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1.
J Vet Pharmacol Ther ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687131

RESUMO

Butorphanol is commonly administered, both by the intravenous and intramuscular routes, to racehorses to facilitate handling for diagnostic procedures. As the administration of butorphanol for therapeutic purposes is considered appropriate, in order to avoid inadvertent positive drug tests, a thorough understanding of the pharmacokinetics of this drug is necessary. In the current study, 12, exercised Thoroughbred horses were administered a single intramuscular dose of 0.1 mg/kg butorphanol, and serum and urine samples were collected at various times post drug administration for determination of butorphanol concentrations using a highly sensitive liquid chromatography tandem mass spectrometry method. Serum data were modeled using a nonlinear mixed effect population PK model. The maximum concentration (Cmax) and time to maximum concentration (Tmax) were 139.9 ± 72.8 ng/mL and 0.43 ± 0.44 h (mean ± SD), respectively. Although likely not clinically relevant, but important for drug testing purposes, a prolonged terminal phase was observed, yielding a terminal half-life of 7.67 ± 1.86 h. Using the blood screening limits proposed by the Horseracing Integrity and Welfare Unit, the detection time for intramuscular administration of butorphanol was estimated to be 96 h.

2.
Drug Test Anal ; 16(3): 289-302, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37439283

RESUMO

Ketoprofen is an anti-inflammatory drug that is commonly administered to racehorses for the alleviation of musculoskeletal pain and inflammation. This study represents a comprehensive examination of the metabolism (in vivo and in vitro), pharmacokinetics and ex vivo pharmacodynamics, of ketoprofen in horses. The in vitro metabolism as well as specific enzymes responsible for metabolism was determined by incubating liver microsomes and recombinant CYP450 and UGT enzymes with ketoprofen. For the in vivo portion, 15 horses were administered a single intravenous dose of 2.2-mg/kg ketoprofen. Blood and urine samples were collected prior to and up to 120 h post-drug administration. Additional blood samples were collected at select time points and were stimulated with calcium ionophore or lipopolysaccharide, ex vivo, to induce eicosanoid production. Drug, metabolite, and eicosanoid concentrations were determined using LC-MS/MS. Incubation of ketoprofen with equine liver microsomes generated 3-hydroxy ketoprofen, an unidentified hydroxylated metabolite, and ketoprofen glucuronide. Recombinant equine CYP2C23 produced the greatest amount of hydroxylated ketoprofen and recombinant equine UGT1A2 generated ketoprofen glucuronide. Dihydro, 3-hydroxy, and glucuronide metabolites were identified in blood and urine samples. The Vdss was 0.280, 0.385, and 0.319 L/kg for total ketoprofen, S (+) ketoprofen, and R (-) ketoprofen, respectively. The mean half-life was 6.01 h for total ketoprofen, 2.22 h for S (+) ketoprofen, and 1.72 h for R (-) ketoprofen. Stimulation of ketoprofen-treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2 , PGE2 , PGF2alpha , LTB4 , and 15(s)-HETE production for up to 120 h post-drug administration.


Assuntos
Cetoprofeno , Cetoprofeno/análogos & derivados , Cavalos , Animais , Cetoprofeno/farmacocinética , Anti-Inflamatórios não Esteroides , Cromatografia Líquida , Ionóforos de Cálcio , Lipopolissacarídeos , Espectrometria de Massas em Tandem , Eicosanoides , Biomarcadores
3.
BMC Vet Res ; 19(1): 225, 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37904169

