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1.
J Vet Intern Med ; 38(2): 1177-1184, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38363029

RESUMO

BACKGROUND: Phenylbutazone is often prescribed to manage pain caused by hyperinsulinemia-associated laminitis, but in diabetic people nonsteroidal anti-inflammatory drugs increase insulin secretion and pancreatic activity. HYPOTHESIS/OBJECTIVES: Investigate the effect of phenylbutazone administration on insulin secretion in horses. It was hypothesized that phenylbutazone will increase insulin secretion in horses with insulin dysregulation (ID). ANIMALS: Sixteen light breed horses, including 7 with ID. METHODS: Randomized cross-over study design. Horses underwent an oral glucose test (OGT) after 9 days of treatment with phenylbutazone (4.4 mg/kg IV q24h) or placebo (5 mL 0.9% saline). After a 10-day washout period, horses received the alternative treatment, and a second OGT was performed. Insulin and glucose responses were compared between groups (ID or controls) and treatments using paired t test and analyses of variance with P < .05 considered significant. RESULTS: In horses with ID, phenylbutazone treatment significantly decreased glucose concentration (P = .02), glucose area under the curve (2429 ± 501.5 vs 2847 ± 486.1 mmol/L × min, P = .02), insulin concentration (P = .03) and insulin area under the curve (17 710 ± 6676 vs 22 930 ± 8788 µIU/mL × min, P = .03) in response to an OGT. No significant effect was detected in control horses. CONCLUSION AND CLINICAL IMPORTANCE: Phenylbutazone administration in horses with ID decreases glucose and insulin concentrations in response to an OGT warranting further investigation of a therapeutic potential of phenylbutazone in the management of hyperinsulinemia-associated laminitis beyond analgesia.


Assuntos
Dermatite , Doenças dos Cavalos , Hiperinsulinismo , Animais , Glicemia/análise , Dermatite/veterinária , Glucose , Teste de Tolerância a Glucose/veterinária , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/veterinária , Insulina/metabolismo , Secreção de Insulina , Fenilbutazona/uso terapêutico
2.
J Vet Intern Med ; 37(6): 2535-2543, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37800408

RESUMO

BACKGROUND: Right dorsal colitis (RDC) is a nonsteroidal anti-inflammatory drug (NSAID) induced, protein losing enteropathy in horses associated with a high case fatality rate. OBJECTIVES: To describe signalment, NSAID usage, clinical presentations, clinical pathology, ultrasonographic findings, treatments, outcomes, and factors associated with survival in horses diagnosed with RDC. ANIMALS: Thirty-five horses from 7 Australian equine hospitals diagnosed with RDC. METHODS: Retrospective case series. Clinical records of cases were accepted if definitively or presumptively diagnosed by an internist with RDC and had ≥3 of: hypoproteinemia or hypoalbuminemia; diarrhea with negative test results for infectious diseases; colic for which other diseases were excluded or right dorsal colon thickening on ultrasound. Descriptive data analysis was performed for categorical and continuous variables. Univariate binominal logistic regressions were used to assess factors associated with survival. RESULTS: An overdose of NSAIDs occurred in 84% (21/25) cases where dose was known. Common clinical presentations included diarrhea (69%; 22/32), colic (61%; 20/33), and tachycardia (53%, 17/32). Common clinicopathological findings included hypoalbuminemia (83%; 26/31), hypocalcaemia (79%, 23/29), and hyperlactatemia (77%, 14/18). The right dorsal colon wall appeared subjectively thickened in 77% (24/31) cases using ultrasonography. Case fatality rate was 43% (15/35). Odds of survival significantly decreased with increasing heart rate (odds 0.84, 95% CI = 0.71-0.92, P = .01), packed cell volume (odds 0.91, 95% CI 0.82-0.98, P = .05) and abnormal appearance of mucous membranes (odds 0.05, 95% CI 0.005-0.28, P = .001) on hospital presentation. CONCLUSIONS AND CLINICAL IMPORTANCE: An overdose of NSAIDs is common in horses diagnosed with RDC. Serum albumin concentrations should be monitored in horses receiving a prolonged course of NSAIDs. Overall prognosis for RDC remains fair.


