Regulation of the functions of human leukocytes by oxametacine

Non steroidal anti-inflammatory drugs, such as oxametacine, are generally used in treatment of rheumatoid disease. In an 'in vitro' experimental model, the drug efficacy was tested on leukocyte functions. Locomotion, both random and directional, phagocytic activity and superoxide production of normal and rheumatoid PMNL were tested in the presence of varying concentrations of oxometacine. Locomotion was evaluated by using modified Boyden chambers; phagocytosis was tested by number of yeast particles injested and by NBT reduction; superoxide production was assayed by reduction of ferricytochrome C. In our conditions the drug exhibited a strong anti-inflammatory effect. In fact, chemotaxis and anion production were specifically depressed in a dose-dependent way.     

呼吸道感染常见致病菌耐药趋势分析

目的：调查我院临床常见的G-致病菌在院内呼吸道感染病人的分布,并检测常用抗生素的种类对致病菌的效价情况,为呼吸道感染病人合理选用抗生素提供依据。方法：对来源于院内呼吸道感染病人的样本300个进行分离培养,用microscan au-toscan4（美国德灵半自动细菌分析仪）菌种鉴定及抗生素的药敏实验,回顾性分析肺部感染患者的痰细菌培养及药物敏感性测定结果。结果：从样本中分离获得825株主要致病菌,其中G＋致病菌389株,占47.2%,G-致病菌380株,占46.1%,真菌46株,占6.7%。G＋致病菌对检测10种抗生素的药敏性主要表现为传统的抗生素的疗效普遍偏低;而G-致病菌对检测的抗生素10种的药敏性情况表现出多元化态势。结论：院内呼吸道感染常见致病菌以革兰阴性菌为主,耐药性高,临床实践应重视病原学的监测,了解细菌的种类分布和耐药趋势,合理使用抗生素。     

Inhibitory effects of phthalimide derivatives on the activity of the hepatic cytochrome P450 monooxygenases CYP2C9 and CYP2C19

Affecting hepatic cytochrome (CYP) activity is one of the major concerns in drug–drug interaction. Thus the testing of drug candidates on their impact on these enzymes is an essential step in early drug discovery. We tested a collection of 480 in-house phthalimide derivatives against different CYP450s using a high throughput inhibition assay. In initial tests with the isoform CYP2C19 about 57.5% of the tested phthalimide derivatives showed significantly enhanced inhibitory effects against this enzyme. In addition similar patterns of phthalimide inhibition for CYP2C9 and CYP2C19 were found, whereas the unrelated isoforms CYP2D6 and CYP3A4 were not specifically affected. Also less than 10% of randomly chosen substances inhibited CYP2C9. Analyses of structure-function relationships revealed that the substituent at the nitrogen atom in the isoindole ring is of crucial impact for the activity of CYP2C9/19.     

Genetic activity of trimethoprim in the Salmonella/microsomal screening system

Trimethoprim, a widely used antibacterial drug was tested for its mutagenic potential in the Ames Salmonella/microsomal test system. The results indicated that, when used in the recommended dose range, the drug produced a several-fold increase in the reversion mutations on his(-)----his+ marker in some of the tester strains, compared with the spontaneous reversions. Dose-dependent curves were also obtained for reversion mutations caused by the drug. Ethyl methanesulfonate and benzo[alpha]pyrene were used a control mutagens.     

Hemodynamic aspects of the hypotensive action of captopril

Captopril was tested in acute experiments on anesthetized cats subject to cardiopulmonary bypass. The drug was shown to reduce total peripheral vascular resistance and to increase vascular bed capacity.     

Significance of antigen, drug, and tumor cell targets in the preclinical evaluation of doxorubicin, daunorubicin, methotrexate, and mitomycin-C monoclonal antibody immunoconjugates

We tested drug monoclonal antibody immunoconjugates in vitro in 72 h 3H-thymidine assays and in vivo in athymic mice bearing human tumor xenografts of the same target cells. Experimental arms included control, monoclonal antibody, drug, drug + antibody, the test immunoconjugate, and a negative control immunoconjugate with an equivalent molar amount of drug for in vitro experiments, and the amount of drug conjugated to 500 micrograms of antibody in the animal experiments. Monoclonal antibodies included T101, an IgG2a that reacts with a rapidly modulating antigen, 9.2.27, an IgG2a that reacts with a slowly modulating antigen, and ME7, an IgG1 that reacts with a slowly modulating antigen. Cells used in testing included MOLT-4 (T lymphoma), 8392 (B lymphoma), and M21 (melanoma). Drugs tested were doxorubicin, daunorubicin, methotrexate, and mitomycin-C. M21 cells were resistant to daunorubicin in vitro but were inhibited by the 9.2.27 daunorubicin immunoconjugate. T101, 9.2.27, and ME7 cis-aconitate anthracycline immunoconjugates and mitomycin-C-glutarate immunoconjugates were specifically cytotoxic only for antigen positive cells in vitro and were superior to free drug in vivo. These results confirm that antigen specific-cytotoxic drug immunoconjugates can be produced that are superior to the same dose of free drug. However, each monoclonal antibody drug target system is unique and must be well-characterized for appropriate interpretation of data.     