RESUMO

BACKGROUND: Lidocaine is a local anesthetic that is sometimes administered in combination with epinephrine. The addition of epinephrine increases the time lidocaine remains at the site of administration, thus prolonging the duration of effect. Due to their potential to prevent the visual detection of lameness, the administration of local anesthetics is strictly regulated in performance and racehorses. Recent reports of positive regulatory findings for lidocaine in racehorses suggests a better understanding of the behavior of this drug is warranted. The objective of the current study was to describe serum and urine concentrations and the pharmacokinetics of lidocaine and its primary metabolites following administration in combination with epinephrine, as a palmar digital nerve block in horses. Twelve horses received a single administration of 1 mL of 2% lidocaine HCl (20 mg/horse) with epinephrine 1:100,000, over the palmar digital nerve. Blood samples were collected up to 30 h and urine samples up to 48 h post administration. Lidocaine and metabolite concentrations were determined by liquid chromatography- mass spectrometry and pharmacokinetic (non-compartmental and compartmental) analysis was performed. RESULTS: Serum concentrations of lidocaine and 3-hydroxylidocaine were above the LOQ of the assay at 30 h post administration and monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were below detectable levels by 24 and 48 h, respectively. In urine, lidocaine, MEGX and GX were all non-detectable by 48 h post administration while 3-hydroxylidocaine was above LOQ at 48 h post administration. The time of maximal concentration for lidocaine was 0.26 h (median) and the terminal half-life was 3.78 h (mean). The rate of absorption (Ka) was 1.92 1/h and the rate of elimination (Kel) was 2.21 1/h. CONCLUSIONS: Compared to previous reports, the terminal half-life and subsequent detection time observed following administration of lidocaine in combination with epinephrine is prolonged. This is likely due to a decrease in systemic uptake of lidocaine because of epinephrine induced vasoconstriction. Results of the current study suggest it is prudent to use an extended withdrawal time when administering local anesthetics in combination with epinephrine to performance horses.


Assuntos
Anestésicos Locais , Bloqueio Nervoso , Cavalos , Animais , Anestésicos Locais/farmacologia , Lidocaína , Epinefrina , Bloqueio Nervoso/veterinária
4.
J Vet Pharmacol Ther ; 46(5): 311-325, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37021661

RESUMO

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate-to-severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6-6.4 mg/kg acetaminophen) in a three-way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter-individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively.


Assuntos
Acetaminofen , Doenças dos Cavalos , Humanos , Cavalos , Animais , Acetaminofen/uso terapêutico , Nociceptividade , Quimioterapia Combinada/veterinária , Codeína/uso terapêutico , Codeína/efeitos adversos , Analgésicos/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/veterinária , Combinação de Medicamentos , Método Duplo-Cego , Doenças dos Cavalos/tratamento farmacológico
5.
J Vet Pharmacol Ther ; 46(4): 238-249, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36883679

RESUMO

The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2 mg/kg morphine and oral doses of 0.2, 0.6, and 0.8 mg/kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (Cmax : 11.6-37.8 ng/mL (0.6 mg/kg); 15.8-42.6 ng/mL (0.8 mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8 mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.


Assuntos
Analgésicos Opioides , Morfina , Animais , Administração Oral , Analgésicos Opioides/farmacologia , Disponibilidade Biológica , Cavalos , Morfina/farmacologia , Derivados da Morfina , Estudos Cross-Over
6.
Equine Vet J ; 55(4): 696-706, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35871470

RESUMO

BACKGROUND: Clodronate is a potent antiresorptive agent labelled for use in horses over 4 years of age, for the treatment of navicular syndrome. Concerns regarding the extra-label use of clodronate in equine athletes, such as racehorses, have been raised as inhibition of osteoclast activity by clodronate has been postulated to interfere with normal bone healing, which is imperative to the repair of microfractures. The paucity of data describing the long-term pharmacokinetics of clodronate and effects on biomarkers of bone resorption necessitates further study. OBJECTIVES: (1) To determine clodronate concentrations in blood and urine over a 6-month period in horses undergoing treadmill exercise and (2) to assess the effects of clodronate on protein biomarkers of bone remodelling in this same group of horses. STUDY DESIGN: Randomised controlled experimental study. METHODS: Seven exercised Thoroughbred horses received a single im administration of 1.8 mg/kg clodronate and four horses received an equivalent volume of saline. Blood and urine samples were collected prior to, during and for 182 days post drug administration for drug concentration determination using liquid chromatography-tandem mass spectrometry, and determination of protein biomarker (CTX-1 and TRAcP5B) concentrations. RESULTS: Clodronate was detectable in blood for 14-175 days and for up to 175 days in urine. For some horses, concentrations were nondetectable at one time point but detectable at a subsequent time point. The terminal serum half-life ranged from 1.80 to 283.9 days. CTX-1 concentrations were significantly higher, relative to baseline, in both treated and control groups while concentrations of TRAcP5B were significantly lower in the treated group. MAIN LIMITATIONS: Relatively small number of horses studied. CONCLUSIONS: Based on assessment of protein biomarkers, clodronate appears to influence osteoclasts at label doses. Furthermore, results of this study support racing regulations that preclude horses administered bisphosphonates for medical reasons, from racing for a prolonged period of time.


