RESUMO
IMPORTANCE: Over the past decade, catfish farming has increased in Southeast Asia. However, there has been no existing for pharmacokinetic data in the hybrid catfish (Clarias macrocephalus x C. gariepinus). OBJECTIVE: This study was designed to evaluate the pharmacokinetic characteristics of oxytetracycline (OTC) in the hybrid catfish, following single intravascular (IV) or oral (PO) administration at a single dosage of 50 mg/kg body weight (BW). METHODS: In total, 140 catfish (each about 100-120 g BW) were divided into two groups (n = 70). Blood samples (0.6-0.8 mL) were collected from ventral caudal vein at pre-assigned times up to 144 h (sparse samples design). OTC plasma concentrations were analyzed using high-performance liquid chromatography-photodiode array detector. RESULTS: The pharmacokinetic parameter of OTC was evaluated using a non-compartment model. OTC plasma concentrations were detectable for up to 144 and 120 h after IV and PO, respectively. The elimination half-life value of OTC was long with slow clearance after IV administration in hybrid catfish. The average maximum concentration value of OTC was 2.72 µg/mL with a time at the maximum concentration of 8 h. The absolute PO bioavailability was low (2.47%). CONCLUSIONS AND RELEVANCE: These results showed that PO administration of OTC at a dosage of 50 mg/kg BW was unlikely to be effective for clinical use in catfish. The pharmacodynamic properties and clinical efficacy of OTC after multiple medicated feed are warranted.
Assuntos
Peixes-Gato , Oxitetraciclina , Animais , Oxitetraciclina/farmacocinética , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Administração Oral , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Injeções Intravenosas/veterinária , Meia-VidaRESUMO
Antibiotic excretion into milk depends on several factors such as the compound's physicochemical properties, the animal physiology, and the milk composition. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the passage of drugs into the milk of lactating species. The udder is described as a permeability limited compartment, divided into vascular, extracellular water (EW), intracellular water (IW) and milk, which was stored in alveolar and cistern compartments. The pH and ionization in each compartment and the binding to IW components and to milk fat, casein, whey protein, calcium, and magnesium were considered. Bidirectional passive diffusion across the blood-milk barrier was implemented, based on in vitro permeability studies. The model application used to predict the distribution of oxytetracycline in cow and goat milk, after different doses and routes of administration, was successful. By integrating inter-individual variability and uncertainty, the model also allowed a suitable estimation of the withdrawal periods. Further work is in progress to evaluate the predictive ability of the PBPK model for compounds with different physico-chemical properties that are potentially actively transported in order to extrapolate the excretion of xenobiotics in milk of various animal species including humans.
Assuntos
Bovinos/sangue , Cabras/sangue , Lactação , Leite/química , Modelos Biológicos , Oxitetraciclina/farmacocinética , Animais , Antibacterianos , Área Sob a Curva , Feminino , Glândulas Mamárias Animais/fisiologia , Oxitetraciclina/sangue , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The aim of this study was to determine to what extent the ions present in hard water (125 mg/L of MgCl2 and 500 mg/L of CaCl2) may intensify the feed-induced decrease in oxytetracycline (OTC) absorption rate in broiler chickens after single oral administration at a dose of 15 mg/kg. Drug concentrations in plasma were determined by liquid chromatography-tandem mass spectrometry and combined, compartmental and non-compartmental approach was used to assess OTC pharmacokinetics. The administration of feed decreased the absolute bioavailability (F) of OTC from 12.70%±4.01 to 6.40%±1.08, and this effect was more pronounced after the combined administration of OTC with feed and hard water (5.31%±0.90). A decrease in the area under the concentration- time curve (AUC0-t), (from 10.18±3.24 µg·h/ml in control to 5.13 µg·h/ml±1.26 for feed and 4.26 µg·h/ml±1.10 for feed and hard water) and the maximum plasma concentration of OTC (Cmax) (from 1.22±0.18 µg/ml in control, to 1.01 µg/ml ±0.10 for hard water, 0.68 µg/ml±0.10 for feed and 0.61 µg/ml±0.10 for feed and hard water) was observed. The results of this study indicate that feed strongly decreases F, AUC0-t and Cmax of orally administered OTC. The ions present in hard water increase this inhibitory effect, which suggests that, therapy with OTC may require taking into account local water quality and dose modification, particularly when dealing with outbreaks caused by less sensitive microorganisms.
