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1.
Xenobiotica ; 54(5): 248-256, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38634734

RESUMEN

Prostate inflammation is often treated with drugs which are ineffective. Antibacterial agents fail to reach the prostate epithelium, and the blood-prostate barrier (BPB) may affect the drug transport process. Factors affecting drug efficacy remain unclear.Rats were categorised into groups A and B, corresponding to adulthood and puberty, respectively. Group C included the model of chronic prostate infection. Dialysates of levofloxacin and cefradine were collected from the prostate gland and jugular vein and evaluated. Pharmacokinetic analysis was conducted.The free concentrations of antimicrobials in the prostate and plasma samples of all groups peaked at 20 min, then gradually decreased. The mean AUC0-tprostate/AUC0-tplasma ratio in the levofloxacin group were 0.86, 0.53, and 0.95, and the mean values of AUC0-∞prostate/AUC0-∞plasma ratio were 0.85, 0.63, and 0.97. The corresponding values in the cefradine group were 0.67, 0.30 and 0.84, and 0.66, 0.31, and 0.85, respectively. The mean values in group B were lower than those in group A, and those in group C were higher than those in group B.The maturity of the prostate may affect the ability of the drug to cross the BPB. Infection may disrupt the BPB, affecting drug permeability.


Asunto(s)
Antibacterianos , Levofloxacino , Próstata , Masculino , Animales , Próstata/metabolismo , Ratas , Levofloxacino/farmacocinética , Antibacterianos/farmacocinética
2.
Antimicrob Agents Chemother ; 68(5): e0158323, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38597667

RESUMEN

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.


Asunto(s)
Antituberculosos , Clofazimina , Cicloserina , Interacciones Farmacológicas , Isoniazida , Levofloxacino , Linezolid , Tuberculosis Resistente a Múltiples Medicamentos , Clofazimina/farmacocinética , Clofazimina/uso terapéutico , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Masculino , Femenino , Linezolid/farmacocinética , Linezolid/uso terapéutico , Isoniazida/farmacocinética , Isoniazida/uso terapéutico , Levofloxacino/farmacocinética , Levofloxacino/uso terapéutico , Cicloserina/farmacocinética , Cicloserina/uso terapéutico , Persona de Mediana Edad , Sudáfrica , Adulto Joven , Quimioterapia Combinada
3.
J Pharm Biomed Anal ; 245: 116156, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38636190

RESUMEN

Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, a traditional Chinese medicinal plant, is often used to treat various urologic disorders in China. P. capitata extracts (PCE) have been used in combination with levofloxacin (LVFX) to treat urinary tract infections (UTIs) for a long time. However, little is known about the absorption of LVFX and transporter expression in the intestine after combined treatment with PCE, restricting the development and utilization of PCE. In view of this, a UPLC-MS/MS method was established for the determination of LVFX in intestinal sac fluid samples and in situ intestinal circulation perfusate samples to explore the effect of PCE on the intestinal absorption characteristics of LVFX ex vivo and in vivo. To further evaluate the interaction between LVFX and PCE, western blotting, immunohistochemistry, and RT-qPCR were utilized to determine the expression levels of drug transporters (OATP1A2, P-gp, BCRP, and MRP2) involved in the intestinal absorption of LVFX after combined treatment with PCE. Using the everted intestinal sac model, the absorption rate constant (Ka) and cumulative drug absorption (Q) of LVFX in each intestinal segment were significantly lower in groups treated with PCE than in the control group. Ka at 2 h decreased most in the colon segment (from 0.088 to 0.016 µg/h·cm2), and Q at 2 h decreased most in the duodenum (from 213.29 to 33.92 µg). Using the intestinal circulation perfusion model, the Ka value and percentage absorption rate (A) of LVFX in the small intestine decreased significantly when PCE and LVFX were used in combination. These results showed that PCE had a strong inhibitory effect on the absorption of LVFX in the rat small intestine (ex vivo and in vivo intestinal segments). In addition, PCE increased the protein and mRNA expression levels of efflux transporters (P-gp, BCRP, and MRP2) and decreased the expression of the uptake transporter OATP1A2 significantly. The effects increased as the PCE concentration increased. These findings indicated that PCE changed the absorption characteristics of levofloxacin, possibly by affecting the expression of transporters in the small intestine. In addition to revealing a herb-drug interaction (HDI) between PCE and LVFX, these results provide a basis for further studies of their clinical efficacy and mechanism of action.