Assuntos
Cólica , Colite , Doenças dos Cavalos , Hipoalbuminemia , Animais , Cavalos , Estudos Retrospectivos , Cólica/veterinária , Fenilbutazona/efeitos adversos , Hipoalbuminemia/veterinária , Doenças dos Cavalos/diagnóstico por imagem , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/induzido quimicamente , Austrália , Colite/veterinária , Anti-Inflamatórios não Esteroides/uso terapêutico , Diarreia/veterinária
3.
J Vet Intern Med ; 37(6): 2544-2551, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37882246

RESUMO

BACKGROUND: Treatment with phenylbutazone (nonselective COX inhibitor) decreases the diuretic and natriuretic effects of furosemide by nearly 30% but the effects of COX-2 specific inhibitors (firocoxib) and atypical NSAIDs (dipyrone) are unknown. HYPOTHESIS: Furosemide-induced diuresis after pretreatment with firocoxib or dipyrone is diminished to a lesser extent than after pretreatment with phenylbutazone. ANIMALS: Eight healthy mares. METHODS: Each mare received 4 treatments in a prospective experimental crossover study using a replicated 4 × 4 Latin Square design: furosemide alone (FU), furosemide and phenylbutazone (PB), furosemide and firocoxib (FX), and furosemide and dipyrone (DP). After 24 hours of NSAID treatment at recommended dosages, ureteral catheters were placed for continual urine collection. After a 30-minute baseline collection period, furosemide (1.0 mg/kg, IV) was administered, and urine and blood samples were collected for 4 hours. Data were assessed by repeated measures ANOVA. RESULTS: Four-hour urine volume was (mean ± SD) ~25% less (P < .001) after pretreatment with all NSAIDs (PB 19.1 ± 2.1 mL/kg, FX 17.7 ± 3.5 mL/kg, DP 19.1 ± 3.9 mL/kg), as compared to FU (23.4 ± 5.1 mL/kg) (P < .001), but there were no differences between PB, FX, or DP. Interindividual variability in furosemide diuresis after pretreatment with different NSAIDs was observed. CONCLUSIONS AND CLINICAL IMPORTANCE: Though COX-2 selective NSAIDs and dipyrone might have less severe or fever gastrointestinal adverse effects in horses, our data suggest minimal differences in effects on furosemide-induced diuresis, and possibly, risk of nephrotoxicosis.


Assuntos
Diuréticos , Furosemida , Animais , Cavalos , Feminino , Diuréticos/farmacologia , Furosemida/farmacologia , Dipirona/farmacologia , Estudos Cross-Over , Ciclo-Oxigenase 2 , Estudos Prospectivos , Fenilbutazona/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-37436880

RESUMO

OBJECTIVES: To investigate if hepatitis A virus cell receptor 1/kidney injury molecule 1 (HAVCR1/KIM1) in urine is detectable concurrently with increases in serum creatinine concentrations in horses receiving a recommended dose of phenylbutazone (PBZ) for 7 days. DESIGN: Preliminary study. METHODS: Ten clinically healthy horses with normal physical examination and laboratory work were randomly assigned to PBZ or placebo groups (5 each). The PBZ group received PBZ at 4.4 mg/kg mixed with corn syrup orally every 12 hours. The placebo group received corn syrup orally every 12 hours. Both groups were treated for 7 days. Kidney ultrasonography was performed, and venous blood and urine samples were collected prior to commencement and at the end of treatment. Samples from 1 additional healthy horse, 3 horses with acute kidney failure, and 1 horse with chronic kidney failure were also evaluated. RESULTS: None of the 10 horses had detectable HAVCR1/KIM1 in urine at baseline. Serum creatinine concentrations in placebo group did not increase, and HAVCR1/KIM1 was undetectable in urine. At the end of treatment, 3 of 5 horses receiving PBZ developed increases in serum creatinine of >26.5 µmol/L (>0.3 mg/dL), and HAVCR1/KIM1 was detectable in urine, despite normal findings on kidney ultrasonography in all horses. CONCLUSIONS: HAVCR1/KIM1 is detectable in urine and is associated with increases in serum creatinine concentrations of >26.5 µmol/L in horses following treatment with PBZ for 7 consecutive days. Thus, HAVCR1/KIM1 might aid in the early detection of acute kidney injury in horses.


