复方磺胺甲(口恶)唑与替卡西林/克拉维酸、头孢哌酮/舒巴坦联用对嗜麦芽寡养单胞菌体外抗菌活性的研究

目的评价复方磺胺甲噁唑分别与替卡西林／克拉维酸、头孢哌酮／舒巴坦两种β-内酰胺酶抑制剂联合应用对于临床分离30株嗜麦芽寡养单胞菌的体外联合抗菌效应。方法采用棋盘法设计，微量肉汤稀释法测定不同浓度组合的2组抗菌药物对30株嗜麦芽寡养单胞菌的最低抑菌浓度，并计算联合抑菌指数（FIC）。判断联合效应。结果复方磺胺甲噁唑对嗜麦芽寡养单胞菌的MIC为2／38，与替卡西林／克拉维酸、头孢哌酮／舒巴坦联合应用后。其MIC50显著降低至0．5／9．5，FIC指数分布范围主要在0～1。结论复方磺胺甲噁唑与替卡西林／克拉维酸、头孢哌酮／舒巴坦两种β-内酰胺／酶抑制剂联合应用后，对嗜麦芽寡养单胞菌表现为协同作用和相加作用。并以协同作用为主。     

喹诺酮类与β-内酰胺类/β-内酰胺酶抑制剂复方联合对嗜麦芽寡养单胞菌的抗菌活性

目的　了解嗜麦芽寡养单胞菌 (Strenotrophomonasmaltophilia)在延时培养时对喹诺酮类与 β 内酰胺 /酶抑制剂复方的MIC影响及联合应用抗菌活性。方法　微量肉汤稀释法测定MIC ,时间杀菌试验进行联合药敏试验并与棋盘法比较 ,并作耐药频率测定。结果　五种抗生素 48h测得MIC较 2 4h的MIC高 1～ 3倍 ;2 4h棋盘法测得头孢哌酮 /舒巴坦、替卡西林 /克拉维酸分别与左氧氟沙星、洛美沙星、环丙沙星联合用药对嗜麦芽寡养单胞菌的协同作用为 73 %～ 80 % ,48h则较 2 4h低 1 0 %～ 2 0 %。与时间杀菌试验测得的协同作用 50 %～ 66 %相近。联合用药的耐药频率明显低于单独用药。结论　 48h判定MIC值可能更准确地反映嗜麦芽寡养单胞菌对抗生素的敏感性。时间杀菌试验较棋盘法更能真实反映出联合用药的效果。联合用药能减少细菌的耐药频率。     

嗜麦芽寡养单胞菌临床分离株对复方磺胺甲(口恶)唑耐药机制探讨

目的 了解临床分离嗜麦芽寡养单胞菌对复方磺胺甲(口恶)唑的耐药情况,探讨其耐药机制.方法 采用微量肉汤稀释法测定MIC,PCR法扩增Ⅰ型整合子特异的整合酶基因和sul1基因.结果 30株嗜麦芽寡养单胞菌中,5株(16.7%)表现为对复方磺胺甲(口恶)唑高MIC,5株菌的Ⅰ型整合酶基因(intI1)和sul1基因扩增阳性,其余均为阴性.结论 嗜麦芽寡养单胞菌对复方磺胺甲(口恶)唑的高度耐药性可能与Ⅰ型整合子的存在有关.     

嗜麦芽寡养单胞菌对黏菌素的耐药特征及体外联合抗菌活性研究

目的 研究黏菌素分别与氯霉素、左氧氟沙星、头孢他啶、米诺环素及复方磺胺甲噁唑联用对多重耐药嗜麦芽寡养单胞菌的体外抗菌活性。方法 收集2015—2018年分离自温州医科大学附属第一医院的431株嗜麦芽寡养单胞菌;采用微量肉汤稀释法检测黏菌素对嗜麦芽寡养单胞菌的最低抑菌浓度(minimal inhibitory concentration, MIC),计算逐年耐药率;通过棋盘法和微量肉汤稀释法检测黏菌素分别与氯霉素、左氧氟沙星、头孢他啶、米诺环素与复方磺胺甲噁唑联用及各自单用时对多重耐药嗜麦芽寡养单胞菌的MIC值,并通过计算部分抑菌浓度指数(FICI)评价联合抑菌效果。结果 2015—2018年间,我院嗜麦芽寡养单胞菌对黏菌素的耐药率呈现逐年上升趋势;黏菌素与氯霉素、左氧氟沙星及米诺环素联用后均表现为协同或相加作用;与头孢他啶及复方磺胺甲噁唑联用都存在无关作用,未发现拮抗作用。结论     

嗜麦芽寡养单胞菌对黏菌素的耐药特征及体外联合抗菌活性研究

目的 研究黏菌素分别与氯霉素、左氧氟沙星、头孢他啶、米诺环素及复方磺胺甲噁唑联用对多重耐药嗜麦芽寡养单胞菌的体外抗菌活性。方法 收集2015—2018年分离自温州医科大学附属第一医院的431株嗜麦芽寡养单胞菌;采用微量肉汤稀释法检测黏菌素对嗜麦芽寡养单胞菌的最低抑菌浓度(minimal inhibitory concentration, MIC),计算逐年耐药率;通过棋盘法和微量肉汤稀释法检测黏菌素分别与氯霉素、左氧氟沙星、头孢他啶、米诺环素与复方磺胺甲噁唑联用及各自单用时对多重耐药嗜麦芽寡养单胞菌的MIC值,并通过计算部分抑菌浓度指数(FICI)评价联合抑菌效果。结果 2015—2018年间,我院嗜麦芽寡养单胞菌对黏菌素的耐药率呈现逐年上升趋势;黏菌素与氯霉素、左氧氟沙星及米诺环素联用后均表现为协同或相加作用;与头孢他啶及复方磺胺甲噁唑联用都存在无关作用,未发现拮抗作用。结论 黏菌素与氯霉素、左氧氟沙星、米诺环素联合对多重耐药嗜麦芽寡养单胞菌具有较好的体外抗菌活性,将对临床联合用药治疗多重耐药嗜麦芽寡养单胞菌的选择更具指导意义。     

134株嗜麦芽寡养单胞菌对12种抗菌药耐药性的测定

为了解广州地区嗜麦芽寡养单胞菌耐药现状和变化趋势以及为预防和治疗该菌感染提供依据。本次调查应用纸片扩散法对广州13家综合医院收集的嗜麦芽寡养单胞菌进行三年抗生素连续监测和结果比较分析，结果显示，12种常用于治疗非发酵菌的抗生素耐药率大于50％的有7种，较低耐药率的抗生素有磺胺甲■唑／甲氧苄氨嘧啶（16．3％），替卡西林／克拉维酸（1．7％），环丙沙星（22．8％）和头孢哌酮／舒巴坦（23.7％）。说明本地区嗜麦芽寡养单胞菌耐药现象较普遍，且耐药率逐年呈上升趋势，因此应加强该菌的耐药性监测，以指导临床医生根据监测结果使用抗生素，控制感染发生的关键在于减少不合理抗菌药物的应用。     

氟喹诺酮类药物对嗜麦芽寡养单胞菌的抗菌活性及羰基氰氯苯腙对其的影响

目的　了解氟喹诺酮类药物 (FQNs)对嗜麦芽寡养单胞菌的抗菌活性及羰基羟基氰氯苯腙(CCCP)对其抗菌活性的影响。方法　采用琼脂二倍稀释法测定抗菌药物的最低抑菌浓度 (MIC) ,同时测定CCCP对 FQNs的 MIC值的影响。结果　 14 4株嗜麦芽寡养单胞菌对多种常用抗生素呈现多重耐药 ,但对SMZ/ TMP、替卡西林 /克拉维酸以及 FQNs的耐药率较低 ,尤其是新型 FQNs具有很高的抗菌活性 ,其中抗菌活性由高到低依次是加替沙星、司帕沙星、左氧氟沙星和环丙沙星。主动外排泵抑制剂 CCCP在体外能增强 FQNs的抗菌活性 ,主动外排机制不仅存在于 FQNs耐药菌株 ,而且也存在于 FQNs敏感菌株 ,但是CCCP对 4种 FQNs耐药菌株的影响更大。结论　嗜麦芽寡养单胞菌的感染经验上可选用 SMZ/ TMP或 FQNs治疗 ,对于严重感染可采用 SMZ/ TMP和替卡西林 /克拉维酸联合或用新型 FQNs治疗。主动外排泵抑制剂在体外的确能降低 FQNs对嗜麦芽寡养单胞菌的 MIC,若能保证安全性 ,可望用于临床克服细菌的耐药性。     

嗜麦芽寡养单胞菌β-内酰胺酶及喹诺酮类耐药基因检测

目的 检测临床分离嗜麦芽寡养单胞菌耐药基因型并分析其与耐药表型的关系,从而为嗜麦芽寡养单胞菌感染的防治提供理论依据和对策.方法 对2005-2008年收集的102株嗜麦芽寡养单胞菌提取全基因组DNA,采用PCR方法检测β-内酰胺酶L1、L2型耐药基因和喹诺酮耐药基因qnr,分析耐药基因与耐药表型的关系.结果 102株嗜麦芽寡养单胞菌对临床常用抗菌药物耐药率以替卡西林/克拉维酸最高达到42.16％,其次为复方磺胺甲基异噁唑29.41％、氯霉素27.45％、头孢他啶22.55％,对米诺环素的耐药率最低11.76％.102株嗜麦芽寡养单胞菌L1基因阳性率76.47％,L2基因阳性率67.65％;其中L1和L2型基因共同阳性率56.86％;头孢他啶及替卡西林/克拉维酸耐药菌株均检测到L1和L2型基因.102株qnrX、qnrY和qnrZ的阳性率都是100％.结论 本地区嗜麦芽寡养单胞菌β-内酰胺酶L1和L2酶检出率较高,喹诺酮耐药基因qnr阳性率达到100％,染色体上Qnr酶单独存在并不会导致对氟喹诺酮类药物高度耐药.     

嗜麦芽窄食单胞菌感染125株临床和耐药性分析

目的了解嗜麦芽窄食单胞菌感染的临床特点及对抗生素的耐药性。方法回顾性分析2006～2008年我院分离的嗜麦芽窄食单胞菌的耐药性以及所致感染病例的临床特点。结果125株嗜麦芽窄食单胞菌对多种抗生素耐药率较高,仅对甲氧苄啶/磺胺甲口恶唑、环丙沙星、替卡西林/克拉维酸、多黏菌素E耐药率较低,分别为11%、29%、12%、23%。结论加强环境消毒和控制广谱抗生素应用可有效降低嗜麦芽窄食单胞菌引起的医院感染的发生,甲氧苄啶/磺胺甲口恶唑、环丙沙星、替卡西林/克拉维酸可作为抗感染治疗的一线用药。     

嗜麦芽寡养单胞菌临床分离株对复方磺胺甲噁唑耐药机制探讨

目的了解临床分离嗜麦芽寡养单胞菌对复方磺胺甲噁唑的耐药情况，探讨其耐药机制。方法采用微量肉汤稀释法测定MⅠC．PCR法扩增Ⅰ型整合子特异的整合酶基因和sul 1基因。结果30株嗜麦芽寡养单胞菌中，5株（16．7％）表现为对复方磺胺甲噁唑高MIC，5株菌的Ⅰ型整合酶基因（intI1）和sul 1基因扩增阳性，其余均为阴性。结论嗜麦芽寡养单胞菌对复方磺胺甲噁唑的高度耐药性可能与Ⅰ型整合子的存在有关。     

Cerebral metabolism of [3H]-p-chloroamphetamine

The time-dependent metabolism of intraventricularly administered $\text{[}{}^3\text{H}\text{]-p-}\text{chloroamphetamine}$ was followed. The parent compound and its metabolites were recovered by high pressure liquid chromatography and characterized by high pressure liquid chromatography, thin-layer chromatography, and gas chromatography-mass spectrometry. By 4 hr after injection, two major toluene-soluble metabolites were present in brain. Their biological half-lives were different from the parent compound. On the basis of their analyses, one of the metabolites is p-chloronorephedrine, the other (P₃) is as yet unidentified. Pretreatment with Lilly 110140 prevented or markedly reduced the synthesis of both p-chloronorephedrine and P₃. Iprindole prevented the synthesis of p-chloronorephedrine. The P₃ appeared first in the brain then in the liver, suggesting that both of these organs can metabolize p-chloroamphetamine to this compound. The metabolites were recovered primarily from the nuclear and microsomal fractions following subcellular fractionation of the brain, with small quantities present in the synaptosomal fraction. The level of metabolites was higher in the brainstem than in the neocortex. Glutathione, administered simultaneously with p-chloroamphetamine either intraventricularly or intraperitoneally failed to alter the toxicity of p-chloroamphetamine.     

Clevudine University of Georgia/Abbott/Bukwang/Triangle/Yale University

The pyrimidine analog, clevudine (L-FMAU: 2'-fluoro-5-methyl-beta-L-arabinofuranosyluridine) is a potent antihepatitis B virus (HBV) and anti-Epstein-Barr virus (EBV) agent, discovered by researchers at the University of Georgia, in collaboration with Yale University and Bukwang. Bukwang transferred its technology to Triangle Pharmaceuticals in 1998 together with a license to develop clevudine worldwide except Korea [279649], [281942]. In June 1999, Triangle and Abbott Laboratories entered into a strategic alliance to copromote antiviral products including L-FMAU [326798]. In September 2000, Triangle Pharmaceuticals Inc initiated a 30-day phase I/II evaluation of clevudine in HBV-infected patients [381755]. Clevudine is a much less toxic derivative of the toxic agent P-D-FMAU. The mechanism of action of clevudine is not yet clear, but the agent induces a rapid decrease in HBV nucleic acid as doses increase from 0.3 to 10 mg/kg [319145]. It is believed that the target for clevudine lies in the viral replication mechanism. Clevudine is phosphorylated to the triphosphate form intracellularly. This is removed slowly from the cells, thus exerting a sustained inhibitory antiviral activity [178173], [320720], [320721].     

Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo

Pitavastatin (nisvastatin) is an HMG CoA reductase inhibitor being developed jointly by Nissan, Kowa Kogyo, Novartis and Sankyo for the potential treatment of atherosclerosis and hyperlipidemia.     

Spotlight from the American Society for Preventive Cardiology on Key Features of the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guidelines on the Management of Blood Cholesterol

The 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol retains focus on recommendations for statin treatment in the original four statin-eligible groups [those with atherosclerotic cardiovascular disease (ASCVD), diabetes, low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL, and higher risk primary prevention] without the use of treatment initiation or target LDL-C levels from the earlier 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline, but has several new features. First, patients with primary prevention are divided into those who are at low (< 5%), borderline (5% to < 7.5%), intermediate (7.5% to < 20%), and high (≥ 20%) risk based on the ASCVD risk estimator. Moreover, the new guideline goes further to consider a wider range of factors [now called “risk enhancers”—premature family history of ASCVD, persistently high LDL-C, chronic kidney disease (CKD), metabolic syndrome, conditions specific to women, inflammatory diseases, and high-risk ethnicities] that can be used to better inform the treatment decision. Moreover, more detailed recommendations on how the results of coronary calcium scanning can be used to inform the treatment decision are provided, including how it may be used to “de-risk” certain patients for delaying or avoiding the use of statin therapy. There are also specific sections for cholesterol management in other patient subgroups including women, children, certain ethnic groups, those with CKD, chronic inflammatory disorders and HIV, as well as discussion on the management of hypertriglyceridemia. Importantly, for persons with known ASCVD, a distinction is made for those who are at “very high risk” based on having had two major ASCVD events or one major event and two or more other high risk conditions, such as diabetes or other major risk factors, or bypass surgery or percutaneous intervention. Finally, the concept of a threshold LDL-C for initiating a non-statin therapy (after considering highest tolerated statin dosage) is provided, with ezetimibe recommended as the key non-statin to be added if the LDL-C still remains ≥ 70 mg/dL for all ASCVD patients, and in those who are at “very high risk”, further consideration for using a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. While the new guideline does have greater detail (and arguably, complexity), the refinements provide a strategy for guiding the clinician to target both statin and non-statin therapy to those most likely to derive benefit.     

Amlodipine/Valsartan/Hydrochlorothiazide

Amlodipine/valsartan/hydrochlorothiazide (HCTZ) is a fixed-dose combination of the well established antihypertensive agents amlodipine (a calcium channel antagonist), valsartan (an angiotensin II receptor antagonist), and HCTZ (a thiazide diuretic). In patients with moderate or severe hypertension, triple combination therapy with amlodipine + valsartan + HCTZ produced significantly greater reductions from baseline in mean sitting systolic and diastolic BP (msSBP and msDBP) than either valsartan + HCTZ, amlodipine + HCTZ, or amlodipine + valsartan in a large, 8-week, randomized, double-blind, multinational, phase III trial. Furthermore, the proportion of patients achieving overall BP control at endpoint was significantly greater with the triple combination regimen than with any of the dual regimens, with significantly more triple combination recipients achieving msSBP and msDBP control at each assessment throughout the trial. Subgroup analyses of this study suggested that amlodipine + valsartan + HCTZ was generally more effective in reducing BP and providing overall BP control than the dual combination therapies, irrespective of age, race, gender, ethnicity, or hypertension severity. Several smaller studies provide data that support the efficacy of amlodipine + valsartan + HCTZ in patients whose BP is inadequately controlled with amlodipine + valsartan, amlodipine + HCTZ, or valsartan + HCTZ dual combination therapy. Treatment with amlodipine + valsartan + HCTZ for up to 8 weeks was generally well tolerated in the large, phase III trial, with most adverse events being transient and of mild to moderate severity.     

N-Nitroso-N-Methyldodecylamine and N-Nitroso-N-Methyltetradecylamine in household dishwashing liquids

Eleven household dishwashing liquids and four household surface cleaners were analysed for N-nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine by gas chromatography with detection using a Thermal Energy Analyzer. Both nitrosamines were found in three of the dishwashing detergents and one of the surface cleaners. [1-¹⁴C]-N-Nitroso-N-methyldodecylamine was used to determine recoveries, which were between 65 and 88%. Levels of N-nitroso-N-methyldodecylamine ranged from 112 to 661 ppb and those of N-nitroso-N-methyltetradecylamine from 46 to 151 ppb. A simple method was developed to screen the products for N,N-dimethyldodecylamine-N-oxide, a surfactant ingredient suspected of being the source of these nitrosamines. By application of this method it was established that all of the products formulated with this amine oxide contained these two nitrosamines, whereas in products that did not contain this ingredient, these nitrosamines were not detected.     

EFFECTS OF THE OPIOID PEPTIDES [MET5]ENKEPHALIN-ARG6-PHE7 AND [MET5]ENKEPHALIN-ARG6-GLY7-LEU8 ON CHOLINERGIC NEUROTRANSMISSION IN THE RABBIT ISOLATED ATRIA

1. The effect of the opioid peptides [Met5]enkephalin-Arg6-Phe7 (MEAP) and [Met5]enkephalin-Arg6-Gly7-Leu8 (MEAGL) were compared with those of [Leu5]enkephalin and [D-Ala2,Met5]enkephalinamide (DAME) on cholinergic neurotransmission in the rabbit isolated atria. 2. Rabbit isolated atria had a resting rate of 190 beats/min. In the presence of the beta-adrenoceptor antagonist propranolol (0.3 mumol/l), atria responded to electrical field stimulation with a cholinergically mediated negative chronotropic response. The opioid peptides had no effect on the resting rate, but inhibited the negative chronotropic response to field stimulation. The IC50 values for inhibiting the cholinergic responses were 1.4 mumol/l for [Leu5]enkephalin (LE), 1.4 mumol/l for MEAP, 1.3 mumol/l for MEAGL and 0.2 mumol/l for DAME. Responses of a similar magnitude to exogenous acetylcholine were unaffected. 3. Thus, MEAP, MEAGL and LE had similar potencies but DAME was about seven times more potent in inhibiting cholinergic neurotransmission in the rabbit isolated atria. The site of inhibition appears to be prejunctional.     

PROTON AND POTASSIUM TRANSPORT BY H+/K+-ATPases

1. H⁺/K⁺-ATPases are members of the P-type ATPase multigene family. The prototypical H⁺/K⁺-ATPase is the protein that acidifies gastric luminal contents. The physiological and pharmacological significance of this pump has led to a detailed investigation of its biochemistry and molecular and cell biology. 2. Recently, a number of closely related H⁺/K⁺-ATPase isoforms have been discovered. These isoforms are present in organs other than the stomach, including the colon and kidney, where they contribute to acid—base and potassium homeostasis. The structure, expression and physiological roles of the gastric H⁺/K⁺-ATPase and other isoforms are reviewed.     

INTERACTIONS OF Na+, H2O2 AND THE Na+-Ca2+ EXCHANGER STIMULATE Ca2+ RELEASE IN CK1.4 CELLS

1. The present study aimed to demonstrate that interactions of cations, hydrogen peroxide (H₂O₂) and the Na⁺-Ca²⁺exchanger stimulate Ca²⁺ release and oscillations of cytosolic Ca²⁺ [Ca²⁺]i in non-transfected Chinese Hamster Ovary (CHO) C1 cells and in transfected CHO (CK1.4) cells that contained an expression vector coding the Na⁺-Ca²⁺ exchanger sequence. 2. The [⁴⁵Ca²⁺] uptake assay, fura-2 fluorescence imaging and 2² and 2³ factorial orthogonal statistics provide comparative, direct, efficient, quantitative and transient methods to delineate the effects of such interactions on Ca²⁺ influx, Ca²⁺release and [Ca²⁺]i in C1 and CK1.4 cells. 3. In contrast to the control of either Na⁺-, Ca²⁺- or H₂O₂-free or CI cells, an elevated [⁴⁵Ca²⁺] uptake was induced by Ca²⁺, Na⁺ and H₂O₂ individually and in combination, intracellular Ca²⁺ release was activated by H₂O₂ and by combinations of either H₂O₂ and Na⁺, H₂O₂ and the Na⁺-Ca²⁺ exchanger, Na⁺ and the Na⁺-Ca²⁺ exchanger or by H₂O₂, Na⁺ and the Na⁺-Ca²⁺ exchanger and a rise in [Ca²⁺]i was triggered by H₂O₂, Na⁺ and a combination of Na⁺ and the Na⁺-Ca²⁺exchanger. 4. These results indicate that interactions between H₂O₂, Na⁺ and the Na⁺-Ca²⁺ exchanger stimulate intracellular Ca²⁺mobilization via Ca²⁺-induced Ca²⁺ release mechanisms, ATP-activated G-protein coupled P_2y-purinoceptor-sensitive pathways, Na⁺-Ca²⁺ exchanger-mediated Ca²⁺ influx and cation-π interaction (a strong non-covalent force between the cation and the π face of an aromatic structure in the transmembrane protein). 5. The present findings provide important clues for understanding Ca²⁺ signal transduction mechanisms from the plasma membrane to the endoplasmic reticulum.