CONTEXTO: Clodronato é um agente antirreabsortivo potente e recomendado para o uso em cavalos com mais de 4 anos de idade, para o tratamento da síndrome do navicular. Há preocupação com o uso indiscriminado de clodronato em equinos atletas, como cavalos de corrida, já que a inibição da atividade dos osteoclastos pelo clodronato tem sido postulada em interferir na cicatrização óssea normal, o que é essencial para a cicatrização de microfraturas. A escassez de informação quanto às ações prolongadas do uso de clodronato e seus efeitos nos biomarcadores de reabsorção óssea requere mais estudos. OBJETIVOS: (1) Determinar a concentração de clodronato no sangue e urina por um período de 6 meses em cavalos submetidos ao exercício em esteira e (2) acessar os efeitos de clodronato nos biomarcadores de remodelação óssea no mesmo grupo de cavalos. DELINEAMENTO DO ESTUDO: Estudo controlado randomizado. METODOLOGIA: Sete cavalos Puro-Sangue Inglês em exercício receberam uma única dose im de 1.8 mg/kg de clodronato e 4 cavalos receberam um volume equivalente de solução fisiológica. Amostras de sangue e urina foram coletadas antes, durante e por 182 dias após a administração de clodronato. Valores de concentração da droga foram determinados utilizando cromatografia líquida-espectrometria de massa (LC-MS/MS), e determinação da concentração de biomarcadores (CTX-1 e TRAcP5B) também foi realizada. RESULTADOS: Clodronato foi detectado no sangue por 14-175 dias e por até 175 dias na urina. Para alguns equinos, a concentração foi não-detectável em um momento, mas detectável no próximo momento. O valor terminal da vida-média em soro foi 1.80-283.9 dias. A concentração de CTX-1 foi significativamente elevada, relativo às amostras iniciais, em ambos os grupos (tratamento e controle), enquanto as concentrações de TRAcP5B foram significativamente menores no grupo de cavalos tratados. PRINCIPAIS LIMITAÇÕES: Número relativamente pequenos de cavalos no estudo. CONCLUSÕES: Baseado nos resultados dos biomarcadores, clodronato parece influencia osteoclastos na dose recomendada. Além disso, os resultados deste estudo suportam o regulamento de cavalos de corrida que impedem que cavalos que receberam bifosfonatos por razão médica de competir por um período de tempo prolongado.


Assuntos
Líquidos Corporais , Reabsorção Óssea , Doenças dos Cavalos , Cavalos , Animais , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/veterinária , Difosfonatos/uso terapêutico , Biomarcadores , Doenças dos Cavalos/tratamento farmacológico
7.
Am J Vet Res ; 84(2)2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36476411

