Fixed dose combination of capecitabine and cyclophosphamide in metastatic breast cancer: Results from THE ENCLOSE phase 2/3 randomized multicenter study

AimTo evaluate pharmacokinetics, efficacy and safety of fixed-dose combination (FDC) of oral capecitabine + cyclophosphamide in metastatic breast cancer (MBC) patients progressing after anthracycline and/or taxane chemotherapy.MethodsIn this prospective, adaptive, phase-2/3, open-label study (CTRI/2014/12/005234), patients were randomized (1:1:1) to three FDC doses (doses/day: D1, capecitabine + cyclophosphamide 1400 mg + 60 mg; D2, 1800 mg + 80 mg; D3, 2200 mg + 100 mg) for 14 days, in 21-day cycles. In Part-I, multiple-dose pharmacokinetics and optimal dose(s) were evaluated with futility analysis. Group(s) with <3 responders based on best overall response rate (BOR, complete response [CR]+partial response [PR]), were discontinued. Efficacy (BOR, disease control rates [DCR; CR + PR + stable disease]) and safety of optimal dose(s) were evaluated in Part-II.ResultsOf 66 patients (n = 22/group) in Part-I, pharmacokinetics (D1 = 7/22, D2 = 9/22, D3 = 8/22) showed dose-proportionality for cyclophosphamide and greater than dose-proportionality for capecitabine. Modified intent-to-treat (mITT) analysis showed BOR of 7.14% (1/14) in D1 (discontinued), and 22.22% (4/18) each in D2 and D3, respectively. In Part-II, 50 additional patients were randomized in D2 and D3 (n = 144; total 72 [22 + 50] patients/group). mITT analysis in D2 (n = 54) and D3 (n = 58) showed BOR of 29.63% (16/54, 95%CI: 17.45–41.81%) and 22.41% (13/58, 95%CI: 11.68–33.15%), respectively. DCR in D2 and D3 were 87.04% (47/54, 95%CI: 78.08–96.00%) and 82.76% (48/58; 95%CI: 73.04–92.48%) after 3 and 57.41% (31/54; 95%CI: 52.41–79.50%) and 50.00% (29/58; 95%CI: 40.40–67.00%), after 6-cycles, respectively. Hand-foot syndrome (16.67%), vomiting (9.72%) in D2, and hand-foot syndrome (18.06%), asthenia (15.28%) in D3 were most-common adverse events.ConclusionFDC of capecitabine + cyclophosphamide (1800 + 80 mg/day) showed high disease control rates and good safety profile in MBC patients.     

多重耐药鲍曼不动杆菌对戊二醛消毒剂的敏感性

目的：探讨鲍曼不动杆菌对消毒剂的敏感性,为医院消毒措施提供参考依据。方法采用消毒剂对细菌最低杀菌浓度（ MBC）和最低抑菌浓度（ MIC）的检测方法,评估鲍曼不动杆菌对3种消毒剂的敏感性。采用PCR方法检测耐消毒剂基因qacEΔ1－sull。结果邻苯二甲醛消毒剂、纯戊二醛消毒剂、2％强化戊二醛消毒剂对多重耐药鲍曼不动杆菌的MBC值分别为500、20000、2500 mg／L,MIC值分别为250、5000、315 mg／L。邻苯二甲醛消毒剂、纯戊二醛消毒剂、2％强化戊二醛消毒剂对敏感鲍曼不动杆菌的MBC值分别为250、10000、1250 mg／L,MIC值分别为125、2500、78 mg／L。邻苯二甲醛消毒剂、纯戊二醛消毒剂、2％强化戊二醛消毒剂对质控菌ATCC27853、ATCC25922的MBC值分别2500、10000、1250 mg／L,MIC值分别为125、2500、78 mg／L。 PCR方法检测到7株多重耐药鲍曼不动杆菌含有耐消毒剂基因qacEΔ1－sull,5株敏感鲍曼不动杆菌和质控菌株未检测出耐消毒剂基因qacEΔ1－sull。结论2％强化戊二醛消毒剂对多重耐药鲍曼不动杆菌的MIC值和MBC值较敏感鲍曼不动杆菌、标准菌株明显升高,多重耐药鲍曼不动杆菌对消毒剂抗性的产生与耐消毒剂基因qacEΔ1－sull有关。     

Slightly acidic electrolyzed water disrupts biofilms and effectively disinfects Pseudomonas aeruginosa

