Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens.

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.

Transferability of oxytetracycline (OTC) from feed to carp muscle and evaluation of the antibiotic effects on antioxidant systems in liver and kidney.

Oxytetracycline (OTC) is employed in fish farms to contest or prevent bacterial infections. We simulated an OTC treatment at therapeutic level (75 mg kg(-1)) and at higher doses (150, 300 mg kg(-1)) for 10 days. A withdrawal period of 10 days was considered for treated carp, carrying out the same chemical and biochemical analyses (total glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase and malondialdehyde). The aim was to obtain data related to the carryover in muscle and on variations in the antioxidant indicators in liver and kidney. The OTC residual levels in muscle showed a dose-response relationship. After 10 days of treatment at the recommended dose (75 mg kg(-1)), the mean value in muscle was 295 µg kg(-1). After 10 withdrawal days, residues in all treated groups were not entirely eliminated by fish. Residues of recommended 75 mg kg(-1) OTC dose were lower than the maximum permitted by EEC regulation: 100 µg kg(-1). Disturbance in the antioxidant systems in liver and kidney was recorded in (150, 300 mg kg(-1)) carp, as well as during the withdrawal period. A lowered superoxide dismutase activity and higher levels of catalase, glutathione peroxidase, glutathione reductase and glutathione were evaluated in liver, while in kidney only higher malondialdehyde and glutathione S-transferase concentrations were recorded for 300 mg kg(-1) dose. The therapeutic OTC dose exerted lower effects, and only in liver, enhancement of GPx and GR activities was recorded. After the withdrawal period, altered antioxidant responses in tissues were restored for all three OTC doses.

Effect of oxytetracycline on biogas production and active microbial populations during batch anaerobic digestion of cow manure.

The aim of this study was to investigate the effect of a common veterinary antibiotic in biogas plants. 20 mg/kg of oxytetracycline was intramuscularly injected into a cow and its concentration in manure, which was sampled daily during the following 20 days, was measured. A total of 20 % of the injected oxytetracycline was detected in manure. Collected manure samples on days 1, 2, 3, 5, 10, 15, and 20 were digested in triplicate serum bottles at 37 °C for 30 days. Control serum bottles produced 255 ± 13 mL biogas, whereas 50-60 % inhibitions were obtained for the serum bottles operated with samples collected for the 5 days after medication. Multivariate statistics used for the evaluation of FISH results showed that Methanomicrobiales were the main methanogenic group responsible for most of the biogas production. Numbers of active Bacteria and Methanomicrobiales were negatively correlated with the presence of oxytetracycline, whereas Methanosarcinales and Methanobacteriales were less affected.

Unión de los antibióticos tilosina, tilmicosina y oxitetraciclina a proteínas presentes en abejas, larvas y productos de la colmena de Apis mellifera L / Binding of tylosin, tilmicosin and oxytetracycline to proteins from honeybees, larvae and beehive products

Las abejas melíferas son afectadas por gran cantidad de enfermedades infecciosas principalmente producidas por bacterias, hongos, virus y parásitos eucariotas. Dentro de las ocasionadas por procariotas, la loque americana es una enfermedad extremadamente grave que afecta a larvas y pupas de abejas; su agente causal es la bacteria esporulada Paenibacillus larvae. La administración de antibióticos es la principal alternativa para el control de esta enfermedad en colmenares con altos niveles de infección. El objetivo del presente trabajo fue determinar, mediante un método biológico, la unión de los antibióticos tilosina, tilmicosina y oxitetraciclina a las proteínas presentes en abejas adultas, larvas menores de 72 horas, larvas mayores de 72 horas, jalea de obreras, miel y polen, con la finalidad de diseñar un modelo de ruta cinética de los antibióticos. Los límites de sensibilidad de la técnica de valoración de estos antibióticos fueron 0,05 μg/ml para tilosina y tilmicosina, y 0,01 μg/ml para oxitetraciclina. Los coeficientes de correlación fueron superiores a 0,90 y los coeficientes de variación intra e inter-ensayo inferiores al 5%. Tanto tilosina como oxitetraciclina presentaron un porcentaje de unión a proteínas de un 15% en promedio en tejidos y subproductos de la colmena, lo cual resultó inferior a lo observado con tilmicosina (29% en promedio). En conclusión, por sus características químicas, su actividad antimicrobiana y su baja tasa de unión a las abejas, larvas y subproductos de la colmena, la tilosina presenta propiedades farmacocinéticas que podrían representar una ventaja terapéutica para el tratamiento de la loque americana en colmenas.

