Comparative pharmacokinetics of phenylbutazone in healthy young-adult and geriatric horses.

OBJECTIVE: To evaluate the effects of aging on phenylbutazone (PBZ) disposition in older horses (≥ 25 years old) compared to young adults (4 to 10 years old) by characterizing the pharmacokinetic profile of PBZ and its active metabolite, oxyphenbutazone (OPBZ), following a 2.2-mg/kg dose, IV. We hypothesized that the disposition of PBZ will be affected by age. ANIMALS: 16 healthy horses (8 young adults aged 4 to 10 years and 8 geriatric horses ≥ 25 years old). METHODS: Horses were administered a single 2.2-mg/kg PBZ dose, IV. Plasma samples were collected at designated time points and frozen at -80 °C until assayed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analyses were performed using Phoenix WinNonlin, version 8.0 (Certara). Both clinical and pharmacokinetic data were compared between age groups using independent samples t tests, with P < .05 considered significant. RESULTS: Baseline characteristics did not differ between groups, with the exception of age, weight, and plasma total solids. Plasma concentrations of PBZ were best described by a two-compartment model. The maximum plasma concentration of OPBZ was reached at 5 hours for both age groups, and the metabolite-to-parent-drug area-under-the-curve ratios were approximately 20% for both groups. None of the pharmacokinetic parameters of PBZ or its metabolite, OPBZ, differed significantly between age groups. CLINICAL RELEVANCE: The hypothesis was rejected as there was no significant difference in PBZ disposition in young-adult horses compared to geriatric horses. Our data do not support the need for dose adjustments of PBZ in clinically healthy geriatric horses.

Evaluation of gastrointestinal tract lesions and serum malondialdehyde levels after repeated oral administration of phenylbutazone in horses.

Phenylbutazone (PBZ) is a widely used nonsteroidal anti-inflammatory drug for horses. However, because of its gastrointestinal side effects, its administration requires careful attention in veterinary practice. Malondialdehyde (MDA) is a serum biomarker associated with increased damage to the equine gastrointestinal system. This study investigated the hematological effects and alterations in the gastrointestinal tract and assessed serum MDA concentrations following repeated oral PBZ administration at clinical doses. Fourteen horses were randomly divided into control and treatment groups. All horses in the treatment group were administered 4.4 milligrams per kilogram of body weight of PBZ syrup orally twice a day for 7 days, whereas the control group received syrup as a placebo. The development of gastrointestinal side effects was investigated using gastroscopy, abdominal ultrasound, and fecal pH; serum MDA concentrations were assessed using a commercially available enzyme-linked immunosorbent assay kit. Data were compared between PBZ-treated and control horses before and after the treatment period. The treatment group exhibited decreased albumin and total protein concentrations. Moreover, this group exhibited a higher thickness of the right dorsal colon wall (p = 0.03) and had higher scores for squamous gastric ulcers (p = 0.01). Fecal pH was lower in the treatment group than in the control group after PBZ administration (p < 0.01). Although MDA concentrations were higher in the treatment group after PBZ administration, they did not differ significantly from those of the control group. This study highlighted the changes in hematological and gastrointestinal lesions resulting from PBZ administration in horses at clinical doses, even without clinical signs. However, MDA may not be an optimal biomarker for the early detection of gastrointestinal damage due to PBZ treatment in horses.

Integrated analysis of gut metabolome, microbiome, and exfoliome data in an equine model of intestinal injury.

