RESUMEN
Bovine pain assessment relies on validated behavioral scales related to normal and pain-related behaviors. This study investigated the reliability and applicability of real-time and video-recorded pain assessment, and their agreement, in young, adult bulls undergoing surgical castration. Ten Nelore and nine Angus bulls underwent general anesthesia and surgical castration. Three-minute real-time observations and simultaneous videos were recorded at - 48 h (M0), before sedation, under fasting (M1), after surgery, 3 h after sternal recumbency (M2), after rescue analgesia (M3) and at 24 h (M4). Animals received morphine (after M2), dipyrone (after M3), and flunixin meglumine after surgical castration (M4). Two trained evaluators assessed real-time (n = 95) and video-recorded time-points (n = 95) using the Unesp-Botucatu Cattle Pain Scale (UCAPS). Both assessment methods inferred 'very good' reliability (≥ 0.81) with minimal bias, however, video-recorded assessment (4.33 ± 2.84) demonstrated slightly higher scores compared to real-time (3.08 ± 2.84). The results from this study suggest that UCAPS can be used in real-time or video-recorded to assess pain and guide analgesic therapy in cattle.
Asunto(s)
Orquiectomía , Dimensión del Dolor , Grabación en Video , Animales , Masculino , Bovinos , Dimensión del Dolor/métodos , Dimensión del Dolor/veterinaria , Orquiectomía/veterinaria , Orquiectomía/efectos adversos , Reproducibilidad de los Resultados , Clonixina/análogos & derivados , Clonixina/uso terapéutico , Dolor/veterinaria , Morfina/uso terapéutico , Dipirona/uso terapéutico , Dolor Postoperatorio/veterinaria , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/diagnósticoRESUMEN
Flunixin (FLU) is a nonsteroidal drug that is widely used in animals, causing severe drug residues in animal-derived foods and environment. The development of antibody-based rapid immunoassay methods is of great significance for the monitoring of FLU and its metabolite 5-hydroxyflunixin (5-FLU). We prepared monoclonal antibodies (mAbs) with different recognition spectra through FLU-keyhole limpet hemocyanin conjugates as immunogen coupled with antibody screening strategies. mAb5E6 and mAb6D7 recognized FLU with high affinity, and mAb2H5 and mAb4A4 recognized FLU and 5-FLU with broad specificity. Through evaluating the recognition of these mAbs against more than 11 structural analogues and employing computational chemistry, molecular docking, and molecular dynamics methodologies, we preliminarily determined the recognition epitope and recognition mechanism of these mAbs. Finally, an indirect competitive enzyme-linked immunosorbent assay for FLU based on mAb6D7 was developed, which exhibited limits of detection as low as 0.016-0.042 µg kg -1 (L-1) in milk and muscle samples.
Asunto(s)
Anticuerpos Monoclonales , Formación de Anticuerpos , Clonixina/análogos & derivados , Animales , Simulación del Acoplamiento Molecular , Inmunoensayo , Ensayo de Inmunoadsorción Enzimática/métodos , Especificidad de AnticuerposRESUMEN
Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.
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Clonixina , Clonixina/análogos & derivados , Enfermedades de los Porcinos , Animales , Porcinos , Administración Intranasal/veterinaria , Inyecciones Intravenosas/veterinaria , Clonixina/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Analgésicos/uso terapéutico , Inyecciones Intramusculares/veterinaria , Enfermedades de los Porcinos/tratamiento farmacológicoRESUMEN
OBJECTIVE: To assess the effects of transdermal flunixin administration on serum prostaglandin E2 (PGE2) and cortisol concentrations in piglets undergoing castration. ANIMALS: 104 litters with at least 4 male piglets/litter. PROCEDURES: Litters were randomly assigned to 1 of 4 treatments: transdermal flunixin (3.33 mg/kg) administration followed by surgical castration (CF; n = 28), transdermal flunixin administration followed by sham castration (SF; n = 26), application of physiologic saline solution followed by sham castration (S; n = 26), and application of physiologic saline solution followed by surgical castration (C; n = 24). Blood samples were collected 24 hours before and 1, 4, and 25 hours after castration or sham castration. RESULTS: Serum PGE2 concentrations for piglets in the C and CF groups did not differ at any time. Piglets in the S group tended to have higher serum PGE2 concentrations 1 hour after sham castration compared with piglets in the SF group. One hour after the procedure, piglets that underwent castration had higher serum cortisol concentrations than did piglets that underwent sham castration. Piglets in the CF group had higher serum cortisol concentrations than did piglets in the SF group 4 hours after the procedure, but serum cortisol concentrations did not differ between the C and S groups. CLINICAL RELEVANCE: Further studies are needed to explore dosing regimens, including effective doses and administration frequencies, and the pharmacokinetics of flunixin following transdermal administration in piglets undergoing castration.
