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 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 Bioavailability pharmacokinetics and residues of marbofloxacin in normal and E.coli infected broiler chicken

2016 ◽  
Vol 4 (2) ◽  
pp. 144
Author(s):  
Ashraf El-Komy ◽  
Taha Attia ◽  
Amera Abd El Latif ◽  
Hanem Fathy
Keyword(s):  
Oral Administration ◽  
Half Life ◽  
Broiler Chickens ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Maximum Serum ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Total Body

The pharmacokinetics of marbofloxacin was studied following a single intravenous, oral administration in normal broiler chickens and repeated oral administrations in normal and experimentally E.coli infected broiler chickens. The pharmacokinetic parameters following a single intravenous injection of 2 mg/kg b.wt., revealed that marbofloxacin obeyed a two compartments open model, distribution half-life (t0.5(α)) was 0.25±0.02 h, volume of distribution (Vdss) was 0.76±0.08 L/kg, elimination half-life (t0.5(β)) was 5.43±0.87 h and total body clearance (CLtot) was 0.09±0.002 l/kg/h. Following a single oral administration, marbofloxacin was rapidly and efficiently absorbed through gastrointestinal tract of chickens as the absorption half-life (t0.5 (ab): 0.62±0.02 h). Maximum serum concentration (Cmax) was 1.15±0.01 μg/ml, reached its maximum time (tmax) at 2.53±0.04 h, elimination half-life (t0.5 (el)) was 7.36±0.20 h indicating the tendency of chickens to eliminate marbofloxacin in slow rate. Oral bioavailability was 73.57± 1.90 % indicating good absorption of marbofloxacin after oral administration. Serum concentrations of marbofloxacin following repeated oral administration of 2 mg/kg b.wt. once daily for five consecutive days, peaked 2 hours after each oral dose with lower significant values recorded in experimentally infected broiler chickens than in normal ones. Tissues residues of marbofloxacin in slaughtered normal chickens was highly in those tissues lung, liver, and kidneys in chickens and the chicken must not be slaughtered before 3 days of stopping of drug administration. It was concluded that the in- vitro protein binding was 12.33±0.82%.

scholarly journals In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin

2007 ◽  
Vol 51 (5) ◽  
pp. 1633-1642 ◽  
Author(s):  
David Andes ◽  
William A. Craig
Keyword(s):  
Half Life ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Gram Positive ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C max]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C max/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R 2 = 78 and 77%, respectively; for C max/MIC, R 2 = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 ± 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 ± 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log10 in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC90 for the target gram-positive organisms would fall within this value.

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.

Stiffness of targeted layer-by-layer nanoparticles impacts elimination half-life, tumor accumulation, and tumor penetration

2021 ◽  
Vol 118 (42) ◽  
pp. e2104826118
Author(s):  
Stephanie M. Kong ◽  
Daniel F. Costa ◽  
Anna Jagielska ◽  
Krystyn J. Van Vliet ◽  
Paula T. Hammond
Keyword(s):  
Drug Delivery ◽  
Half Life ◽  
Tumor Targeting ◽  
Layer By Layer ◽  
Elimination Half Life ◽  
Tumor Penetration ◽  
Anticancer Drug Delivery ◽  
Elimination Half ◽  
Tumor Accumulation

Nanoparticle (NP) stiffness has been shown to significantly impact circulation time and biodistribution in anticancer drug delivery. In particular, the relationship between particle stiffness and tumor accumulation and penetration in vivo is an important phenomenon to consider in optimizing NP-mediated tumor delivery. Layer-by-layer (LbL) NPs represent a promising class of multifunctional nanoscale drug delivery carriers. However, there has been no demonstration of the versatility of LbL systems in coating systems with different stiffnesses, and little is known about the potential role of LbL NP stiffness in modulating in vivo particle trafficking, although NP modulus has been recently studied for its impact on pharmacokinetics. LbL nanotechnology enables NPs to be functionalized with uniform coatings possessing molecular tumor-targeting properties, independent of the NP core stiffness. Here, we report that the stiffness of LbL NPs is directly influenced by the mechanical properties of its underlying liposomal core, enabling the modulation and optimization of LbL NP stiffness while preserving LbL NP outer layer tumor-targeting and stealth properties. We demonstrate that the stiffness of LbL NPs has a direct impact on NP pharmacokinetics, organ and tumor accumulation, and tumor penetration—with compliant LbL NPs having longer elimination half-life, higher tumor accumulation, and higher tumor penetration. Our findings underscore the importance of NP stiffness as a design parameter in enhancing the delivery of LbL NP formulations.

Clozapine Intoxication in a Dog

2002 ◽  
Vol 38 (5) ◽  
pp. 421-424
Author(s):  
Boel A. Fransson ◽  
Katrina A. Mealey ◽  
Sarah R. Dutta
Keyword(s):  
Supportive Care ◽  
Half Life ◽  
Peak Concentration ◽  
Clinical Signs ◽  
Serum Levels ◽  
Auditory Stimulation ◽  
Successful Outcome ◽  
Elimination Half Life ◽  
Elimination Half

Intoxication with clozapine in a dog, suspected from history and clinical signs at presentation, was confirmed by demonstration of decreasing serum levels of this drug. Clozapine is a tricyclic dibenzodiazepine used for treatment of human schizophrenia, and clinical signs of intoxication in humans include tachycardia, seizures, muscle fasciculations, agitation, and sialorrhea. This dog showed ptyalism, hyperthermia, tachycardia, and was easily excited by tactile or auditory stimulation. The calculated peak concentration of clozapine in this dog was approximately 6,000 ng/mL, and the elimination half-life (t1/2) was 5 hours. Charcoal administration and supportive care led to a successful outcome in this patient.

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.

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