scholarly journals Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 858 ◽  
Author(s):  
Alba Calvo ◽  
Esther Moreno ◽  
Esther Larrea ◽  
Carmen Sanmartín ◽  
Juan Manuel Irache ◽  
...  
Keyword(s):  
Parasite Burden ◽  
Isoquinoline Alkaloid ◽  
Free Drug ◽  
Immunomodulatory Activity ◽  
Drug Concentrations ◽  
Ic50 Values ◽  
Mean Size ◽  
Rapid Clearance ◽  
Selective Delivery

Berberine (BER)—an anti-inflammatory quaternary isoquinoline alkaloid extracted from plants—has been reported to have a variety of biologic properties, including antileishmanial activity. This work addresses the preparation of BER-loaded liposomes with the aim to prevent its rapid liver metabolism and improve the drug selective delivery to the infected organs in visceral leishmaniasis (VL). BER liposomes (LP-BER) displayed a mean size of 120 nm, negative Z-potential of −38 mV and loaded 6 nmol/μmol lipid. In vitro, the loading of BER in liposomes enhanced its selectivity index more than 7-fold by decreasing its cytotoxicity to macrophages. In mice, LP-BER enhanced drug accumulation in the liver and the spleen. Consequently, the liposomal delivery of the drug reduced parasite burden in the liver and spleen by three and one logarithms (99.2 and 93.5%), whereas the free drug only decreased the infection in the liver by 1-log. The organ drug concentrations—far from IC50 values— indicate that BER immunomodulatory activity or drug metabolites also contribute to the efficacy. Although LP-BER decreased 10-fold—an extremely rapid clearance of the free drug in mice—the value remains very high. Moreover, LP-BER reduced plasma triglycerides levels.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

scholarly journals In Vitro Human Onychopharmacokinetic and Pharmacodynamic Analyses of ME1111, a New Topical Agent for Onychomycosis

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Natsuki Kubota-Ishida ◽  
Naomi Takei-Masuda ◽  
Kaori Kaneda ◽  
Yu Nagira ◽  
Tsubasa Chikada ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Nail Plate ◽  
Free Drug ◽  
Content Type ◽  
Clinical Dose ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Human Nails

ABSTRACT ME1111 is a novel antifungal agent currently under clinical development as a topical onychomycosis treatment. A major challenge in the application of topical onychomycotics is penetration and dissemination of antifungal agent into the infected nail plate and bed. In this study, pharmacokinetic/pharmacodynamic parameters of ME1111 that potentially correlate with clinical efficacy were compared with those of marketed topical onychomycosis antifungal agents: efinaconazole, tavaborole, ciclopirox, and amorolfine. An ME1111 solution and other launched topical formulations were applied to an in vitro dose model for 14 days based on their clinical dose and administration. Drug concentrations in the deep layer of the nail and within the cotton pads beneath the nails were measured using liquid chromatography-tandem mass spectrometry. Concentrations of ME1111 in the nail and cotton pads were much higher than those of efinaconazole, ciclopirox, and amorolfine. Free drug concentrations of ME1111 in deep nail layers and cotton pads were orders of magnitude higher than the MIC90 value against Trichophyton rubrum (n = 30). Unlike other drugs, the in vitro antifungal activity of ME1111 was not affected by 5% human keratin and under a mild acidic condition (pH 5.0). The in vitro antidermatophytic efficacy coefficients (ratio of free drug concentration to MIC90s against T. rubrum) of ME1111, as measured in deep nail layers, were significantly higher than those of efinaconazole, tavaborole, ciclopirox, and amorolfine (P < 0.05). This suggests that ME1111 has excellent permeation of human nails and, consequently, the potential to be an effective topical onychomycosis treatment.

scholarly journals Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

2002 ◽  
Vol 46 (12) ◽  
pp. 4029-4034 ◽  
Author(s):  
Ayman M. Noreddin ◽  
Danielle Roberts ◽  
Kim Nichol ◽  
Aleksandra Wierzbowski ◽  
Daryl J. Hoban ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Compartment Model ◽  
Free Drug ◽  
Pharmacodynamic Modeling ◽  
Epithelial Lining ◽  
Bacterial Killing ◽  
Epithelial Lining Fluid ◽  
Initial Inoculum ◽  
Drug Concentrations

ABSTRACT The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug Cp maximum of 2 μg/ml, t 1/2 of 6 h; in ELF, C ELF(total) maximum of 35μg/ml, t 1/2 of 6 h; CELF(free) maximum of 14 μg/ml, t 1/2 of 6 h). Starting inocula were 106 CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of ≥90% (AUC0-24/MIC ratio, ≥61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC0-24/MIC ratios of ≥30.5 to 38) resulted in a 1.2 to 2.0 log10 CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of ≤8% (AUC0-24/MIC ratio, ≤17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 μg/ml. However, mef(A) isolates for which MICs are ≥16 μg/ml along with erm(B) may result in bacteriological failures.

scholarly journals Comparison of the Activity of a Human Simulated, High-Dose, Prolonged Infusion of Meropenem against Klebsiella pneumoniae Producing the KPC Carbapenemase versus That against Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

2009 ◽  
Vol 54 (2) ◽  
pp. 804-810 ◽  
Author(s):  
Catharine C. Bulik ◽  
Henry Christensen ◽  
Peng Li ◽  
Christina A. Sutherland ◽  
David P. Nicolau ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
High Performance ◽  
Resistance Mechanisms ◽  
Free Drug ◽  
Pharmacodynamic Model ◽  
High Dose ◽  
Prolonged Infusion ◽  
Drug Concentrations

