Synergistic effect between nisin and polymyxin B against pandrug-resistant and extensively drug-resistant Acinetobacter baumannii

Acinetobacter baumannii is an opportunistic pathogen predominantly associated with nosocomial infections. The World Health Organization's data on antibiotic-resistant ‘priority pathogens’ reports carbapenem-resistant A. baumannii as a pathogen which is in critical need of research and development of new antimicrobials. Emerging resistance against polymyxins, last-resort drugs for carbapenem-resistant A. baumannii, increases the need for new therapeutic approaches such as synergistic combinations. Nisin, an antibacterial peptide produced by the Gram-positive bacteria L. lactis, is a US Food and Drug Administration approved food preservative with bactericidal action predominantly against other Gram-positive bacteria. A 2008 study reported that topical nisin was effective against staphylococcal mastitis in humans. Additionally, nisin has shown activity against Gram-negative bacteria in combination with antimicrobials such as polymyxin B. A recent in vitro study reported that nisin and polymyxin B exhibited synergistic activity against one isolate each of A. baumannii, Acinetobacter lwoffii and Acinetobacter calcoaceticus using time-kill assay and checkerboard technique. We evaluated the synergistic potential of nisin and polymyxin B against 15 unique clinical A. baumannii isolates using time-kill assay. Three of eight (38%) extensively drug-resistant and six of seven (86%) pandrug-resistant A. baumannii isolates showed synergy with one or more combinations of nisin and polymyxin B. The synergy seen with the use of lower concentrations of polymyxin B may help in reducing the dose-dependent side effects. Additional studies involving pharmacokinetics and pharmacodynamics of nisin are required to explore clinical possibilities.     

Action of (E)-2'-deoxy-2'-(fluoromethylene)cytidine on DNA metabolism: incorporation, excision, and cellular response.

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC) is a new analog of deoxycytidine with promising anticancer activity. We investigated the action of FMdC on DNA metabolism by evaluating its incorporation into DNA, its excision from DNA in vitro, and the role of the incorporation of FMdC into DNA in causing cytotoxicity. In vitro DNA primer extension demonstrated that FMdC nucleotides were incorporated with relatively high substrate efficiency into the C sites of the elongating DNA strand. Once incorporated, FMdC became a poor substrate for further chain elongation by DNA polymerases, resulting in a termination of DNA synthesis at the sites of incorporation. Furthermore, the 3' --> 5' exonuclease activity of DNA polymerase epsilon or wild-type p53 protein was ineffective in removing the incorporated FMdC from DNA in vitro. FMdC also showed potent cytotoxic activity against human leukemia and solid tumor cells. Incubation with a low concentration of FMdC (10 nM) induced cell cycle arrest at S or G1 phases, but the cells eventually died as the time of incubation increased. Compared with HL-60 cells, human myeloid ML-1 cells with wild-type p53 were more sensitive to FMdC, but the S or G1 phase arrest did not seem to depend on the presence or absence of p53. Inhibiting the incorporation of FMdC into cellular DNA by aphidicolin suppressed the cytotoxic effect of the compound. We conclude that the incorporated FMdC nucleotide profoundly disrupts DNA synthesis and resists excision by exonucleases, and that incorporation of this analog into DNA is a key molecular event responsible for the drug's cytotoxicity.     

Optimized and Validated Stability Indicating RP-HPLC Method for Estimation of Nadolol

Pharmaceutical Chemistry Journal - A stability indicating RP-HPLC method for the determination of nadolol was developed and validated using Enable C18 (250 mm × 4.6 mm, 5 μm) column with...     

Estimation of Amlodipine Besylate, Valsartan and Hydrochlorothiazide in Bulk Mixture and Tablet by UV Spectrophotometry

A simple, precise, accurate and economic simultaneous UV spectrophotometric method has been developed for the estimation of amlodipine besylate, valsartan and hydrochlorothiazide in combination in bulk mixture and tablet. The estimation was based upon measurement of absorbance at absorbance maxima of 359 nm, 317 nm and 250 nm for amlodipine besylate, hydrochlorothiazide and valsartan in methanol, respectively in bulk mixture and tablet. The Beer Lambert''s law obeyed in the concentration range 5-25 μg/ml, 10-50 μg/ml and 5-25 μg/ml for amlodipine besylate, hydrochlorothiazide and valsartan, respectively. The estimation of bulk mixture and tablet was carried out by simultaneous equation, Q-analysis and area under curve method for estimation of amlodipine besylate and hydrochlorothiazide and standard curve method for estimation of valsartan. The results were found to be in the range of 99.6±1.52% to 102±0.51%. Method was validated with respect to specificity, linearity, range, accuracy, precision, LOD, LOQ, robustness, ruggedness and can be applied for routine analysis of tablet dosage forms.     

