β－内酰胺类抗生素联合舒巴坦对产酶大肠杆菌的体外抗菌活性研究

４种β－内酰胺类抗生素与舒巴坦（ＳＢＴ）以２：１比例联合对临床分离产酶大肠杆菌的体外抗菌活性研究结果表明：氨苄西林（ＡＭＰＣ）、哌拉西林（ＰＩＰＣ）、头孢唑林（ＣＥＺ）、头孢哌酮（ＣＰＺ）联合舒巴坦对４５株产酶大肠杆菌的体外抗菌活性均优于抗生素自身的抗菌活性，尤以ＡＭＰＣ／ＳＢＴ、ＰＩＰＣ／ＳＢＴ、ＣＥＺ／ＳＢＴ明显；８０％以上的产酶株对ＰＩＰＣ／ＳＢＴ、ＣＥＺ／ＳＢＴ、ＣＰＺ／ＳＢＴ和ＣＰＺ敏感；ＣＰＺ／ＳＢＴ与ＣＰＺ的抗菌活性比较差异不明显，可能与ＣＰＺ具有酶稳定性有关。     

22种抗生素对铜绿假单胞菌抑菌浓度研究

用ＡＭＳ法测定了２２种抗生素对铜绿假单胞菌临床菌株的抑菌浓度。ＣＰＬＸ对铜绿假单胞菌的抑菌浓度为０．６４ｍ ｇ／Ｌ,ＴＯＢ、ＩＭＰ、ＧＭ 和ＡＭＫ为１．９５～７．７３ｍｇ／Ｌ,ＣＡＺ、ＡＺ、ＣＰＺ、ＴＣ、ＰＩＰＣ、ＣＴＸ、ＣＥＺ、ＣＸＭ－Ｓ、ＣＸＭ－Ａ、ＣＥＴ和ＡＢＰＣ为９．４１～３２．００ｍｇ／Ｌ,ＣＦＸ、ＴＩＰＣ、ＴＩＰＣ／ＣＡ、ＭＺＰＣ和ＣＢＰＣ为３３．９８～１００．３０ｍ ｇ／Ｌ,ＮＦＴ为１９３．００ｍ ｇ／Ｌ。在不同标本的分离菌中,痰液与伤口、痰液与粪便和伤口与尿液有４种抗生素、痰液与尿液和伤口与粪便有５ 种抗生素、粪便与尿液有１１ 种抗生素的抑菌浓度有显著性差异（Ｐ＜０．０５０～０．００１）。     

β—内酰胺类抗生素联合舒巴坦对产酶大肠杆菌的体外抗菌活…

４种β－内酰胺类抗生素与舒巴坦以２：１比例联合对临床分离酶大肠杆菌的体外抗菌活性研究结果表明：氨苄西林、哌拉西林、头阢 唑林、头孢哌酮联合舒巴埋对４５株产酶大肠杆菌的体外抗菌活性无益成于抗生素自身的抗菌活性，尤以ＡＭＰＣ／ＳＢＴ、ＰＩＰＣ／ＳＢＴ、ＣＥＺ／ＳＢＴ明显；８０％以上的产酶株对ＰＩＰＣ／ＳＢＴ、ＣＥＺ／ＳＢＴ、ＣＰＺ／ＳＢＴ和ＣＰＺ敏感；ＣＰＺ／ＳＢＴ与ＣＰＺ的抗菌活比较差异不明显，可能     

4种抗生素血清和胰液杀菌效价的比较

报道６例行胰管引流病人应用４种抗性素后的血清菌效价（ＳＢＡ）格胰液杀菌效价（ＰＢＡ）。结果：头孢哌酮（ＣＰＺ）的ＳＢＡ和ＢＰＡ最高，哌拉西林（Ｐｉｐ）较高；头孢唑林（ＣＺ）对金黄色葡萄球菌的ＳＢＡ和ＢＰＡ较高；对肠杆菌科细菌作用较弱；氨苄西林（Ａｍｐ）的ＰＢＡ低于治疗水平。提示ＣＰＺ和Ｐｉｐ可能为治疗胰腺感染最有效的药物。     

4种抗生素血清和胰液杀菌效价的比较

报道６例行胰管引流病人应用４种抗生素后的血清杀菌效价（ＳＢＡ）和胰液杀菌效价（ＰＢＡ）。结果：头孢哌酮（ＣＰＺ）的ＳＢＡ和ＰＢＡ最高，哌拉西林（Ｐｉｐ）较高；头孢唑林（ＣＺ）对金黄色葡萄球菌的ＳＢＡ和ＰＢＡ较高；对肠杆菌科细菌作用较弱；氨苄西林（Ａｍｐ）的ＰＢＡ低于治疗水平。提示ＣＰＺ和Ｐｉｐ可能为治疗胰腺感染最有效的药物。     