RESUMO

OBJECTIVE: The goal of this study was to determine plasma, urine, and synovial fluid concentrations and describe the effects on biomarkers of cartilage toxicity following intra-articular dexmedetomidine administration to horses. ANIMALS: 12 research horses. PROCEDURES: Horses received a single intra-articular administration of 1 µg/kg or 5 µg/kg dexmedetomidine or saline. Plasma, urine, and synovial fluid were collected prior to and up to 48 hours postadministration, and concentrations were determined. The effects on CS846 and C2C were determined in synovial fluid at 0, 12, and 24 hours postadministration using immunoassays. RESULTS: Plasma concentrations of dexmedetomidine fell below the limit of quantification (LOQ) (0.005 ng/mL) by 2.5 and 8 hours postadministration of 1 and 5 µg/kg, respectively. Synovial fluid concentrations were above the LOQ (0.1 ng/mL) of the assay at 24 hours in both dose groups. Drug was not detected in urine samples at any time postdrug administration. CS846 concentrations were significantly decreased relative to baseline at 12 hours postadministration in the saline group and significantly increased in the 5-µg/kg-dose group at 24 hours. Concentrations of C2C were significantly decreased at 12 and 24 hours postadministration in the saline treatment group. There were no significant differences in CS846 or C2C concentrations between dose groups at any time. CLINICAL RELEVANCE: Systemic concentrations of dexmedetomidine remained low, compared to synovial fluid concentrations. CS846, a marker of articular cartilage synthesis, increased in a dose-dependent fashion. Based on these findings, further dose titration and investigation of analgesic and adverse effects are warranted.


Assuntos
Cartilagem Articular , Dexmedetomidina , Doenças dos Cavalos , Cavalos , Animais , Dexmedetomidina/toxicidade , Injeções Intra-Articulares/veterinária , Líquido Sinovial , Biomarcadores
8.
BMC Vet Res ; 18(1): 436, 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36514067

RESUMO

BACKGROUND: Intra-articular corticosteroids, such as isoflupredone acetate, are commonly used in the treatment of joint inflammation, especially in performance horses. Following administration in a non-inflamed joints blood concentrations of isoflupredone were low and detectable for only a short period of time post-administration compared to synovial fluid concentrations. For some drugs, inflammation can affect pharmacokinetics, therefore, the goal of the current study was to describe the pharmacokinetics of isoflupredone acetate following intra-articular administration using a model of acute synovitis. Secondarily, pharmacodynamic effects, including effects on joint circumference, joint flexion, and lameness following intra-articular administration of isoflupredone acetate in the experimental model were described. METHODS: Sixteen horses received a single intra-articular dose of 8 mg of isoflupredone acetate or saline 12 h post-administration of lipopolysaccharide. Blood and urine samples were collected up to 72 h and synovial fluid for 28 days post-administration, drug concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Joint circumference, maximum angle of pain free joint flexion and lameness were evaluated prior to and post-treatment. RESULTS: The maximum isoflupredone plasma concentration was 2.45 ± 0.61 ng/mL at 2.5 ± 0.75 h and concentrations were less than the limit of quantitation by 72 h. Isoflupredone was below detectable concentrations in urine by 72 h post-administration in all horses and no longer detectable in synovial fluid by 96 h post-administration. Joint circumference was significantly decreased in the isoflupredone treatment group compared to the saline group at 24 and 48 h post drug administration. Pain free joint flexion was significantly different between the saline and isoflupredone treatment groups on day 4 post-treatment. CONCLUSIONS: Synovial fluid concentrations and maximum plasma concentrations of isoflupredone differed slightly between the current study and a previous one describing administration into a non-inflamed joint, however, the detection time of isoflupredone in blood was comparable. Effects of isoflupredone on joint circumference and degree of pain free joint flexion suggest a short duration of effect with respect to alleviation of lipopolysaccharide induced synovitis, however, results of this study support future studies of the anti-inflammatory effects of intra-articular isoflupredone acetate.


Assuntos
Doenças dos Cavalos , Sinovite , Cavalos , Animais , Lipopolissacarídeos , Coxeadura Animal/induzido quimicamente , Coxeadura Animal/tratamento farmacológico , Injeções Intra-Articulares/veterinária , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico , Sinovite/veterinária , Líquido Sinovial , Inflamação/tratamento farmacológico , Inflamação/veterinária , Doenças dos Cavalos/induzido quimicamente , Doenças dos Cavalos/tratamento farmacológico
9.
Vet Anaesth Analg ; 49(6): 634-644, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35999165