Identification of 1-[4-Benzyloxyphenyl)-but-3-enyl]-1H-azoles as New Class of Antitubercular and Antimicrobial Agents

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Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice

The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F₁ mice were dosed with 3 mg kg^?1 DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg^?1, respectively) and euthanized a week after the last dose. Mass spectrometry‐based and nuclear magnetic resonance spectrometry‐based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg^?1 cumulative doses, respectively. After a cumulative dose of 6 mg kg^?1, 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline‐treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg^?1. A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA     

Differential phosphorylation and dephosphorylation of beta2-adrenoceptor sites Ser262 and Ser355,356

Activated beta2-adrenoceptors are rapidly desensitized by phosphorylation of Ser262 by protein kinase A (PKA) and of Ser355,356 by G-protein-coupled receptor kinase (GRK). We sought to determine whether the phosphorylation and subsequent dephosphorylation of these sites had similar kinetics and requirements for receptor endocytosis. The phosphorylation of the PKA and GRK sites were measured using antibodies that recognize phosphoserine 262 and phosphoserine 355,356. Endocytosis in stably transfected HEK293 cells was blocked by inducible expression of dominant-negative dynamin-1 K44A or by treatment with hypertonic sucrose. The phosphorylation of the GRK site Ser355,356 during a 10 microM isoprenaline treatment rapidly reached a steady state, and the extent of kinetics of phosphorylation were unaffected by dynamin-1 K44A expression, and minimally by hypertonic sucrose. In contrast, phosphorylation of the PKA site Ser262 during a 10 microM isoprenaline treatment peaked after 2 min and then rapidly declined, while inhibition of endocytosis enhanced and prolonged phosphorylation. Treatment with 300 pM isoprenaline, a concentration too low to provoke endocytosis, also resulted in prolonged PKA site phosphorylation. The dephosphorylation of these sites was measured after removal of agonist. Significant dephosphorylation of phosphoserines 262 and 355,356 was observed under conditions of very low endocytosis, however dephosphorylation of the GRK site was greater if antagonist was present after removal of agonist. The results indicate that the kinetics of beta2-adrenoceptor GRK and PKA site phosphorylation are distinct and differently affected by endocytosis, and that receptor dephosphorylation can occur either at the plasma membrane or in internal compartments.     

Role of Orbscan II in screening keratoconus suspects before refractive corneal surgery

OBJECTIVE: To evaluate the relationship between videokeratographic keratoconus screening programs and Orbscan II topography. DESIGN: Prospective, observational case series and instrument validation study. PARTICIPANTS: Sixty consecutive eyes with suspicious videokeratography (TMS-1, Tomey Technology, Waltham, MA) were evaluated before undergoing laser in situ keratomileusis (LASIK) surgery. A control group of 50 consecutive eyes without suspicious features by videokeratography was also evaluated. METHODS: Keratoconus screening programs, using the Rabinowitz and Klyce/Maeda methods and Orbscan II (Bausch & Lomb, Claremont, CA) topographies were performed on these patients. MAIN OUTCOME MEASURES: Specific parameters evaluated on the Orbscan II topographies were anterior elevation, posterior elevation, and thinnest pachymetry. RESULTS: Compared with a control group of patients without suspicious videokeratography, there was a statistically significant difference in the mean posterior elevation and mean anterior elevation in the groups with positive keratoconus testing with the Rabinowitz or Klyce/Maeda methods. For patients who met both the Rabinowitz and Klyce/Maeda criteria for keratoconus, the mean posterior elevation was 44 +/- 2.5 micro m compared with a posterior elevation of 21 +/- 0.6 micro m for the control group. There was no statistically significant difference in the mean thinnest pachymetry between the control group and all keratoconus suspect groups. CONCLUSIONS: Patients with positive keratoconus screening tests have higher anterior and posterior elevation on Orbscan II topography. When used in combination with videokeratography, the Orbscan II topography system may be helpful in identifying patients who are potentially at high risk for developing ectasia after LASIK.     

Outcomes of Intra- and Extraocular Retinoblastomas from a Single Institute in South India

Aim: To report treatment outcomes of intra- and extraocular retinoblastomas seen at Aravind Eye Hospital, Coimbatore, South India.

Methods: Retrospective case series from January 2006 to December 2011 involving 106 babies. Clinical records were reviewed and data collected on presenting signs, gender, age, family history, ocular findings and treatment outcomes. All eyes were classified using the International Retinoblastoma Classification.

Results: The mean follow up was 35.4 months (range 1–75 months, SD 20.2, median 33 months). The mean age of presentation was 20.8 months (range 5 days to 120 months). There were 68 unilateral and 38 bilateral cases. Globe salvage rates were 100% for group A (11 eyes), B (16 eyes) and C (2 eyes). For group D, eye salvage rate was 29.5% (10/34 eyes). Survival rate of orbital retinoblastoma in our study was 55.5% (5/9 cases) at a mean follow up of 33.6 months. The overall patient survival rate was 89.6% with 11 deaths (10.4%). The commonest cause of death (7/11) was distant metastasis due to refusal to take initial treatment.

Conclusion: Greater improvement in patient survival can be achieved not only by early treatment of intraocular disease but also to convince patients to accept treatments including enucleation in this part of the world.