American Foulbrood (AFB) caused by the spore-forming bacterium Paenibacillus larvae is the most serious disease of bacterial origin affecting larvae and pupae of honeybees. Antibiotics are used in many countries for the control of AFB in high incidence areas, but their misuse may lead to antibiotic resistance of bacterial strains and honey contamination. The objective of the present work was to determine, through a biological method, the protein binding of tylosin, tilmicosin and oxytetracycline to worker jelly; honey; pollen; adult bees and larvae in order to propose their kinetic routes. The sensitivity limit of the technique used was 0.05 μg/ml for tylosin and tilmicosin and 0.01 μg/ml for oxytetracycline, respectively. The method had intra and inter-assay correlation coefficients over 0.90, respectively and a coefficient variation of intra-and inter-assay for all antibiotics and processed samples under 5%. Tylosin and oxytetracycline presented lower percentages of protein binding in tissues and hive products (average 15%) in relation to those observed for tilmicosin (29%). In conclusion, tylosin is useful for AFB control in honey bee colonies due to its chemical characteristics, antimicrobial activity and levels of protein binding in bees, larvae, and beehive products.

Avaliação dos teores de oxitetraciclina por cromatografia à líquido de alta eficiência em gado leiteiro com doença do casco / Oxytetracycline residue evaluation by High Pressure Liquid Chromatography in milk cows with foot lameness

O presente trabalho visa desenvolver métodos analíticos que permitam determinar as concentrações de oxitetraciclina por Cromatografia Liquida de Alta Eficiência, no leite, plasma e liquido sinovial, alem de analisar as concentrações correspondentes em gado leiteiro em lactação portadoras de doenças do casco submetidos aos tratamentos intramuscular e tópico. Adicionalmente, são tecidos comentários sobre a eficácia clinica destes tratamentos. Desta forma, objetivando determinar a depuração de oxitetraciclina no organismo dos animais tratados, a concentração no sitio de ação e a quantidade residual em leite, as amostras biológicas foram colhidas e quantificadas em diferentes tempos pré e pós-administração do fármaco. Os métodos analíticos validados apresentaram linearidade, limite de detecção, quantificação, exatidão, precisão e recuperação adequadas a quantificação do antibiótico nas matrizes estudadas. Através da administração do medicamento por via intramuscular, observou-se resíduos acima dos limites máximos (1OOppb) estabelecidos pela legislação brasileira para oxitetraciclina no leite ate 120 horas após a última administração do medicamento pelo esquema seriado de doses. Já pela via tópica, não foram observados valores residuais na matriz biológica. Do ponto de vista clinico, o tratamento tópico foi eficiente nos animais tratados, levando a cura das lesões. Com relação ao tratamento intramuscular, não foram observados resultados satisfatórios, pois a maioria das lesões não regrediu após as administrações.

Pharmacokinetics of oxytetracycline in the American horseshoe crab, Limulus polyphemus.

The American horseshoe crab, Limulus polyphemus, is regularly cultured and maintained in research laboratories and public aquaria. Rising concerns over the health of these captive animals makes the diagnosis and treatment of pathological conditions in L. polyphemus essential. This study investigated the kinetics of oxytetracyline following either intravascular or oral dosing. Oxytetracylcine is a broad-spectrum antibiotic used in the treatment of various bacterial diseases of aquatic animals. A noncompartmental model was developed to describe the pharmacokinetics of oxytetracycline (OTC) in the horseshoe crab. The following parameters were determined for a single intravascular bolus of 25 mg/kg OTC: AUC = 9524.60 microg.h/mL, MRT = 443.65 h, Clb = 0.044 mL/min/kg, Vd(ss) = 1.164 L/kg, t(1/2) = 128.3 h, Cmax = 55.90 microg/mL, C(ave) = 27.39 microg/mL. Following a single oral bolus of 25 mg/kg, these parameters were calculated: AUC = 5861.81 microg.h/mL, MRT = 395.89 h, Clb = 0.071 mL/min/kg, Vd(ss) = 1.688 L/kg, t(1/2) = 210.0 h, Cmax = 7.83 microg/mL, C(ave) = 2.89 microg/mL, F = 61.56%.

P-glycoprotein-mediated transport of oxytetracycline in the Caco-2 cell model.

ATP-dependent drug transporters such as P-glycoprotein (P-gp), multi-drug resistance associated protein (MRP2) and breast cancer resistant protein (BCRP) are expressed at the brush border membrane of enterocytes. These efflux transporters excrete their substrates, among other various classes of antibiotics, into the lumen thus reducing net absorption as indicated by a low bioavailability after oral administration. Oxytetracycline (OTC) has been used for decennia in veterinary medicine for its extensive spectrum of antimicrobial activity. A major limitation has been, and still remains, its low bioavailability following oral administration. The present study aimed to investigate to what extent this low bioavailability is attributable to the fact that OTC is a substrate for one or more efflux transporters. As an experimental model to study the transmembrane transport of OTC, differentiated Caco-2 cells grown as monolayers on permeable supports were used. With this model it was shown that the secretion of OTC is slightly higher than its absorption. PSC833, a potent inhibitor of P-gp, decreased the secretion of OTC without affecting its absorption, while the MRP-inhibitor MK571 did not exert any effect. These data indicate that OTC is a substrate for P-gp. The affinity of OTC to these transporters seems to be rather low, as suggested by the low efflux ratio of 1:1.3. In competition experiments, OTC decreased the effluxes of other P-gp substrates such as Rhodamine123 and ivermectin. These findings are of clinical relevance, as they clearly indicate potential drug-drug interactions at the level of P-gp-mediated drug transport.