Assuntos
Anti-Inflamatórios não Esteroides , Vírus da Hepatite A , Cavalos , Animais , Creatinina , Fenilbutazona/uso terapêutico , Rim
5.
PLoS One ; 18(4): e0283371, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37023045

RESUMO

In Europe, equines destined for human consumption (hereafter called slaughter equines) are subject to the same restrictions of usage of veterinary drugs as other food-producing animals, with amendments regulated in the so-called 'positive list', Regulation (EC) No. 1950/2006. Due to the complex legal requirements for drug administration in slaughter equines, it might be that specific knowledge regarding the legislation of slaughter equines may be insufficient among veterinarians, equine owners, and equine keepers. To study this assumption, three target group-specific surveys were conducted in 2021. Answers from 153 equine treating veterinarians, 170 equine owners, and 70 equine keepers were included in the analysis. In total 68.4% (91/133) of the participating veterinarians, the regulations of the 'positive list', Regulation (EC) No. 1950/2006, were 'rather complicated' to 'complicated'. Among the participating veterinarians, 38.4% (58/151) did not or could not answer correctly how to proceed if a slaughter equine is scheduled to receive phenylbutazone, usage of which is prohibited in all livestock by Regulation (EU) No. 37/2010. Simultaneously, 56.2% (86/153) of the participating veterinarians named phenylbutazone as the, or one of the, most often used non-steroidal anti-inflammatory drugs. Altogether, 41.2% (70/170) of participating equine owners and 42.9% (30/70) of equine keepers did not know under which circumstances an equine can legally be slaughtered for human consumption. In total, 34.3% (24/70) of the equine keepers classified their knowledge of national regulations for animal keepers regarding the documentation of drug usage in equines as 'poor' to 'nonexistent'. This lack of knowledge in all three surveyed groups, combined with the complex legal regulations regarding the usage and documentation of drugs in slaughter equines, could result in missing and false documentation, treatment of slaughter equines with prohibited substances and therefore pose a risk factor for drug residues in equine meat.


Assuntos
Médicos Veterinários , Drogas Veterinárias , Animais , Cavalos , Humanos , Criação de Animais Domésticos , Fenilbutazona , Alemanha , Gado
6.
Spectrochim Acta A Mol Biomol Spectrosc ; 297: 122707, 2023 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-37054568

RESUMO

Spectrophotometric resolution of severely overlapped binary mixtures with minor component is challenging. Herein, coupling of mathematical manipulation steps with sample enrichment was conducted on the binary mixture spectrum of Phenylbutazone (PBZ) and Dexamethasone sodium phosphate (DEX) to resolve, for the first time each component separately. Simultaneous determination of both components in a mixture ratio of 1:0.002 was achieved in their zero or first order spectra by the recent factorized response method along with ratio subtraction and constant multiplication methods; all coupled with spectrum subtraction. In addition, a novel second derivative concentration value and second derivative constant value methods were developed for PBZ determination. The concentration of the minor component DEX was obtained, without preliminary separation steps by derivative ratio after sample enrichment by either spectrum addition or standard addition. Spectrum addition approach showed superior characteristics compared to standard addition technique. All proposed methods were placed through a comparative study. Linear correlation was found to be 1.5-18.0 µg/mL for PBZ, and 4.0-45.0 µg/mL for DEX. The proposed methods were validated in accordance with ICH guidelines. The greenness assessment of the proposed spectrophotometric methods was evaluated by AGREE software. Results obtained from the statistical data were evaluated by comparing to one another as well as the official USP methods. These methods offer a cost and time effective platform to analyze bulk materials and combined veterinary formulation.


Assuntos
Dexametasona , Fenilbutazona , Espectrofotometria/métodos
7.
Am J Vet Res ; 84(3)2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36662603

RESUMO

Nearly all of the American horses exported to Mexico and Canada are slaughtered for human consumption, and their meat is either exported around the world or consumed locally. Previous work showed that 18 Thoroughbred racehorses purchased by rescues that would have otherwise been sold for export for the sole purpose of slaughter to produce meat for human consumption were administered phenylbutazone. We report the number of American horses exported to Canada and Mexico from 2016 to 2021, the presence of contaminated horsemeat from Canadian slaughterhouses, and the human use and idiosyncratic effects of veterinary phenylbutazone and side effects of clenbuterol, 2 of the drugs that were found in contaminated Canadian horsemeat. The number of live American horses exported to Canada declined precipitously from 2016 to 2017, and a second decline occurred in 2020. All food-producing animals are under strict regulatory control to prevent animals administered banned drugs to enter the food chain. A major principle of this program is zero tolerance for banned drugs and testing for compliance. No regulatory process is in place to remove horses administered banned drugs such as phenylbutazone. The efficacy lasts for more than 24 hours as a result of the irreversible binding to cyclooxygenase, slow elimination, and long elimination half-life of its metabolite oxyphenbutazone. High or frequent doses of phenylbutazone result in disproportionately increased plasma concentrations, which result in the residual presence in tissues. It is this fact that underlies the ban of this drug in food-producing animals. No human clinical surveillance program is in place to monitor individuals on the possible short- and long-term consequences of banned drugs in contaminated horsemeat. If the United States is unable to put in place a regulatory program to remove horses administered banned drugs as exists for all food-producing animals, the exportation of American horses across both borders for the sole purpose of slaughter for human consumption must end.


