Current Issue : October - December Volume : 2017 Issue Number : 4 Articles : 6 Articles
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum\nmalaria that threatens the long-term clinical utility of artemisinin-based combination\ntherapies, the cornerstone of modern day malaria treatment. Here we describe a\nmultinational drug discovery programme that has delivered a synthetic tetraoxane-based\nmolecule, E209, which meets key requirements of the Medicines for Malaria Venture drug\ncandidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of\nP. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models,\nproduces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic\nand pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies\nwith transgenic parasites expressing variant forms of K13 show no cross-resistance with the\nC580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next\ngeneration endoperoxide with combined pharmacokinetic and pharmacodynamic features\nthat overcome the liabilities of artemisinin derivatives....
The aim of this work was to develop a novel and more efficient platform for sublingual drug delivery\nusing mosapride citrate (MSP) as a model drug. The engineering of this delivery system had two\nstages, the first stage was tuning of MSP physicochemical properties by complexation with pure\nphosphatidylcholine or phosphatidylinositol enriched soybean lecithin to form MSP-phospholipid complex\n(MSP-PLCP). Changes in physicochemical properties were assessed and the optimum MSP-PLCP\nformula was then used for formulation into a flushing resistant platform using two mucoadhesive polymers;\nsodium alginates and sodium carboxymethylcellulose at different concentrations. Design of\nexperiment approach was used to characterize and optimize the formulated flushing resistant platform.\nThe optimized formulation was then used in a comparative pharmacokinetics study with the market\nformulation in human volunteers. Results showed a marked change in MSP physicochemical properties\nof MSP-PLCP compared to MSP. Addition of mucoadhesive polymers to flushing resistant platform at\nan optimum concentration balanced between desired mucoadhesive properties and a reasonable drug\nrelease rate. The optimized formulation showed significantly a superior bioavailability in humans when\ncompared to the market sublingual product. Finally, the novel developed sublingual flushing resistant\nplatform offers a very promising and efficient tool to extend the use of sublingual route and widen its\napplications....
Objectives: The emergence of carbapenem-resistant Enterobacteriaceae, especially\nKlebsiella pneumoniae, has become a major concern in clinic settings. Combination\ntherapy is gaining momentum to counter the secondary resistance and potential\nsuboptimal efficacy of monotherapy. The aim of this study was to evaluate the bactericidal\neffect of fosfomycin (FM), amikacin (AMK), or colistin (COL) alone and combinations\nagainst KPC2-producing K. pneumoniae using dynamic model by simulating human\npharmacokinetics in vitro.\nMethods: The Pharmacokinetics Auto Simulation System 400 system was employed\nto simulate different dosing regimens of FM, AMK, and COL alone and combination.\nBacterial growth recovery time (RT) and the area between the control growth and\nantibacterial killing curves (IE) were used as unbiased and comprehensive means for\ndetermining the antimicrobial effect.\nResults: We observed that COL alone was much pronounced than FM or AMK against\nKPC-Kp. IE of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily) and FM (8 g every\n8 h) plus COL (75,000 IU/kg every 12 h) were higher (>170 and >200 LogCFU/mLÃ?·hâË?â??1,\nrespectively) than that of monotherapies against sensitive strains. Of note, the rate of\nresistance was lower when using the combination of FM (8 g every 8 h) plus COL (75,000\nIU/kg every 12 h) than using COL (75,000 IU/kg every 12 h) alone.\nConclusions: The combination of FM (8 g every 8 h) plus AMK (15 mg/kg once-daily)\nand FM (8 g every 8 h) plus COL (75,000 IU/kg every 12 h) were effective at maximizing\nbacterial killing and suppressing emergence of resistance....
The pharmacokinetics of marbofloxacin in pigs after intravenous (i.v.), intramuscular (i.m.), and peroral (p.o.) administration\nand pharmacokinetic/pharmacodynamic indices of this drug against Korean local isolates of Actinobacillus pleuropneumoniae\nwere determined in this study. Marbofloxacin (2.50mg/kg of body weight) was administered, and blood samples were collected\nwith designated time intervals. Plasma-extracted marbofloxacin was injected into the LC-MS/MS system. The in vitro and ex\nvivo antibacterial activities of marbofloxacin were evaluated against 20 isolates of A. pleuropneumoniae. The mean peak plasma\nconcentrations (...
The purpose of this study was to evaluate the activity of cyadox against Clostridium perfringens in\nswine and optimize the dosage regimen using ex vivo pharmacokinetic-pharmacodynamic (PK-PD)\nmodeling. After oral administration, the ileum fluid of pigs containing the free cyadox was collected\nby implanted ultrafiltration probes. The Tmax, AUC24h, and CL/F of free cyadox in the ileum fluid were\n1.96 h, 106.40 �¼g/h/mL, and 0.27 L/kg/h, respectively. Cyadox displayed a concentration-dependent\nkilling action against C. perfrignens. The minimum inhibitory concentration (MIC) of cyadox against 60\nclinical isolates ranged from 0.5 to 8 �¼g/mL, with MIC50 and MIC90 values of 2 and 4 �¼g/mL, respectively.\nThe MIC was 2 �¼g/mL against the pathogenic C. perfrignens isolate CPFK122995 in both broth and ileum\nfluid. According to the inhibitory sigmoid Emax modeling, the AUC24h/MIC ratios of ileum fluid required to\nachieve the bacteriostatic, bactericidal, and virtual bacterial elimination effects were 26.72, 39.54, and\n50.69 h, respectively. Monte Carlo simulations for the 90% target attainment rate (TAR) predicted daily\ndoses of 29.30, 42.56, and 54.50 mg/kg over 24 h to achieve bacteriostatic, bactericidal, and elimination\nactions, respectively. The results of this study suggest that cyadox is a promising antibacterial agent for\nthe treatment of C. perfringens infections, and can be used to inform its clinical use....
Background: This study focused on utilizing pharmacokinetics/pharmacodynamics (PK/PD) modeling to optimize\ntherapeutic dosage regimens of sarafloxacin against avian pathogenic Escherichia. coli O78 strain in Muscovy ducks.\nThe ex vivo PK/PD study of sarafloxacin was conducted in Muscovy ducks after intravenous (i.v.) and oral (p.o.)\nadministrations at a single dose of 10 mg/kg bodyweight (BW). The serum samples were analyzed by reverse phase\nhigh-performance liquid chromatography (RP-HPLC) using a fluorescence detection method. Sarafloxacin PK data\nwere analyzed by a non-compartmental method using Winnonlin software.\nResults: Calculations of the area under the concentration-time curves (AUC0-24h) were 8.57 �± 0.59 and 8.37 �± 0.29 �¼g �· h/ml\nfollowing i.v. and p.o. administration, respectively. Elimination half-lives (t1/2�²) were 6.11 �± 0.99 h and 8.21 �± 0.64 h\nfor i.v. injection and p.o. administration, respectively. The mean in vitro plasma protein binding of sarafloxacin\nwas 39.3%. Integration using the sigmoid Emax model, the mean values of AUC0-24h/MIC needed for bacteriostatic,\nbactericidal and bacterial eradication action were 25.4, 40.6, and 94.4 h, respectively.\nConclusions: Sarafloxacin administered at a 10 mg/kg dose may be insufficient for treatment of E. coli O78\ninfections with an MIC equally to or over 0.125 �¼g/ml. Furthermore, higher doses of sarafloxacin are required to\nminimize antimicrobial resistance considering the MPC theory....
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