scholarly journals Activity and Diffusion of Tigecycline (GAR-936) in Experimental Enterococcal Endocarditis

2003 ◽  
Vol 47 (1) ◽  
pp. 216-222 ◽  
Author(s):  
Agnès Lefort ◽  
Matthieu Lafaurie ◽  
Laurent Massias ◽  
Yolande Petegnief ◽  
Azzam Saleh-Mghir ◽  
...  
Keyword(s):  
Body Weight ◽  
Half Life ◽  
Type Strain ◽  
Postantibiotic Effect ◽  
Bacteriostatic Effect ◽  
Elimination Half ◽  
Resistant Mutants ◽  
And Diffusion

ABSTRACT The activity of tigecycline (GAR-936), a novel glycylcycline, was investigated in vitro and in experimental endocarditis due to the susceptible Enterococcus faecalis JH2-2 strain, its VanA type transconjugant BM4316, and a clinical VanA type strain, E. faecium HB217 resistant to tetracycline. MICs of GAR-936 were 0.06 μg/ml for the three strains. In vitro pharmacodynamic studies demonstrated a bacteriostatic effect of GAR-936 that was not enhanced by increasing concentrations to more than 1 μg/ml and a postantibiotic effect ranging from 1 to 4.5 h for concentrations of 1- to 20-fold the MIC. Intravenous injection of [14C]GAR-936 to five rabbits with enterococcal endocarditis sacrificed 30 min, 4 h, or 12 h after the end of the infusion evidenced a lower clearance of GAR-936 from aortic vegetations than from serum and a homogeneous diffusion of GAR-936 into the vegetations. In rabbits with endocarditis, GAR-936 (14 mg/kg of body weight twice a day [b.i.d.]) given intravenously for 5 days was bacteriostatic against both strains of E. faecalis. Against E. faecium HB217, bacterial counts in vegetations significantly decreased during therapy (P < 0.01), and the effect was similar with GAR-936 at 14 mg/kg b.i.d., 14 mg/kg once a day (o.d.), and 7 mg/kg o.d., which provided concentrations in serum constantly above the MIC. Mean serum elimination half-life ranged from 3.3 to 3.6 h. No GAR-936-resistant mutants were selected in vivo with any regimen. We concluded that the combination of prolonged half-life, significant postantibiotic effect, and good and homogeneous diffusion into the vegetations may account for the in vivo activity of GAR-936 against enterococci susceptible or resistant to glycopeptides and tetracyclines, even when using a o.d. regimen in rabbits.

scholarly journals Pharmacokinetics, tissue residues of tilmicosin phosphate (tilmicor-al®) and its in vitro and in vivo evaluation for the control of Mycoplas-ma gallisepticum infection in broiler chickens

2017 ◽  
Vol 5 (1) ◽  
pp. 11 ◽  
Author(s):  
Mohamed Elbadawy ◽  
Mohamed Aboubakr
Keyword(s):  
Half Life ◽  
Broiler Chickens ◽  
Peak Plasma ◽  
Clinical Signs ◽  
In Vivo Evaluation ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Residue Study

The aim of present study was to determine the pharmacokinetics and tissue residues of tilmicosin phosphate (tilmicoral®) as well as its in vitro and in vivo evaluation for control of Mycoplasma gallisepticum (MG) infection in broiler chickens. Pharmacokinetics (single oral dose) and tissues residues (daily for five days) of tilmicosin (25 mg/kg b.wt) in broilers were investigated. Peak plasma concentration of tilmicosin was 1.25±0.0.09 μg/mL and achieved at 3.15±0.34 h. Elimination half-life was long (44.3±7.22 h) and Vdarea was large (1.25±0.082 L/kg). Residue study revealed a good distribution and penetration of tilmicosine in lung, liver, kidney and muscles. Tilmicosin could not be detected in all tested tissues (except in lung) at 6 days after last administration. The MIC of tilmicosin and tylosin against MG were 0.054 and 0.319 μg/mL, respectively. MG infected chickens and treated by tilmicosin or tylosin showed a significant (p<0.05) improvement in mean body weights gain and a significant (p<0.05) decline in mean clinical signs score, air sac lesion score and mortality rate, however tilmicosin was a superior drug. In conclusion, timicoral® was a very effective medication for controlling MG infection in broiler chickens due to its rapid absorption, long elimination half-life, rapid and extensive penetration from blood into tissues especially lungs and air sacs. Additionally, tilmicoral® had a short withdrawal time. Moreover, its superior efficacy (in vitro and in vivo) against MG.