Asunto(s)
Interacciones de Hierba-Droga , Absorción Intestinal , Mucosa Intestinal , Levofloxacino , Ratas Sprague-Dawley , Animales , Levofloxacino/farmacología , Levofloxacino/farmacocinética , Absorción Intestinal/efectos de los fármacos , Ratas , Masculino , Mucosa Intestinal/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Espectrometría de Masas en Tándem/métodos , Extractos Vegetales/farmacología , Proteínas de Transporte de Membrana/metabolismo , Antibacterianos/farmacocinética
4.
Br J Clin Pharmacol ; 90(5): 1213-1221, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38317382

RESUMEN

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.


Asunto(s)
Antibacterianos , Levofloxacino , Modelos Biológicos , Método de Montecarlo , Neumonía , Humanos , Levofloxacino/farmacocinética , Levofloxacino/administración & dosificación , Levofloxacino/sangre , Anciano , Masculino , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Femenino , Anciano de 80 o más Años , Estudios Prospectivos , Neumonía/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Tasa de Filtración Glomerular , Simulación por Computador
5.
CNS Neurosci Ther ; 29(1): 445-457, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36253925

RESUMEN

AIMS: The aim of this study was to assess the influence of the major transporters at blood-brain barrier and blood-cerebrospinal fluid barrier on levofloxacin (LVFX) pharmacokinetics in rat. To explore the different effects of transporters on drug concentrations in cerebrospinal fluid (CSF) and brain extracellular fluid (ECF). METHODS: High-performance liquid chromatography coupled with microdialysis was used to continuously and synchronously measure unbound concentrations of LVFX in rat blood, hippocampal ECF, and lateral ventricle CSF for comprehensive characterization of brain pharmacokinetics. The role of transporters in the brain efflux mechanism of LVFX was analyzed in the absence and presence of various transporter inhibitors. RESULTS: Following LVFX (50 mg/kg) administration, the unbound partition coefficient of LVFX in brain ECF and CSF (Kp,uu,ECF and Kp,uu,CSF ) were 34.0 ± 1.7% and 41.2 ± 2.4%, respectively. When probenecid was coadministered with LVFX, the AUC and the mean residence time (MRT) in rat blood increased significantly (p < 0.05). After MK571 intervention, 1.35-fold and 1.16-fold increases in Kp,uu,ECF and Kp,uu,CSF were observed, respectively (p < 0.05). Treatment with Ko143 increased the levels of LVFX in brain ECF. The difference in LVFX concentration in brain ECF and CSF was <3-fold with or without treatment with transporter inhibitors. CONCLUSION: Efflux of LVFX from the central nervous system (CNS) involves multidrug resistance-associated proteins (MRPs), breast cancer resistance protein (BCRP), and organic anion transporters (OATs). MRPs play an important role in mediating the brain/CSF-to-blood efflux of LVFX. LVFX concentrations in CSF can be used as a surrogate to predict the concentrations inside brain parenchyma.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Encéfalo , Levofloxacino , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Animales , Ratas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Levofloxacino/farmacocinética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo
6.
Acta Pharmacol Sin ; 42(11): 1930-1941, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34462563