RESUMO

OBJECTIVE: To describe the pharmacokinetics, behavioral and physiologic effects and effects on thermal thresholds of morphine, morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) following administration to horses. STUDY DESIGN: Randomized balanced crossover study. ANIMALS: A total of seven University-owned horses, five mares and two geldings, aged 3-6 years. METHODS: Horses were treated with a single intravenous dosage of saline, morphine (0.2 mg kg-1), M6G (0.01 mg kg-1) and M3G (0.03 mg kg-1). Blood was collected prior to (baseline) and at several times post administration. Drug and metabolite concentrations were determined by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were calculated. Behavioral observations and physiologic variables (heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were determined at baseline and for up to 6 hours. The effects on thermal nociception were determined and thermal excursion was calculated. RESULTS: The volumes of distribution were 4.75-10.5, 0.244-0.295 and 0.215-0.356 L kg-1 for morphine, M6G and M3G, respectively. Systemic clearances were 26.8-39.6, 3.16-3.88 and 1.46-2.13 mL minute-1 kg-1 for morphine, M6G and M3G, respectively. Morphine administration resulted in signs of excitation as evidenced by an increase in step counts and subjective behavioral observations, whereas M6G and M3G, based on the same criteria, appeared to cause sedative-like effects. Significant effects on thermal nociception were observed until 4 hours post morphine administration, 1 hour post M6G administration and at various times post M3G administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study provide additional information regarding the use of morphine in horses. Less locomotor excitation and gastrointestinal adverse effects, compared with morphine, coupled with favorable effects on thermal nociception are encouraging for further study of the pharmacodynamics of both M6G and M3G in horses.


Assuntos
Glucuronídeos , Nociceptividade , Cavalos , Animais , Masculino , Feminino , Estudos Cross-Over , Derivados da Morfina/farmacocinética , Morfina
10.
Can J Vet Res ; 86(3): 172-180, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35794968

RESUMO

Although morphine has demonstrated antinociceptive effects in horses, its administration has been associated with dose-dependent adverse effects. In humans and rats, part of the analgesic effect of morphine has been attributed to the active metabolite, morphine-6-glucuronide (M6G). Although morphine can cause several undesirable effects, M6G has a more favorable safety profile. The objective of this study was to characterize the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of M6G following intravenous administration to a small group of horses. In Part 1 of the study, 3 horses received a single intravenous administration of saline, 0.5 mg/kg body weight (BW) M6G, or 0.5 mg/kg BW morphine in a 3-way crossover design. Blood samples were collected up to 96 hours post-administration, concentrations of drug and metabolites measured, and pharmacokinetics determined. Behavioral and physiological effects were then recorded. In Part 2 of the study, 2 horses scheduled to be euthanized for other reasons, were administered 0.5 mg/kg BW M6G. Blood, cerebrospinal fluid (CSF), and various tissue samples were collected post-administration and concentrations of drug were determined. The clearance of M6G was more rapid and the volume of distribution at steady state was smaller for M6G compared to morphine. A reaction characterized by head shaking, pawing, and slight ataxia was observed immediately following administration of both morphine and M6G to horses. After M6G administration, these behaviors subsided rapidly and were followed by a longer period of sedation. Following administration, M6G was detected in the kidney, liver, CSF, and regions of the brain. Results of this study encourage further investigation of M6G in order to assess its clinical feasibility as an analgesic in horses.