BACKGROUND: The equine gastrointestinal (GI) microbiome has been described in the context of various diseases. The observed changes, however, have not been linked to host function and therefore it remains unclear how specific changes in the microbiome alter cellular and molecular pathways within the GI tract. Further, non-invasive techniques to examine the host gene expression profile of the GI mucosa have been described in horses but not evaluated in response to interventions. Therefore, the objectives of our study were to (1) profile gene expression and metabolomic changes in an equine model of non-steroidal anti-inflammatory drug (NSAID)-induced intestinal inflammation and (2) apply computational data integration methods to examine host-microbiota interactions. METHODS: Twenty horses were randomly assigned to 1 of 2 groups (n = 10): control (placebo paste) or NSAID (phenylbutazone 4.4 mg/kg orally once daily for 9 days). Fecal samples were collected on days 0 and 10 and analyzed with respect to microbiota (16S rDNA gene sequencing), metabolomic (untargeted metabolites), and host exfoliated cell transcriptomic (exfoliome) changes. Data were analyzed and integrated using a variety of computational techniques, and underlying regulatory mechanisms were inferred from features that were commonly identified by all computational approaches. RESULTS: Phenylbutazone induced alterations in the microbiota, metabolome, and host transcriptome. Data integration identified correlation of specific bacterial genera with expression of several genes and metabolites that were linked to oxidative stress. Concomitant microbiota and metabolite changes resulted in the initiation of endoplasmic reticulum stress and unfolded protein response within the intestinal mucosa. CONCLUSIONS: Results of integrative analysis identified an important role for oxidative stress, and subsequent cell signaling responses, in a large animal model of GI inflammation. The computational approaches for combining non-invasive platforms for unbiased assessment of host GI responses (e.g., exfoliomics) with metabolomic and microbiota changes have broad application for the field of gastroenterology. Video Abstract.

Treatment of mares with the non-steroidal anti-inflammatory drug (NSAID) phenylbutazone transiently affects in vitro maturation of equine oocytes and blastocyst development after Intracytoplasmic Sperm Injection (ICSI).

Mares enrolled in assisted reproductive technologies (ARTs) programs are often treated with non-steroidal anti-inflammatory drugs (NSAIDs), particularly phenylbutazone (Bute), due to chronic lameness. The current study was performed to determine the effect of Bute administration on the developmental competence of in vitro-matured equine oocytes subjected to Intracytoplasmic Sperm Injection (ICSI). In a Preliminary Study, immature cumulus-oocyte complexes (COCs) recovered by post-mortem ovary harvested from two healthy mares (n = 2) treated for 10 days with Bute (4.4 mg/kg, PO, BID), and four non-treated healthy mares (n = 4), were matured in vitro and subjected to Piezo-driven ICSI. Lower oocyte in vitro maturation [Bute: 25% (3/12) vs. Control: 61% (28/46)] and blastocyst rates [Bute: 0% (0/12) vs. Control: 18% (5/28)] were observed in the Bute-treated when compared to the Control mares (P < 0.05). In the Main Experiment, a group of healthy mares (n = 9) received a daily dose of Bute (4.4 mg/kg, orally, SID) for 10 days. A control group of mares (n = 10) was treated with an equal volume of placebo. Mares in both groups were subjected to ultrasound-guided transvaginal oocyte aspiration (TVA) on days 3, 33, and 77 following the last dose of Bute (PT). Recovered COCs from both mare groups were matured in vitro and subjected to Piezo-driven ICSI. By day-3 PT, oocyte in vitro maturation rate was similar between mare groups [Bute: 65% (36/55) vs. Control: 67% (78/116); P > 0.05], while oocyte recovery [Bute: 53% (55/103) vs. Control: 70% (116/166)], cleavage [Bute: 31% (11/36) vs. Control: 62% (48/78)] and blastocyst rates [Bute: [0%] (0/36) vs. Control: 28% (22/78)] were significantly different (P < 0.05). By day 33 PT and 77 PT, differences on oocyte recovery, in vitro maturation, cleavage, and blastocyst rates were not observed between mare groups. In summary, the administration of Bute for 10 consecutive days (4.4 mg/kg, PO, SID, or BID) is associated with a decrease in the ability of immature equine oocytes to undergo in vitro-maturation (Preliminary Study) and develop to the blastocyst stage following ICSI (Preliminary Study and Main Experiment). This negative effect appeared to be transient, as 30- and 77-days post-treatment, no differences on in vitro maturation, cleavage or blastocyst rates were observed.

Effect of phenylbutazone on insulin secretion in horses with insulin dysregulation.

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.

Single-dose nonsteroidal anti-inflammatory drugs in horses have no impact on concentrations of cytokines or growth factors in autologous protein solution and platelet-rich plasma.