Bioequivalencias de cuatro marcas de oxitetraciclina / Pharmacological bioequivalence of four oxytetracycline commercial preparations

La bioequivalencia de cuatro presentaciones comerciales de oxitetraciclina fue determinada en 40 vacas secas (10 por grupo). Se inyectó por vía intramuscular a cada animal una dosis estándar de 20 mg/Kg en cuatro sistios de inyección para determinar los niveles séricos de este producto durante las 120 horas posinyección, mediante un método de espectrofotometría UV-Vis La Emicina L.A. obtuvo la mayor concentración sérica y presentó dos picos iniciales a los 30 minutos y las 8 horas posinyección, con una concentración de 9.95 y 16.95 µg/ml, respectivamente, y una concentración sérica a las 120 horas de 3.99 µg/ml. Un comportamiento similar, pero con niveles séricos menores, se observó en el producto denominado A (L.A.) Terramicina Plus y en el producto B, las cuales demostraron menores niveles séricos y no se observaron claramente los picos, como en el caso de las preparaciones ya mencionadas. Con base en las diferencias encontradas en los perfiles séricos de las cuatro presentaciones de oxitetraciclina analizadas, se propone que las empresas farmacéuticas presenten información con datos más precisos en la literatura técnica de cada uno de sus productos

Distribution of oxytetracycline to tissue cages and granuloma pouches in calves and effect of acute inflammation on distribution to tissue cages.

The effect of acute inflammation on oxytetracycline (OTC) distribution was studied in a tissue cage model in calves. An acute inflammatory reaction was induced in tissue cages by injecting lipopolysaccharide (LPS) from Salmonella typhimurium. The distribution of OTC to tissue cage fluid (TCF) was also compared with distribution to fluid from granuloma pouches (GPF). Tissue from LPS-injected cages showed histological changes indicating an acute inflammatory reaction. Concentrations of OTC were higher in LPS cages than in controls; at 1, 2, 4 and 10 h the difference was statistically significant (P less than 0.05). Numerically the overall elimination rate constant (kel) was larger, elimination half-life (t1/2) shorter, peak concentration (Cmax) higher, and time of peak concentration (Tmax) shorter in LPS cages than in controls. The area under the curve (AUC) of OTC was greater and the ratio AUCTCF/AUCserum was higher in LPS cages than in controls. Although statistically significant differences were not found for all the pharmacokinetic parameters, it was concluded that distribution to and elimination from LPS cages were both faster than in controls. Concentration-time profiles of OTC were similar in TCF and GPF in that concentrations were lower and elimination was more prolonged than in serum. Levels were higher in GPF than in TCF up to 3 h after injection; thereafter the relationship was reversed. Distribution to and elimination processes from GPF appeared to be faster than from TCF as numerically kel was higher, t1/2 shorter and Tmax shorter in GPF than in TCF. It was concluded that the granuloma pouch model and the tissue cage model have similarities in distribution and elimination patterns and that differences are most probably due to differences in the ratio of the surface area to the volume.

Triple bone labeling of canine mandibles.

Fluorescence microscopy was used for evaluation of new bone formation in 16 canine mandibles augmented with hydroxylapatite (HA) granules. Three fluorochromes were injected at different time intervals during therapeutic radiation treatment. Oxytetracycline, DCAF, and alizarin-complexone were given intravenously to mark the bone level at these times, respectively. Oxytetracycline, which defined the baseline of bone at implantation of HA, was detectable in 42% of animals that were irradiated and in no animal of the nonirradiated control group. The marker DCAF, designating levels of bone at the start of radiation, was demonstrated in 92% of irradiated animals, and in 75% of animals in the control group. The uptake of alizarin-complexone determined the level of bone found at the end of irradiation. This marker was demonstrated in 50% of the dogs irradiated and in 75% of the control dogs. Bony trabeculae were found between and at the surface of the HA granules. New generation of bone directly on the HA granule and in the surrounding haversian systems as part of normal bone turnover was demonstrated to take place more than 5 months after implantation of HA.

The role of rigid skeletal fixation in bone-graft augmentation of the craniofacial skeleton.

The type of fixation (rigid skeletal vs. wire) was assessed against embryologic origin (membranous vs. endochondral) and recipient site (depository vs. resorptive) as variables affecting inlay and onlay bone-graft survival in 20 mature dogs. Wet weight and volume measurements were made at operation and at sacrifice (16 weeks). The results were as follows: (1) Rigid skeletal fixation increased bone-graft volume survival over wire fixation (p less than 0.05). (2) Fixation (i.e., rigid skeletal) and embryologic origin (i.e., membranous) were equal determinants of bone-graft volume survival (p less than 0.001); the recipient site was not significant for onlay bone graft survival. (3) Embryologic origin was the only significant determinant of weight survival (p less than 0.001). (4) Inlay bone grafts demonstrated greater weight and volume survival than onlay bone grafts (p less than 0.05). (5) Histologic and microradiographic studies demonstrated bony union of bone grafts fixed with rigid skeletal fixation, while fibrous union predominated in bone grafts fixed with wire technique.