Phosphorylation of lens membrane: identification of the catalytic subunit of Na+, K+-ATPase

Receptor mediated endocytosis appears to depend on the action of a transglutaminase (TGase). Endocytosis can be induced in intact human RBC by the action of several classes of drugs. We tested the hypothesis that drugs acted by stimulating TGase activity. Of the endocytosis inducing drugs tested, neither primaquine nor vinblastine nor chlorpromazine enhanced TGase activity. We next tested the hypothesis that TGase activity was required for drug endocytosis in RBC by adding known TGase inhibitors. Paradoxically, m-Dansyl cadaverine, the most potent TGase inhibitor, produces endocytosis in human RBC. Therefore despite apparent striking morphologic similarities, drug induced endocytosis in RBC appears to proceed via different mechanisms from those involved in receptor mediated endocytosis in other cells.In the receptor-mediated endocytosis of some hormones and growth factors, it appears that the receptor-ligand complex forms clusters over clathrin coated pits which are then internalized as endocytic vacuoles. Both the clustering and internalization of ligands are inhibited by a variety of agents shown to inhibit transglutaminase (TGase) and it is therefore proposed that TGase participates in receptor-mediated endocytosis (1–3). Human erythrocytes undergo endocytosis when exposed to drugs like primaquine, chlorpromazine, and vinblastine (4), all of which are amphipathic cations (4). However, the mechanism of drug action is not known nor is it clear that this is a form of receptor-mediated endocytosis (4). Furthermore, clustering of receptors can occur in neonatal but not adult human RBC (5). TGase has been measured in human red cells (6) although its physiologic role is unknown. Like all TGases, it is calcium dependent (6,7), and primaquine induced red cell endocytosis is enhanced by Ca⁺⁺ addition (8). Therefore, we tested the hypothesis that TGase participates in drug induced endocytosis in intact human red cells.     

15年前后细菌L型临床耐药性的变迁

目的检测15年前后细菌L型临床耐药性的变迁,分析影响因素,指导临床用药。方法对新乡市中心医院15年来临床检出的常见细菌L型菌株逐个进行药敏监测,逐年进行耐药性变化分析研究。结果1990年至1999年细菌L型常见菌株耐药性逐年上升,特别是青霉素类大部耐药;2000年至2005年,耐药性趋势变缓,青霉素类耐药率有所下降。结论合理应用抗生素,不滥用抗生素是细菌L型耐药性变迁的重要原因,药物敏感试验是良好的监测方法。     

112株志贺菌菌群分布和药敏特点分析

目的研究本地区2001年至2005年志贺菌菌群分布及其药敏特点,以指导临床合理抗菌治疗。方法经大便培养筛选志贺菌,用生化和血清学方法鉴定菌群和血清型,采用K-B法检测病原菌耐药性。结果在112例细菌性痢疾患者中,男女比例相似,年龄分布以婴幼儿最高,临床表现不典型者较多,菌群分布以福氏志贺菌最多,F2b为优势血清型,对抗菌药物敏感性差异有显著性。结论近5年来本地区细菌性痢疾患者发病特点有年龄差异,菌群仍以福氏志贺菌为主,血清型以F2b为主,第3代头孢菌素是治疗细菌性痢疾最佳的抗菌药物。     

雄黄纳米微粒在细胞水平上抑制呼吸道合胞病毒复制的初步研究

建立呼吸道合胞病毒A型(RSV-A型)感染Hep-2细胞模型,通过预防、治疗及直接灭活三种不同给药方式,观察中药雄黄对RSV-A型感染Hep-2细胞病变(CPE)的抑制作用。用高能球磨机研磨双蒸水水飞处理制备雄黄纳米微粒,应用砷钼蓝染色法测定雄黄纳米微粒浓度并在Nano Series粒度测定仪上测定其粒度。以MTT法计算药物的半数中毒剂量(TC50)。通过三种不同给药方式即预防给药、治疗给药及直接灭活给药方式进行体外实验,以利巴韦林为阳性对照药,观察雄黄纳米微粒对RSV-A型感染Hep-2细胞病变所起的作用,并对药物的量效关系进行分析。雄黄纳米微粒TC50值为0.649μg/mL。预防、治疗及直接灭活给药方式均可减轻RSV-A感染Hep-2细胞的CPE程度,其抑制RSV-A型感染Hep-2细胞病变的半数有效浓度(IC50)分别为0.20μg/mL、0.13μg/mL、0.16μg/mL,治疗指数(TI)分别为3.18、4.99和4.11,雄黄纳米微粒对RSV-A型感染Hep-2细胞病变的抑制作用存在着明显的量效关系。雄黄纳米微粒按预防、治疗及直接灭活给药方式给药时,其中治疗给药方式更有利于减轻RSV-A感染Hep-2细胞引起的病变。     