OBJECTIVE: To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP). ANIMALS: 6 adult university-owned horses. METHODS: For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-ß1, IL-1ß, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays. RESULTS: There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP. CLINICAL RELEVANCE: These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

Quiste subcondral a nivel de la articulación interfalángicaproximal en una potranca criolla colombiana: reporte de caso / Subchondral cyst in the proximal interphalangeal joint in a paso fino colombian horse: a case report / Cisto subcondral na articulação proximal interfalângicaem um potro crioulo colombiano: relato de caso

Se reporta el caso de una paciente equina, evaluada por Especial•Vet práctica privada, la cual presentaba alexamen clínico ortopédico un grado de claudicación II/V en ambos miembros posteriores (según clasificaciónde la AAEP), la cual no presento mejoría después de realizar un tratamiento médico de tipo parenteral confenilbutazona. Posteriormente se realizó un nuevo examen clínico ortopédico en el cual se realizó bloqueoanestésico perineural abaxial en ambos miembros posteriores encontrando una mejoría del 90% con respectoal grado de claudicación inicial. Se realizó evaluación radiológica digital, con las siguientes proyecciones:dorso plantar y lateromedial en las cuales se evidenció un área radiolúcida circunscrita a nivel del terciodistal de la primera falange, con comunicación a la articulación interfalángica proximal en ambos miembros posteriores, seguidamente se realizó evaluación ultrasonográfica en la cual se observa un área anecóica y lafalta de continuidad de la superficie ósea a nivel de la articulación interfalángica proximal de ambos miembrosposteriores. Estableciendo de esta forma como diagnóstico definitivo quiste subcondral a nivel del tercio distalde la primera falange, con comunicación a la articulación interfalángica proximal. Se realizó infiltración conacetato de triamcinolona, betametasona y ácido hialurónico a nivel intrarticular; antibioterapia de maneraprofiláctica al procedimiento, descanso en pesebrera por 4 semanas y reincorporación al ejercicio de maneraprogresiva, suministro de complementos condroprotectores de manera enteral (Flexequin® 40 gr/día VO yCortaflex® 20 ml/día VO). Al momento de la publicación de este artículo, la paciente no presenta ningún gradode claudicación y se encuentra realizando un trabajo físico y atlético normal.

We report the case of an equine patient, assessed by Especial Vet private practice, whose orthopedic clinicalexamination showed a degree of lameness II / V in both hind limbs (according to AAEP classification), whichdemonstrated no improvement after medical treatment with parenteral phenylbutazone. Subsequently a neworthopedic clinical examination was performed in which an abaxial, perineural anesthetic block was applied to both hind legs, which produced 90% improvement compared to the initial degree of lameness. Digital radiographicevaluation was performed with the following results: dorsal-plantar and lateral-medial images which showeda circumscribed, radiolucent area at the level of the distal third of the first phalanx, with communication to theproximal interphalangeal joint on both hind limbs. Following, an ultrasound evaluation was carried out in whichthere was an anechoic area and lack of continuity of the bone surface at the proximal interphalangeal joint of bothhind limbs. These findings established a definitive diagnosis of a subchondral bone cyst at the distal third of the firstphalanx, with communication to the proximal interphalangeal joint. Intra-articular infiltration was performed with triamcinolone acetonide, betamethasone and hyaluronic acid; antibiotics as prophylaxis, rest in a stable for 4 weekswith a gradual return to exercise, and provision of enteral, chondroprotective supplements (p.o. Flexequin ® 40 gr/day and p.o. Cortaflex ® 20ml/day). At the time of publication of this article, the patient does not present any degreeof lameness and is performing normal athletic and physical activity.

Relatamos um caso de um paciente eqüino, avaliado pela prática privada Especial Vet, cujo exame clínicoortopédico mostrou um grau de claudicação II / V em ambos os membros posteriores (de acordo com aclassificação do AAEP), o qual não demonstrou melhora após o tratamento médico com fenilbutazona parenteral.Após a aplicação de um bloqueio anestésico perineural abaxial em ambas as pernas traseiras, foi realizadoum novo exame clínico ortopédico, mostrando uma melhora de 90% em comparação com o grau inicial declaudicação. Realizou-se também uma avaliação radiográfica digital obtendo-se os seguintes resultados: imagensdorso-plantar e latero-medial que mostrou uma área radiolúcida circunscrita ao nível do terço distal da primeirafalange, com comunicação para a articulação interfalângica proximal em ambos os membros posteriores. E após,a realização de um ultra-som, verificou-se que houve uma área anecóica e falta de continuidade da superfície óssea ao nível da articulação interfalângica proximal dos dois membros posteriores. Desta forma estabeleceu umdiagnóstico definitivo de um cisto ósseo subcondral no terço distal da primeira falange, com comunicação para aarticulação interfalângica proximal. Uma infiltração intra-articular foi realizada com acetato de triamcinolona,betametasona e ácido hialurônico; antibióticos como profilaxia, um descanso em estábulo durante 4 semanas, com um retorno gradual aos exercícios, e administração de suplementos condroprotetores de maneira enteral(Flexequin® 40 gr/día VO e Cortaflex® 20 ml/día VO). No momento da publicação deste artigo, o paciente nãoapresenta qualquer grau de claudicação e está realizando atividades atléticas e físicas normais.