Asunto(s)
Dinoprostona , Hidrocortisona , Administración Cutánea , Animales , Antiinflamatorios no Esteroideos , Clonixina/análogos & derivados , Masculino , Orquiectomía/métodos , Orquiectomía/veterinaria , Solución Salina , PorcinosRESUMEN
This study performed population-pharmacokinetic/pharmacodynamic (pop-PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail-docking, utilizing previously published data. Six-day-old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post-dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 µg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 µg/ml. A large degree of inter-individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 µg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen-PGE2), 40.75% (ketoprofen-cortisol), and 81.05% (flunixin-cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail-docking pain at the current label dose.
Asunto(s)
Cetoprofeno , Animales , Antiinflamatorios no Esteroideos , Clonixina/análogos & derivados , Dinoprostona , Hidrocortisona , Cetoprofeno/farmacología , Cetoprofeno/uso terapéutico , Masculino , Orquiectomía/veterinaria , Dolor/veterinaria , Porcinos , Cola (estructura animal)RESUMEN
Objective: The objective was to evaluate the pharmacokinetics of compounding non-steroidal anti-inflammatory drugs (NSAIDs) meloxicam or flunixin meglumine with iron dextran (ID) in piglets. Animal: Forty piglets (8 d of age) were randomly allocated into 5 groups (8 piglets/group) and received 1 intramuscular injection in the neck of the following treatments: flunixin meglumine (2.2 mg/kg) administered alone (F) or mixed with ID (F+ID); or meloxicam (0.4 mg/kg) administered alone (M) or mixed with ID (M+ID); or ID alone. Procedure: Blood samples were collected via indwelling jugular catheters at pre-dose, and 10, 20, 30, 45, and 60 min, and 2, 4, 8, 12, 24, 36, 48, and 72 h post-treatment to determine plasma NSAIDs concentrations using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters for plasma meloxicam and flunixin meglumine concentration-time profiles were determined for each piglet using noncompartmental analysis approaches. Statistical analyses were performed using SAS software with significance set at P < 0.05. Results: The AUC0-tlast, AUC0-∞, Cmax, and relative bioavailability values in the M+ID and F+ID groups were lower than corresponding M and F groups. The M+ID group elimination half-life was lower, whereas λz and tmax values were greater than the corresponding M group. Conclusion: Relative bioavailability of meloxicam and flunixin meglumine were reduced when compounded with ID in the same bottle and administered to piglets. Clinical relevance: Further research is warranted to evaluate if decreased NSAID exposure when compounded with ID alters analgesic efficacy or drug residue depletion.
Objectif: L'objectif était d'évaluer la pharmacocinétique de la combinaison d'anti-inflammatoires non stéroïdiens (NSAID) méloxicam ou flunixine méglumine avec du fer dextran (ID) chez les porcelets. Animal: Quarante porcelets (âgés de 8 jours) ont été répartis au hasard en cinq groupes (8 porcelets/groupe) et ont reçu une injection intramusculaire dans le cou des traitements suivants : flunixine méglumine (2,2 mg/kg) administrée seule (F) ou mélangée avec ID (F+ID); soit du méloxicam (0,4 mg/kg) administré seul (M) ou en mélange avec ID (M+ID); ou du ID seul. Procédure: Des échantillons de sang ont été prélevés via des cathéters jugulaires à demeure à la pré-dose, et 10, 20, 30, 45 et 60 min, et 2, 4, 8, 12, 24, 36, 48 et 72 h après le traitement pour déterminer la concentration plasmatique de NSAID par chromatographie liquide-spectrométrie de masse en tandem. Les paramètres pharmacocinétiques des profils concentration-temps du méloxicam et de la flunixine méglumine plasmatiques ont été déterminés pour chaque porcelet à l'aide d'approches d'analyse non compartimentale. Les analyses statistiques ont été effectuées à l'aide du logiciel SAS avec un seuil de signification fixé à P < 0,05. Résultats: Les valeurs AUC0tlast, AUC0∞, Cmax et de biodisponibilité relative dans les groupes M+ID et F+ID étaient inférieures à celles des groupes M et F correspondants. La demi-vie d'élimination du groupe M+ID était plus faible, tandis que les valeurs λz et tmax étaient supérieures à celles du groupe M correspondant. Conclusion: La biodisponibilité relative du méloxicam et de la méglumine de flunixine était réduite lorsqu'ils étaient combinés avec ID dans le même flacon et administrés aux porcelets. Pertinence clinique: Des recherches supplémentaires sont nécessaires pour évaluer si une diminution de l'exposition aux NSAID lorsqu'elle est associée à une ID modifie l'efficacité analgésique ou l'épuisement des résidus de médicaments.(Traduit par Dr Serge Messier).
