Pharmacokinetics, Pharmacodynamic Efficacy Prediction Indexes and Monte Carlo Simulations of Enrofloxacin Hydrochloride Against Bacterial Strains That Induce Common Clinical Diseases in Broiler Chickens

Pharmacokinetic parameters and efficacy prediction indexes (Cmax/MIC90 and AUC0−24/MIC90) of an enrofloxacin hydrochloride (ENR-HCl) veterinary product soluble in water were determined in healthy broiler chickens of both sexes after a single oral dose of ENR-HCl (equivalent to 10 mg ENR base/kg bw). Monte Carlo simulations targeting Cmax/MIC90 = 10 and AUC0−24/MIC90 =125 were also performed based on a set of MIC (minimum inhibitory concentration) values of bacterial strains that induce common clinical diseases in broiler chickens and that showed to be susceptible to ENR-HCl. Plasma concentrations of ENR and its main metabolite ciprofloxacin (CIP) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time curves were found to fit a non-compartmental open model. The ratio of the area under the plasma concentration-time curve (AUC) of CIP/ENR was 4.91%. Maximum plasma concentrations of 1.35 ± 0.15 μg/mL for ENR-HCl and 0.09 ± 0.01 μg/mL for CIP were reached at 4.00 ± 0.00 h and 3.44 ± 1.01 h, respectively. Areas under the plasma vs. time concentration curve in 24 h (AUC0−24) were 18.91 ± 1.91 h × μg/mL and 1.19 ± 0.12 h × μg/mL for ENR-HCl and CIP, respectively. Using a microbroth dilution method, the minimum inhibitory concentration (MIC90) values were determined for ENR-HCl for 10 bacterial strains (Mycoplasma gallisepticum, Mycoplasma synoviae, Avibacterium paragallinarum, Clostridium perfringens, Escherichia coli, Pseudomonas aeruginosa, Salmonella ser. Enteritidis, Salmonella ser. Gallinarum, Salmonella ser. Pullorum, and Salmonella ser. Typhimurium), which are the most common causes of infectious clinical diseases in broiler chickens. In summary, the PK/PD ratios and Monte Carlo simulation were carried out for ENR-HCl in poultry, which due to its solubility was administered in drinking water. The PK/PD efficacy prediction indexes and Monte Carlo simulations indicated that the ENR-HCl oral dose used in this study is useful for bacterial infections in treating C. perfringens (Gram-positive), E. coli and S. ser. Enteritidis (Gram-negative) and M. gallisepticum bacteria responsible for systemic infections in poultry, predicting a success rate of 100% when MIC ≤ 0.06 μg/mL for E. coli and S. ser. Enteritidis and MIC ≤ 0.1 μg/mL for M. gallisepticum. For C. perfringens, the success rate was 98.26% for MIC ≤ 0.12. However, clinical trials are needed to confirm this recommendation.

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Changing the Drug Delivery System: Does it Add to Non-Compliance Ramifications Control? A Simulation Study on the Pharmacokinetics and Pharmacodynamics of Atypical Antipsychotic Drug

Pharmaceutics ◽

10.3390/pharmaceutics12040297 ◽

2020 ◽

Vol 12 (4) ◽

pp. 297

Author(s):

Mohammed H. Elkomy

Keyword(s):

Monte Carlo ◽

Plasma Concentration ◽

Monte Carlo Simulations ◽

Time Course ◽

Rating Scale ◽

Test Dose ◽

Immediate Release ◽

State Recovery ◽

Psychiatric Rating ◽

Psychiatric Rating Scale

This study investigates the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of shifting from Quetiapine fumarate immediate-release (IR) to extended-release (XR) formulation in non-adherent schizophrenia patients. Monte-Carlo simulations using population PK and PD models were implemented to predict the time course of plasma concentration and Brief Psychiatric Rating Scale (BPRS) scores following the oral administration of 200 mg Seroquel® every 12 h and 400 mg Seroquel XR® every 24 h in patients experiencing dose delay, omission or doubling. Parameters were computed and their distributions were compared using the Kolmogorov–Smirnov test. Dose irregularities with both formulations had different effects on plasma concentration and %reduction in BPRS scores from baseline. However, the odds ratio of getting a %reduction in BPRS below 14%, or plasma concentration exceeding 500 µg/L, were comparable for adherent and non-adherent patients. Plasma therapeutic concentration after treatment cessation was maintained for <24 h in 48% and 29.6% of patients, and a steady state recovery time of <48 h was achieved in 51% and 13.4% of patients on the IR and XR formulations, respectively. Monte-Carlo simulations predict that the risks associated with the IR dose irregularities are not worsened when the XR formulation is used instead. Non-adherence events involving a single dose of either formulation do not require rescue doses.