Muerte súbita asociada a hipersensibilidad tipo I en un equino pura sangre de carrera / Sudden death associated to type I hypersensitivity in a racing horse

El objetivo de este estudio fue reportar un caso de hipersensibilidad tipo I con muerte súbita en un equino Pura Sangre de Carrera en el Hipódromo “La Rinconada” Caracas, Venezuela. Se tomaron muestras de sangre y orina para estudios toxicológicos mediante la técnica de ELISA competitivo. Se le práctico la técnica de necropsia, fueron colectadas muestras de musculo, tejido pulmonar, hepático, renal, gástrico, esplénico, corazón y sistema nervioso central para estudio histopatológico, las muestras fueron procesados por los métodos convencionales histológicos. Los hallazgos de necropsia fueron flebitis severa en vena yugular derecha, con hematoma en el surco yugular. Edema severo de glotis, edema, congestión y hemorragia pulmonar. Hemorragia petequial subendocardica. Bazo esplenocontraido y con focos de necrosis de coagulación. Hidronefrosis aguda con hematuria. Hígado con patrón lobulillar acentuado. El resto de los órganos con evidente congestión y hemorragia. Los cortes histológicos evidenciaron edema, congestión y hemorragia pulmonar severa. Hemorragia subepicardica marcada. Edema subcapsular esplénico y necrosis centro-folicular. Degeneración hidropica tubular, necrosis tubular aguda. Necrosis de corteza renal. Los estudios toxicológicos permitieron la detección de furosemida y fenilbutazona en las muestras de sangre y orina. En conclusión se reporta un síndrome de hipersensibilidad tipo I asociado a la administración de un producto comercial a base de Vitamina E 80mg, Pangamato sódico (B15) 1 mg, Selenio Sódico 0.6 mg, Antioxidantes y Vehículos Solubles c.s.p. con colapso, shock y muerte aguda en un equino Pura Sangre de Carrera mediante un estudio multidisciplinario clínico, anatomopatologico y toxicológico.

The aim of this study was to report a case of type I hypersensitivity to sudden death in a Thoroughbred race horses at the Hippodrome “La Rinconada” Caracas, Venezuela. Samples of blood and urine for toxicology studies using competitive ELISA. He practiced the technique of necropsy, samples were collected from muscle, lung tissue, liver, kidney, stomach, spleen, heart and central nervous system for histopathological examination, samples were processed by conventional histological methods. Autopsy findings were severe phlebitis right jugular vein, with hematoma in the jugular groove. Severe edema of glottis edema, pulmonary congestion and hemorrhage. Subendocardial petechial hemorrhage. Esplenocontraido Spleen foci of necrosis and coagulation. Hydronephrosis with acute hematuria. Liver accentuated lobular pattern. The rest of the organs with obvious congestion and hemorrhage. The histological sections showed edema, severe pulmonary congestion and hemorrhage. Marked subepicardial hemorrhage. Edema and necrosis subcapsular splenic follicular center. Tubular hydropic degeneration, acute tubular necrosis. Necrosis of renal cortex. Toxicological studies allowed the detection of furosemide and phenylbutazone in samples of blood and urine. In conclusion we report type I hypersensitivity syndrome associated with the administration of a commercial product based Vitamin E 80mg, sodium pangamate (B15) 1 mg, 0.6 mg; Sodium Selenium, Soluble Antioxidants and Vehicle qs with collapse, shock and acute death in a race Thoroughbred horses by a multidisciplinary clinical, pathological and toxicological.