Asunto(s)
Antiinflamatorios no Esteroideos , Dextranos , Animales , Clonixina/análogos & derivados , Hierro , Meloxicam , PorcinosRESUMEN
Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.
Asunto(s)
Residuos de Medicamentos , Animales , Bovinos , Clonixina/análogos & derivados , Residuos de Medicamentos/análisis , Medicamentos Genéricos , Modelos Biológicos , Penicilina G/farmacocinética , Porcinos , Tianfenicol/análogos & derivadosRESUMEN
The objective of this study was to evaluate the effect of the nonsteroidal anti-inflammatory drug transdermal flunixin meglumine (Finadyne Transdermal) on plasma cortisol, average daily weight gain, and standing and lying behavior of calves, when given at the time of disbudding combined with local anesthesia. A sedative was not used to minimize pharmacological interactions. Seventy-one female Holstein Friesian calves aged 13 ± 2 d, with an average weight of 48.9 ± 4.26 kg were enrolled in the study. All calves were randomly assigned to one of 3 treatment groups: (1) control group (CON, n = 27), (2) 1-flunixin group (1-FLU, n = 26) with a single administration of transdermal flunixin meglumine at disbudding, and (3) 2-flunixin group (2-FLU, n = 24) with 2 administrations of transdermal flunixin meglumine, the first treatment at disbudding and the second 6 h after disbudding. Although the CON group received a placebo, 1-FLU and 2-FLU received flunixin meglumine transdermally. To account for plasma cortisol changes due to manipulation and handling of the calves, a sham disbudding procedure was performed one week before disbudding took place. Sham disbudding was conducted by using a cold cautery dehorner applied to each horn bud for 10 s. Disbudding was performed in a similar way by using a hot cautery dehorner. Plasma samples were collected to measure the stress biomarker cortisol at 7 different time points. Body weights were measured 4 times in 2 wk. Standing and lying behavior was assessed via 3-dimensional accelerometer. During sham disbudding and disbudding mean plasma cortisol concentrations were 6.09 ± 2.5 ng/mL and 5.16 ± 2.8 ng/mL, respectively. Treatment tended to have an effect on plasma cortisol concentrations during sham disbudding and had an effect on plasma cortisol concentrations during disbudding. Plasma cortisol concentrations were affected by treatment 2 h after disbudding in comparison to CON group. Furthermore, there was a significant effect on plasma cortisol concentrations 6 h after disbudding in contrast to CON. A return to baseline plasma cortisol levels (initial concentrations) was not achieved in CON during disbudding. There was no statistical difference between average daily weight gain and the treatment procedure. Total lying time was not affected by treatment after disbudding. In conclusion, transdermal flunixin meglumine given at the time of disbudding combined with local anesthesia decreased concentrations of the stress biomarker cortisol, but a second dose 6 h after disbudding had no further effect on plasma cortisol levels.