Assuntos
Antibacterianos/farmacocinética , Galinhas/sangue , Oxitetraciclina/farmacocinética , Água/química , Administração Oral , Ração Animal/análise , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Disponibilidade Biológica , Meia-Vida , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Distribuição AleatóriaRESUMO
A high performance liquid chromatography method had been developed and validated for rapid simultaneous separation and determination of three anti-helicobacter drugs, oxytetracycline (OXY), tinidazole (TIN) and esomeprazole (ESM) in human plasma within 6 minutes. Drugs extraction method from plasma was based on protein precipitation technique. Separation was carried out on a Equisil BDS C18 column (5 µm, 150 × 4.60 mm) using a mobile phase of acetonitrile: 0.025 M KH2PO4 (25: 75, v/v) adjusted to pH 3.50 with ortho-phosphoric acid at ambient temperature. The flow rate was 1 mL/min and maximum absorption was measured using Diode Array (DAD) detector at 285 nm. The retention times of OXY, TIN and ESM were recorded to be 2.68, 3.52 and 5.17 minutes, respectively, indicating a shorter analysis time. Limits of detection were also reported to be 0.10, 0.07 and 0.04 µg/mL for OXY, TIN and ESM, respectively, showing a high degree of the method sensitivity. The method was then validated according to FDA guidelines for the determination of the drugs clinically in human plasma specially regarding pharmacokinetic and bioequivalence studies.
Assuntos
Antibacterianos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Esomeprazol/sangue , Oxitetraciclina/sangue , Tinidazol/sangue , Humanos , Limite de Detecção , Plasma/químicaRESUMO
A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞ )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞ /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively.
Assuntos
Antibacterianos/farmacocinética , Mannheimia haemolytica/efeitos dos fármacos , Oxitetraciclina/farmacocinética , Infecções por Pasteurella/veterinária , Pasteurella multocida/efeitos dos fármacos , Pneumonia Enzoótica dos Bezerros/tratamento farmacológico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/farmacologia , Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/veterinária , Bovinos , Feminino , Injeções Intramusculares/veterinária , Testes de Sensibilidade Microbiana/veterinária , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Oxitetraciclina/farmacologia , Infecções por Pasteurella/tratamento farmacológicoRESUMO
The penetration of oxytetracycline (OTC) into the oral fluid and plasma of pigs and correlation between oral fluid and plasma were evaluated after a single intramuscular (i.m.) dose of 20 mg/kg body weight of long-acting formulation. The OTC was detectable both in oral fluid and plasma from 1 hr up to 21 day after drug administration. The maximum concentrations (Cmax ) of drug with values of 4021 ± 836 ng/ml in oral fluid and 4447 ± 735 ng/ml in plasma were reached (Tmax ) at 2 and 1 hr after drug administration respectively. The area under concentration-time curve (AUC), mean residence time (MRT) and the elimination half-life (t1/2ß ) were, respectively, 75613 ng × hr/ml, 62.8 hr and 117 hr in oral fluid and 115314 ng × hr/ml, 31.4 hr and 59.2 hr in plasma. The OTC concentrations were remained higher in plasma for 48 hr. After this time, OTC reached greater level in oral fluid. The strong correlation (r = .92) between oral fluid and plasma OTC concentrations was observed. Concentrations of OTC were within the therapeutic levels for most sensitive micro-organism in pigs (above MIC values) for 48 hr after drug administration, both in the plasma and in oral fluid.