Bien que la morphine ait démontré des effets antinociceptifs chez les chevaux, son administration a été associée avec des effets non-désirés d'une manière dose-dépendante. Chez les humains et les rats, une partie de l'effet analgésique de la morphine a été attribuée au métabolite actif, morphine-6-glucuronide (M6G). Bien que la morphine puisse causer plusieurs effets indésirables, M6G a un profil de sécurité plus favorable. L'objectif de cette étude était de caractériser la pharmacocinétique, la distribution tissulaire, et le comportement et sélectionner des effets physiologiques de M6G suivant son administration intraveineuse à un petit groupe de chevaux. Dans la Partie 1 de l'étude, trois chevaux ont reçu l'administration intraveineuse d'une dose unique de saline, 0,5 mg/kg de poids corporel (BW) de M6G, ou 0,5 mg/kg BW de morphine selon un essai croisé à trois voies. Des échantillons sanguins ont été prélevés jusqu'à 96 h post-administration, les concentrations de drogues et de métabolites mesurées, et les pharmacocinétiques déterminées. Les effets physiologiques et sur le comportement ont par la suite été notés. Dans la Partie 2 de l'étude, deux chevaux devant être euthanasiés pour d'autres raisons, ont reçu 0,5 mg/kg BW de M6G. Du sang, du liquide céphalo-rachidien (CSF), et différents échantillons de tissu ont été prélevés post-administration et les concentration de drogue furent déterminées. La clairance de M6G a été plus rapide et le volume de distribution à l'état d'équilibre était plus petit pour M6G comparativement à la morphine. Une réaction caractérisée par le tremblement de la tête, du piaffage, et une légère ataxie a été observée immédiatement à la suite de l'administration soit de morphine ou de M6G aux chevaux. Après administration de M6G, ces comportements diminuèrent rapidement et furent suivis par une période plus longue de sédation. À la suite de l'administration, M6G a été détecté dans les reins, le foie, le CSF, et des régions du cerveau. Les résultats de cette étude incitent à réaliser des études additionnelles sur M6G afin d'évaluer son potentiel clinique comme analgésique chez les chevaux.(Traduit par Docteur Serge Messier).


Assuntos
Analgésicos Opioides , Glucuronídeos , Administração Intravenosa/veterinária , Animais , Cavalos , Morfina/farmacologia , Derivados da Morfina/farmacocinética , Ratos , Distribuição Tecidual
11.
J Vet Pharmacol Ther ; 45(5): 467-472, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35652132

RESUMO

Grapiprant is a prostaglandin E2 receptor antagonist that has been found to be an effective anti-inflammatory in dogs and that is devoid of some of the adverse effects associated with traditional NSAIDs that elicit their effects through inhibition of PGE2 production. Previously published reports have described the pharmacokinetics of this drug in horses when administered at 2 mg/kg; however, pharmacodynamic effects in this species have yet to be described. The objective of the current study was to describe the pharmacokinetics and pharmacodynamics of grapiprant at a higher dose. Eight horses received a single oral administration of 15 mg/kg. Plasma concentrations were determined for 96 h using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was used to determine pharmacokinetic parameters. Pharmacodynamic effects were assessed ex vivo by stimulating blood samples with PGE2 and determining TNF-ɑ concentrations. Maximum concentration, time to maximum concentration and area under the curve were 327.5 (188.4-663.0) ng/ml, 1 (0.75-2.0) hour and 831.8 (512.6-1421.6) h*ng/ml, respectively. The terminal half-life was 11.1 (8.27-21.2) hr. Significant stimulation of TNF alpha was noted for 2-4 h post-drug administration. Results of this study suggest a short duration of EP4 receptor engagement when administered at a dose of 15 mg/kg.


Assuntos
Cavalos , Compostos de Sulfonilureia , Fator de Necrose Tumoral alfa , Administração Oral , Animais , Área Sob a Curva , Meia-Vida , Cavalos/sangue , Imidazóis , Prostaglandinas E , Piridinas , Compostos de Sulfonilureia/farmacocinética
12.
BMC Vet Res ; 18(1): 196, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35614473

RESUMO

BACKGROUND: In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency. RESULTS: Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied. CONCLUSIONS: The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.


Assuntos
Codeína , Glucuronídeos , Nociceptividade , Analgésicos Opioides , Animais , Codeína/efeitos adversos , Codeína/farmacocinética , Glucuronídeos/efeitos adversos , Glucuronídeos/farmacocinética , Cavalos , Morfina , Derivados da Morfina/efeitos adversos , Derivados da Morfina/farmacocinética
13.
J Vet Diagn Invest ; 34(1): 23-27, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34918585