Asunto(s)
Anestesia Local , Cuernos , Anestesia Local/veterinaria , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Bovinos , Cauterización/veterinaria , Clonixina/análogos & derivados , Femenino , Cuernos/cirugía , HidrocortisonaRESUMEN
The objective of this study was to determine the effects of flunixin meglumine or meloxicam on behavioral response and performance characteristics associated with surgical castration in crossbred bulls. Intact male Bos taurus calves (n = 252; averaging 176 kg) were randomly allocated into one of three treatment groups within pen: control (CON), flunixin meglumine (FLU; 2.2 mg/kg intravenous injection), or meloxicam (MEL; 2.0 mg/kg per os). The individual animal was the experimental unit. Calves were individually weighed on days 0 and 14 of the trial to evaluate performance outcomes. On study day 0, treatments were administered, according to their random allocation, immediately prior to surgical castration using the Henderson tool method. Visual analog scale (VAS) assessment and categorical attitude score (CAS) were collected on days -1, 0 (6 h post-castration), 1, 2, 3, and 4 in the study. The VAS was assigned using a 100 mm horizontal line with "normal" labeled at one end of the line and "moribund" at the other end of the horizontal line. The masked observer assigned a mark on the horizontal line based upon the observed severity of pain exhibited by that individual animal. The CAS was assigned by the same observer using five different categories with a score of 0 being "normal". Average daily gain tended (P = 0.09) to be associated with the treatment group, and MEL had a greater (P = 0.04) average daily gain through day 14 compared with CON. A significant (P < 0.01) treatment by day interaction was indicated for VAS score, and MEL had lower VAS scores on days 0, 1, 2, and 3 post-castration compared with CON; FLU had lower VAS scores on days 0 and 1 compared with CON. A significant treatment by day interaction was not present (P = 0.25) for CAS. The FLU had lesser percent CAS ≥1 (17.5%; P = 0.05) compared with CON (29.4%); MEL has lesser percent CAS ≥1 observations (14.9%; P = 0.01) compared with CON. The median VAS increased as CAS was more severe. Results indicated MEL and FLU calves temporally improved behavioral responses following surgical castration with positive numerical trends for a 14 d average daily gain (ADG). The VAS system appeared to be an effective method of subjective evaluation of pain in beef calves in this study. Route of administration, duration of therapy, and low relative cost make oral meloxicam a reasonable analgesic treatment in calves when administered at the time of surgical castration.
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Antiinflamatorios no Esteroideos , Dolor , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Bovinos , Clonixina/análogos & derivados , Masculino , Meloxicam/farmacología , Orquiectomía/métodos , Orquiectomía/veterinaria , Dolor/tratamiento farmacológico , Dolor/veterinariaRESUMEN
This study aimed to evaluate the possible protective actions of chrysin and flunixine meglumine on testicular and spermatological injuries experimentally stimulated by copper. We separated 36 male Sprague-Dawley rats into six equal groups: control, chrysin, flunixine meglumine, copper, copper +chrysin and copper +flunixine meglumine. Chrysin (50 mg/kg/bw/po), flunixine meglumine (2.2 mg/kg/bw/ip) and copper (500 mg/kg/bw/po) were administered day to day for 21 days. Copper administration caused significant morphological, physiological and biochemical alterations compared to the control group, which are as follows: production of oxidative stress, thanks to rise in testis lipid peroxidation and fall in antioxidant enzyme concentrations, decrease in sperm quality and increase in morphologic sperm abnormalities, suppression of spermatogenesis and prominent alterations in the testis histomorphology and induction of apoptosis in the testis tissues. On the other hand, compared to the copper group, treatment with chrysin or flunixine meglumine significantly attenuated these alterations. In conclusion, chrysin and flunixine meglumine have benefits such as antioxidant, antiapoptotic and anti-inflammatory against copper-induced testicular and spermatological damages in rats via the modulation of oxidative stress and apoptosis. Consequently, chrysin is a natural product which has comparable therapeutic actions to flunixine meglumine on the male reproductive system.