亚胺培南/西司他丁对肺炎大鼠的免疫调节作用

研究亚胺培南／西司他丁（ＩＰＭ／ＣＳ）对肺炎大鼠的免疫调节作用。采用气管内注入感染法建立肺炎克雷伯氏菌肺炎模型,按临床治疗剂量折算出大鼠等效剂量,连续７ｄ腹腔注射ＩＰＭ／ＣＳ及阿米卡星（ＡＭＫ）,活性取材测定免疫指标。     

特美汀治疗医院获得性肺炎临床分析

特美汀与头孢哌酮（ＯＰＺ）、舒巴坦（ＳＲ）随机对照治疗医院获得性肺炎各４０例,对其临床疗效和细菌学效果及安全性作评价,用法为特美汀３．２ｇ,静滴,ｑ８ｈ,ＣＰＺ／ＳＢ２ｇ,静滴,ｑ１２ｈ,ＣＰＺ／ＳＢ２ｇ,静滴,ｑ１２ｈ,疗程均为７ｄ～１４ｄ。结果显示：特美汀组与ＣＰＺ／ＳＢ组的临床有效率分别是９２．５％５和９０％,痊愈率分别为７７．５％和７５％。细菌清除率分别为７６．２％和７３．７％（无统计学差异）,不良反应发生率为７．５％和７．５％（无统计学差异）,认为特美汀是治疗医院获得性肺炎理想的药物。     

乳酸左氧氟沙星与头孢哌酮／舒巴坦对照治疗老年人下呼 …

乳酸左氧氟沙星（ＬＶＬＸＬ）与头孢哌酮（ＣＰＺ?／舒巴坦（ＳＢ）随机照治疗老年人呼吸道感染各４０例,对其临床疗效和细菌学效果及安全性作出评价,用法为ＬＶＬＸＬ０．２ｇ,每日２次;ＣＰＺ／ＳＢ２ｇ,每日２次疗程均为７～１４ｄ。结果显示：ＬＶＬＸＬ组与ＣＰＺ／ＳＢ组的临床有效率分别是９２．５％和９２．５％,痊愈率分别是７５％和７７．５％,细菌清除率分别是８４．３％和８３．５％（无统计学差异）,不良反应     

糖尿病患者RBC—S与MAU关系的研究

观察了１１０例糖尿病人及３０例正常人的红细胞山梨醇（ＲＢＣ－Ｓ）与水微量白蛋白（ＭＡＵ）之间的关系。结果显示：（１）正常人ＲＢＣ－ＳＯ０－１μｍｏｌ／Ｌ,２４小时尿微量白蛋白（ＭＡＵ）小于２６ｍｇ（２）３组糖尿病病人ＲＢＣ－Ｓ均〉２．２５μｍｏｌ／Ｌ,且与ＭＡＵ呈正相关。（３）使用小剂量开搏通治疗后,随着ＭＡＵ的降低,ＲＢＣ－Ｓ也下降。以上结果表明,ＲＢＣ－Ｓ的变化可以作为预报早期糖尿病肾病和判断     

地尔硫Zhou对大鼠离体肝脏灌注中安替比林代谢的影响

以安替比林（ＡＰ）为模型药,采用大鼠离体肝脏灌流模型（ＩＰＲＬ）,研究钙离子拮抗剂地尔硫Ｚｈｏｕ（ＤＺ）对ＡＰ代谢的影响。方法：１５只雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ大鼠随机分为３组,Ａ、Ｂ组灌胃（ｉｐ）生理盐水３ｄ,第４天分别用５ｍｇＡＰ及加用２ｍｇＤＺ循环灌流３ｈ,Ｃ组ｉｐＤＺ（１００ｍｇ．ｋｇ＾－１）３ｄ,第４天同Ｂ组灌流。ＨＰＬＣ法测定灌流液中ＡＰ及其代谢的浓度。结果：Ｂ、Ｃ组中,ＡＰ的Ｔ     

A comparative study on the efficacy, safety, and cost-effectiveness of bimatoprost/timolol and dorzolamide/timolol combinations in glaucoma patients

Aim:

This study was designed to compare the bimatoprost/timolol combination and dorzolamide/timolol combination in glaucoma for efficacy, safety, and cost-effectiveness in a local population of Trichy in the state of Tamilnadu.