RESUMO

Bisphosphonates are potent anti-resorptive agents that have the potential to adversely affect bone healing in equine athletes, and normal bone adaption in young racehorses. A concern exists that bisphosphonate inhibition of normal bone metabolism could lead to increased bone fractures during high-intensity exercise. We found only a single report describing concentrations of tiludronate in the bone of horses, and no studies describing clodronate. Knowledge of the residence time in bone could allow for a better understanding of the long-term effects of these compounds. Our objectives were to develop a method for detection of bisphosphonates in bone and add to the limited information available regarding the disposition of these drugs in the bone of horses. Two horses received clodronate and 2 tiludronate disodium. Postmortem collection of bones and teeth occurred either 4 or 30 d post drug administration. Additionally, postmortem blood, synovial fluid, aqueous humor, and bone samples from racehorses with various histories of bisphosphonate administration were collected, and concentrations determined using the developed LC-MS/MS method. Bisphosphonates were detected in bones and teeth tested at 4 and 30 d. In a postmortem sample, clodronate was detected in bone from a horse with reported administration 18 mo prior; clodronate was not detected in other sample types collected from this horse. Bisphosphonates reside in bone for extended periods of time, which could lead to potential long-term effects, increasing the potential for bone fractures in young and/or athletic horses.


Assuntos
Difosfonatos , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida/veterinária , Cavalos , Espectrometria de Massas em Tandem/veterinária
14.
J Vet Pharmacol Ther ; 44(5): 745-753, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34173263

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/farmacocinética , Doenças dos Cavalos , Administração Cutânea , Animais , Biomarcadores , Bovinos , Cromatografia Líquida/veterinária , Clonixina/análogos & derivados , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Inflamação/veterinária , Espectrometria de Massas em Tandem/veterinária
15.
Am J Vet Res ; 82(6): 502-509, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34032479

RESUMO

OBJECTIVE: To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses. ANIMALS: 12 healthy adult horses. PROCEDURES: In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days). RESULTS: Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings. CONCLUSIONS AND CLINICAL RELEVANCE: Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.


Assuntos
Imunossupressores , Ácido Micofenólico , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Cavalos
16.
Equine Vet J ; 53(1): 102-116, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32145701

RESUMO

BACKGROUND: Flunixin meglumine (FM) and phenylbutazone (PBZ) are potent anti-inflammatory agents and as such their potential to mask injuries that would otherwise keep a horse from training or racing is concerning. A common practice in racetrack medicine in the USA is to administer the two drugs within close proximity (24 hours apart) of each other, raising the concern of pharmacokinetic interactions and enhanced anti-inflammatory effects. OBJECTIVES: Describe the pharmacokinetics and effects of PBZ on the clearance of FM when administered in close proximity as well as effects on inflammatory mediators. STUDY DESIGN: Two-way randomised balanced crossover experiment. METHODS: Twelve Thoroughbred exercised horses received 500 mg FM IV alone or in combination with 2 g of IV PBZ 24 hours later. Blood and urine samples were collected prior to and for up to 120 hours post-drug administration. Whole blood samples were collected at various times and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of FM, PBZ and eicosanoids were measured using LC-MS/MS and noncompartmental pharmacokinetic analysis performed on concentration data. RESULTS: Flunixin meglumine clearance was significantly increased when horses received PBZ 24 hours post-administration (P = .03). No other differences in pharmacokinetic parameters were noted between groups. Thromboxane B2 was significantly suppressed, relative to baseline for 96 hours post-FM administration. Subsequent administration of PBZ prolonged the suppression. Prostaglandin E2 was decreased for 24 hours following administration of FM with subsequent administration of PBZ prolonging the suppression until 120 hours. PGF2alpha concentrations were decreased for up to 168 hours post-FM administration. FM administration significantly decreased 15-HETE. MAIN LIMITATIONS: Small sample size and lack of a phenylbutazone-only treatment group. CONCLUSIONS: Administration of PBZ post-FM administration increased FM clearance. The anti-inflammatory effects of FM appear to be prolonged when PBZ is administered 24 hours post-administration.