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Cobre , Testículo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis , Clonixina/análogos & derivados , Cobre/toxicidad , Flavonoides , Masculino , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Espermatozoides/metabolismo , Testículo/metabolismoRESUMEN
Pleuritic chest pain from bacterial pneumonia is often reported in human medicine. However, studies investigating pain associated with bovine respiratory disease (BRD) are lacking. The objectives of this study were to assess if bacterial pneumonia elicits a pain response in calves with experimentally induced BRD and to determine the analgesic effects of transdermally administered flunixin. A total of 26 calves, 6-7 mo of age, with no history of BRD were enrolled into one of three treatment groups: 1) experimentally induced BRD + transdermal flunixin at 3.3 mg/kg twice, 24 h apart (BRD + FTD); 2) experimentally induced BRD + placebo (BRD + PLBO); and 3) sham induction + placebo (CNTL + PLBO). Calves induced with BRD were inoculated with Mannheimia haemolytica via bronchoalveolar lavage. Outcomes were collected from -48 to 192 h post-treatment and included serum cortisol, infrared thermography, mechanical nociceptive threshold, substance P, kinematic gait analysis, visual analog scale (VAS), clinical illness score, computerized lung score, average activity and rumination level, prostaglandin E2 metabolite, plasma serum amyloid A, and rectal temperature. Outcomes were evaluated using either a generalized logistic mixed model for categorical variables or a generalized linear mixed model for continuous variables. Right front force differed by treatment (P = 0.01). The BRD + PLBO had lower mean force applied to the right front limb (85.5 kg) compared with BRD + FTD (96.5 kg; P < 0.01). Average VAS differed by a treatment by time interaction (P = 0.01). The VAS scores differed for BRD + PLBO at -48 (3.49 mm) compared with 168 and 192 h (13.49 and 13.64 mm, respectively) (P < 0.01). Activity for BRD + PLBO was higher at -48 h (27 min/h) compared with 48, 72, 120, and 168 h (≤ 22.24 min/h; P < 0.01). Activity differed by a treatment by time interaction (P = 0.01). Activity for BRD + FTD was higher at -48 and 0 h (28.2 and 28.2 min/h, respectively) compared to 48, 72, 96, and 168 h (≤23.7 min/h; P < 0.01). Results show a combination of reduced activity levels, decreased force on the right front limb, and increased VAS pain scores all support that bacterial pneumonia in cattle is painful. Differences in right front force indicate that flunixin transdermal may attenuate certain pain biomarkers in cattle with BRD. These findings suggest that BRD is painful and analgesic drugs may improve the humane aspects of care for cattle with BRD.
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Enfermedades de los Bovinos , Neumonía Bacteriana , Animales , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Clonixina/análogos & derivados , Dolor/tratamiento farmacológico , Dolor/veterinaria , Dimensión del Dolor , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/veterinariaRESUMEN
Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.
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Clonixina , Lactancia , Administración Cutánea , Animales , Antiinflamatorios no Esteroideos , Bovinos , Clonixina/análogos & derivados , Femenino , Cabras , Leche/químicaRESUMEN
Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135â; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.
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Tecnología de Extrusión de Fusión en Caliente , Gusto , Administración Oral , Animales , Clonixina/análogos & derivados , Perros , Composición de Medicamentos , Solubilidad , ComprimidosRESUMEN
BACKGROUND: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine-treated horses. OBJECTIVE: To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation. STUDY DESIGN: Experimental study. METHODS: Drug plasma and urine concentrations following single intravenous administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 hours for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the international screening limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/mL, urine; 100 ng/mL). RESULTS: For a regimen of 1.1 mg/kg BW q 24 hours, the IPC and IUC values were 2.0 and 73.0 ng/mL respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 hours after a single 1.1 mg/kg dose administration, 149 and 199 hours after multiple doses over 5 days at either 24- or 12-hour intervals respectively. Corresponding detection times in urine were 46, 68 and 104 hours respectively. MAIN LIMITATION: Only female horses were investigated. CONCLUSIONS: Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL.