Assuntos
Fenilbutazona , Saúde Pública , Cavalos , Humanos , Animais , Estados Unidos , Canadá , Oxifenilbutazona
8.
Equine Vet J ; 55(3): 524-533, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-35633196

RESUMO

BACKGROUND: Acetaminophen has been used clinically in horses alone or combined with traditional non-steroidal anti-inflammatory drugs for treatment of musculoskeletal pain in horses. OBJECTIVES: To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control. STUDY DESIGN: In vivo experiment. METHODS: Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four-way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC-MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10-point scales. RESULTS: Mean maximum plasma concentration (Cmax ) for A20 was 20.01 µg/ml within 0.66 h (Tmax ) after administration; The mean Cmax for A30 was 30.02 µg/ml with a Tmax of 0.43 h. Post-treatment heart rate for A30 was significantly lower than A20 at 1 and 7 h; lower than PB at 2, 3, 4.5 and 7 h; lower than C at 2, 3.5, 4.5, 6, 7 and 8 h. 10-point Lameness scores were significantly improved for A30 than C at 2 and 4 h post-treatment; PB was significantly improved than C at 8 h post treatment. There were no significant differences in lameness between A20, A30 and PB. MAIN LIMITATIONS: Small sample size, lack of objective lameness measurement. CONCLUSIONS: Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility.


CONTEXTO: Acetaminofeno tem sido usado rotineiramente em cavalos com dor musculoesquelética, tanto como terapia solo quanto em associação com outros anti-inflamatórios não esteroides tradicionais. OBJETIVOS: Determinar a farmacocinética e eficácia de duas doses de acetaminofeno em cavalos com claudicação mecanicamente induzida, e comparar com fenilbutazona e placebo. DELINEAMENTO DO ESTUDO: Estudo randomizado, cego e controlado utilizando quadrado latino. METODOLOGIA: Nove éguas adultas com claudicação induzida mecanicamente pelo método de aplicação de pressão na sola através de ferradura foram tratadas com acetaminofeno (20 mg/kg VO; A20), acetaminofeno (30 mg/kg VO; A30), fenilbutazona (2.2 mg/kg, VO; PB) e placebo oral (C) em um estudo quadrado latino de forma randômica. Concentração plasmática dos grupos A20 e A30 foram analisadas pelo método LC-MS/MS e análise farmacocinética não compartimentar. Frequência cardíaca e variação da frequência cardíaca foram mensuradas usando telemetria portátil. O grau de claudicação foi avaliado usando a escala de 10 pontos da AAEP por três cirurgiões especialistas (board-certified) que estavam cegos ao tratamento. RESULTADOS: A média máxima da concentração plasmática (Cmax ) do grupo A20 foi 20.01 µg/ml dentro de 0.66 h (Tmax ) da administração. A média Cmax do grupo A30 foi 30.02 µg/ml dentro da Tmax de 0.43 h. A frequência cardíaca do grupo A30 foi significativamente mais baixa do que a do grupo A20 nos momentos 1 e 7 h; mais baixa do que o grupo PB nos momentos 2, 3, 4.5 e 7 h; e mais baixa do que as do grupo C nos momentos 2, 3.5, 4.5, 6, 7 e 8 h. O grau de claudicação diminuiu significativamente no grupo A30 quando comparado com o grupo C nos momentos 2 e 4 h pós tratamento, e no grupo PB quando comparado com o grupo C no momento 8 h pós tratamento. Não houve diferença significativa em grau de claudicação quando os grupos A20, A30 e PB foram comparados. PRINCIPAIS LIMITAÇÕES: Número pequeno de animais, ausência de mensuração de claudicação objetiva. CONCLUSÕES: A dose de 30 mg/kg de acetaminofeno proporcionou uma superior melhora na escala de claudicação e frequência cardíaca quando comparada com os outros tratamentos avaliados neste estudo. Mais informações sobre a farmacocinética e efeitos da repetida dosagem de 30 mg/kg de acetaminofeno precisam ser avaliadas para determinar a sua aplicabilidade clínica.