RESUMEN

Intracellular Staphylococcus aureus (S. aureus) often causes clinical failure and relapse after antibiotic treatment. We previously found that 20(S)-ginsenoside Rh2 [20(S)-Rh2] enhanced the therapeutic effect of quinolones in a mouse model of peritonitis, which we attributed to the increased concentrations of quinolones within bacteria. In this study, we investigated the enhancing effect of 20(S)-Rh2 on levofloxacin (LVF) from a perspective of intracellular bacteria. In S. aureus 25923-infected mice, coadministration of LVF (1.5 mg/kg, i.v.) and 20(S)-Rh2 (25, 50 mg/kg, i.g.) markedly increased the survival rate, and decreased intracellular bacteria counts accompanied by increased accumulation of LVF in peritoneal macrophages. In addition, 20(S)-Rh2 (1, 5, 10 µM) dose-dependently increased the uptake and accumulation of LVF in peritoneal macrophages from infected mice without drug treatment. In a model of S. aureus 25923-infected THP-1 macrophages, we showed that 20(S)-Rh2 (1, 5, 10 µM) dose-dependently enhanced the intracellular antibacterial activity of LVF. At the cellular level, 20(S)-Rh2 increased the intracellular accumulation of LVF by inhibiting P-gp and BCRP. PK-PD modeling revealed that 20(S)-Rh2 altered the properties of the cell but not LVF. At the subcellular level, 20(S)-Rh2 did not increase the distribution of LVF in lysosomes but exhibited a stronger sensitizing effect in acidic environments. Molecular dynamics (MD) simulations showed that 20(S)-Rh2 improved the stability of the DNA gyrase-LVF complex in lysosome-like acidic conditions. In conclusion, 20(S)-Rh2 promotes the cellular pharmacokinetics and intracellular antibacterial activities of LVF against S. aureus through efflux transporter inhibition and subcellular stabilization, which is beneficial for infection treatment.


Asunto(s)
Antibacterianos/farmacocinética , Ginsenósidos/farmacocinética , Líquido Intracelular/metabolismo , Levofloxacino/farmacocinética , Staphylococcus aureus/metabolismo , Fracciones Subcelulares/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Femenino , Humanos , Líquido Intracelular/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana/métodos , Staphylococcus aureus/efectos de los fármacos , Fracciones Subcelulares/efectos de los fármacos , Células THP-1
7.
Biomed Pharmacother ; 142: 112053, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34435591

RESUMEN

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.


Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Enfermedades Óseas Infecciosas/tratamiento farmacológico , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacocinética , Artropatías/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Femenino , Fluoroquinolonas/sangre , Humanos , Levofloxacino/administración & dosificación , Levofloxacino/sangre , Levofloxacino/farmacocinética , Masculino , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Ofloxacino/administración & dosificación , Ofloxacino/sangre , Ofloxacino/farmacocinética , Estudios Prospectivos , Staphylococcus/efectos de los fármacos , Adulto Joven
8.
Biopharm Drug Dispos ; 42(7): 329-337, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34117648

RESUMEN

Levofloxacin is considered a key component of a multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of the currently used doses and the development of drug resistance. Therefore, this study aimed to describe the population pharmacokinetics (PPK) of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Data of levofloxacin in healthy volunteers from a previous study were used to construct a PPK model. Monte Carlo simulations were performed to derive the PTAs of various regimens. A two-compartment model with linear elimination and transit absorption compartments best described the pharmacokinetics (PK) of levofloxacin. The estimated PK parameters (interindividual variability, %) were: apparent clearance 8.32 L h-1 (22.6%), apparent central volume of distribution 35.8 L (45.2%), apparent peripheral volume of distribution 39.7 L, intercompartmental clearance 40.6 L h-1 (43.8%), absorption rate constant 7.45 h-1 (150%), mean absorption transit time 0.355 h (52.4%), and total number of transit compartments 6.01 (131.9%). Monte Carlo simulations using levofloxacin 750-1000 mg yielded a probability of achieving a target free area under the concentration-time curve/minimum inhibitory concentration (MIC) of 100 at greater than 90% for Mycobacterium tuberculosis with an MIC < 0.5 mg L-1 , while a dose of 1500 mg was required for strains with an MIC of 1 mg L-1 . A higher dose of levofloxacin might be needed to treat tuberculosis. However, further studies on the efficacy and safety of this dose are needed to confirm our findings.


Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/farmacocinética , Levofloxacino/administración & dosificación , Levofloxacino/farmacocinética , Modelos Biológicos , Administración Oral , Adolescente , Adulto , Simulación por Computador , Voluntarios Sanos , Humanos , Levofloxacino/sangre , Masculino , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto Joven
9.
Int J Biol Macromol ; 179: 206-216, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33675827

RESUMEN

Chitosan/zeolite-A nanocomposite (CH/ZA) was synthesized as a potential carrier for levofloxacin (LVOX) of enhanced technical properties. The CH/ZA composite displayed enhanced loading capacity (425 mg/g) as compared to chitosan (188.8 mg/g) and zeolite-A (234.6 mg/g). The loading behavior follows Pseudo-Second-order and Langmuir as kinetic and isotherm models. The equilibrium studies, Gaussian energy (8.15 KJ/mol), and thermodynamic parameters demonstrate homogenous and monolayer loading by complex chemical and physical reactions that are of spontaneous and exothermic nature. The CH/ZA composite is of slow and continuous release profile (200h) with 94.3% as the maximum release percentage. The release reactions are of non-Fickian behavior involving both diffusion and erosion mechanisms. The loading of LVOX into CH/ZA induced its anti-inflammatory effect against the cytokine production (IL-6 and IL-8) within the human bronchial epithelia cells (NL20). The cytotoxicity studies on the normal cells demonstrated a high safety value for the composite.


Asunto(s)
Antiinflamatorios , Quitosano , Portadores de Fármacos , Levofloxacino , Nanocompuestos , Zeolitas , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Línea Celular , Quitosano/química , Quitosano/farmacocinética , Quitosano/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Levofloxacino/química , Levofloxacino/farmacocinética , Levofloxacino/farmacología , Ensayo de Materiales , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Zeolitas/química , Zeolitas/farmacocinética , Zeolitas/farmacología
10.
Int J Mycobacteriol ; 9(4): 411-416, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33323657

RESUMEN

Background: Levofloxacin is a preferred drug for multidrug-resistant (MDR)-tuberculosis (TB) with bactericidal activity that correlates with the pharmacokinetic exposures of serum peak concentration (Cmax) and total area under the concentration time curve (AUC0-24). Pharmacokinetic exposures can be measured to personalize dosing to reach targets, but this practice requires venepuncture, chromatographic or mass spectrometry equipment, and technical expertise. We sought to demonstrate the accuracy of using urine colorimetry as a more feasible estimation of levofloxacin exposure. Method: A colorimetric method using bromocresol green was tested on spiked urine samples with levofloxacin measured using a spectrophotometer. This method was tested in urine samples of healthy volunteers given one 750 mg dose of levofloxacin with urine collected at 0-4 h, 4-8 h, and 8-24 h intervals, and concomitant serum samples were collected and analyzed by high-performance liquid chromatography. Validation of this assay was done in a cohort of people living with human immunodeficiency virus (PLWH), initiating a levofloxacin containing MDR-TB regimen. Results: Urine colorimetry was reproducible in spiked samples and the calibration was curve linear for levofloxacin concentrations ranging from 7.8 µg/ml to 250 µg/ml, with r = 0.98. In healthy volunteers, correlation between urine absorbance values and serum AUC0-24 was highest in urine collected between 4 and 8 h (r = 0.91, P = 0.01), yet in PLWH, urine collected between 0 and 4 h had highest correlation (r = 0.66, P = 0.05). The area under the receiver operating characteristics curve was >0.8 in the derivation, as well as the validation cohort for the urine absorbance values identifying people with total serum exposure below target. Conclusion: Urine colorimetry was highly sensitive in predicting target serum concentrations. Colorimetric methods to determine levofloxacin in urine may improve the feasibility of therapeutic drug monitoring and personalized dose adjustment in TB endemic settings.