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Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

Pharmaceutical Research ◽

10.1007/s11095-020-02964-z ◽

2020 ◽

Vol 37 (12) ◽

Author(s):

Hannah Britz ◽

Nina Hanke ◽

Mitchell E. Taub ◽

Ting Wang ◽

Bhagwat Prasad ◽

...

Keyword(s):

Plasma Concentration ◽

Organic Anion ◽

Plasma Concentrations ◽

Whole Body ◽

Time Profiles ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Anion Transporter ◽

Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

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Exposure to Retinoic Acids in Non-Pregnant Women Following High Vitamin A Intake with a Liver Meal

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.75.3.187 ◽

2005 ◽

Vol 75 (3) ◽

pp. 187-194 ◽

Cited By ~ 11

Author(s):

Hartmann ◽

Brørs ◽

Bock ◽

Blomhoff ◽

Bausch ◽

...

Keyword(s):

Plasma Concentration ◽

Vitamin A ◽

Safety Concern ◽

Peak Plasma ◽

Plasma Concentrations ◽

Pregnant Female ◽

Time Curve ◽

High Vitamin ◽

Concentration Time ◽

Plasma Concentration Time Curve

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

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Interaction of Metoprolol, Propranolol and Atenolol with Cimetidine

Clinical Science ◽

10.1042/cs063451s ◽

1982 ◽

Vol 63 (s8) ◽

pp. 451s-453s ◽

Cited By ~ 3

Author(s):

W. Kirch ◽

H. Spahn ◽

H. Köhler ◽

E. Mutschler

Keyword(s):

Plasma Concentration ◽

Healthy Volunteers ◽

Peak Plasma ◽

Plasma Concentrations ◽

Concurrent Administration ◽

Time Curve ◽

Concentration Time ◽

Plasma Concentration Time Curve

1. Pharmacokinetics of metoprolol, propranolol and atenolol were investigated in six healthy volunteers after 7 days of oral monotherapy with these drugs and after 7 days concurrent administration, with each of these β-adrenoceptor antagonists with cimetidine. 2. Cimetidine did not interact with atenolol, whereas mean peak plasma concentrations of metoprolol were increased by 70%, and those of propranolol by 95% with concurrent administration of cimetidine (P < 0.05). 3. The area under the plasma concentration-time curve for propranolol and metoprolol was similarly increased (P < 0.05).

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Antibacterial effect of TiO2 modified with poly-amidoamine dendrimer – G3 on S. aureus and E. coli in aqueous solutions

Water Science & Technology ◽

10.2166/wst.2022.007 ◽

2022 ◽

Author(s):

Soudabeh Alizadeh Matboo ◽

Shahram Nazari ◽

Ali Niapour ◽

Mehdi Vosoughi Niri ◽

Esrafil Asgari ◽

...

Keyword(s):

Inhibitory Concentration ◽

Antibacterial Properties ◽

Plate Count ◽

Bacterial Strains ◽

Solution Ph ◽

E Coli ◽

Bacterial Removal ◽

Mic Minimum Inhibitory Concentration ◽

Paper Disc ◽

Surface Plate

Abstract This study investigated the bacterial removal using TiO2 nanoparticles (NPs) modified with poly-amidoamine dendrimer macromolecule (PAMAM, G3). The PAMAM G3/TiO2 (nanohybrid) was used to specify antibacterial properties via broth microdilution (MBC-Minimum Bactericidal Concentration and MIC-Minimum Inhibitory Concentration- determination), paper disc diffusion, and surface plate count methods. The nanohybrid was characterized via the different techniques. The effects of different factors including initial bacteria count, run time, solution pH, and the nanohybrid concentration were studied. The nanohybrid cytotoxicity was studied on AGS and MKN45 cells line by MTT assay. It was revealed that the nanohybrid was effective in intercepting both bacterial strains growth. The MIC value for S. aureus and E. coli were determined to be 4 and 2 μg/mL, respectively. The MBC value for both strains were calculated to be 32 μg/mL. The results showed removal efficiency of 100% for S. aureus and E. coli bacteria in optimum situation. The decrease in cell viability in the dosage of 32 μg/mL after 72 h treatment for AGS and MKN45 cells line were shown to be 6.2 and 4.6%, respectively. The nanohybrid was able to decrease the S. aureus and E. coli count in solution, which meets the drinking water criterions aligned with WHO guidelines.