scholarly journals JPC-2997, a New Aminomethylphenol with HighIn VitroandIn VivoAntimalarial Activities against Blood Stages of Plasmodium

2014 ◽  
Vol 59 (1) ◽  
pp. 170-177 ◽  
Author(s):  
Geoffrey W. Birrell ◽  
Marina Chavchich ◽  
Arba L. Ager ◽  
Hong-Ming Shieh ◽  
Gavin D. Heffernan ◽  
...  
Keyword(s):  
Half Life ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Parasite Line ◽  
Content Type ◽  
Elimination Half Life ◽  
Highly Active ◽  
Elimination Half

ABSTRACT4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly activein vitroagainst the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2BPlasmodium falciparumlines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more activein vitroagainstP. falciparumlines and 3-fold less cytotoxic. The compound possesses potentin vivosuppression activity againstPlasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing threeAotusmonkeys infected with a chloroquine- and pyrimethamine-resistant strain ofPlasmodium vivaxat a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The highin vivopotency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

scholarly journals Optimisation of a Microfluidic Method for the Delivery of a Small Peptide

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1505
Author(s):  
Felicity Y. Han ◽  
Weizhi Xu ◽  
Vinod Kumar ◽  
Cedric S. Cui ◽  
Xaria Li ◽  
...  
Keyword(s):  
Half Life ◽  
Drug Loading ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
The Body ◽  
Related Factors ◽  
Elimination Half ◽  
Therapeutic Peptides

Peptides hold promise as therapeutics, as they have high bioactivity and specificity, good aqueous solubility, and low toxicity. However, they typically suffer from short circulation half-lives in the body. To address this issue, here, we have developed a method for encapsulation of an innate-immune targeted hexapeptide into nanoparticles using safe non-toxic FDA-approved materials. Peptide-loaded nanoparticles were formulated using a two-stage microfluidic chip. Microfluidic-related factors (i.e., flow rate, organic solvent, theoretical drug loading, PLGA type, and concentration) that may potentially influence the nanoparticle properties were systematically investigated using dynamic light scattering and transmission electron microscopy. The pharmacokinetic (PK) profile and biodistribution of the optimised nanoparticles were assessed in mice. Peptide-loaded lipid shell-PLGA core nanoparticles with designated size (~400 nm) and a sustained in vitro release profile were further characterized in vivo. In the form of nanoparticles, the elimination half-life of the encapsulated peptide was extended significantly compared with the peptide alone and resulted in a much higher distribution into the lung. These novel nanoparticles with lipid shells have considerable potential for increasing the circulation half-life and improving the biodistribution of therapeutic peptides to improve their clinical utility, including peptides aimed at treating lung-related diseases.

scholarly journals Efficacy of Cefepime and Imipenem in Experimental Murine Pneumonia Caused by Porin-Deficient Klebsiella pneumoniae Producing CMY-2 β-Lactamase

2005 ◽  
Vol 49 (8) ◽  
pp. 3311-3316 ◽  
Author(s):  
Cristina Pichardo ◽  
José Manuel Rodríguez-Martínez ◽  
María E. Pachón-Ibañez ◽  
Carmen Conejo ◽  
José Ibáñez-Martínez ◽  
...  
Keyword(s):  
Body Weight ◽  
Survival Rate ◽  
Klebsiella Pneumoniae ◽  
Untreated Control ◽  
In Vitro Activity ◽  
Postantibiotic Effect ◽  
Bacterial Concentration ◽  
Inoculum Effect

ABSTRACT Previous studies have shown decreased in vitro activity of zwitterionic cephalosporins and carbapenems against porin-deficient Klebsiella pneumoniae expressing a plasmid-mediated AmpC-type β-lactamase (PACBL). The in vitro and in vivo activities of cefepime and imipenem were evaluated against the porin-deficient strain K. pneumoniae C2 and its CMY-2-producing derivative [K. pneumoniae C2(pMG248)]. The MICs (in micrograms/milliliter) of cefepime and imipenem against K. pneumoniae C2 were 0.125 and 0.25, respectively, while the corresponding values against K. pneumoniae C2(pMG248) were 8 and 16. Cefepime showed a greater inoculum effect than imipenem against both strains. Imipenem showed a significant postantibiotic effect (>2 h) against K. pneumoniae C2(pMG248) at 1×, 2×, 4×, 6×, and 8× MIC. The maximum concentrations of drug in serum of cefepime and imipenem in a pneumonia model using mice were 124.1 and 16.9 μg/ml, respectively. ΔT/MIC for K. pneumoniae C2 and C2(pMG248) were 1.29 h and 0.34 h for imipenem and 2.96 h and 1.27 h for cefepime. Both imipenem (30 mg/kg of body weight every 3 h) and cefepime (60 mg/kg every 4 h), administered for 72 h, increased the survival rate (86.6% and 100%) compared with untreated control animals (26.6%, P < 0.003) infected with K. pneumoniae C2. For the CMY-2-producing strain, imipenem, but not cefepime, increased the survival rate compared to the controls (86.6% and 40% versus 40%, P < 0.01). Bacterial concentration of the lungs was significantly decreased by both antimicrobials. In conclusion, imipenem was more active in terms of survival than cefepime for the treatment of murine pneumonia caused by a porin-deficient K. pneumoniae expressing PACBL CMY-2.