Efeito da associação de furosemida e fenilbutazona sobre variáveis hidroeletrolíticas de cavalos antes e após a corrida / The effect of furosemide and phenylbutazone association on the fluid and electrolyte characteristics of horses before and after a race

Verificaram-se os efeitos da associação de furosemida e fenilbutazona sobre variáveis hidroeletrolíticas de cavalos antes e após a corrida. Dezenove equinos foram distribuídos em três grupos, de acordo com os protocolos de tratamento. O primeiro grupo, de cinco animais, não recebeu medicação (grupo-controle); o segundo grupo, de sete animais, foi tratado com furosemida, na dose de 1mg/kg, por via intramuscular, até quatro horas antes do páreo; o terceiro, de sete animais, recebeu furosemida, por via intramuscular, e fenilbutazona, por via intravenosa, nas doses de 1,0 e 4,4mg/kg, respectivamente, até quatro horas antes da corrida. Amostras de sangue foram colhidas antes, imediatamente após e duas horas após o páreo, para avaliação da osmolalidade plasmática e das concentrações plasmáticas de sódio, potássio e cloreto. A utilização de furosemida e da associação furosemida e fenilbutazona até 4h antes dos páreos nas dosagens descritas alterou (P<0,05) a osmolalidade plasmática dos equinos, mas não alterou (P>0,05) as concentrações de sódio, potássio e cloreto. Os páreos alteraram de forma fisiológica a osmolalidade plasmática e a concentração sanguínea de K+ devido ao exercício de alta intensidade.

The objective of this study was to verify the effects of furosemide and phenylbutazone association on fluid and electrolyte balance characteristics of horses before and after a race. Nineteen horses were divided into three groups according to treatment protocols. The first group (five animals - control) was not medicated. A second group (seven animals) was treated with furosemide (1mg/kg, intramuscular up to four hours before the race). A third group (seven animals) received furosemide (1mg/kg) and phenylbutazone (4.4mg/kg), both intramuscular, up to four hours before race. Blood samples were collected before, immediately after and two hours after a race to evaluate the plasma osmolality and sodium, potassium and chloride concentrations. The use of furosemide and furosemide plus phenylbutazone up to four hours before the race altered (P<0.05) the plasma osmolality but did not change (P>0.05) the sodium, potassium and chloride concentrations. It was not possible to determine an antagonist effect of phenylbutazone on furosemide, based on fluid and electrolyte balance. Due to the high intensity exercise, the increase in plasma osmolality and potassium concentration was attributed to the race effect.

Intoxicación con fenilbutazona en un equino: reporte de un caso / Toxicity with phenylbutazone in a horse: a case report

Se describe el caso de un equino que desarrolló graves lesiones digestivas después de recibir dosis altasde fenilbutazona (FBZ) para tratar una claudicación. Al momento de la consulta tenía 9 días de evolución.Desde su llegada al hospital, se observó cojera grave de las cuatro extremidades, deshidratación y diarreafétida. Luego del examen físico, la anamnesis y las ayudas diagnósticas se propuso un dictamen de laminitis traumática, gastritis ulcerativa y colitis por intoxicación con antiinflamatorios no esteroides (AINES). Lacondición empeoró a pesar de la terapia y cuando se presentaron signos neurológicos se sugirió la eutanasia.Durante la necropsia se observaron lesiones graves en el tracto gastrointestinal, cascos y encéfalo. El objetivo de este artículo es describir la sintomatología, terapia y evolución de un paciente intoxicado con aines.

It is described a clinic case of an equine that developed severe digestive lesions after taking high dosage ofphenylbutazone to treat a lameness. At the moment of checking, it had nine days of evolution. Since its arrivingto the hospital, it was seen an intense lameness of the four limbs, dehydration and fetid diarrhea. After the physicexam, the interrogatory and the diagnostic aids it was proposed a diagnosis of traumatic laminitis, ulcerative gastritis and colitis by intoxication with Non-steroidal anti-inflamatory drug (NSAIDs). The condition became worse despite the therapy and when the neurological signs were presented. It was suggested the euthanasia. During the necropsy, it was seen severe lesions in the gastrointestinal tract, hooves and brain. The objective of this article is to describe la symptomatology, therapy and evolution of the intoxicated patient with NSAIDs.