IntroductionBiofilm formation is an important issue in the healthcare industry, but conventional disinfectants are not effective for biofilms formed in the hospital environment and on medical instruments. In this study, aim at determine the effectiveness of slightly acidic electrolyzed water (SAEW) on biofilm removal and the disinfection of biofilm-forming Pseudomonas aeruginosa.MethodsMucoid and non-mucoid strains were used for biofilm formation. Biofilms were incubated with SAEW and the reduction in biofilm volume was determined based on the optical density. Furthermore, to investigate the mechanism underlying the effects of SAEW, a biofilm was produced with alginate and structural changes in response to incubation with SAEW were observed by fluorescence microscopy. The minimum bactericidal chlorine concentration of SAEW for P. aeruginosa cells was evaluated.ResultsThe amounts of alginate and biofilm decreased by 99.9% and 56.8% immersed by 30 ppm of SAEW at 25 °C for 10 min. The effectiveness of SAEW increased as the temperature increased, and the biofilm volume was reduced by 85.4% at 45 °C. Furthermore, 30 ppm SAEW completely disinfected P. aeruginosa in the biofilm, even for immersion at 15 °C for 5 min.ConclusionOur results suggest that SAEW, a low-cost and safe chlorine disinfectant, is a useful disinfectant for biofilm-forming bacteria.     

Antioxidant,anti-microbial and antimutagenicity activities of pistachio (Pistachia vera) green hull extract

Antioxidant, anti-microbial and antimutagenicity activities of pistachio (Ahmadaghaei variety) green hull extracts (crude and purified extracts) were studied. At first, different solvents were compared for determining of the best solvent for extraction of phenolic compounds from pistachio green hull. Water and acetonitrile with 49.32 and 6.22 (mg of gallic acid equivalents/g sample) were the best and the worst solvent in the extraction of phenolic compounds, respectively. The antioxidant capacity of crude and purified extracts were assessed through ABTS assay, DPPH assay and β-carotene bleaching (BCB) method. A concentration-dependent antioxidative capacity was verified in ABTS, DPPH assays and BCB method. The anti-microbial capacity was screened against Gram positive and Gram negative bacteria, and fungi. Aqueous and purified extracts inhibited the growth of Gram positive bacteria; Bacillus cereus was the most susceptible one with MIC of 1 mg/mL and 0.5 mg/mL for the crude and purified extracts, respectively. The results of antimutagenicity test showed that phenolic compounds of pistachio green hull have antimutagenicity activity against direct mutagen of 2-nitrofluorene. The results obtained indicate that pistachio green hull may become important as a cheap and noticeable source of compounds with health protective potential and anti-microbial activity.     

Effect of an alkaloidal fraction of Tabernaemontana elegans (Stapf.) on selected micro-organisms

Ethnopharmacological relevance

Bacterial infections remain a significant threat to human health. Due to the emergence of widespread antibiotic resistance, development of novel antibiotics is required in order to ensure that effective treatment remains available. There are several reports on the ethnomedical use of Tabernaemontana elegans pertaining to antibacterial activity.

Aim of the study

The aim of this study was to isolate and identify the fraction responsible for the antimicrobial activity in Tabernaemontana elegans (Stapf.) root extracts.

Materials and methods

The active fraction was characterized by thin layer chromatography (TLC) and gas chromatography–mass spectrometry (GC–MS). Antibacterial activity was determined using the broth micro-dilution assay and antimycobacterial activity using the BACTEC radiometric assay. Cytotoxicity of the crude extract and fractions was assessed against primary cell cultures; lymphocytes and fibroblasts; as well as a hepatocarcinoma (HepG2) and macrophage (THP-1) cell line using the Neutral Red uptake and MTT assays.

Results

The crude root extracts were found to contain a high concentration of alkaloids (1.2%, w/w). GC–MS analysis identified the indole alkaloids, voacangine and dregamine, as major components. Antibacterial activity was limited to the Gram-positive bacteria and Mycobacterium species, with MIC values in the range of 64–256 μg/ml. When combined with antibiotics, additive antibacterial effects were observed. Marked cytotoxicity to all cell lines tested was evident in the MTT and Neutral Red uptake assays, with IC₅₀ values <9.81 μg/ml.

Conclusions

This study confirms the antibacterial activity of Tabernaemontana elegans and supports its potential for being investigated further for the development of a novel antibacterial compound.     