Assuntos
Antibacterianos/farmacocinética , Oxitetraciclina/farmacocinética , Saliva/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/análise , Antibacterianos/sangue , Preparações de Ação Retardada , Meia-Vida , Injeções Intramusculares/veterinária , Oxitetraciclina/administração & dosagem , Oxitetraciclina/análise , Oxitetraciclina/sangue , Suínos/metabolismoRESUMO
Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslX. However, acslX has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of 4 PBPK modeling software packages (acslX, Berkeley Madonna, MATLAB, and R language) tested using 2 existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslX to Berkeley Madonna, MATLAB, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field. Simulation results of plasma/tissue concentrations/amounts of oxytetracycline and gold from different models were compared visually and statistically with linear regression analyses. Simulation results from the original models were correlated well with results from the recoded models, with time-concentration/amount curves nearly superimposable and determination coefficients of 0.86-1.00. Step-by-step explanations of the recoding of the models in different software programs are provided in the Supplementary Data. In summary, this article presents a tutorial of PBPK model code conversion for a small molecule and a nanoparticle among 4 software packages, and a performance comparison of these software packages in PBPK model implementation. This tutorial helps beginners learn PBPK modeling, provides suggestions for selecting a suitable tool for future projects, and may lead to the transition from acslX to alternative modeling tools.
Assuntos
Ouro/farmacocinética , Nanopartículas Metálicas/química , Modelos Biológicos , Oxitetraciclina/farmacocinética , Animais , Cães , Ouro/sangue , Ouro/química , Oxitetraciclina/sangue , Suínos , Distribuição TecidualRESUMO
The present study aimed to characterize the pharmacokinetic profile of oxytetracycline long-acting formulation (OTC-LA) in Thai swamp buffaloes, Bubalus bubalis, following single intramuscular administration at two dosages of 20 and 30 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 504 h. The plasma concentrations of OTC were measured by high-performance liquid chromatography (HPLC). The concentrations of OTC in the plasma were determined up to 264 h and 432 h after i.m. administration at doses of 20 and 30 mg/kg b.w., respectively. The Cmax values of OTC were 12.11 ± 1.87 µg/mL and 12.27 ± 1.92 µg/mL at doses of 20 and 30 mg/kg, respectively. The AUClast values increased in a dose-dependent fashion. The half-life values were 52.00 ± 14.26 h and 66.80 ± 10.91 h at doses of 20 and 30 mg/kg b.w, respectively. Based on the pharmacokinetic data and PK-PD index (T > MIC), i.m. administration of OTC at a dose of 30 mg/kg b.w once per week might be appropriate for the treatment of susceptible bacterial infection in Thai swamp buffaloes.
Assuntos
Antibacterianos/farmacocinética , Búfalos/sangue , Oxitetraciclina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Preparações de Ação Retardada , Feminino , Meia-Vida , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangueRESUMO
The influence of the composition of calcium (Ca(2+)), magnesium (Mg(2+)), and iron (Fe(3+)) ions in two concentration levels (low-500 mg/L of CaCl2, 125 mg/L of MgCl2, and 10 mg/L of FeCl3 and high-2,500 mg/L of CaCl2, 625 mg/L of MgCl2, and 50 mg/L of FeCl3) contained in water on the pharmacokinetics (PK) of oxytetracycline (OTC) was determined. OTC hydrochloride was administered at a dose of 25 mg/kg of body weight to broiler chickens divided into four groups of nine birds each, including 3 oral groups (in deionized water -control, in water with low ion concentration, and in water with high ion concentration) and 1 intravenous group. OTC concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry, after which non-compartmental pharmacokinetic analysis was conducted.The absolute bioavailability of OTC in the group of birds exposed to higher ions concentration was reduced (8.68% ± 2.56) as compared to the control (13.71% ± 2.60). Additionally, in this group, decrease in PK parameters such as: area under the concentration-time curve from 0 to infinity (15.36 µg × h/mL ± 4.36), from 0 to t (14.78 µg × h/mL ± 4.37), area under the first moment of curve from 0 to t (107.54 µg × h/mL ± 36.48), and maximum plasma concentration (2.13 µg/mL ± 0.32) were also observed. It is noteworthy, all mentioned parameters demonstrated a downward trend with high correlation coefficient (P = 0.004, P = 0.002, P = 0.005, P = 0.004, P = 0.011, respectively), reflecting the influence of increasing concentrations of Ca(2+), Mg(2+), and Fe(3+) ions on the decreasing absorption rate of OTC.Based on the current research results, it can be assumed that high concentrations of several ions applied concomitantly are able to decrease the absorption of OTC from gastrointestinal tract in broiler chickens. This occurrence might impair the drug's clinical efficacy toward some pathogenic microorganisms. It implies that using OTC on a farm may require administration of higher doses than the routine one when infections are caused by less sensitive pathogens.