Descreve-se o caso de um cavalo que desenvolveu lesões digestivas graves após receber altas doses defenilbutazona (FBZ) para tratar uma claudicação. No momento da consulta havia 9 dias de evolução. Desdesua chegada ao hospital, observou-se manqueira grave nas quatro extremidades, desidratação e diarréia fétida. Após o exame físico, a anamnese e os meios diagnósticos concluiu-se se tratar de laminite traumática, gastriteulcerativa e colite por intoxicaçãocom anti-inflamatórios não esteróides (AINES). A condição piorou apesardo tratamento e, quando apresentou sinais neurológicos, sugeriu-se a eutanásia. Na necrópsia observaram-selesões graves no trato gastrointestinal, cascos e enféfalo. O objetivo deste trabalho é descrever os sintomas, otratamento e a evolução de um paciente intoxicado com AINES.

Efeitos da fenilbutazona na cicatrização de feridas cutâneas experimentais em equinos / Phenylbutazone effects on experimental wound healing in horses

No processo de cicatrização por segunda intenção de feridas cutâneas experimentalmente induzidas em equinos, avaliaram-se os efeitos da fenilbutazona e comparou-se a cicatrização entre as regiões torácica e lombar. Utilizaram-se dez equinos, dos quais se retirou fragmentos circulares de pele de dois centímetros de diâmetro das regiões lombares e torácicas direita e esquerda. Os equinos foram distribuídos em dois grupos, sendo o primeiro controle, recebendo água destilada a cada 12 horas, durante cinco dias. O outro grupo foi tratado com fenilbutazona (4,4 mg/kg) com o mesmo intervalo e período do grupo controle. As feridas foram tratadas diariamente com Líquido de Dakin, momentos quando se procederam as observações macroscópicas. A cada 72 horas procederam-se as mensurações das feridas. Para análise histológica realizou-se biópsias no sexto e décimo quinto dia. O tempo total de reparo das feridas no grupo tratado foi maior em aproximadamente 12 dias (37 dias para o grupo controle e 49 dias para o grupo tratado). Não se observou diferença significativa do tempo de cicatrização entre as feridas torácicas e lombares de um mesmo grupo. As avaliações macroscópicas e histopatológicas mostraram o efeito inibidor da fenilbutazona quando comparada com o grupo controle na cicatrização de feridas cutâneas por segunda intenção em equinos.

The purpose of this study was to investigate phenylbutazone effects on second intention wound healing, and to compare the healing process between the thoracic and lumbar areas. Ten horses were submitted to circular full-thickness wound produced on both sides of the thoracic and lumbar areas. Animals were gathered into two experimental groups, one receiving daily IV injections of phenylbutazone (4,4mg/kg) and the other (control group) distillated water for five days. All wounds were daily treated with local Dakin's solution. The wound contraction rates were determined by serial measurements each 72 hours. At the 6th and 15th post surgical days, biopsies were performed for histological analysis. Thoracic and lumbar wound contraction was decreased in the phenylbutazone group. The time to complete healing was significantly greater in phenylbutazone group (49 days) than in control group (37 days). There was no significant difference between thoracic and lumbar area in the same group. Gross and histopathology analysis showed the inhibitory effect of phenylbutazone on the second-intention wound healing when compared to the control group.

Histopatologia das lâminas do casco de equinos com laminite aguda induzida e tratados com ketoprofeno, fenilbutazona e flunixin meglumine / Histopathology of the digital laminae from horses with acute induced laminitis treated with ketoprophen, phenylbutazone, and flunixin meglumin