Trypanosoma cruzi: 4-aminopyrazolopyrimidine in the treatment of experimental Chagas' disease

An allopurinol metabolite, 4-aminopyrazolopyrimidine, was tested on two different strains of mice (NMRI-IVIC and C57Bl/6J) that had been infected 4 days earlier with the virulent Ya strain of Trypanosoma cruzi. Low doses of 4-aminopyrazolopyrimidine (0.125-0.500 mg/kg body wt/day) for 10 days induced a significant reduction in parasitemia (direct counts and subinoculation experiments) and increased survival time (without any evidence of toxicity) compared with untreated animals. When tested in vitro, 4-aminopyrazolopyrimidine was sixfold more active than allopurinol as a trypanostatic drug. The low therapeutic doses of 4-aminopyrazolopyrimidine suggest that this drug may be useful in the treatment of acute Chagas' disease.     

In vitro testing of chemotherapeutic combinations in a rapid thymidine incorporation assay

A total of 199 solid human tumors were tested with a rapid thymidine incorporation assay for sensitivity to one of several clinically used multi-drug combinations and to each agent in the combination separately. Melanomas, lung and breast cancers accounted for the majority of specimens. In 120 specimens, at least one single agent exhibited in vitro activity (80% or greater inhibition of thymidine incorporation), and in 116 of these (96.7%) the drug combination was active in vitro. In the 79 specimens where no single agent was active in vitro, the combination was also inactive in 62 (78.5%). Overall, there was concordance of in vitro activity of the most active single agent and the combination of agents in 89.5% of specimens tested. A lack of significant in vitro synergy was noted in all of the drug combinations and tumor types tested. Of note is the fact that in 141 of the 199 tests (70.9%) either no drug (n = 79) or only 1 drug (n = 62) demonstrated in vitro activity. We conclude that the rapid thymidine incorporation assay can be used to test for in vitro sensitivity to drug combinations, and that sensitivity to a drug combination can be inferred if a tumor is sensitive to any component drug of the combination.     

Pyrazole acids as niacin receptor agonists for the treatment of dyslipidemia

Niacin is an effective drug for raising HDL cholesterol and reducing coronary risks, but patients show low compliance with treatment due to severe facial flushing upon taking the drug. A series of bicyclic pyrazole carboxylic acids were synthesized and tested for their ability to activate the niacin receptor. One analog, 23, showed improved potency and lacked flushing at doses that effectively altered the lipid profile of rats.     

In vitro and in vivo antimycobacterial activity of antiinflammatory drug, diclofenac sodium

The non-steroidal antiinflammatory drug diclofenac sodium exhibited remarkable inhibitory action against both drug sensitive and drug resistant clinical isolates of Mycobacterium tuberculosis, as well as other mycobacteria. This agent was tested in vitro against 45 different strains of mycobacteria, most of which were inhibited by the drug at 10-25 microg/ml concentration. When tested in vivo, diclofenac, injected at 10 mg/kg body weight of a Swiss strain of white mice, could significantly protect them when challenged with a 50 median lethal dose of M. tuberculosis H37 Rv102. According to Chi-square test, the in vivo data were highly significant (P<0.01).     

肠杆菌新解释标准指导临床用药的实用性

采用新旧肠杆菌的2种解释标准,分析肠杆菌的耐药性,比较2种解释标准的临床意义。收集本院2009至2010两年临床分离的912株大肠埃希菌、328株肺炎克雷伯菌,用Kirby-Bauer法作药敏试验,用WO-NET5.4软件先设置CLSI推荐的旧的肠杆菌解释标准,分析耐药性。再设置CLSI推荐的新的肠杆菌解释标准[1]修改头孢曲松、头孢他啶、头孢噻肟、氨曲南和亚胺培南的解释标准,分析其耐药性。用肠杆菌旧的解释标准分析常规检测分离出的大肠埃希菌236株产酶株;肺炎克雷伯66株产酶株;产酶株比非产酶株的耐药率高。用新的头孢菌素和氨曲南的解释标准:对于大肠埃希菌头孢曲松的耐药率提高5.2%;头孢他啶提高10.4%;头孢噻肟提高10.2%;氨曲南提高7.1%;对于肺炎克雷伯菌头孢曲松的耐药率提高6.7%;头孢他啶提高4.3%;头孢噻肟提高10.1%;氨曲南提高2.5%;未向临床报产酶株。采用碳青霉烯类抗生素新的解释标准大肠埃希菌和肺炎克雷伯菌对亚胺培南的耐药分别提高了0.4%和0.6%,对美罗培南的耐药率分别提高了0.2%和0.6%。新的肠杆菌解释标准更能客观分析肠杆菌的耐药性,对指导临床合理用药,控制耐药株的蔓延更具实用价值。     