Assuntos
Cálcio/farmacocinética , Galinhas/metabolismo , Ferro/farmacocinética , Magnésio/farmacocinética , Oxitetraciclina/farmacocinética , Administração Oral , Animais , Cálcio/administração & dosagem , Galinhas/sangue , Interações Medicamentosas , Feminino , Injeções Intravenosas/veterinária , Ferro/administração & dosagem , Magnésio/administração & dosagem , Masculino , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangueRESUMO
The impact of 4-epi-oxytetracycline (4-EOTC), one of the main oxytetracycline (OTC) metabolites, on the gut microbiota and physiological metabolism of Wistar rats was analyzed to explore the dynamic alterations apparent after repeated oral exposure (0.5, 5.0 or 50.0 mg/kg bw) for 15 days as shown by 16S rRNA pyrosequencing and UPLC-Q-TOF/MS analysis. Both principal component analysis and cluster analysis showed consistently altered patterns with distinct differences in the treated groups versus the control groups. 4-EOTC treatment at 5.0 or 50.0 mg/kg increased the relative abundance of the Actinobacteria, specifically Bifidobacteriaceae, and improved the synthesis of lysophosphatidylcholine (LysoPC), as shown by the lipid biomarkers LysoPC(16:0), LysoPC(18:3), LysoPC(20:3), and LysoPC(20:4). The metabolomic analysis of urine samples also identified four other decreased metabolites: diacylglycerol, sphingomyelin, triacylglycerol, and phosphatidylglycerol. Notably, the significant changes observed in these biomarkers demonstrated the ongoing disorder induced by 4-EOTC. Blood and urine analysis revealed that residual 4-EOTC accumulated in the rats, even two weeks after oral 4-EOTC administration, ceased. Thus, through thorough analysis, it can be concluded that the alteration of the gut microbiota and disorders in blood metabolomics are correlated with 4-EOTC treatment.
Assuntos
Antibacterianos/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma , Oxitetraciclina/farmacocinética , Animais , Antibacterianos/sangue , Antibacterianos/urina , Biomarcadores/sangue , Biomarcadores/urina , Fezes/microbiologia , Feminino , Metabolismo dos Lipídeos , Masculino , Oxitetraciclina/análogos & derivados , Oxitetraciclina/sangue , Oxitetraciclina/urina , Ratos WistarRESUMO
Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.
Assuntos
Cyprinidae/metabolismo , Oxitetraciclina/farmacocinética , Absorção Fisico-Química , Administração Oral , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Meia-Vida , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangueRESUMO
Oxytetracycline (OTC) is a commonly used tetracycline antibiotic in veterinary and human medicine. To establish a quantitative model for predicting OTC plasma and tissue exposure, a permeability-limited multiroute physiologically based pharmacokinetic model was developed in dogs. The model was calibrated with plasma pharmacokinetic data in beagle dogs following single intravenous (5 mg/kg), oral (100 mg/kg), and intramuscular (20 mg/kg) administrations. The model predicted other available dog data well, including drug concentrations in the liver, kidney, and muscle after repeated exposure, and data in the mixed-breed dog. The model was extrapolated to humans and the human model adequately simulated measured plasma OTC concentrations after intravenous (7.14 mg/kg) and oral exposures (6.67 mg/kg). The dog model was applied to predict 24-h OTC area-under-the-curve after three therapeutic treatments. Results were 27.75, 51.76, and 64.17 µg/mL*h in the plasma, and 120.93, 225.64, and 279.67 µg/mL*h in the kidney for oral (100 mg/kg), intravenous (10 mg/kg), and intramuscular (20 mg/kg) administrations, respectively. This model can be used to predict plasma and tissue concentrations to aid in designing optimal therapeutic regimens with OTC in veterinary, and potentially, human medicine; and as a foundation for scaling to other tetracycline antibiotics and to other animal species. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:233-243, 2015.