Assuntos
Anti-Inflamatórios não Esteroides , Clonixina , Cavalos/metabolismo , Fenilbutazona/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Cromatografia Líquida/veterinária , Clonixina/análogos & derivados , Clonixina/farmacocinética , Espectrometria de Massas em Tandem/veterinária
17.
J Vet Pharmacol Ther ; 44(1): 36-46, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32757313

RESUMO

The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug-drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450-mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma-hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5-OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5-OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug-drug interactions and identification of reasons for varying pharmacokinetics between horses.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/análogos & derivados , Sistema Enzimático do Citocromo P-450/metabolismo , Cavalos/metabolismo , Fenilbutazona/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Clonixina/química , Clonixina/metabolismo , Clonixina/farmacocinética , DNA Complementar/genética , DNA Complementar/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fenilbutazona/química , Fenilbutazona/metabolismo
18.
BMC Vet Res ; 16(1): 368, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32998730

RESUMO

BACKGROUND: Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated. RESULTS: Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg). CONCLUSIONS: Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Meperidina/farmacologia , Meperidina/farmacocinética , Administração Intravenosa/veterinária , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Cavalos , Temperatura Alta , Masculino , Meperidina/administração & dosagem , Meperidina/efeitos adversos , Meperidina/análogos & derivados , Meperidina/sangue , Meperidina/urina , Nociceptividade/efeitos dos fármacos , Urticária
19.
Vet Anaesth Analg ; 47(5): 694-704, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32654915

RESUMO

OBJECTIVE: To describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 12 Thoroughbred horses, nine geldings and three mares, aged 4-8 years. METHODS: Horses were administered codeine (0.6 mg kg-1) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration. RESULTS: Codeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The Cmax, tmax and elimination t½ were 270.7 ± 136.0 ng mL-1, 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (Cmax 492.7 ± 35.5 ng mL-1), followed by C6G (Cmax 96.1 ± 33.8 ng mL-1) and M6G (Cmax 22.3 ± 4.96 ng mL-1). Morphine and norcodeine were the least abundant metabolites with Cmax of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL-1, respectively. No significant adverse or excitatory effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Following oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.


Assuntos
Codeína/farmacocinética , Cavalos/metabolismo , Administração Oral , Animais , Área Sob a Curva , Codeína/sangue , Codeína/metabolismo , Codeína/urina , Esquema de Medicação , Feminino , Meia-Vida , Masculino
20.
Drug Test Anal ; 12(8): 1087-1101, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32436346

RESUMO

Corticosteroids are potent anti-inflammatory drugs and as such are commonly administered to performance and racehorses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics and effects on cortisol and inflammatory mediator concentrations, following intravenous and oral administration to 12 exercised horses. Horses received an intravenous administration of 40 mg of dexamethasone sodium phosphate and 20 mg of dexamethasone tablets with a 4 week washout in between administrations. Blood and urine samples were collected prior to and for up to 96 hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. The concentrations of dexamethasone and eicosanoids were measured using LC-MS/MS and the concentrations from both routes of administration fit simultaneously using a three-compartment pharmacokinetic model. A turnover model with inhibition of Kin gave an adequate fit to the dexamethasone-cortisol PKPD data. Serum and urine dexamethasone concentrations were at the limit of quantitation at 96 and 48 hours post administration, respectively. The volume of distribution, systemic clearance, and terminal half-life was 0.907 L/kg, 7.89 mL/h/kg, and 1.34 h, respectively. The IC50 for cortisol suppression was 0.007 ng/mL. Stimulation of dexamethasone treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of inflammatory biomarker production for a prolonged period of time post drug administration. The results of this study suggest that dexamethasone has a prolonged anti-inflammatory effect following intravenous or oral administration to horses.


Assuntos
Anti-Inflamatórios/administração & dosagem , Dexametasona/análogos & derivados , Glucocorticoides/administração & dosagem , Modelos Biológicos , Administração Intravenosa , Administração Oral , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Cromatografia Líquida/métodos , Dexametasona/administração & dosagem , Dexametasona/farmacocinética , Dexametasona/farmacologia , Glucocorticoides/farmacocinética , Glucocorticoides/farmacologia , Meia-Vida , Cavalos , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Concentração Inibidora 50 , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo , Distribuição Tecidual
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