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Pharmacokinetics and Pharmacodynamics of Linezolid in Patients With Sepsis Receiving Continuous Venovenous Hemofiltration and Extended Daily Hemofiltration

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz566 ◽

2020 ◽

Vol 221 (Supplement_2) ◽

pp. S279-S287

Author(s):

Junbo Zheng ◽

Zhidan Sun ◽

Lei Sun ◽

Xing Zhang ◽

Guiying Hou ◽

...

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Inhibitory Concentration ◽

Compartment Model ◽

Blood Levels ◽

Continuous Venovenous Hemofiltration ◽

Pharmacokinetics And Pharmacodynamics ◽

Target Attainment ◽

Blood Samples ◽

Failure Assessment

Abstract Background This prospective study compared pharmacokinetics (PK) and pharmacodynamics (PD) of linezolid in patients with sepsis receiving continuous venovenous hemofiltration (CVVH) with patients receiving extended daily hemofiltration (EDH). Methods Patients with sepsis treated with linezolid and CVVH or EDH were included. Serial blood samples were collected and linezolid concentrations measured. PKs were analyzed using Pmetrics. Monte Carlo simulations were used to evaluate PD target achievement. Results From 20 patients, 320 blood samples were collected for PK and PD analysis. PK profiles of linezolid were best described by a 2-compartment model. PK parameters were not significantly different between EDH and CVVH groups and were associated with body weight, renal replacement therapy (RRT) duration, and sequential organ failure assessment score. Monte Carlo simulations showed poor fractional target attainment for a minimum inhibitory concentration (MIC) of 2 mg/L with standard 600 mg intravenous administration every 12 hours. Conclusions Patients with sepsis receiving RRT exhibited variability in PK/PD parameters for linezolid. PK parameters were not significantly different between CVVH- and EDH-treated patients. Higher probability of target attainment would be achievable at a MIC of 2 mg/L in EDH patients. Higher linezolid doses should be considered for patients on RRT to achieve adequate blood levels.

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Antibacterial activity and stability of microencapsulated lemon grass essential oil in feeds for broiler chickens

Revista Brasileira de Saúde e Produção Animal ◽

10.1590/s1519-99402017000400009 ◽

2017 ◽

Vol 18 (4) ◽

pp. 587-593 ◽

Cited By ~ 1

Author(s):

Yhago Patrycky Antunes Souza Assis ◽

Anna Christina de Almeida ◽

Wedson Carlos Lima Nogueira ◽

Cintya Neves de Souza ◽

Samuel Ferreira Gonçalves ◽

...

Keyword(s):

Essential Oil ◽

Broiler Chickens ◽

Inhibitory Concentration ◽

Minimum Bactericidal Concentration ◽

Antibacterial Effect ◽

Cymbopogon Citratus ◽

E Coli ◽

Lemon Grass ◽

Oil Concentration ◽

The Stability

SUMMARY The antibacterial effect of microencapsulated lemon grass (Cymbopogon citratus) essential oil on strains of Escherichia coli (ATCC8739), Staphylococcus aureus (ATCC 6538) and Salmonella enterica subsp. enterica (ATCC 6017), and the stability of this oil in feeds for broiler chickens were evaluated. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were determined by the macrodilution method, using the microencapsulated lemon grass essential oil at concentrations of 160 μL mL−1, 80 μL mL−1, 40 μL mL−1, 20 μL mL−1, and 10 μL mL−1. The oil concentration of 80 μL mL−1 presented the best results against the three bacteria evaluated. Samples of 200 g of feed mixed with 120 μL g−1 of the microencapsulated lemon grass essential oil was stored to evaluate the oil stability. Feed without microencapsulated lemon grass essential oil was prepared as control. The oil remained active for seven days, with significant reduction of S. aureus (3.08 CFU), E. coli (3.01 CFU), and S. enterica (3.10 CFU). The microencapsulated lemon grass essential oil at concentration of 80 μL mL−1 had antibacterial effect against the E. coli, S. enterica and S. aureus, and maintained stability of the feed for seven days, even with presence of organic matter, which is source of nutrients for pathogens.