The Activity of Pipemidic Acid and Piromidic Acid against Escherichia coli In Static Culture and in Conditions Simulating the Treatment of Bacterial Cystitis

The activity of the new pyridopyrimidine compounds, pipemidic and piromidic acids, against Escherichia coli was compared with that of nalidixic acid in vitro . In a static turbidimetric system nalidixic and pipemidic acids were found to be more active than piromidic acid when tested against sensitive E. coli strains, but pipemidic acid was the most active of the three compounds against nalidixic acid-resistant clinical isolates. When tested in an in vitro model designed to mimic the conditions in which bacteria and drug interact in the treatment of bacterial cystitis, all three drugs were found to be able to suppress bacterial growth for long periods, but a high, sustained drug level was necessary in order to prevent the emergence of resistant variants.     

Antimicrobial potentiality of a phenothiazine group of antipsychotic drug-prochlorperazine

The antipsychotic drug, prochlorperazine (Pcp), was tested for its antimicrobial efficacy against 103 strains belonging to both gram positive and gram negative bacteria. The drug was found to possess maximum activity against Staphylococcus aureus, Vibrio cholerae and Shigella spp. Pcp was moderately active against E. coli but most of the strains belonging to Bacillus spp, Klebsiella spp, Salmonella spp and Lactobacillus spp were found to be resistant to this drug. The drug was tested for its mode of antibacterial activity against Shigella dysenteriae 1 and it was found to be bacteriostatic in action. In in vivo studies, Pcp offered significant protection to Swiss albino mice at concentrations of 0.75 micro g/g (P < 0.01) and 1.5 microg/g (P < 0.001) body weight when challenged with 50 median lethal dose of Salmonella typhimurium NCTC 74. Thus the result depicts that prochlorperazine may emerge as a strong antimicrobial drug to replace the conventional antibiotics and to overcome the problem of drug resistance.     

c-myc oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer

A pilot study on relationships of selected molecular factors (c-myc oncogene average gene copy numbers (AGCN); serum CEA and CA 15.3 antigen levels; tumor cells' DNA values), to the ex vivo chemosensitivity of primary female human breast cancer in a modified adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA), was performed. Four drug combinations were tested. A group of 75 cases of female primary breast cancer was assessed. Numerous correlations were found among molecular factors tested but none, with the exception of tumor grading, of these reflected ex vivo chemosensitivity of tumors tested. The results suggest that the parameters tested may not be important factors related to adjuvant chemoresponsiveness of primary human breast cancer to tested drug combinations.     

Proteins fro Escherichia coli ribosomes involved in the binding of erythromycin.

When 50 S subunits from Escherichia coli ribosomes were incubated with 1·3 m-LiC1 the resulting 1·3c core was inactive both with respect to peptidyltransferase activity and erythromycin binding (tested by equilibrium dialysis). Reconstitution experiments with purified proteins from the corresponding split fraction SP1·3 revealed that only L16 (reconstituted with the 1·3c core in a tenfold excess) could restore high activity in both systems.When 30 out of the 34 isolated ribosomal proteins were tested directly for binding or erythromycin, L15 was able to bind the drug, in contrast to all other proteins including L16. Total reconstitution experiments with the 50 S subunit demonstrated an absolute requirement for L15 and L16 with respect to both drug binding and peptidyltransferase activity.     

Specific and nonspecific macromolecule-drug conjugates for the improvement of cancer chemotherapy

Antineoplastic drugs such as daunomycin, adriamycin, methotrexate, 5-fluorouridine, cytosine arabinoside, and platinate were bound to antibodies directly or via a polymeric bridge. The drug antibody conjugates retained most of their drug and antibody activities when tested in vitro. Daunomycin–antibody conjugates were shown to penetrate tumor cells in the conjugated form. In animals, daunomycin–antibody conjugates were at least as effective chemotherapeutically as the corresponding free drugs and considerably less toxic. In some tumor systems, the daunomycin–antibody conjugates represented an improvement over the free drug. This improvement was restricted in some tumors to a particular injection route of the tumor and the treatment.