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Clonixina , Espectrometría de Masas en Tándem , Animales , Antiinflamatorios no Esteroideos , Cromatografía Liquida/métodos , Cromatografía Liquida/veterinaria , Clonixina/análogos & derivados , Femenino , Caballos , Método de Montecarlo , Espectrometría de Masas en Tándem/veterinariaRESUMEN
This study assessed the efficacy of meloxicam, flunixin, and ketoprofen in piglets undergoing routine castration and tail-docking. Six-day-old male piglets (8/group) received one of five randomized treatments: intramuscular saline (SAL PROC), meloxicam (MEL; 0.4 mg/kg), flunixin (FLU; 2.2 mg/kg), ketoprofen (KETO; 3.0 mg/kg) or sham (SAL SHAM; saline injection, no processing). Two hours post-dose, piglets were castrated and tail-docked. Plasma cortisol, interstitial fluid (ISF) prostaglandin E2 (PGE2) and activity levels via Actical® monitoring were used to estimate pain. SAL SHAM and FLU exhibited lower cortisol concentrations than SAL PROC at the time of processing (p = 0.003 and p = 0.049, respectively), and all NSAIDs exhibited lower PGE2 than SAL PROC at 3.69 hours (MEL p = 0.050; FLU p = 0.043 and KETO p = 0.031). While not statistically significant, PGE2 was higher in SAL PROC piglets vs. other treatment groups at most time points. There was also a high degree of variability between piglets, especially for SAL PROC. Activity levels were significantly decreased at multiple time points in SAL PROC and MEL piglets following processing. However, FLU and KETO piglets had increased activity levels closer to that of the SAL SHAM group, suggesting that these NSAIDs are more effective than MEL in providing analgesia. These results demonstrate that management strategies including administration of intramuscular flunixin or ketoprofen to reduce pain associated with processing will likely improve piglet health and welfare in the United States.
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Crianza de Animales Domésticos/métodos , Antiinflamatorios no Esteroideos/uso terapéutico , Castración/efectos adversos , Dolor/tratamiento farmacológico , Animales , Animales Recién Nacidos , Castración/métodos , Clonixina/análogos & derivados , Clonixina/uso terapéutico , Dinoprostona/análisis , Líquido Extracelular/química , Hidrocortisona/sangre , Cetoprofeno/uso terapéutico , Masculino , Meloxicam/uso terapéutico , Dolor/etiología , Manejo del Dolor , Porcinos , Cola (estructura animal)RESUMEN
Periodontal pain is a public health problem derived from different conditions, including periodontal diseases, prosthetic complications, and even extractions performed by dentist. There are various treatments to control acute dental pain, being the administration of analgesics, such as Lysine Clonixinate (LC), a common practice. Unfortunately, higher and repeated dosages are usually required. The purpose of this work was to develop a prolonged release pharmaceutical form as an alternative treatment for dental pain. Hence, we conceived a film based on guar gum and loaded different concentrations of LC. We evaluated the film's appearance, brittleness, strength, and flexibility, and then chose one formulation for adequate characteristics. Subsequently, we assessed the morphology, thermal behavior, and swelling properties of the films (LC-free and -loaded). Finally, we performed the release studies of LC from the films in vitro using a simulated saliva medium and employed several mathematical models to evaluate the release kinetics. Guar gum is a natural polymer obtained from the endosperm of Cyamopsis tetragonolobus that presents properties such as biosafety, biocompatibility, and biodegradability. Thus, it represents a potential excipient for use in pharmaceutical formulations. Moreover, our results revealed that the LC-loaded film presented a high adherence, suitable swelling behavior, high LC content, and a prolonged drug release. Therefore, the LC-loaded film may be considered a potential option to be applied as an alternative to treat dental pain.
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Clonixina/análogos & derivados , Lisina/análogos & derivados , Dolor/tratamiento farmacológico , Enfermedades Periodontales/tratamiento farmacológico , Polisacáridos Bacterianos/química , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Clonixina/farmacocinética , Clonixina/uso terapéutico , Liberación de Fármacos , Excipientes/química , Humanos , Cinética , Lisina/farmacocinética , Lisina/uso terapéutico , Membranas Artificiales , Microscopía Electrónica de Rastreo , Dolor/complicaciones , Enfermedades Periodontales/complicaciones , Polímeros/química , Polisacáridos Bacterianos/ultraestructura , Temperatura , Termogravimetría/métodosRESUMEN
INTRODUCTION: Eating and rumination variables were recorded using a pressure sensor integrated into the noseband of a halter in 60 cows with left displaced abomasum (LDA) before and after postoperative administration of flunixin meglumine (FM). Group 1 comprised 9 healthy control cows that were used to establish reference intervals. Group 2 included 60 cows with LDA that received one of the following three treatments: intravenous saline solution (2A, n=20), 1.1 mg/kg FM (2B, n=20) or 2.2 mg/kg FM (2C, n=20) once daily for 3 days after right-flank omentopexy. Median eating times on the day before surgery were 93 (2A), 80 (2B) and 114 (2C) min, which were below the reference interval (246 to 381 min). On the day after surgery, eating times had increased significantly to 201 (2A), 172 (2B) and 216 (2C) min, after which time they continued to increase. Eating and rumination times, numbers of regurgitated feed boluses per day and chewing cycles per bolus did not differ among treated groups. Postoperative administration of FM did not affect eating and rumination variables in this study, and normalisation of these variables was attributable to surgical correction of LDA.