Assuntos
Antibacterianos/farmacocinética , Cães , Modelos Biológicos , Oxitetraciclina/farmacocinética , Farmacologia Clínica/métodos , Fisiologia Comparada/métodos , Medicina Veterinária/métodos , Administração Oral , Animais , Animais Endogâmicos , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/metabolismo , Biologia Computacional , Simulação por Computador , Bases de Dados de Produtos Farmacêuticos , Relação Dose-Resposta a Droga , Humanos , Injeções Intramusculares , Injeções Intravenosas , Rim/metabolismo , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Oxitetraciclina/metabolismo , Eliminação Renal , Reprodutibilidade dos Testes , Especificidade da Espécie , Distribuição TecidualRESUMO
Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens.
Assuntos
Antibacterianos/farmacocinética , Galinhas/sangue , Oxitetraciclina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Feminino , Meia-Vida , Injeções Intramusculares , Masculino , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangueRESUMO
INTRODUCTION: Great interest is raising in food intolerances due to the lack, in many cases, of a particular sensitizing agent. OBJECTIVE: We investigated the serum level of possible new haptens in 15 heavy meat consumers for sport fitness affected by various kinds of food intolerance and who had ever been administered antibiotics in their life for clinical problems. METHODS: Forty ml of blood were drawn from each patient and analyzed, by means of an ELISA test, in order to possibly identify the presence of an undue contaminant with hapten properties. RESULTS: Four out of fifteen subjects (26%) showed a serum oxytetracycline amount > 6 ng/g (which is considered the safety limit), 10 of 15 (66%) a serum doxycycline amount > of 6 ng/g and 3 out of 15 (30%) subjects had high serum level of both molecules. CONCLUSIONS: Although a direct ratio between body antibiotics remnant storage in the long run and chronic gut dysfunctions and/or food allergy did not reached the evidence yet, the blood traces of these compounds in a food intolerant otherwise healthy population might be considered the preliminary putative step of a sensitizing pathway. Our next goals foresee a deeper insight into the sensitizing trigger from human chronic antibiotic exposure via the zootechnical delivery of poultry food.
Introducción: La falta, en muchos casos, de un agente sensibilizador está despertando un enorme interés en la tolerancia a los alimentos. Objetivo: Investigamos el nivel sérico de posibles nuevos haptenos en 15 grandes consumidores de carne para entrenamiento deportivo afectados por diversos tipos de intolerancia a los alimentos y que habían recibido antibióticos en algún momento de sus vidas por problemas médicos. Métodos: Se realizaron extracciones de sangre de 40ml a cada paciente y se analizaron empleando un test ELISA, para identificar la posible presencia de un elemento contaminante indebido con propiedades de hapteno. Resultados: 4 de 15 sujetos (26%) mostraron una cantidad de oxitetraciclina en suero > 6 ng/g (considerado el límite de seguridad); 10 de 15 (66%) sujetos presentaron una cantidad de doxiciclina > 6 ng/g; y 3 de 15 (30%) sujetos presentaron un alto nivel sérico de ambas moléculas. Conclusiones: Aunque no se llegó a obtener evidencia de una relación directa entre la acumulación de antibióticos corporales a largo plazo y una disfunción intestinal crónica y/o alergias a los alimentos, las trazas en sangre de estos compuestos en una población con alguna intolerancia a los alimentos pero por lo demás sana, podría considerarse el primer paso de una vía de sensibilización. Nuestros próximos objetivos prevén un estudio más profundo del desencadenante sensibilizador a partir de la exposición crónica a antibióticos en humanos por medio de la administración zootécnica de comida avícola.