Asunto(s)
Levofloxacino , Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/uso terapéutico , Colorimetría , Monitoreo de Drogas , Femenino , Humanos , Levofloxacino/farmacocinética , Curva ROC , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico
11.
Pharmazie ; 75(11): 554-558, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-33239128

RESUMEN

A prodrug of levofloxacin (LVFX), cilexetil ester of LVFX (LVFX-CLX), was synthesized to examine whether the prodrug can avoid chelate formation with metal cations in the gastrointestinal tract. LVFX-CLX exhibited a 10-times higher partition coefficient than LVFX. In vitro, LVFX was precipitated by 76.1% in the presence of a 10-times higher concentration of aluminium chloride (Al3+), but LVFX-CLX was not. LVFX-CLX was rapidly hydrolyzed enzymatically by rat plasma, intestinal mucosal and liver homogenates at 37 °C, but not by pancreatic enzymes and luminal fluid. The minimum inhibitory concentration values of LVFX-CLX against S. aureus, E. coli and P. aeruginosa were far higher than that of LVFX. In rats, area under the plasma concentration-time curve from zero to 4 h (AUC0-4h) of LVFX after oral administration of LVFX-CLX was 1.34-fold higher than that after LVFX, though it did not reach significance level. Co-administration of Al3+ with LVFX and LVFX-CLX in rats decreased AUC0-4h of plasma LVFX by 75% and 60%, respectively, however, the AUC0-4h of plasma LVFX after co-administration of LVFX-CLX and Al3+ was 2.2-times higher than that after co-administration of LVFX and Al3+. These results suggested that the use of LVFX-CLX may reduce the modulation of intestinal microflora caused by LVFX and the suppressive effect of Al3+ on intestinal absorption of LVFX.


Asunto(s)
Aluminio/química , Antibacterianos/farmacocinética , Levofloxacino/farmacocinética , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Área Bajo la Curva , Disponibilidad Biológica , Escherichia coli/efectos de los fármacos , Ésteres/química , Absorción Intestinal , Levofloxacino/administración & dosificación , Levofloxacino/química , Masculino , Pruebas de Sensibilidad Microbiana , Profármacos , Pseudomonas aeruginosa/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Staphylococcus aureus/efectos de los fármacos
12.
Res Vet Sci ; 133: 283-288, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33039880

RESUMEN

This study aimed to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) of levofloxacin in non-lactating goats. Using a randomized cross-over study design, each group of animals (n = 7) received 2 mg/kg of levofloxacin intravenously (IV) and subcutaneously (SC). Plasma concentrations of levofloxacin were quantified by High Performance Liquid Chromatography with fluorescence detector (HPLC-FL). Rectal swabs were collected prior and after the treatment to identify the main bacterial population and to evaluate in vitro antimicrobial susceptibility using minimal inhibitory concentration (MIC) method. Mean values of terminal half-life for IV and SC groups were 4.56 and 5.14 h, respectively. After SC administration, the peak plasma concentration was achieved at 2 h, with a Cmax of 3681 ng/mL. Mean bioavailability was 92.12%. Bacteria isolation showed the presence of Escherichia coli (E. coli) that quickly becomes resistant to levofloxacin potentially rendering the drug ineffective. Results seem to suggest that levofloxacin is able to reach considerable plasma concentrations after both IV and SC administration, but it must be considered that both routes of administration can lead to a reversible selection of resistance in gastro-intestinal bacteria.


Asunto(s)
Antibacterianos/farmacocinética , Farmacorresistencia Bacteriana , Escherichia coli/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Cabras/microbiología , Levofloxacino/farmacocinética , Recto/microbiología , Administración Intravenosa/veterinaria , Animales , Antibacterianos/farmacología , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión/veterinaria , Estudios Cruzados , Escherichia coli/aislamiento & purificación , Femenino , Cabras/sangre , Levofloxacino/farmacología , Pruebas de Sensibilidad Microbiana/veterinaria
13.
Int J Biol Macromol ; 164: 2370-2379, 2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-32758607