scholarly journals Activities of Dalbavancin In Vitro and in a Rabbit Model of Experimental Endocarditis Due to Staphylococcus aureus with or without Reduced Susceptibility to Vancomycin and Teicoplanin

2004 ◽  
Vol 48 (3) ◽  
pp. 1061-1064 ◽  
Author(s):  
Agnès Lefort ◽  
Juliette Pavie ◽  
Louis Garry ◽  
Françoise Chau ◽  
Bruno Fantin
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Half Life ◽  
Rabbit Model ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Once Daily ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACT For the treatment of rabbit endocarditis, dalbavancin given once daily (10 mg/kg of body weight for 4 days) or as a single 40-mg/kg dose was active against Staphylococcus aureus with or without reduced susceptibility to glycopeptides, as expected from its good in vitro activity, even in broth supplemented with 90% serum and given its prolonged elimination half-life.

scholarly journals Efficacy of continuous flucytosine infusion against Candida lusitaniae in experimental hematogenous murine candidiasis.

1996 ◽  
Vol 40 (12) ◽  
pp. 2907-2908 ◽  
Author(s):  
N C Karyotakis ◽  
E J Anaissie
Keyword(s):  
Body Weight ◽  
Antifungal Activity ◽  
Continuous Infusion ◽  
Half Life ◽  
Immunocompromised Host ◽  
Total Dosage ◽  
Life Threatening ◽  
Candida Lusitaniae

Candida lusitaniae may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. Flucytosine (5-FC) is very active against C. lusitaniae isolates in vitro, while the in vivo response of murine infection to 5-FC is not as good. To evaluate the hypothesis that this discrepancy may be primarily due to the short half-life of 5-FC in mice, we compared the same total dosage of 75 mg of 5-FC per kg of body weight per day given by bolus injections or infused continuously via a subcutaneously implanted pump in immunosuppressed CF1 mice infected with C. lusitaniae. The fungal titers in the kidneys of mice treated with the continuous 5-FC infusion were significantly lower (P < or = 0.05) than those in the kidneys of mice that received bolus injections once or thrice daily. The antifungal activity of 5-FC against murine candidiasis is best evaluated when the drug is administered by continuous infusion.

scholarly journals Influence of Resistance to Streptogramin A Type Antibiotics on the Activity of Quinupristin-Dalfopristin In Vitro and in Experimental Endocarditis Due toStaphylococcus aureus

2000 ◽  
Vol 44 (5) ◽  
pp. 1168-1173 ◽  
Author(s):  
Virginie Zarrouk ◽  
Bülent Bozdogan ◽  
Roland Leclercq ◽  
Louis Garry ◽  
Claude Carbon ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Body Weight ◽  
Bactericidal Activity ◽  
Resistant Bacteria ◽  
Clinical Strains ◽  
Resistant Mutants ◽  
Reduced Activity

ABSTRACT We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureussusceptible to Q (MIC, 8 μg/ml) and Q-D (MICs, 0.5 to 1 μg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 μg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 μg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2×MIC) produced reductions of 4.3, 3.9, and 5.8 log10 CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8×MIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 × 10−8 to 2 × 10−7 for the three strains on agar containing 2×MIC of Q-D; no resistant bacteria were detected at 4×MIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 μg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.