INTRODUCTION: Les variables d'alimentation et de rumination ont été enregistrées à l'aide d'un capteur de pression intégré à la muserolle d'un licol chez 60 vaches avec déplacement à gauche de la caillette (LDA) avant et après l'administration postopératoire de flunixine méglumine (FM). Le groupe 1 comprenait 9 vaches témoins en bonne santé qui ont été utilisées pour établir des intervalles de référence. Le groupe 2 comprenait 60 vaches avec LDA qui ont reçu l'un des trois traitements suivants : solution saline intraveineuse (2A, n=20), 1,1 mg/kg FM (2B, n=20) ou 2,2 mg/kg FM (2C, n= 20) une fois par jour pendant 3 jours après omentopexie par le flanc droit. La durée médiane des repas la veille de la chirurgie était de 93 (2A), 80 (2B) et 114 (2C) minutes, ce qui était inférieur à l'intervalle de référence (246 à 381 min). Le lendemain de la chirurgie, la durée des repas avait augmenté de manière significative à 201 (2A), 172 (2B) et 216 (2C) minutes, après quoi elle a continué à augmenter. Les temps de repas et de rumination, le nombre de bolus alimentaires régurgités par jour et les cycles de mastication par bolus ne différaient pas entre les groupes traités. L'administration postopératoire de FM n'a pas affecté les variables d'alimentation et de rumination dans cette étude et la normalisation de ces variables était attribuable à la correction chirurgicale de la LDA.
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Enfermedades de los Bovinos , Gastropatías , Abomaso/cirugía , Animales , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/cirugía , Clonixina/análogos & derivados , Femenino , Masticación , Gastropatías/tratamiento farmacológico , Gastropatías/cirugía , Gastropatías/veterinariaRESUMEN
This study aimed to determine the effect of flunixin meglumine treatment during and after the transfer of in vivo produced embryos to Angus (cows) and Holstein (cows and heifers) breeds of cattle on pregnancy rate. Holstein cows were used as donors in the study. A double dose of prostaglandin F2α was administered to the recipient animals for synchronization. Uterine flushing was performed in donors on day 7 after artificial insemination. A total of 295 transferable embryos were obtained. These embryos were transferred to Angus cows (n = 85), Holstein heifers (n = 80) and Holstein cows (n = 130). After the transfer, these animals were divided into three subgroups. The first subgroup (TI) was administered flunixin meglumine during embryo transfer, and the second subgroup (TII) was administered flunixin meglumine both during embryo transfer and on days 8 and 9 after the transfer. The third subgroup (TIII) was not administered anything and it was considered the control group. Pregnancy examination of the recipients was performed on days 30-35 after the transfer using real-time ultrasonography. The pregnancy rates after embryo transfer were found to be 43.52% in Angus cows, 42.5% in Holstein heifers, and 24.61% in Holstein cows (p < .05). When the animals were not classified according to breed, the pregnancy rates in subgroups TI, TII and TIII were found to be 29.29%, 45.10% and 29.79%, respectively (p < .05). In addition, the pregnancy rates were higher in TII and TIII subgroups of Angus cows and Holstein heifers compared to that of Holstein cows (p < .05). As a result, the pregnancy rates obtained after embryo transfer in Angus cows and Holstein heifers were found to be higher than that in Holstein cows. In addition, it was concluded that the administration of flunixin meglumine during and during/after embryo transfer has a positive effect on pregnancy rates in Angus cows and Holstein heifers.