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Ontogeny and secretory patterns of plasma insulin-like growth factor-I concentrations in meat-type chickens

Journal of Endocrinology ◽

10.1677/joe.0.1240081 ◽

1990 ◽

Vol 124 (1) ◽

pp. 81-87 ◽

Cited By ~ 20

Author(s):

R. J. Johnson ◽

J. P. McMurtry ◽

F. J. Ballard

Keyword(s):

Plasma Concentration ◽

Broiler Chickens ◽

Plasma Insulin ◽

Plasma Concentrations ◽

Blood Samples ◽

Factor I ◽

Igf I ◽

Plasma Gh ◽

Secretory Pattern ◽

Meat Type

ABSTRACT The ontogeny and secretory pattern of plasma insulin-like growth factor-I (IGF-I) in relation to GH secretion were studied in meat-type (broiler) poultry during prepubertal and post-pubertal growth. Male and female broiler chickens of two commercial strains (strains A and B) were reared from 1 to 198 days of age. From 1 to 49 days of age birds were reared in raised-wire cages and thereafter in deep-litter pens, with food available ad libitum. Blood samples were taken at regular intervals during growth, and at 29 and 43 days of age representative birds were cannulated and serial blood samples taken at 10-min intervals for 5 to 7 h. Plasma concentrations of GH and IGF-I were measured by radioimmunoassay. Birds of strain A were heavier (P<0·05) than those of strain B from 12 to 35 days of age. In general, male birds were heavier (P<0·01) than females from 12 to 35 days of age. Plasma GH concentrations were significantly higher (P<0·05) from 12 to 35 days of age, while plasma IGF-I concentrations were lower (P<0·05) from 6 to 21 days of age in male compared with female birds. Plasma IGF-I concentration increased with age, reaching a plateau at 28 days of age, while plasma GH concentration declined over the same period. Plasma IGF-I concentrations declined in a linear manner from 49 to 198 days of age, and there was no evidence of a pubertal increase. There were no differences between strains in the plasma concentrations of GH or IGF-I. Serial blood sampling at 29 and 43 days of age showed that there was no relationship between GH and IGF-I, despite a highly pulsatile GH secretory pattern which existed at 29 days of age. These results show that as the plasma concentration of GH declines that of IGF-I increases. Plasma concentration of both GH and IGF-I in broiler chickens was sexually dimorphic, especially during the early growth phase to about 35 days of age. Journal of Endocrinology (1990) 124, 81–87

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Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose

The Scientific World JOURNAL ◽

10.1100/tsw.2003.122 ◽

2003 ◽

Vol 3 ◽

pp. 1344-1358

Author(s):

Tom B. Vree ◽

Erik Dammers ◽

Ivan Ulc ◽

Stefan Horkovics-Kovats ◽

Miroslav Ryska ◽

...

Keyword(s):

Body Weight ◽

Plasma Concentration ◽

Active Metabolite ◽

Plasma Concentrations ◽

Parent Drug ◽

Male And Female ◽

Concentration Time ◽

Males And Females ◽

The Difference ◽

Hydrolysis Of

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 � 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50�100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = mg.h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation.There is a large variation in the ramiprilat t1/2β(50�60% CV). There is a group of subjects who showed a t1/2βof approximately 80 h (15% CV), and two apparent groups with a longer t1/2βfor each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean � SD) of ramiprilat in males and females were identical. Thus, with identical Cmaxand half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females.This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

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Strontium absorption and excretion in normocalciuric subjects: relation tocalcium metabolism

Clinical Chemistry ◽

10.1093/clinchem/44.3.586 ◽

1998 ◽

Vol 44 (3) ◽

pp. 586-590 ◽

Cited By ~ 24

Author(s):

Giuseppe Vezzoli ◽

Ivano Baragetti ◽

Simona Zerbi ◽

Andrea Caumo ◽

Laura Soldati ◽

...

Keyword(s):

Plasma Concentration ◽

Kidney Stones ◽

Stepwise Regression ◽

Renal Excretion ◽

Plasma Concentrations ◽

Time Curve ◽

Renal Handling ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Concentration Time

Abstract The relationships of Sr intestinal absorption and renal excretion with biohumoral factors regulating Ca metabolism were studied in 47 normocalciuric subjects with Ca kidney stones. Sr concentrations were measured in serum and urine after an oral load of stable Sr (30.2 μmol/kg body wt). Enteral absorption of the ion (9.77 ± 0.438 mmol · L−1 · min, 240 min after Sr administration), expressed as the area under the plasma concentration–time curve (AUC), and renal clearance (CRE) in these subjects during the test (2.80 ± 0.336 mL/min) were not different from values for 27 controls. CRE was not correlated with AUCs. Plasma concentrations of parathyroid hormone (PTH) negatively correlated with AUCs (P <0.01) and correlated with CRE after one outlier was excluded (P <0.05). Plasma concentrations of 1,25-dihydroxyvitamin D correlated positively with AUCs (P <0.01) when normalized to the plasma concentration of PTH. Multiple stepwise regression showed that PTH and phosphatemia were significantly related to AUC values at 240 min (P <0.01). These findings suggest that Sr absorption and excretion reflect the regulation of Ca metabolism, but some differences in renal handling of the two ions may exist.

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