RESUMEN

The non-gelatinous and thermo-responsive properties were introduced in chitosan by incorporating the chain of poly(N-isopropylacrylamide) via reversible addition-fragmentation chain transfer (RAFT) polymerization. To achieve this, the reaction was carried out at 80 °C by modifying the chitosan(CS) with RAFT agent as a macroinitiator (CS-RAFT), where the amine group of CS was protected with phthalic anhydride and then reacted with 4-cyano-4-[(dodecyl sulfanyl thiocarbonyl)sulfanyl]-pentanoic acid (CDSTSP) to form CS-RAFT agent. Further, the addition of NIPAAm chains onto CS-RAFT was carried out in N,N'-dimethylformamide (DMF) solvent by using 2,2'-azobisisobutyronitrile (AIBN) as an initiator in N2 atmosphere. The controlled addition of NIPAAm chains on to CS was confirmed by 1H NMR spectroscopy, further, a kinetic study was performed to get the characteristic features of the RAFT reaction. The product was characterized by 1H NMR, FT-IR, UV-Visible spectroscopy, XRD, SEM, and TGA analyses. The product in aqueous solution showed LCST at 2.0 mg/mL on 33 ± 0.1 °C. Further, beads were prepared with the sodium alginate and loaded the water-soluble levofloxacin drug (60% w/w loading was achieved). The drug delivery process was studied in-vitro at 37 ± 0.1 °C & pH 7.4, which shown controlled release of drug up to 32 h and it was 71% of the loaded levofloxacin.


Asunto(s)
Acrilamidas/química , Quitosano/química , Calor , Levofloxacino , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Levofloxacino/química , Levofloxacino/farmacocinética
14.
Xenobiotica ; 50(12): 1490-1493, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32628058

RESUMEN

The study aims to establish the plasma pharmacokinetic parameters of levofloxacin in mixed-breed dogs, at a single dose of 5 mg/kg, intravenously, orally only and orally with sucralfate pre-treatment (1 g per animal), to evaluate its influence on antimicrobial absorption. Concentrations of levofloxacin in plasma were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. After iv of levofloxacin, the mean (±SD) of AUC0-24, Vz, t½λz and MRT, was 19.05 ± 6.4 µg-h/ml, 2.43 ± 0.5 L/kg, 7.93 ± 1.41 hours and 8.7 ± 1.5 hours, respectively. After oral administration, the C max, t½λz and bioavailability were 1.95 ± 0.7 µg/ml, 7.65 ± 1.38 hours and 71.93 ± 9.75%, respectively. In animals given an oral dose of levofloxacin with sucralfate pre-treatment, there was a significant decrease (p < 0.05) in C max (0.57 ± 0.23 µg/ml), AUC (5.73 ± 2.26 µg-h/ml) and bioavailability (31.92 ± 14.19%). In the dogs studied, it is suggested that the dose 5 mg/kg of levofloxacin for both routes is inadequate to meet PK-PD targets for susceptible bacteria using breakpoints established by the Institute of Clinical and Laboratory Standards (CLSI).


Asunto(s)
Antibacterianos/farmacocinética , Levofloxacino/farmacocinética , Sucralfato/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Antiinfecciosos , Área Bajo la Curva , Bacterias , Disponibilidad Biológica , Perros , Interacciones Farmacológicas , Masculino
15.
Acta Vet Hung ; 68(1): 65-70, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32384070

RESUMEN

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.


Asunto(s)
Antibacterianos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Clonixina/análogos & derivados , Levofloxacino/farmacocinética , Oveja Doméstica/metabolismo , ortoaminobenzoatos/administración & dosificación , Animales , Área Bajo la Curva , Clonixina/administración & dosificación , Semivida , Inyecciones Intravenosas/veterinaria
16.
Eur J Clin Pharmacol ; 76(7): 929-937, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32285142