Avaliaram-se as alterações histológicas do tecido laminar, obtido por biopsia, em 20 equinos portadores de laminite induzida por sobrecarga de carboidratos e tratados com ketoprofeno, fenilbutazona ou flunixin meglumine. A biopsia foi colhida dos dígitos torácicos 72 horas após a indução. Os achados histológicos foram comparados com os achados de amostras de equinos isentos de laminite. Infiltrado inflamatório neutrofílico foi observado em 80 por cento, congestão em 50 por cento, hemorragia em 35 por cento e hiperplasia na túnica íntima das arteríolas das lâminas dérmicas primárias em 15 por cento das amostras. As taxas de microtrombos e coágulos foram 15 por cento e 20 por cento, respectivamente. Estes achados parecem decorrer dos distúrbios circulatórios que ocasionaram edema, congestão e hiperemia, seguidos de degeneração. Em 70 por cento das análises realizadas nos animais tratados, as lesões histológicas foram inferiores aos graus de claudicação observados. Conclui-se que a biopsia de tecido laminar digital de equinos é viável, os artefatos decorrentes da técnica de biopsia não prejudicam a análise histológica das amostras e os anti-inflamatórios não esteroidais não são capazes de evitar as lesões laminares quando administrados após o início da sintomatologia clínica de laminite.

Experimental laminitis caused by carbohydrate overload was induced in 20 healthy horses. Seventy two hours after induction, samples of the laminar tissue were obtained by biopsy from the thoracic limbs digits for histopathology. The histological findings were compared to samples from horses without laminitis. Neutrophilic infiltrate was observed in 80 percent of the samples, congestion in 50 percent, hemorrhage in 35 percent, and hyperplasia of the arteriolar intima layer of the primary dermal lamina in 15 percent. Thrombi and intravascular blood clots were observed in 15 percent and 20 percent of the samples, respectively. Apparently, these findings were due to circulatory changes that resulted in edema, congestion, and hyperemia, followed by degeneration. In 70 percent of analyses performed on treated horses, the histological lesions were less severe than the clinical signs of lameness. It is concluded that: (i) the biopsy technique of laminar digital tissue from horses is viable; (ii) the artifacts generated by the biopsy technique do not compromise the histological analyses; and (iii) non-steroidal anti-inflammatory drugs do not avoid laminar lesions when administered after the beginning of clinical signs of laminitis.

Inibição e reversão da agregação plaquetária de eqüinos in vitro com o uso de ketoprofeno, fenilbutazona e flunixim meglumine / In vitro inibition and reversion of equine platelet aggregation using ketoprophen, phenylbutazone and flunixin meglumin

Como são várias as enfermidades e os distúrbios que induzem à hipercoagulabilidade e à pré-ativação de plaquetas em eqüinos. A atividade de medicamentos utilizados para controle dessas enfermidades sobre a agregação de plaquetas pode, não apenas servir para avaliar sua evolução, como também a resposta terapêutica. Com o objetivo de avaliar a prevenção e a reversão da agregação plaquetária de eqüinos in vitro foram utilizados os antiinflamatórios não esteroidais (AINES): ketoprofeno, fenilbutazona e flunixim meglumine. A comparação demonstrou que a fenilbutazona e o ketoprofeno previnem a agregação de plaquetas de eqüinos induzida pelo ADP, de forma mais eficaz do que o flunixim-meglumine e, superior ao fragmento monoclonal de anticorpo Reopro, sendo semelhante a dos bloqueadores de receptores de membrana Ro-438857 e RGDS. Quanto a reverão da agregação plaquetária tanto a fenilbutazona quanto o ketoprofeno demonstraram efeitos dose-dependente.

Several diseases may lead to platelet pre-activation and hypercoagulability states in horses. The activity of many drugs against platelet aggregation may, not only contribute to the evaluation of a disease but also its response to the therapy. With the aim to study in vitro prevention and reversion of platelet aggregation, the non steroidal anti-inflammatory drug (NSAID): ketoprophen, phenylbutazone and flunixin-meglumin were evaluated. The comparison demonstrated that phenylbutazone and ketoprophen prevented platelet aggregation induced by ADP better than flunixin-meglumin, in a superior manner to the monoclonal antibody Reopro, and in a better way than the membrane receptor blockers Ro-438857 and RGDS. The reversion of platelet aggregation demonstrated that even phenylbutazone or ketoprophen have a dose-dependent effect.