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Clonixina , Transferencia de Embrión , Animales , Bovinos , Clonixina/análogos & derivados , Clonixina/farmacología , Transferencia de Embrión/veterinaria , Femenino , Inseminación Artificial/veterinaria , Embarazo , Índice de EmbarazoRESUMEN
The objective of this randomized clinical study was to compare the effect of 2 antimicrobial interventions, tildipirosin or florfenicol + flunixin meglumine, used for treatment of pneumonia and extralabel treatment for otitis on health parameters and upper respiratory tract (URT) microbiota of preweaned Holstein calves. Housed preweaned Holstein heifers diagnosed with either otitis or pneumonia were assigned into 1 of 2 treatment groups, receiving a single subcutaneous injection of either 4 mg/kg of tildipirosin (TLD; n = 444) or 40 mg/kg of florfenicol combined with 2.2 mg/kg of a nonsteroidal anti-inflammatory, flunixin meglumine (FLF; n = 442). Calves were enrolled and treated on the day of diagnosis of the first case of pneumonia or otitis. If a calf had a recurrent case, the opposite drug was administered, respecting an interval of 5 d between drug injections. Blood samples for leukocyte counts were collected at 0, 2, 4, and 6 d after treatment, and rectal temperature was measured daily during the 5 d after treatment. Ear scores were observed from calves with otitis. Additionally, swabs of the URT were collected from a subset of 20 calves in each treatment group at d 0, 3, 6, 9, and 11 following enrollment for analysis of URT microbiota through next-generation sequencing of the 16S rRNA gene and quantitative PCR. Swabs were also collected from a comparative group of 20 healthy calves that did not receive any drug. No differences were observed between groups for recurrence risk of either pneumonia (TLD = 32.4%; FLF = 29.7%) or otitis (TLD = 72.7%; FLF = 73.6%). Similarly, no differences were observed for the total number of treatments for pneumonia (TLD = 1.45; FLF = 1.42) or otitis (TLD = 2.96; FLF = 3.07). On the other hand, both drugs reduced rectal temperature, ear scores, and leukocyte counts, with FLF calves having a greater reduction in rectal temperature within 4 d after treatment. Both TLD and FLF reduced the total bacterial load when compared with healthy untreated calves, but no differences were observed between treatment groups. Furthermore, compared with the untreated group, treated calves had lower mean relative abundances (MRA) of the genera Mannheimia, Moraxella, and Pasteurella within 11, 9, and 3 d after treatment, respectively; however, no significant differences were observed between TLD and FLF. On the other hand, MRA of Mycoplasma was not decreased by both treatments compared to untreated animals, and a higher MRA was observed in the TLD group during 11 d after treatment in comparison to FLF and untreated calves. Based on this data, we concluded that both drugs used in the study were effective in reducing rectal temperature, ear scores, leukocyte counts, and MRA of the genera Mannheimia, Pasteurella, and Moraxella in the URT, and calves treated with FLF had a greater reduction in rectal temperature.
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Enfermedades de los Bovinos , Microbiota , Otitis Media , Neumonía , Animales , Bovinos , Enfermedades de los Bovinos/tratamiento farmacológico , Clonixina/análogos & derivados , Femenino , Meglumina , Otitis Media/veterinaria , Neumonía/tratamiento farmacológico , Neumonía/veterinaria , ARN Ribosómico 16S , Sistema Respiratorio , Tianfenicol/análogos & derivados , Tilosina/análogos & derivadosRESUMEN
Flunixin meglumine is a highly efficacious nonsteroidal anti-inflammatory drug commonly used in equine medicine and especially in performance horses. Recently, a new transdermal flunixin meglumine product has been approved for use in cattle. Although not currently approved for use in the horse, the convenience of this product may prove appealing for use in horses, warranting study. Six horses were administered a single transdermal dose of 500 mg and blood and urine samples collected for up to 96 h post-administration. Serum for determination of thromboxane concentrations and whole blood samples was collected at various time and challenged with lipopolysaccharide, calcium ionophore, or methanol to induce ex vivo synthesis of eicosanoids. Concentrations of flunixin, 5-OH flunixin, and eicosanoids were measured using LC-MS/MS and non-compartmental pharmacokinetic analysis performed on concentration data. Serum concentrations of flunixin and 5-OH flunixin were above the limit of quantitation at 96 h post-administration in both serum and urine. The mean (range) for Cmax , Tmax and the terminal half-life were 515.6 (369.7-714.0) ng/ml, 8.67 (8.0 12.0) h, and 22.4 (18.3-42.5) h, respectively. Following transdermal administration, based on effects on eicosanoid synthesis, flunixin meglumine inhibited cyclooxygenase 1 and 2 and 15-lipooxygenase activity, with anti-inflammatory effects lasting for 24-72 h.