Assuntos
Acetaminofen , Doenças dos Cavalos , Animais , Feminino , Acetaminofen/uso terapêutico , Cromatografia Líquida/veterinária , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Coxeadura Animal/tratamento farmacológico , Fenilbutazona/farmacocinética , Espectrometria de Massas em Tandem/veterinária , Resultado do Tratamento
9.
J Equine Vet Sci ; 118: 104088, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35908599

RESUMO

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), like phenylbutazone (PBZ), are prescribed to treat pain and inflammation in the equine. However, experimentally their use has been associated with the development of Equine Glandular Gastric Disease (EGGD). To evaluate the prophylactic effects of Glycyrrhiza glabra root extracts (GGRE) on EGGD induction following oral administration of PBZ, 12 donkeys were used. Animals were divided into three equal groups (A, B and C) in a randomized block design. A: placebo, B: PBZ (4.4 mg/kg PO q 12 h) and C: PBZ plus GGRE (17.6 mg/kg PO q 24h). Gastroscopy and blood sampling for CBC, biochemical tests and antioxidant status were performed days 0 and 7. All but 1 animal had no EGGD lesions on day 0, but on day 7, severe EGGD lesions were seen in group B animals (grade 1/4 (× 1), grade 2/4 (× 2), and grade 3/4 (× 1)). Only mild changes were seen in group C animals, the most severe lesions being grade 1/4 lesions in 2 animals. No change was observed in Group A. Hematology and serum antioxidant status did not change significantly in any group. In group B glucose decreased and ALT and ALP increased, while in group C only ALP increased. In conclusion, GGRE reduced the severity of EGGD caused by PBZ. Further, GGRE prevented PBZ induced hypoglycemia and might reduce the possible hepatic injury of PBZ.


Assuntos
Glycyrrhiza , Doenças dos Cavalos , Gastropatias , Animais , Antioxidantes/farmacologia , Doenças dos Cavalos/induzido quimicamente , Cavalos , Fenilbutazona/toxicidade , Gastropatias/induzido quimicamente , Gastropatias/veterinária
10.
J Pharm Sci ; 111(10): 2839-2847, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35580691

RESUMO

Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs-PIP salts, such as ibuprofen-piperazine (IBU-0.5PIP) salt, indomethacin-piperazine (IND-0.5PIP) salt, sulindac-piperazine (SUL-0.5PIP) salt, phenylbutazone-piperazine (PBZ-0.5PIP) salt, ketoprofen-piperazine (KPF-0.5PIP) salt and flurbiprofen-piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X-ray diffraction. Powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts.


Assuntos
Flurbiprofeno , Cetoprofeno , Anti-Inflamatórios não Esteroides/química , Varredura Diferencial de Calorimetria , Ibuprofeno/química , Indometacina/química , Cetoprofeno/química , Fenilbutazona , Piperazina , Pós , Sais , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Sulindaco , Água/química , Difração de Raios X
11.
Res Vet Sci ; 147: 44-49, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35447388

RESUMO

BACKGROUND: Apoptosis is an important mechanism underlying chondrocyte loss in osteoarthritis that could be affected by modulation of lipid signaling via inhibition of cyclooxygenases (COX) and soluble epoxide hydrolase (sEH). OBJECTIVE: To determine the impact of inhibiting COX and sEH alone or in combination on apoptosis of equine chondrocytes. METHODS: Cultured primary equine chondrocytes were subjected to serum deprivation or incubation with 1 µg/ml tunicamycin for 24 h to induce apoptosis via caspase activation and endoplasmic reticulum (ER) stress, respectively. Cells were treated with the non-selective COX inhibitor phenylbutazone, the COX-2 selective inhibitor firocoxib and the sEH inhibitor t-TUCB alone or in combination. The inhibitors were used at half-maximal (IC50), 80% of maximal (IC80) and 10-fold the 80% inhibitory concentration (10xIC80) for the equine enzymes. Apoptosis was quantified via ELISA technique. Data were analyzed with unpaired two-tailed t-test or one-way ANOVA followed by Bonferroni's post-hoc while correcting for multiple comparisons via statistical hypothesis testing. P < 0.05 was considered significant. RESULTS: In the caspase model, 10xIC80t-TUCB significantly decreased whereas 10xIC80 phenylbutazone significantly enhanced apoptosis. Apoptosis enhancement by phenylbutazone was significantly attenuated by concurrent 10xIC80t-TUCB. The remaining treatments and concentrations had no effect on apoptosis development. In the ER stress model, IC50 and IC80 phenylbutazone and firocoxib significantly enhanced apoptosis, which was fully prevented by concurrent 10xIC80t-TUCB. MAIN LIMITATIONS: In vitro findings that will need to be verified in vivo. CONCLUSIONS: Chondrocyte apoptosis caused by ER stress can be enhanced by COX inhibition but prevented by concurrent inhibition of sEH.