RESUMEN

PURPOSE: To evaluate the penetration of levofloxacin and dexamethasone sodium phosphate into the aqueous humour (AH) after administration in combination and as single molecules. Evaluation of the penetration of those agents in the site of action and their pharmacodynamic potential activity in view of the intended clinical use after cataract surgery. METHODS: Randomised, assessor-blinded, parallel-group. Patients scheduled for cataract surgery were assigned in a 1:1:1 ratio to: levofloxacin + dexamethasone sodium phosphate (L-DSP), Levofloxacin (L) or Dexamethasone sodium phosphate (DSP) eye drops. Either test or reference drugs were instilled in the cul-de-sac twice, 90 and 60 min before paracentesis. RESULTS: A total of 125 patients completed the study. Fraction of dose absorbed in the anterior chamber was 3.8-4.2 · 10-4 for levofloxacin and 0.3-0.4 · 10-4 for dexamethasone, respectively. No notable differences in concentration of levofloxacin were found between L-DSP arm (1.970 nmol/ml) and L arm (2.151 nmol/ml). The concentrations of levofloxacin were well above the MICs for the most frequent Gram-positive and Gram-negative eye pathogens. Dexamethasone concentrations were slightly lower in L-DSP arm (0.030 nmol/ml) than in DSP arm (0.042 nmol/ml), but still in the pharmacodynamically active range in the site of action. The difference was not clinically relevant. DSP was not detected in any HA sample, suggesting its full hydrolysis to free dexamethasone. CONCLUSION: Our results confirm that no interaction is evident on the corneal penetration of levofloxacin and dexamethasone which reach pharmacologically active concentrations when instilled as fixed combination eye drops to patients undergoing cataract surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03740659.


Asunto(s)
Antibacterianos/farmacocinética , Antiinflamatorios/farmacocinética , Humor Acuoso/metabolismo , Dexametasona/farmacocinética , Levofloxacino/farmacocinética , Soluciones Oftálmicas/farmacocinética , Administración Tópica , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antiinflamatorios/administración & dosificación , Extracción de Catarata , Córnea/metabolismo , Dexametasona/administración & dosificación , Combinación de Medicamentos , Femenino , Humanos , Levofloxacino/administración & dosificación , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas/administración & dosificación , Método Simple Ciego
17.
J Vet Sci ; 21(2): e32, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32233138

RESUMEN

Levofloxacin pharmacokinetic profiles were evaluated in 6 healthy female rabbits after intravenous (I/V), intramuscular (I/M), or subcutaneous (S/C) administration routes at a single dose of 5 mg/kg in a 3 × 3 cross-over study. Plasma levofloxacin concentrations were detected using a validated Ultra Performance Liquid Chromatography method with a fluorescence detector. Levofloxacin was quantifiable up to 10 h post-drug administration. Mean AUC0-last values of 9.03 ± 2.66, 9.07 ± 1.80, and 9.28 ± 1.56 mg/h*L were obtained via I/V, I/M, and S/C, respectively. Plasma clearance was 0.6 mL/g*h after I/V administration. Peak plasma concentrations using the I/M and S/C routes were 3.33 ± 0.39 and 2.91 ± 0.56 µg/mL. Bioavailability values, after extravascular administration were complete, - 105% ± 27% (I/M) and 118% ± 40% (S/C). Average extraction ratio of levofloxacin after I/V administration was 7%. Additionally, levofloxacin administration effects on tear production and osmolarity were evaluated. Tear osmolarity decreased within 48 h post-drug administration. All 3 levofloxacin administration routes produced similar pharmacokinetic profiles. The studied dose is unlikely to be effective in rabbits; however, it was calculated that a daily dose of 29 mg/kg appears effective for I/V administration for pathogens with MIC < 0.5 µg/mL.


Asunto(s)
Antiinfecciosos/farmacocinética , Levofloxacino/farmacocinética , Pruebas de Sensibilidad Microbiana/veterinaria , Conejos/metabolismo , Animales , Estudios Cruzados , Inyecciones Intramusculares/veterinaria , Inyecciones Intravenosas/veterinaria , Inyecciones Subcutáneas/veterinaria
18.
J Pharm Pharmacol ; 72(8): 1026-1037, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32337714