Materials and Methods:

Eight-week, randomized, parallel group, open-label study was conducted on 48 patients of open angle glaucoma or ocular hypertension. After initial clinical assessment and baseline investigations, bimatoprost/timolol combination (Group A) was prescribed to 22 patients (2 patients lost after initial assessment) and dorzolamide/timolol combination (Group B) to 24 patients. The patients were reviewed after second and eighth weeks for cure rate and adverse drug reaction monitoring.

Results:

At the end of 8 weeks, the mean reduction in intraocular pressure from baseline was 13.04 mmHg (95% confidence interval (CI): 10.67–14.70) with bimatoprost/timolol combination once daily (P < 0.01) and 9.46 mmHg (95% CI: 7.47–10.5) with dorzolamide/timolol combination twice daily. Both the treatments were safe. Cost-effective range of bimatoprost/timolol combination was lower than that of dorzolamide/timolol combination.

Conclusion:

The fixed combination of bimatoprost/timolol was slightly more effective than that of dorzolamide/timolol combination in reducing IOP, and both treatments were generally well tolerated. Bimatoprost/timolol combination was more cost-effective (cost-effective analysis) than dorzolamide/timolol combination.     

Quantitative determination of apogossypol, a pro-apoptotic analog of gossypol, in mouse plasma using LC/MS/MS

A simple and selective liquid chromatography/tandem mass spectrometry (LC/MS/MS) method based on internal standard quantitation using apigenin as the internal standard has been developed and validated for the analysis of the gossypol analog apogossypol, a pro-apoptotic compound, in mouse plasma. The methodology involves protein precipitation of plasma samples followed by LC/MS/MS analysis. Ascorbic acid was added to the spiking solutions and plasma samples to stabilize the easily oxidized compound. Separation of apogossypol and the internal standard from the plasma matrix was achieved using a C18 column with a gradient elution profile consisting of 5 mM ammonium acetate and methanol. The validated range of the method extended from 10 to 2000 ng/mL with accuracies of 85–115% and precision of <15%. The average recovery of apogossypol at three concentrations (50, 200 and 1000 ng/mL) assayed in triplicate using this methodology was determined to be 90.8 ± 12.9%. Recovery for the internal standard (apigenin) at a concentration of 500 ng/mL was found to be 99.9 ± 6.41%. Apogossypol concentrations of 50 ng/mL and above were found to be stable in extracted plasma for 24 h when stored at 25 °C. This method has been applied to the determination of apogossypol concentrations in plasma collected from mice given an IV dose of apogossypol.     

液相色谱-电喷雾离子阱质谱法研究人尿中1,5-二咖啡酰奎宁酸的代谢产物

目的 研究健康受试者口服1,5-二咖啡酰奎宁酸后尿液中的代谢产物.方法 健康受试者每人口服1,5-二咖啡酰奎宁酸600 mg,收集0-24 h的尿样,经C_(18)小柱固相萃取纯化后,用液相色谱-电喷雾离子阱质谱联用技术对人尿中的代谢产物进行分析鉴定.结果 在人尿中发现了1,5-二咖啡酰奎宁酸的甲基化、葡萄糖醛酸化及甲基-葡萄糖醛酸化代谢产物共28个.其中,有2个代谢产物结构经标准品对照得到确证.结论 甲基化、葡萄糖醛酸化和异构化反应是1,5-二咖啡酰奎宁酸在人体内的3种重要代谢途径.     

Depsipeptide (FR901228, NSC-630176) pharmacokinetics in the rat by LC/MS/MS

Depsipeptide, a cyclic peptide (FR), isolated from Chrombacterium violaceum strain WB968 by Fujisawa Company during a screening program for anti-oncogene agents, possesses potent antitumor activity against human tumor cell lines and xenografts. This compound has been selected for preclinical and early clinical development by the National Cancer Institute. The pharmacokinetics and oral bioavailability of this depsipeptide in the rat were investigated in the present study. A sensitive and specific electrospray LC-tandem mass spectrometry method was first developed and validated for the analysis of this depsipeptide in plasma using t-boc--d-glutamic acid benzyl ester as the internal standard. The routine sensitivity limit was 1 or 10 ng/ml using 1.0 or 0.1 ml of plasma sample. The within-run CV values were 11.8, 17.9, 11.0, and 5.0% at 1, 10, 100, and 500 ng/ml levels, respectively, with corresponding accuracy of 94.4, 109, 95, and 97% (all n=6). A formulation based on ethanol, normal saline and PEG400 was then developed and Fischer rats were given this formulated drug separately by intravenous and oral route. Plasma drug concentrations were measured by this method and pharmacokinetics were analyzed by the standard techniques. Plasma concentration-time profiles were found to follow a biexponential decline with a mean terminal t1/2 of 97 min and mean total clearance (CLt) of 425.3 ml/min/kg following iv dosing at 10 mg/kg. Following oral dosing at 50 mg/kg, the peptide was absorbed but produced erratic drug levels also with a bioavailability of 15.6%. Thus, active plasma concentrations can be produced up to 3 hrs in the rat following a single dose at 10 mg/kg and the peptide represents one of the very few orally absorbed peptides reported.     

Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma.     

LC/MS/MS法测定人血浆中罗红霉素的血药浓度

目的建立LC/MS/MS法测定人血浆中罗红霉素的浓度。方法采用Diamonsil C18色谱柱,流动相甲醇-水-甲酸(75∶25∶0.5),流速为0.5mL·min-1。质谱检测方式:SIM。克拉霉素为内标,血浆样品用乙醚提取浓集,进行LC/MS/MS分析。结果本方法在0.1～40.0μg·mL-1内线性关系良好(r=0.9997),平均回收率87.6%,日内和日间RSD<10%。结论本方法快速、准确,适用于罗红霉素的临床药动学研究和血药浓度检测。     

Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog,TAK-448, for its anti-tumor efficacy in a rat xenograft model

TAK-448 is the investigational metastin/kisspeptin analog, which is known to have an anti-tumor effect through suppression of androgen hormones (luteinizing hormone and testosterone) levels. This study developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat vertebral-cancer of the prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. A potential contribution of the hormone-independent direct effects of TAK-448 to the tumor growth inhibition was also investigated in the in vivo rat xenograft model, because our in vitro experiments revealed that TAK-448 may also directly suppress VCaP cellular proliferation. The PK/PD model successfully described the time course of tumor growth inhibition after drug treatment as well as the development of resistance to the inhibition of androgen hormones, following drug treatment or castration. The EC₅₀ of the hormone-dependent inhibitory effect of TAK-448 was much lower than that of TAP-144, and TAK-448 also has a faster onset of anti-tumor effect than TAP-144, demonstrating that TAK-448 has a stronger overall anti-tumor effect than TAP-144. In addition, model inference, by incorporating a hormone-independent inhibition pathway of TAK-448 into the PK-PD model, suggested that such a direct inhibition pathway for TAK-448 cannot be excluded, as also indicated by in vitro studies, but its EC₅₀ would be approximately three orders of magnitude higher than that of the hormone-dependent pathway. This study helps to understand the potential and mechanism of TAK-448 as a prostate cancer treatment.     

LC/MS/MS与GC/MS法分析鉴定小鼠尿中沙美特罗的代谢产物

目的:鉴定沙美特罗在小鼠尿中的主要代谢产物.方法:ig给药后,收集小鼠尿液,经固相提取,葡萄糖醛酸酶水解,进行LC/MS/MS分析和硅烷化后进行GC/MS分析同时分离鉴定沙美特罗代谢产物.结果和结论:在给药后尿样中发现沙美特罗原型和4种代谢产物M1～M4,其结构推测为19-羟基沙美特罗(M1)、2-羰基沙美特罗(M2)、19-羰基沙美特罗(M3)和19-羟基-8-甲氧基沙美特罗(M4).     

Involvement of the GABA/benzodiazepine receptor in the axiolytic-like effect of nociceptin/orphanin FQ

We investigated the mechanism underlying the anxiolytic actions of the neuropeptide nociceptin/orphanin FQ (N/OFQ) with an elevated plus-maze test. In mice, intracerebroventricular (i.c.v.) infusions of N/OFQ (0.1 and 0.32 nmol) led to an increase in time spent in the open arms (anxiolytic-like effects). A non-peptidyl N/OFQ receptor (NOP) antagonist, J-113397(1-{(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl}-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one), (1.0 and 3.2 mg/kg, s.c.) blocked the increase induced by N/OFQ. On the other hand, a benzodiazepine receptor antagonist, flumazenil, (10 mg/kg, i.p.) and a GABAA receptor antagonist, (+)-bicuculline, (5.6 mg/kg, i.p.) also inhibited the increase induced by N/OFQ. In rats, microinfusions of N/OFQ (10 and 32 pmol) into the amygdala led to an increase in time spent in the open arms. However, intracranial infusions of N/OFQ (10-100 pmol) into the dorsal hippocampus did not affect the time spent in the open arms. These findings suggest that the anxiolytic-like effects of N/OFQ may be related to the GABA/benzodiazepine system in the amygdala.