Assuntos
Condrócitos , Epóxido Hidrolases , Animais , Apoptose , Caspases , Ciclo-Oxigenase 2 , Cavalos , Fenilbutazona
12.
Vet Med Sci ; 8(2): 553-560, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34989156

RESUMO

INTRODUCTION/BACKGROUND: The number of publications for most common drug violations in racehorses is limited. This study reports the most common medication violations in racehorses at four major racetracks in Louisiana between 2016 and 2020. METHODS: During this 5-year period, 27,237 blood samples and 25,672 urine samples collected during the course of normal race meeting activities were analysed by initial screening procedure utilizing Liquid Chromatography Mass Spectrometry (LC-MS/MS). Following initial screening, suspect samples were subject to quantitative or semi- quantitative confirmation analysis by LC-MS/MS. RESULTS: The total number of violations reported was 534 (1.01% of the total number of specimens analysed). The total number of violations reported in Thoroughbred horses was 210 while the total number of violations reported in Quarter Horses was 324. The percentage of total violations was %0.59 for all the specimens analysed in Thoroughbred horses while this percentage was %1.9 for all the specimens analysed in Quarter Horses during this 5-year period. The most frequent violations included the overages (concentrations of permitted medications equal to or exceeding the set threshold) of clenbuterol (165 violations), non-steroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone (73 violations), combination of phenylbutazone with flunixin (45 violations) and muscle relaxant methocarbamol (40 violations). DISCUSSION/CONCLUSIONS: The total number of violations were relatively low during 5-year period, but wide varieties of medications with different pharmacological actions were confirmed in performance horses in Louisiana. The most frequently reported violations in Louisiana were for permitted therapeutic medications (clenbuterol, phenylbutazone, flunixin methocarbamol) with established threshold and/or withdrawal guidelines in racehorses.


Assuntos
Clembuterol , Metocarbamol , Animais , Cromatografia Líquida/veterinária , Cavalos , Fenilbutazona , Espectrometria de Massas em Tandem/veterinária
13.
J Vet Pharmacol Ther ; 45(2): 196-202, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34894412

RESUMO

Southern white rhinoceros (Ceratotherium simum simum) frequently develop painful conditions, such as traumatic injuries or osteoarthritis, necessitating the administration of pain-relieving medications. One of the preferred treatments is the nonsteroidal anti-inflammatory drug phenylbutazone because of the availability of oral formulations and the familiarity of its use in horses. For the main study, a single oral dose of phenylbutazone at 2 mg/kg was administered to healthy adult rhinoceros (n = 33) housed at six North American zoological institutions. Each rhinoceros had up to four blood samples collected under voluntary behavioural restraint at up to four predetermined time points (0, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 30 and 48 h). Drug analysis was performed by high-performance liquid chromatography. The population pharmacokinetic parameters were calculated with nonlinear mixed-effects modelling, and analysis showed a peak concentration (CMAX ) of 3.8 µg/ml at 1.8 h and an elimination half-life of 9 h. The concentrations achieved were similar to what has been reported for horses and were within the half maximal effective concentration for horses for at least 10 h. A multi-dose trial in five rhinoceros receiving 2 mg/kg orally once daily for five days found mild accumulation at a predicted factor of 1.2. This study represents the first pharmacokinetic data of phenylbutazone in any rhinoceros species.


Assuntos
Perissodáctilos , Fenilbutazona , Administração Oral , Animais , Anti-Inflamatórios não Esteroides , Cavalos
14.
J Biomol Struct Dyn ; 40(18): 8312-8323, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-33870854

