium antagonist YH334

Antihypertensive effect of YH334 was examined in various experimental hypertension rat models and the systemic and regional hemodynamic profiles of the compound were investigated in conscious spontaneously hypertensive rats (SHR). The antihypertensive potency of YH334 is found to be more than 10 times stronger than that of nitrendipine in the all hypertensive models. The effective doses to lower the initial blood pressure by 20% (ED₂₀) of YH334 were 1.4 mg/kg in normotensive rats (NR), 0.7 mg/kg in SHR, 0.1 mg/kg in DOCA salt hypertensive rats (DHR) and 0.4 mg/kg in renal hypertensive rats (RHR), and the ED₂₀ values of nitrendipine were 15.8 mg/kg in NR, 7.1 mg/kg in SHR, 1.7 mg/kg in DHR and 4.8 mg/kg in RHR. The primary hemodynamic effect of YH334 was characterized by increasing CI and SVI and reducing TPRI of which hemodynamic profile is similar to that of nitrendipine. Both compounds seem to produce potent antihypertensive effects by lowering peripheral resistance in the skeletal muscles. In the organ bath study using isolated rabbit aorta, YH334 was found to be a potent voltage dependent calcium channels blocker without significant inhibitory effect on the receptor operated calcium channels like the most of other dihydropyridine type calcium antagonists. Furthermore, YH334 showed acute diuretic and natriuretic effects in conscious SHR, which may render the unnecessary restriction of sodium in the diet of those patients on long term hypertension therapy. This effect would provide an additional benefit to its potent antihypertensive activity.     

左旋氧氟沙星衍生物(YH54,YH57)体外抗菌活性

ＹＨ5 4、ＹＨ5 7是以左旋氧氟沙星为先导化合物合成的新氟喹诺酮[1] 。其化学名分别为 :(Ｓ) 9 氟 2 ,3 二氢 3 甲基 8 氨基 10 (4 甲基 1 哌嗪基 ) 7 氧代 7Ｈ 吡啶并 [1,2 ,3 ｄｅ][1,4]苯并 口恶嗪 6 羧酸、(Ｓ) 9 氟 2 ,3 二氢 3 甲基 8 氨基 10 (3 甲基 1 哌嗪基 ) 7 氧代 7Ｈ 吡啶并 [1,2 ,3 ｄｅ][1,4]苯并口恶嗪 6 羧酸。本文研究其抗菌活性。1　材料与方法1.1　细菌来源　 1998年至 1999年从上海、南通等地医院门诊及住院患者经常规分离获得的临床致病菌株 (Ｔａｂ 1)。1.2　培养基与药物　选用ＭＨ培养基。Ｙ…     

Effect of food on the pharmacokinetics of YH439 and its metabolites in rats

The pharmacokinetics of YH439 and its metabolites were investigated after oral administration of YH439 to rats to investigate the food effect. After oral administration of YH439, its metabolites, M4 and M5 were detected in plasma. YH439 was not detected in the plasma for both fasted and fed rats for all doses studied. The pharmacokinetic parameters of the metabolites were not affected by food at all doses studied. The results of this study indicated that there are no significant food effects on the pharmacokinetics of YH439 and its metabolites in rats.     

Two new metabolites with cytotoxicities from deep-sea fungus,aspergillus sydowi YH11-2

Two new compounds, 2, 3, 5-trimethyl-6-(3-oxobutan-2-yl)-4H-pyran-4-one (1) and (2R)-2, 3- dihydro-7-hydroxy-6, 8-dimethyl-2-[(E)-prop-1-enyl] chromen-4-one (2), together with six known compounds (3-8), were isolated from a deep-sea fungus, identified as Aspergillus sydowi, by a bioassay-guided method. Their structures were elucidated by spectroscopic methods and the cytotoxicities were evaluated by SRB method.     

硫酸软骨素裂解酶发酵培养基的获得及发酵条件的优化

目的考察发酵培养基中碳源、氮源及无机盐等因素及各种发酵条件对温和气单孢菌YH311产硫酸软骨素裂解酶的影响,获得硫酸软骨素裂解酶最佳发酵培养基和发酵条件。方法采用单因素实验法、均匀设计法及正交设计法。结果获得的最优培养基配方(g·L-1)为:葡萄糖2 5 ,牛肉膏5 0 0 ,硫酸软骨素10 0 ,尿素0 5 ,MgSO4·7H2 O 9 0 ( pH 7 0 ) ;最适产酶条件为:2 % ( φ)种子液,2 8℃,2 0 0r·min-1,振荡通气培养2 4h。在优化条件下,硫酸软骨素裂解酶的产率可达110 0 0U·L-1。结论通过对发酵培养基及发酵条件的优化可将硫酸软骨素裂解酶的产量提高5倍。     

Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.     

YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model

G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic β cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-4 inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP-IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes.