Aryl phosphate derivatives of AZT retain activity against HIV1 in cell lines which are resistant to the action of AZT.

Novel aryl phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials are designed to act as membrane-soluble pro-drugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective antiviral activity, which, in one case, was more potent than the parent nucleoside AZT. The magnitude of the biological effect varied considerably with the nature of the phosphate-blocking group. Moreover, one of the compounds, a phosphoramidate, is particularly active in a cell line restrictive to the activity of AZT, due to poor phosphorylation therein. These data support the suggestion that the phosphate derivatives exert their biological effects via intracellular release of the nucleotide forms.     

The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific

The L-isomer of verapamil is a more potent calcium antagonist than the D-isomer. We have examined the two stereoisomers of verapamil for their ability to increase the chemosensitivity in vitro of three drug resistant cell lines (2780AD, MCF7/AdrR and H69LX10). Neither racemic verapamil nor its individual isomers had any effect on the drug sensitivity of the parent cell lines (A2780, MCF7 and NCI-H69). Verapamil (6.6 microM) increased the sensitivity of all three resistant cell lines to Adriamycin by 10-12-fold. This activity was concentration dependent and was maximal at 6-7 microM. The increase in sensitivity was only 2-3-fold at 2 microM, the maximum plasma concentration achieved in patients. Both the D- and L-isomers of verapamil alone at 6.6 microM were as effective as racemic verapamil and the D-isomer demonstrated the same concentration dependent activity as racemic verapamil. The total cellular Adriamycin concentration of both 2780AD and MCF7/AdrR was increased by two-fold in the presence of verapamil (6.6 microM). Both D- and L-verapamil alone increased the amount of drug accumulated to the same extent as racemic verapamil. These results indicate that the resistance modification activity of verapamil is not stereospecific. Use of D-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thus D-verapamil may be a more effective resistance modifier in vivo than racemic verapamil.     

三氧化二砷单用或联用化疗药物对多药耐药白血病细胞的毒性研究

目的探讨三氧化二砷（As     

Effects of isoprenoid analogues of SDB-ethylenediamine on multidrug resistant tumor cells alone and in combination with chemotherapeutic drugs

Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major obstacle for successful treatment of cancer. Inhibition of Pgp transport is important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines with at least one tertiary N atom, such as verapamil, are classical PgP-blocking agents. In a search for novel accessible compounds potent against MDR tumor cells, we synthesized a series of arylalkylamines that contain isoprenoid side chains of different length. Two out of seven new analogues of the known N,N'-bis(3,4-dimethoxybenzyl)-N-solanesylethylenediamine (SDB-ethylenediamine), namely, compounds with C10 and C15 side chains, at low micromolar concentrations were preferentially toxic for several mammalian tumor cell lines that acquired MDR during prolonged drug selection. Moreover, at noncytotoxic concentrations, these compounds potently sensitized MDR cells to Pgp substrates vinblastine and adriamycin. We conclude that these analogues of SDB-ethylenediamine may have dual therapeutic advantage because (i) they are preferentially toxic for MDR cells when administered alone and (ii) they potentiate the cytotoxicity of Pgp-transported anticancer drugs.     

Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

Recently discovered chemically modified tetracyclines (CMTs) have shown in vitro and in vivo anti-proliferative and anti-tumour activities. Here, we evaluated in vitro the anti-proliferative and apoptotic activity of six different dedimethylamino chemically modified tetracyclines (CMT-1, CMT-3, CMT-5, CMT-6, CMT-7 and CMT-8) in sensitive and multidrug resistant myeloid leukaemia cells (HL60 and HL60R) in vitro. Three of these compounds (CMT-5, CMT-6, CMT-7) showed low cytotoxic activity both in sensitive and in resistant cells, CMT-3 was endowed with a high anti-proliferative activity only in sensitive cells and was moderately effective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT-1 and CMT-8 were very effective as programmed cell death inducing agents. The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase-9 and, for CMT-1, also the activation of FAS: Interestingly CMT-8, but not CMT-1, was able to induce apoptosis in multidrug resistant HL60R and in Fas-ligand resistant HUT78B1 cell lines. These properties, together with others previously described (e.g. anti-metastatic and anti-osteolytic activities), suggest that CMT-8 may have important applications in the clinical management of cancer. The comparative analysis of structure-activity relationship of CMT-8 and doxycycline suggests that the C-5 hydroxy moiety may play an important role in conferring activity in multidrug resistant cells. These findings appear to support the hypothesis that CMT-8 may represent an interesting lead for the development of a new class of potent apoptosis inducer agents active in multidrug resistant and Fas-ligand resistant malignancies.     

替加环素联合5种抗菌药物对多重耐药鲍曼不动杆菌的体外活性

目的 评价替加环素分别联合5种临床常用抗不动杆菌属抗菌药物对57株多重耐药鲍曼不动杆菌的体外抗菌作用.方法 琼脂棋盘稀释法测定替加环素分别联合美罗培南、阿米卡星、环丙沙星、粘菌素、舒巴坦对57株对美罗培南、阿米卡星、环丙沙星、米诺环素均耐药的多重耐药鲍曼不动杆菌的最低抑菌浓度(MIC),并计算部分抑菌浓度指数(FICI).结果 替加环素与5种抗菌药物联合后表现为协同或不相关作用,其中协同率较高的组合为替加环素+阿米卡星组,50.9％;其次为替加环素+美罗培南组,29.8％,未发现拮抗现象.结论 替加环素与5种抗菌药物联合对本组多重耐药鲍曼不动杆菌主要表现为不相关作用,但与阿米卡星联合具有相对较高的协同率.     

三种局部抗菌药物对甲氧西林耐药金黄色葡萄球菌的抗菌活性研究

目的：研究分析三种局部抗菌药物对甲氧西林耐药金黄色葡萄球菌的抗菌活性研究。方法：回顾性分析我院于2014年3月～2015年3月收治的100例烧伤患者的病历资料,对烧伤创面分泌物制作标本,共分离100株非重复并连续的MRSA,应用棋盘格法对磺胺嘧啶银、莫匹罗星、克霉唑单用以及联用时对MRSA的抗菌活性予以分析。结果：磺胺嘧啶银对MRSA的MIC为8μg/mL, MIC50为9μg/mL,MIC90为16μg/mL,莫匹罗星对MRSA的MIC为2μg/mL,MIC50为16μg/mL,MIC90为64μg/mL,克霉唑对MRSA的MIC分别为2μg/mL,MIC50为3μg/mL,MIC90为4μg/mL。莫匹罗星和克霉唑联用,和磺胺嘧啶银单用比较,MIC50降低75%,MIC90降低87.5%;和莫匹罗星单用比较,MIC50降低87.5%,MIC90降低96.9%;和克霉唑单用比较,MIC50降低50%,MIC90降低50.0%;磺胺嘧啶银和莫匹罗星联用,有70例相同,20例相加,10例无关,没有拮抗现象。磺胺嘧啶银和克霉唑联用,92例抗菌效果相加,8例无关,没有协同和拮抗现象。两种药物联用的抗菌活性明显优于单用。结论：MRSA感染的烧伤创面,就要应用较低剂量的磺胺嘧啶银联合其他药物,不仅可以实现感染的有效控制,也能将药物对创面愈合的一种不良反应降低,值得临床推广。     

Antifungal activity of ribavirin used alone or in combination with fluconazole against Candida albicans is mediated by reduced virulence

The incidence of fungal infections has increased continuously in recent years, and drug resistance, especially resistance to fluconazole (FLC), has emerged. To overcome this challenge, research on the antifungal activities of non-antifungal agents has gained more attention. In this study, we determined the anti-Candida activity of ribavirin (RBV), an antiviral drug commonly used in the clinic, and found that RBV displayed potent antifungal activity when used alone or in combination with FLC in vitro and in vivo. In vitro, the MIC₈₀ values of RBV were 2–4 µg/mL for FLC-susceptible Candida albicans and 8 µg/mL for FLC-resistant C. albicans. When RBV at a dose of 1 µg/mL was combined with FLC, significant synergistic effects were exhibited against FLC-resistant C. albicans, and the MICs of FLC decreased from >512 µg/mL to 0.25–1 µg/mL. Synergism was also exhibited against C. albicans biofilms. In vivo, RBV plus FLC significantly improved the survival of infected Galleria mellonella larvae compared with the FLC-treated group over a 4-day period and attenuated the damage of FLC-resistant C. albicans to G. mellonella larvae tissue. Furthermore, mechanistic studies indicated that the antifungal effects of RBV used alone or in combination with FLC might be associated with inhibition of biofilm formation, reduced extracellular phospholipase activity and inhibition of hyphal growth, but is not related to promotion of FLC uptake and inhibition of FLC efflux. These results provide a promising direction for overcoming drug resistance and for expanding the clinical application of existing drugs.     

In vitro antibacterial activity of cefotaxime and desacetylcefotaxime, alone or in combination, against gram-positive cocci

The in vitro activity of cefotaxime and desacetylcefotaxime against Staphylococcus aureus, Staph. epidermidis and Streptococcus pyogenes was investigated. Synergy studies were performed using time-kill curves and the chequerboard test. The time-kill curves were performed on five strains each of Staph. aureus, Staph. epidermidis and Strep. pyogenes; cefotaxime and desacetylcefotaxime were tested alone or in combination at MIC and sub-MIC values. The chequerboard test was performed in microtitre plates on ten strains each of Staph. aureus, Staph. epidermidis and Strep. pyogenes: the results were interpreted by the fractional inhibitory concentration index. In some cases both methods showed synergistic interaction against the staphylococci tested. Indifference was observed against Strep. pyogenes.     

The effects on memory of pipequaline,alone or in combination with diazepam

Pipequaline (PK 8165) is a putative mixed agonist/antagonist at benzodiazepine receptors. The effects of pipequaline and diazepam on memory were assessed in 12 normal volunteers. Diazepam 10 mg or placebo was added to two doses of pipequaline, 50 and 150 mg, or to placebo in a double-blind crossover design. Diazepam produced impairments of episodic memory. In contrast, the effects of pipequaline were minor. Addition of diazepam to pipequaline increased drowsiness and general lethargy, with a less marked effect occurring for the higher dose of pipequaline alone. Pipequaline did not antagonise any of the effects of diazepam.     

Effects of heroin,alone or in combination with other drugs,on the locomotor activity in two inbred strains of mice

The locomotor activity of C57B1/6J and DBA/2J mice was studied, under the influences of heroin, amphetamine, strychnine, or ethanol, and of combinations of the opiate with each one of the other drugs. Heroin treatment was followed by the typical running fit in the C57 mice, while the DBA strain was unaffected. Amphetamine enhanced the activity in the C57 strain only. The combination of heroin with amphetamine or ethanol increased the locomotor activity only in the DBA strain, while heroin + strychnine exerted a clear stimulating effect on the activity of the C57 mice. The strychnine + heroin mixture was more toxic than heroin alone when the lethal doses (LD50) were determined in the 2 strains.     

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.     

Effects of intranasal xylometazoline,alone or in combination with ipratropium,in patients with common cold

Abstract

Background:

Common cold is one of the most prevalent conditions that family doctors encounter. One of the first symptoms to occur is nasal congestion, which can have a negative impact on daily life and prompts many patients to seek treatment for relief. Xylometazoline nasal spray (Otrivin^*) is a topical decongestant that has been used successfully for many years and is generally recognized as an effective and safe therapy. However, most studies have investigated its clinical efficacy in healthy patients and few have included patients with common cold.     

苯丁酸钠单用与氟尿嘧啶或顺铂联用对喉癌Hep-2细胞株的影响

目的:研究苯丁酸钠(sodiumphenylbu-tyrate,PB)对体外喉癌Hep-2细胞株生长和分化的影响,及其能否增强氟尿嘧啶、顺铂对喉癌细胞的细胞毒性。方法:采用流式细胞仪检测PB作用后喉癌细胞的细胞周期,应用四氮唑蓝法检测PB单独及联用氟尿嘧啶或顺铂时,喉癌细胞的存活能力。结果:经PB作用4d后,细胞周期出现G1-S期阻滞和剂量依赖性生长抑制作用;PB的半数抑制浓度(IC50)是4.21mmol·L-1。1mmol·L-1PB与氟尿嘧啶或顺铂联用3d后,2药的IC50分别由(11.4±s1.7)mg·L-1和(1.60±0.05)mg·L-1下降至(8.2±0.8)mg·L-1和(1.36±0.11)mg·L-1P<0.05。结论:PB能诱导体外喉癌细胞发生分化和生长抑制作用,增强氟尿嘧啶、顺铂对喉癌细胞株的细胞毒性作用。     

复方藤梨根制剂体外对MDR细胞株K562/ADR和K562/VCR细胞积聚和外排阿霉素(ADR)的影响研究

目的 :探讨复方藤梨根制剂 (FFTLG)对肿瘤化疗增敏的作用机理。方法 :以MTT法观察FFTLG对MDR细胞的逆转作用 ,以FCM技术测定FFTLG作用MDR细胞后对阿霉素的积聚和外排影响。结果 :10mg/ml和 2 0mg/ml的FFTLG对K5 6 2 /ADR的逆转倍数是 7.5 3和 10 .31倍 (P <0 .0 5 ) ;2 0mg/ml的FFTLG对K5 6 2 /VCR的逆转倍数是 6 .18倍 ;10mg/ml和2 0mg/ml的FFTLG可增加K5 6 2 /ADR和K5 6 2 /VCR细胞内ADR的积聚分别是 77.6 % ,80 .1%和 5 0 .9% ,4 5 .2 % ,且可减少ADR的外排。结论 :FFTLG通过增加MDR细胞内的ADR积聚及减少外排机制而实现对化疗的增敏作用