RESUMO

Pazopanib (PZP) is a multi-targeting tyrosine kinase inhibitor and is currently approved by FDA for the treatment of soft tissue sarcoma and renal cancer. Molecular interaction mechanism of PZP with human serum albumin (HSA) was explored under simulated physiological conditions (pH = 7.4), using fluorescence and UV absorption spectroscopy along with computational methods. Based on the inverse correlation between the Stern-Volmer constant (Ksv) and temperature, it was concluded that PZP quenched the protein fluorescence through static quenching mechanism. This was also confirmed from the UV-vis absorption spectral results. Moderate binding affinity between PZP and HSA was evident from the Ka values (5.51 - 1.05 × 105 M-1) while PZP-HSA complex formation was driven by hydrophobic and van der Waals interactions as well as hydrogen bonds, as revealed by positive entropy change (ΔS = +98.37 J mol-1 K-1) and negative enthalpy change (ΔH = -60.31 kJ mol-1). Three-dimensional fluorescence spectral results disclosed microenvironmental perturbations around Trp and Tyr residues of the protein upon PZP binding. Interestingly, the addition of PZP to HSA significantly protected the protein against thermal stress. Competitive drug displacement results obtained with warfarin, phenylbutazone and diazepam elucidated Sudlow's Site I, positioned in subdomain IIA of HSA, as the preferred binding site of PZP which was well supported by molecular docking analysis, while molecular dynamics simulation results suggested the stability of the PZP-HSA complex.Communicated by Vsevolod Makeev.


Assuntos
Antineoplásicos , Albumina Sérica Humana , Antineoplásicos/química , Sítios de Ligação , Dicroísmo Circular , Diazepam , Humanos , Indazóis , Simulação de Acoplamento Molecular , Fenilbutazona , Ligação Proteica , Inibidores de Proteínas Quinases , Pirimidinas , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Sulfonamidas , Termodinâmica , Varfarina
15.
J Equine Vet Sci ; 101: 103451, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33993934

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) can cause right dorsal colitis, but longitudinal clinical studies are lacking. This study investigates whether NSAID treated horses develop right dorsal colonic pathology in a clinical setting. Non-gastrointestinal hospitalized horses treated with NSAIDs >4 days, and untreated hospital-owned teaching horses and non-gastrointestinal client-owned hospitalized horses were included. All horses were monitored over time with clinical examinations (focusing on presence of colic, depression, reduced appetite, unstructured feces), ultrasonographic intestinal wall measurements, fecal occult blood tests (semi-quantitative results), and blood analysis (total protein and albumin concentrations, white blood cell and neutrophil counts). Outcomes were recorded as "ultrasonographically thickened right dorsal colon (RDC) walls", "colitis" and "right dorsal colitis". Findings over time were compared to baseline values and to control horses. Seventeen NSAID treated horses and 5 controls were included. NSAID treated horses developed thickened RDC walls (4/9), and subclinical and mild colitis (9/11) and right dorsal colitis (4/10), whereas all control horses remained healthy. The first changes were identified on treatment day 2. RDC walls of treated horses were significantly thicker compared to their own baseline values and compared to control horses. In conclusion, presumptive colon pathology was identified with a high incidence, starting early in the course of treatment, but with low severity. Appropriate monitoring should be advised throughout NSAID treatment. Additional research for noninvasive diagnostic tests for colon pathology is required.


Assuntos
Doenças dos Cavalos , Preparações Farmacêuticas , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Colo/diagnóstico por imagem , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Fenilbutazona
16.
J Equine Vet Sci ; 98: 103375, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33663725

RESUMO

In this controlled, blinded, randomized block pilot study, the main objective was to evaluate the effectiveness of intravenous flunixin meglumine, phenylbutazone, and acupuncture on ocular pain relief using a multifactorial pain scale in the horse. Four experimental horses underwent corneal epithelial debridement in four sessions, when a randomly selected treatment or a control was used. All horses were pain scored before corneal wounding, then at 18 time points, when 11 parameters were allocated. Differences in the area under the curve of pain scores between the treatment groups were analyzed using a paired t-test. Corneal pain was significantly reduced by the third postoperative day (P = .03) when all 11 parameters were considered. Five ocular signs showed significant differences between treatments and proved to be good indicators of ocular pain. The other parameters (heart rate, corneal touch threshold, respond to palpation, and three behavioral parameters) were determined to be irrelevant when evaluating the degree of pain. When considering the five ocular signs, the lowest pain score was attributed to the flunixin meglumine group (1114), followed by the electroacupuncture group (1356), the phenylbutazone group (1397), and the control group (1580). There were significantly lower pain scores (P = .01) in the flunixin meglumine group when compared with those recorded in the control group during the first 46 hours. Flunixin meglumine was the most effective treatment at reducing ocular pain in the horse. In the future, a reduction in the number of pain score parameters and more precisely defined image evaluation criteria could be used.