Assuntos
Antibacterianos/sangue , Doxiciclina/sangue , Hipersensibilidade Alimentar/sangue , Oxitetraciclina/sangue , Adulto , Feminino , Humanos , MasculinoRESUMO
The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oxytetracycline were investigated, when administered both alone and in the presence of carprofen, in healthy calves. The study comprised a four treatment, four sequences, and four period cross-over design and used a tissue cage model, which permitted the collection of serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). There were no clinically relevant differences in the PK profile of oxytetracycline when administered alone and when administered with carprofen. PK-PD integration was undertaken for a pathogenic strain of Mannheimia haemolytic (A1 76/1), by correlating in vitro minimum inhibitory concentration (MIC) and time-kill data with in vivo PK data obtained in the cross-over study. Based on in vitro susceptibility in cation adjusted Mueller Hinton Broth (CAMHB) and in vivo determined PK variables, ratios of maximum concentration (Cmax) and area under curve (AUC) to MIC and time for which concentration exceeded MIC (T>MIC) were determined. The CAMHB MIC data satisfied integrated PK/PD relationships predicted to achieve efficacy for approximately 48 h after dosing; mean values for serum were 5.13 (Cmax/MIC), 49.3 h (T>MIC) and 126.6 h (AUC(96h)/MIC). Similar findings were obtained when oxytetracycline was administered in the presence of carprofen, with PK-PD indices based on MIC determined in CAMHB. However, PK-PD integration of data, based on oxytetracycline MICs determined in the biological fluids, serum, exudate and transudate, suggest that it possesses, at most, limited direct killing activity against the M. haemolytica strain A1 76/1; mean values for serum were 0.277 (Cmax/MIC), 0 h (T>MIC) and 6.84 h (AUC(96h)/MIC). The data suggest that the beneficial therapeutic effects of oxytetracycline may depend, at least in part, on actions other than direct inhibition of bacterial growth.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacocinética , Oxitetraciclina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Anti-Inflamatórios não Esteroides/administração & dosagem , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Bovinos , Interações Medicamentosas , Quimioterapia Combinada , Exsudatos e Transudatos/química , Injeções Intramusculares/veterinária , Mannheimia haemolytica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Oxitetraciclina/farmacologia , Pneumonia Enzoótica dos Bezerros/tratamento farmacológicoRESUMO
Oxytetracycline (OTC), a broad-spectrum antibiotic, has been extensively used as a food additive for livestock. Its extensive use has greatly increased the risk of chronic drug abuse and has also increased the risk of the resulting diseases. Therefore, in light of this emerging situation, the detection of OTC in both food and livestock is very important to reduce the risks and for diagnosis purposes . In this work, we have proposed an electrochemical aptasensor to quantify OTC. The biosensor shows considerable sensitivity and selectivity, and it can be easily operated and regenerated. Furthermore, for the first time, we have shown that an electrochemical aptasensor can be directly used to detect OTC in mouse blood serum and urine. This biosensor has the potential to aid in the analysis of residual OTC levels, as well as providing more pharmacokinetic information in the future.
Assuntos
Antibacterianos/sangue , Antibacterianos/urina , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Oxitetraciclina/sangue , Oxitetraciclina/urina , Animais , Aptâmeros de Nucleotídeos/química , Feminino , Camundongos , Sensibilidade e EspecificidadeRESUMO
A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 µg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Carbazóis/farmacocinética , Bovinos/metabolismo , Oxitetraciclina/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Carbazóis/administração & dosagem , Carbazóis/sangue , Bovinos/sangue , Estudos Cross-Over , Cultura em Câmaras de Difusão/veterinária , Dinoprostona/antagonistas & inibidores , Interações Medicamentosas , Meia-Vida , Injeções Intramusculares/veterinária , Injeções Subcutâneas/veterinária , Masculino , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Tromboxano B2/antagonistas & inibidoresRESUMO
The pharmacokinetic-pharmacodynamic predictor of antimicrobial activity for tetracyclines is reported to be the area under the concentration-time curve at steady state (AUC(ss)) divided by the minimal inhibitory concentration of the targeted pathogen. Here, we estimate AUC(ss) values for oxytetracycline (OTC) in serum of rainbow trout Oncorhynchus mykiss by using a destructive sampling study design. Seventy-two rainbow trout were fed OTC-medicated feed at 74.7 +/- 1.5 mg/kg (mean +/- SD) body weight (BW) by oral gavage for 10 consecutive days. Serum was collected from nine fish at 1, 3, 6, 8, 10, 12, 15, and 22 d after dosing began. Serum OTC concentrations were measured by high-performance liquid chromatography with a 0.01-microg/mL limit of detection. The average OTC AUC(ss) was 29.2 microg x h/mL and was estimated using nonlinear mixed-effects modeling and bootstrap resampling techniques. The elimination half-life was estimated as 85.0 h, and the fraction of steady state achieved was estimated as 0.85. The calculated AUC(ss) (24.8 microg x h/mL) following 10 d of oral dosing with 75 mg OTC/kg BW was less than the estimated AUC(ss). Results suggest that the pharmacokinetics of OTC exposure, including the AUC(ss), is better evaluated by using multiday dosimetry than by using a standard single-dose protocol.