RESUMEN

OBJECTIVES: The aim of this study was to develop and optimize levofloxacin loaded PLGA nanoparticles (LN) for pulmonary delivery employing screening and experimental design and evaluate their in-vitro and in-vivo performance. The objective was to achieve Mass Median Aerodynamic Diameter (MMAD) of LN of less than 5µm, sustain the drug release up to 120 h and a higher AUC/MIC at the site of action. METHODS: LN were prepared by modified emulsion solvent evaporation technique employing high speed homogenization, probe sonication and subsequent lyophilization. KEY FINDINGS: The Pareto chart from Placket Burman screening design revealed that homogenization speed and amount of PLGA were found to be significant (P < 0.05). Further analysis by 3 full-factorial design revealed that F-ratio was found to be far greater than the theoretical value (P < 0.05) for each regression model. CONCLUSION: The optimized formulation with desirability value 0.9612 showed mean particle size of 146 nm, MMAD of 4.40 µm and sustained the drug release up to 120 h in simulated lung fluid. Augmentation in Cmax (1.71-fold), AUC 0-∞ (5.46-fold), Mean Residence Time (6.64-fold) and AUC/MIC (6.21-fold) of LN through pulmonary route was found to significantly higher (P < 0.05) than levofloxacin (p. o.).


Asunto(s)
Antituberculosos/farmacocinética , Portadores de Fármacos , Levofloxacino/farmacocinética , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Administración por Inhalación , Animales , Antituberculosos/administración & dosificación , Antituberculosos/química , Preparaciones de Acción Retardada , Composición de Medicamentos , Liberación de Fármacos , Femenino , Levofloxacino/administración & dosificación , Levofloxacino/química , Pulmón/metabolismo , Masculino , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Ratas Wistar , Solubilidad , Distribución Tisular
19.
BMC Pharmacol Toxicol ; 21(1): 20, 2020 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-32131897

RESUMEN

BACKGROUND: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16-20 mL/min) renal function. Common clinical administration regimens to provide reference values were further evaluated. METHODS: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853), which simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. Total and resistant populations were quantified. Drug concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8 h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6 h, and was seen at 0 h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0 h, there was a definite downward trend after 8 h, while resistant population in the normal renal function group increased after 16 h. CONCLUSIONS: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.


Asunto(s)
Antibacterianos/farmacología , Ceftazidima/farmacología , Enfermedades Renales/tratamiento farmacológico , Levofloxacino/farmacología , Modelos Biológicos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/farmacocinética , Ceftazidima/farmacocinética , Enfermedad Crítica , Combinación de Medicamentos , Farmacorresistencia Bacteriana/genética , Humanos , Levofloxacino/farmacocinética , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/genética
20.
Expert Opin Pharmacother ; 21(6): 637-644, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32004097

RESUMEN

INTRODUCTION: Urinary tract infections (UTIs) are among the most common causes of sepsis presenting to hospitals. Treating complicated UTIs is extremely important due to their potential mortality. Levofloxacin is a fluoroquinolone antibacterial that has become one of the cornerstones of antibiotic therapy of complicated UTIs and pyelonephritis since its introduction in the 1990s because of its exceptional pharmacokinetic (PK) and pharmacodynamic (PD) profile. However, the emergence of widespread fluoroquinolone resistance over the past decade has prompted investigators to reexamine its place in the treatment of UTI. AREAS COVERED: This literature review summarizes data about the efficacy and the tolerability of levofloxacin in treating complicated UTIs and pyelonephritis. EXPERT OPINION: In the early 2000s, fluoroquinolones became the most commonly prescribed antibiotic in the US. Since then, the resistance rate of Escherichia coli to fluoroquinolones has increased, largely hampering the use of this class of drugs. These data, in association with emerging data about inappropriate prescription and toxicity, have limited its clinical use. For these reasons, a judicious use of levofloxacin and other fluoroquinolones and a careful implementation of infection control procedures are the main available tools for the management of UTIs and pyelonephritis.


Asunto(s)
Antibacterianos/uso terapéutico , Levofloxacino/uso terapéutico , Pielonefritis/tratamiento farmacológico , Infecciones Urinarias/tratamiento farmacológico , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Farmacorresistencia Bacteriana/efectos de los fármacos , Femenino , Humanos , Control de Infecciones , Levofloxacino/efectos adversos , Levofloxacino/farmacocinética , Pielonefritis/microbiología , Sepsis/tratamiento farmacológico , Infecciones Urinarias/microbiología
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