Activity and Diffusion of LY333328 in Experimental Endocarditis Due to Vancomycin-Resistant Enterococcus faecalis

1999 ◽  
Vol 43 (1) ◽  
pp. 115-120 ◽  
Author(s):  
Azzam Saleh-Mghir ◽  
Agnès Lefort ◽  
Yolande Petegnief ◽  
Sophie Dautrey ◽  
Jean-Marie Vallois ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Type Strain ◽  
Acquired Resistance ◽  
Rabbit Serum ◽  
Loading Dose ◽  
Vancomycin Resistant Enterococcus ◽  
Vancomycin Resistant ◽  
And Diffusion

ABSTRACT The activity of LY333328 against Enterococcus faecalisJH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 μg/ml on agar and 0.25 μg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 μg/ml and against BM4316 at a concentration of 30 μg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides inE. faecalis either in vitro or in experimental endocarditis.

scholarly journals Characterization of the Preclinical Pharmacology of the New 2-Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Geoffrey W. Birrell ◽  
Gavin D. Heffernan ◽  
Guy A. Schiehser ◽  
John Anderson ◽  
Arba L. Ager ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Half Life ◽  
Antimalarial Activity ◽  
Dose Range ◽  
Liver Microsomes ◽  
Content Type ◽  
Elimination Half Life ◽  
Elimination Half

ABSTRACTThe new 2-aminomethylphenol, JPC-3210, has potentin vitroantimalarial activity against multidrug-resistantPlasmodium falciparumlines, low cytotoxicity, and highin vivoefficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and the results ofin vitroscreening assays, including the inhibition of cytochrome P450 (CYP450) isozymes. In mice, JPC-3210 was rapidly absorbed and had an extensive tissue distribution, with a brain tissue-to-plasma concentration ratio of about 5.4. JPC-3210 had a lengthy plasma elimination half-life of about 4.5 days in mice and 11.8 days in monkeys. JPC-3210 exhibited linear single-oral-dose pharmacokinetics across the dose range of 5 to 40 mg/kg of body weight with high oral bioavailability (∼86%) in mice. Systemic blood exposure of JPC-3210 was 16.6% higher inP. berghei-infected mice than in healthy mice.In vitrostudies with mice and human hepatocytes revealed little metabolism and the high metabolic stability of JPC-3210. The abundance of human metabolites from oxidation and glucuronidation was 2.0% and 2.5%, respectively. CYP450 studies in human liver microsomes showed JPC-3210 to be an inhibitor of CYP2D6 and, to a lesser extent, CYP3A4 isozymes, suggesting the possibility of a metabolic drug-drug interaction with drugs that are metabolized by these isozymes.In vitrostudies showed that JPC-3210 is highly protein bound to human plasma (97%). These desirable pharmacological findings of a lengthy blood elimination half-life, high oral bioavailability, and low metabolism as well as highin vivopotency have led the Medicines for Malaria Venture to select JPC-3210 (MMV892646) for further advanced preclinical development.

scholarly journals Duration and Clinical Relevance of Postantibiotic Effect in Relation to the Dosing Interval

1998 ◽  
Vol 42 (4) ◽  
pp. 749-754 ◽  
Author(s):  
Jan G. den Hollander ◽  
Kurt Fuursted ◽  
Henri A. Verbrugh ◽  
Johan W. Mouton
Keyword(s):  
Standard Method ◽  
Half Life ◽  
Clinical Relevance ◽  
In Vitro Model ◽  
Clinical Importance ◽  
Postantibiotic Effect ◽  
Dosing Interval ◽  
Vitro Model

ABSTRACT The influence of half-life on the postantibiotic effect (PAE) of tobramycin against Pseudomonas aeruginosa andStaphylococcus aureus was investigated during one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an in vitro model, and the PAE was determined by an enzymatic inactivation method at different time points, i.e., when the tobramycin concentrations were 20×, 5×, and 1× the MIC. At the time point during therapy when the tobramycin concentrations had declined to 1× the MIC, at a tobramycin half-life of 0.5 h, the times of the PAEs were approximately 0.7 and 1.7 h for P. aeruginosa andS. aureus, respectively, and the PAE disappeared completely at half-lives corresponding to those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully explained by the presence of free intrabacterial tobramycin or the emergence of resistant subpopulations. The explanation for the disappearance of the PAE during the dosing interval may therefore be explained by the repair of sublethal damage. Since the standard method of determining the PAE in animal models is somewhat different from the method used for measurement of the PAE in vitro, the conditions under which the PAE is measured in vivo were also simulated in the in vitro model. This resulted in PAEs longer than those found by the standard method of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin, as determined by conventional in vitro methods, has virtually no clinical importance. PAEs determined in vivo may have some clinical relevance, but they are probably primarily caused by sub-MIC effects.

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