中药奇蒿提取物体外抗菌活性的实验研究

目的研究中药奇蒿80%乙醇粗提取物及其石油醚、氯仿、乙酸乙酯、正丁醇提取物对临床常见菌种的抗菌活性。方法对中药奇蒿进行系统性分离提取,以80%乙醇粗提取物和石油醚、氯仿、乙酸乙酯、正丁醇提取物进行体外药敏实验,序贯使用纸片扩散法和常量肉汤稀释法,选用临床常见的致病菌株,包括金黄色葡萄球菌（标准型ATCC25923）、大肠埃希氏菌（标准型ATCC25922）、铜绿假单胞菌（标准型ATCC27853）、无乳链球菌（临床型）、粪肠球菌（临床型）、福氏志贺菌（临床型）和痢疾志贺菌（临床型）。结果奇蒿80%乙醇粗提取物对痢疾志贺菌的最小杀菌浓度（MBC）为25 mg/ml;奇蒿氯仿提取物对大肠埃希氏菌的MBC为6.25 mg/ml,对金黄色葡萄球菌的MBC为12.5 mg/ml;奇蒿乙酸乙酯提取物对福氏志贺菌、痢疾志贺菌、无乳链球菌的MBC均为6.25 mg/ml,对金黄色葡萄球菌的MBC为12.5 mg/ml;奇蒿正丁醇提取物对无乳链球菌的MBC为12.5 mg/ml,对痢疾志贺菌的MBC为25 mg/ml;石油醚提取物未对测试的细菌表现出明显的抗菌活性。结论奇蒿不同提取物对临床多种致病菌表现出了良好的杀菌作用,在抗感染治疗领域具有较好的开发和应用前景,其有效单体及杀菌机制有待进一步研究发现。     

Comparison of effects of estradiol with those of octylmethoxycinnamate and 4-methylbenzylidene camphor on fat tissue, lipids and pituitary hormones

Octylmethoxycinnamate (OMC) and 4-methylbenzylidene camphor (4MBC) are commercially used absorbers of ultraviolet (UV) light. In rats, they were shown to exert endocrine disrupting including uterotrophic, i.e. estrogenic effects. Estrogens have also metabolic effects, therefore the impact of oral application of the two UV absorbers at 2 doses for 3 months on lipids and hormones were compared with those of estradiol-17beta (E2). E2, OMC and 4MBC reduced weight gain, the size of fat depots and serum leptin, a lipocyte-derived hormone, when compared to the ovariectomized control animals. Serum triglycerides were also reduced by the UV screens but not by E2. On the other hand, E2 and OMC reduced serum cholesterol, low density lipoproteins and high density lipoproteins; this effect was not shared by 4MBC. While E2 inhibited, OMC and 4MBC stimulated serum LH levels. In the uterus, both UV filters had mild stimulatory effects. 4MBC inhibited serum T4 resulting in increased serum TSH levels. It is concluded that OMC and 4MBC have effects on several metabolic parameters such as fat and lipid homeostasis as well as on thyroid hormone production. Many of these effects are not shared by E2. Hence, other than estrogen-receptive mechanisms may be responsible for these effects.     

Inhibitory and bactericidal activities of gemifloxacin and other antimicrobials against Mycoplasma pneumoniae

The MIC of gemifloxacin was compared with that of sparfloxacin, levofloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, doxycycline, erythromycin, azithromycin and clarithromycin using 97 clinical isolates of Mycoplasma pneumoniae. MBCs of fluoroquinolones were determined for a subgroup of 12 isolates. Macrolides were the most potent agents with MIC₉₀s for all drugs 0.001 mg/l. The doxycycline MIC₉₀ was 0.5 mg/l. Gemifloxacin MICs ranged from 0.001 to 0.25 mg/l. The gemifloxacin MIC₉₀ (0.125 mg/l) was equivalent to moxifloxacin and gatifloxacin, was 2-fold lower than sparfloxacin, 8-fold lower than levofloxacin and 32-fold lower than ciprofloxacin. MBCs for gemifloxacin were predominantly within 2–4 times the corresponding MIC values, indicating a bactericidal effect.     

乳酸左氧氟沙星体外抗菌作用研究

乳酸左氧氟沙星（ｌｅｖｏｆｌｏｘａｃｉｎ ｌａｃｔａｅ）具有对革兰氏阳性菌,阴性菌抗菌作用强的特点。从临床分离的３０２株细菌敏感试验结果显示,该药对金葡萄球菌甚为敏感,其ＭＩＣ５０为０．０６ｍｇ／ＬＭ,ＭＩＣ９０为０．２５ｍｇ／Ｌ,ＭＢＣ５０为０．０６ｍｇ／Ｌ,ＭＢＣ９０为０．５ｍｇ／Ｌ,与日产左氧氟沙星基本一致,较氟沙星强。