Assuntos
Terapia por Acupuntura , Anti-Inflamatórios não Esteroides , Terapia por Acupuntura/veterinária , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Clonixina/análogos & derivados , Cavalos , Dor/veterinária , Fenilbutazona/uso terapêutico , Projetos Piloto
17.
J Vet Intern Med ; 35(2): 1121-1130, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33656183

RESUMO

BACKGROUND: Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known. OBJECTIVE: Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone-induced GI injury could be ameliorated by the use of a nutritional therapeutic. ANIMALS: Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic. METHODS: This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability. RESULTS: Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02-fold (95% confidence interval [CI], 0.1.89-4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes.


Assuntos
Doenças dos Cavalos , Microbiota , Úlcera Gástrica , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças dos Cavalos/induzido quimicamente , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Permeabilidade , Fenilbutazona/efeitos adversos , RNA Ribossômico 16S/genética , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/veterinária
18.
Aust Vet J ; 99(3): 86-88, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33398883

RESUMO

A 38-year-old white rhinoceros bull (Ceratotherium simum) was treated with phenylbutazone over a period of four years for chronic osteoarthritic and neuropathic pain of the thoracic limbs. Initially the lameness was sporadic and responded well to phenylbutazone (4 mg/kg PO SID). The lameness increased in severity during the winter months. Four years after treatment was initiated, there was an increase in the severity and incidence of the lameness. Analgesia was augmented by the addition of non-conventional analgesic drugs. Pentosan polysulfate was administered IM at 3 mg/kg once a week for two treatments and thereafter monthly when possible. Gabapentin was used at 8 mg/kg but produced ataxia and anorexia. The dose was reduced to 4-5 mg/kg PO SID. Amantadine (3 mg/kg PO BID) was added to the multimodal analgesia and produced a significant improvement in the clinical lameness. Chronic inflammation was monitored using both automated and manual fibrinogen methods. Eventually the rhinoceros was euthanized on humane grounds when treatment was unable to produce suitable clinical relief.


Assuntos
Analgesia , Dor Crônica , Amantadina/uso terapêutico , Analgesia/veterinária , Animais , Bovinos , Dor Crônica/veterinária , Eutanásia Animal , Gabapentina/uso terapêutico , Masculino , Poliéster Sulfúrico de Pentosana , Perissodáctilos , Fenilbutazona
19.
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
20.
Equine Vet J ; 53(2): 356-363, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32697849

RESUMO

BACKGROUND: Phenylbutazone is commonly prescribed for treatment of various painful or inflammatory disorders in horses, but is associated with gastrointestinal (GI) adverse effects. Anecdotally, many practitioners prescribe omeprazole concurrently with phenylbutazone to reduce development of equine gastric ulcer syndrome (EGUS), but the efficacy and safety of this practice remains unknown. OBJECTIVES: To evaluate the effect of omeprazole on phenylbutazone-induced equine glandular gastric disease (EGGD) and equine squamous gastric disease (ESGD). STUDY DESIGN: Randomised block experimental design. METHODS: Twenty-two horses with EGGD and ESGD scores ≤2 were included. Horses were assigned to treatment groups: phenylbutazone (4.4 mg/kg PO q 12 h; PBZ), phenylbutazone plus omeprazole (4 mg/kg PO q. 24 h; PBZ/OME) or placebo (CON) in a randomised block design based upon initial EGGD score. Horses were treated for up to 14 days. Gastroscopy was performed weekly; CBC and biochemistry were performed at Day 0 and study end. Horses were monitored for signs of colic and/or diarrhoea. RESULTS: EGGD score increased in PBZ (median change 1, inter-quartile range, [IQR], 0-2) compared to PBZ/OME (median change 0, IQR -1 to 0; P = .05). PBZ/OME (6/8) had more intestinal complications than CON (0/6; difference between proportions = 75%; 95% CI, 23%-93%; P = .03). Plasma protein concentrations decreased in PBZ, compared to CON (mean difference between groups, 14 g/L; 95% CI, 1.04-27; P = .03). Five horses were withdrawn from the study due to intestinal complications (n = 3 PBZ/OME and n = 2 PBZ); one horse (PBZ) was withdrawn due to severe grade 4 EGGD. MAIN LIMITATIONS: Small sample size and changes in management for the 2-3 days prior to study initiation; variable treatment duration among groups due to development of complications. CONCLUSIONS: Administration of omeprazole ameliorated PBZ-induced EGGD, but was associated with an increase in intestinal complications. Caution should be exercised when co-prescribing NSAIDs and omeprazole in horses, particularly in association with change in management.


Assuntos
Doenças dos Cavalos , Úlcera Gástrica , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças dos Cavalos/induzido quimicamente , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Omeprazol/efeitos adversos , Fenilbutazona/efeitos adversos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/veterinária
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