Importancia de una descripción detallada de todo incidente crítico / Importance of giving a detailed description of all critical events

No disponible

Dos casos de shock anafiláctico al Metamizol en el postoperatorio inmediato / Two cases of anaphylactic shock after metamizol given during postoperative recovery

No disponible

Efecto de los antiinflamatorios, solos y asociados con ofloxacino, en la explosión respiratoria de los leucocitos polimorfonucleares humanos / Effect of antiinflammatory drugs, alone and combined with ofloxacin, on the respiratory burst of human polymorphonuclear leukocytes

La actividad bactericida de los polimorfonucleares (PMN) depende de la producción de radicales oxidantes (anión superóxido, H2O2, etc.) generados en la explosión respiratoria, y puede modificarse de diferentes formas. La administración conjunta de un antiinflamatorio y una quinolona es frecuente en enfermos inmunodeprimidos en los cuales la explosión respiratoria puede estar disminuida. En este trabajo hemos estudiado in vitro la influencia de los antiinflamatorios dexametasona (0,4, 4 y 40 mg/ml), metilprednisolona (0,37, 3,7 y 37 mg/ml), hidrocortisona (0,048, 0,48 y 4,8 mg/ml), betametasona (0,1, 1, 5 y 10 mg/ml), fenilbutazona (1000 mg/ml) y &aacmte;cido acetilsalicílico (25, 250, 2500 mg/ml) en la generación de radicales oxidantes en los PMN pretratados durante 30 minutos a 37 ºC con dichos fármacos solos y asociados con 10 mg/ml de ofloxacino. La producción de anión superóxido se midió utilizando la técnica de reducción de citocromo c, y la de H2O2 por la del rojo fenol. El pretratamiento con los antiinflamatorios solos disminuyó la producción de H2O2 (excepto dexametasona y metilprednisolona) y la de anión superóxido (excepto betametasona) entre un 15 por ciento y un 45 por ciento, dependiendo del antiinflamatorio y de su concentración; en cambio, el ofloxacino sólo aumento la generación de radicales superóxido en un 20,2 ñ 6,7 por ciento. La asociación de los antiinflamatorios con ofloxacino contrarrestó el efecto inhibidor de la explosión respiratoria de los primeros. Es importante conocer el efecto de los fármacos en la explosión respiratoria con el fin de elegir aquellos que, consiguiendo el mismo efecto terapéutico, la afecten en menor cuantía. (AU)

Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.

Ulcera cecal inespecífica en una paciente con insuficiencia renal crónica en programa de hemodiálisis: caso clínico / Unspecific cecal ulcer in a patient undergoing hemodialysis for chronic renal failure: clinical case

We report a 65 years old female undergoing hemodialysis, presenting with intense pain in the lower right quadrant and moderate hematochezia. Since symptoms did not abate after an appendectomy, a colonoscopy and barium enema were performed, whose results suggested an advanced cecal carcinoma. Biopsies were negative for cancer. A new surgical abdominal exploration disclosed a cecal inflammatory and transmural lesion. A right colectomy was performed and the patient had a satisfactory postoperative evolution. Pathological study of the surgical piece showed a six cm perforated profound ulceration and a two cm ulcer. Both had precise limits. Unspecific cecal ulcers are rare entities that must be born in mind in the differential diagnosis of abdominal pain or hematochezia, specially in patients undergoing chronic hemodialysis

Molecular pharmacological interaction of phenylbutazone to human neutrophil elastase

Human neutrophil elastase (HNElastase, EC 3.4.21.37), a causative factor of inflammatory diseases, was purified by Ultrogel AcA54 gel filtration and CM-Sephadex ion exchange chromatography. HNElastase was inhibited by phenylbutazone in a concentration dependent manner up to 0.4 mm, but as the concentration increased, the inhibitory effect gradually diminished. Binding of phenylbutazone to the human neutrophil elastase caused strong Raman shifts at 200, 440, and 1194 cm-1. The peak at 1194 cm-1 might be evidence of the presence of -N=N-PHI radical. The core area of the elastase, according to the visual molecular model of human neutrophil elastase, was structurally stable. A deeply situated active center was at the core area surrounded by hydrophobic amino acids. Directly neighboring the active site was one positively charged atom and two atoms carrying a negative charge, which enabled the enzyme and the drug to form a strong interaction. Phenylbutazone may form a binding, similar to a key & lock system to the atoms carrying opposite charges near the active site of the enzyme molecule. Furthermore, the hydrophobicity of the surrounding amino acid near the active site seemed to enhance the binding strength of phenylbutazone. Binding of phenylbutazone near the active site may cause masking of the active site, preventing the substrate from approaching the active site and inhibiting elastase activity.