Assuntos
Ração Animal/análise , Oncorhynchus mykiss/metabolismo , Oxitetraciclina/farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Dieta/veterinária , Meia-Vida , Oxitetraciclina/sangueRESUMO
The penetration of oxytetracycline (OTC) in plasma and nasal secretions of healthy pigs was evaluated during the first study, in response to oral dose of 20 mg of OTC per kg of body weight (bwt) per day as a 400 mg/kg feed medication (n = 5) and to intramuscular (i.m.)-administered formulations at 10 mg/kg bwt (n = 5), 20 mg/kg bwt (n = 5), 40 mg/kg bwt (n = 5). Concentrations of OTC in plasma and nasal secretions were determined by a validated ultra-high performance liquid chromatography associated to tandem mass spectrometry method (UPLC/MS/MS). The objectives were to select the efficacy treatment and to evaluate the possibility to predict nasal secretions concentrations from those determined in plasma. The animals were housed together in each experiment. In each group, the treatment was administered once daily during 6 consecutive days, and nasal secretions and plasma were collected after 4 and 24 h at day 2 and day 6. For oral administration, only one medicated feed was prepared and distributed to all the animals together and was consumed in approximately 1 h. To meet recommendations of efficacy for OTC in nasal secretions, only the i.m. of 40 mg/kg bwt associated to an inter-dosing interval of 24 h provides and maintains concentrations in nasal secretions ≥1 µg/mL, appropriate to the MIC 50 and 90 of Pasteurella multocida and Bordetella bronchiseptica, respectively, the main pathological strains in nasal secretions. It has been demonstrated that, using a generalized linear mixed model (GLMM), OTC in the nasal secretions (µg/mL) can be predicted taking into account the OTC concentrations in plasma (µg/mL), according to the following equation: OTC(nasal secretions) = 0.28 OTC(plasma) -1.49. In a second study, the pharmacokinetic behaviour of OTC in plasma and nasal secretions of healthy pigs was investigated, after single-dose i.m. of 40 mg/kg bwt of the drug. Blood samples and nasal secretions were collected at predetermined times after drug administration. The data collected in 10 pigs for OTC were subjected to non-compartmental analysis. In plasma, the maximum concentration of drug (C(max) ), the time at which this maximum concentration of drug (T(max) ) was reached, the elimination half-life (t½) and the area under the concentration vs. time curve (AUC) were, respectively, 19.4 µg/mL, 4.0, 5.1 h and 150 µg·h/mL. In nasal secretions, C(max) , T(max) , t½ and AUC were, respectively, 6.29 µg/mL, 4.0, 6.6 h and 51.1 µg·h/mL.
Assuntos
Antibacterianos/farmacocinética , Cavidade Nasal/química , Oxitetraciclina/farmacocinética , Suínos/metabolismo , Administração Oral , Animais , Animais Recém-Nascidos , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/veterinária , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Injeções Intramusculares/veterinária , Masculino , Oxitetraciclina/administração & dosagem , Oxitetraciclina/sangue , Suínos/sangueRESUMO
A simple and sensitive methodology to simultaneously quantify tetracycline and oxytetracycline in bovine serum samples is described. The method combines the advantages of the lanthanide-sensitized luminescence (i.e., sensitivity and selectivity) with partial least-squares (PLS) analysis, and requires no previous separation steps. Due to the strong overlapping of emission and excitation spectra of the analytes and their europium complexes, the luminescence decay curve (intensity of luminescence vs. time) of analyte-Eu complex was selected to resolve mixtures of tetracycline and oxytetracycline. Partial least-squares uses the luminescence decay as discriminatory parameter and regresses the luminescence versus time onto the concentrations of standards. Using a 16-sample aqueous calibration set, 10 validation samples, 11 spiked serum bovine samples and a blank of serum were studied. The analyte recoveries from serum samples ranged from 87 to 104% for tetracycline and from 94 to 106% for oxytetracycline. The results obtained by the developed method were statistically comparable to those obtained with high performance liquid chromatography.