ABSTRACT We have previously demonstrated that a high-dose, prolonged-infusion meropenem regimen (2 g every 8 h [q8h]; 3-hour infusion) can achieve 40% free drug concentration above the MIC against Pseudomonas aeruginosa with MICs of ≤16 μg/ml. The objective of this experiment was to compare the efficacy of this high-dose, prolonged-infusion regimen against carbapenemase-producing Klebsiella pneumoniae isolates with the efficacy against P. aeruginosa isolates having similar meropenem MICs. An in vitro pharmacodynamic model was used to simulate human serum concentrations. Eleven genotypically confirmed K. pneumoniae carbapenemase (KPC)-producing isolates and six clinical P. aeruginosa isolates were tested for 24 h, and time-kill curves were constructed. High-performance liquid chromatography (HPLC) was used to verify meropenem concentrations in each experiment. Meropenem achieved a rapid ≥3 log CFU reduction against all KPC isolates within 6 h, followed by regrowth in all but two isolates. The targeted %fT>MIC (percent time that free drug concentrations remain above the MIC) exposure was achieved against both of these KPC isolates (100% fT>MIC versus MIC = 2 μg/ml, 75% fT>MIC versus MIC = 8 μg/ml). Against KPC isolates with MICs of 8 and 16 μg/ml that did regrow, actual meropenem exposures were significantly lower than targeted due to rapid in vitro hydrolysis, whereby targeted %fT>MIC was reduced with each subsequent dosing. In contrast, a ≥3 log CFU reduction was maintained over 24 h for all Pseudomonas isolates with meropenem MICs of 8 and 16 μg/ml. Although KPC and P. aeruginosa isolates may share similar meropenem MICs, the differing resistance mechanisms produce discordant responses to a high-dose, prolonged infusion of meropenem. Thus, predicting the efficacy of an antimicrobial regimen based on MIC may not be a valid assumption for KPC-producing organisms.

scholarly journals Liposomal Antioxidants for Protection against Oxidant-Induced Damage

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Zacharias E. Suntres
Keyword(s):  
Cell Structure ◽  
Cellular Systems ◽  
Amphiphilic Molecules ◽  
Significant Damage ◽  
Rapid Clearance ◽  
Selective Delivery ◽  
High Concentrations ◽  
Structure And Functions ◽  
Pass Metabolism

Reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide, and hydroxyl radical, can be formed as normal products of aerobic metabolism and can be produced at elevated rates under pathophysiological conditions. Overproduction and/or insufficient removal of ROS result in significant damage to cell structure and functions.In vitrostudies showed that antioxidants, when applied directly and at relatively high concentrations to cellular systems, are effective in conferring protection against the damaging actions of ROS, but results from animal and human studies showed that several antioxidants provide only modest benefit and even possible harm. Antioxidants have yet to be rendered into reliable and safe therapies because of their poor solubility, inability to cross membrane barriers, extensive first-pass metabolism, and rapid clearance from cells. There is considerable interest towards the development of drug-delivery systems that would result in the selective delivery of antioxidants to tissues in sufficient concentrations to ameliorate oxidant-induced tissue injuries. Liposomes are biocompatible, biodegradable, and nontoxic artificial phospholipid vesicles that offer the possibility of carrying hydrophilic, hydrophobic, and amphiphilic molecules. This paper focus on the use of liposomes for the delivery of antioxidants in the prevention or treatment of pathological conditions related to oxidative stress.

scholarly journals LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant Staphylococcus aureus

2004 ◽  
Vol 48 (11) ◽  
pp. 4322-4327 ◽  
Author(s):  
Jacques Vouillamoz ◽  
José M. Entenza ◽  
Peter Hohl ◽  
Philippe Moreillon
Keyword(s):  
Staphylococcus Aureus ◽  
Serum Proteins ◽  
Binding Protein ◽  
Free Drug ◽  
Penicillin Binding Protein ◽  
Methicillin Resistant ◽  
Drug Concentrations ◽  
Mrsa Strains ◽  
Infusion Period

ABSTRACT LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a). LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant Staphylococcus aureus (MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom). The MICs of LB11058 for the organisms were 1 mg/liter. The MICs of vancomycin and ceftriaxone were 1 and ≥64 mg/liter, respectively. In population analysis profiles, none of the MRSA strains grew at ≥2 mg of LB11058/liter. Rats with endocarditis were treated for 5 days. LB11058 was highly bound to serum proteins in rats (≥98%). However, binding was saturable above a threshold of 250 mg/liter. Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (≥5 mg/liter) above the drug's MIC for the entire infusion period. Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC, ≥90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period). LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively. This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively). Ceftriaxone was inactive. Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters. At appropriate doses, LB11058 was highly effective both in vitro and in vivo. This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections.

scholarly journals Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 465 ◽  
Author(s):  
Lília I. L. Cabral ◽  
Sébastien Pomel ◽  
Sandrine Cojean ◽  
Patrícia S. M. Amado ◽  
Philippe M. Loiseau ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Parasite Burden ◽  
Selectivity Index ◽  
Antileishmanial Activity ◽  
Diverse Range ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Antileishmanial Drug ◽  
Intraperitoneal Treatment

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.

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